Methods and intermediates for making therapeutic compounds

Abstract

The present disclosure relates to methods and intermediates useful for preparing a compound of Formula I, or a salt thereof: I.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 560,122, filed March 1, 2024, the entire contents of which are hereby incorporated by reference. Technical Field

[0002] This disclosure relates to methods and intermediates for synthesizing substituted pyridotriazine compounds for treating human immunodeficiency virus (HIV) infection. Background Technology

[0003] This disclosure relates in general to the field of organic synthetic methodologies for preparing antiviral compounds and their synthetic intermediates.

[0004] Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. HIV encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are widely used and have shown effectiveness, especially when used in combination, toxicity and the development of drug-resistant strains may limit their usefulness (Palella et al., N. Engl. J Med. (1998) 338:853–860; Richman, DD Nature (2001) 410:995–1001). Therefore, new agents to inhibit HIV replication are needed.

[0005] U.S. Patent No. 11,613,546 discloses novel compounds that can be used to treat infections caused by the HIV virus. One specific compound identified therein is a compound of formula IA: IA Currently, there is a need for synthetic methods and intermediates for compounds and their salts that can be used to prepare formula IA. Summary of the Invention

[0006] This disclosure relates to a novel synthetic method for preparing compounds of formula I or salts thereof: I Where R 1 Selected from hydrogen and hydroxyl protecting groups.

[0007] In some embodiments, this disclosure provides a compound for preparing formula IA: IA Or its salts. Compounds of formula IA may also be named or identified as (1S,2R,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-bridged methylenepyrido[1,2-b][1,2,5]triazacyclononane-10-carboxamide.

[0008] This disclosure also relates to specific individual steps of the method and intermediates used in the method.

[0009] In some embodiments, this document discloses a method for preparing a compound of formula I or a salt thereof, wherein R 1 Selected from hydrogen and hydroxyl protecting groups; This method involves making a compound of formula II: II The compound or its salt reacts with a first catalyst to give a compound of formula I or its salt.

[0010] In some embodiments, this document discloses a method for preparing a compound of formula IA or a salt thereof: IA The method includes deprotecting a compound of formula I or a salt thereof, wherein R 1 It is a hydroxyl protecting group, which yields a compound of formula IA or its salt.

[0011] In some embodiments, this document discloses a method for preparing a compound of formula I or a salt thereof, wherein R 1 The method comprises: (selected from hydrogen and hydroxyl protecting groups) Compounds of formula R-1: R-1 Or its salt and: Methylene reagent and The eighth acid or the fourteenth base reaction, The compound of formula I or its salt is obtained.

[0012] This document provides additional embodiments of the present disclosure, including additional synthetic intermediates and methods for preparing such intermediates. Detailed Implementation

[0013] It should be understood in the following description that this disclosure is considered illustrative of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and should not be construed as limiting the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0014] When a trade name is used in this article, it is intended to refer independently to the product under that trade name and the active pharmaceutical ingredient of that product.

[0015] Definition The following description illustrates exemplary methods, parameters, etc. However, it should be understood that such description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0016] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings described below, unless the context in which they are used indicates otherwise.

[0017] prefix "C" u-v "Indicates that the following groups have u to v carbon atoms. For example, "C 1-8 "alkyl" indicates that the alkyl group has 1 to 8 carbon atoms.

[0018] "Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers.

[0019] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds but with different three-dimensional structures that are not interchangeable.

[0020] An enantiomer is a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture. A mixture of enantiomers in a different 1:1 ratio is a non-racemic mixture.

[0021] A "diastereomer" is a stereoisomer that has at least two asymmetric atoms but is not a mirror image of each other.

[0022] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified by R or S. Resolved compounds with unknown absolute configurations can be specified as (+) or (-) based on the direction (right-handed or left-handed) of their rotation on the sodium D line at its wavelength. Some compounds described herein contain one or more asymmetric centers and / or hindered rotation around bond axes, and thus can produce enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)-. This disclosure is intended to include all such possible isomers, including racemic mixtures, non-racemic mixtures, diastereomers, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0023] Unless otherwise expressly defined, this disclosure includes all tautomers of the compounds detailed herein, even if only one tautomer is explicitly indicated (e.g., both tautomer forms are anticipated and described by presenting a tautomer form that may have a pair of two tautomers). For example, if a compound containing an amide is referred to (e.g., by its structure or chemical name), it should be understood that the corresponding imine tautomer is included in this disclosure and described as if the amide alone or together with the imine is explicitly stated. In cases where more than two tautomers may exist, this disclosure includes all such tautomers, even if the chemical name and / or structure describes only a single tautomer form.

[0024] The compounds described herein may have chiral centers and / or geometric isomer centers (E- and Z-isomers), and it should be understood that all such optical, enantiomeric, diastereomeric, and geometric isomers are included. When a compound is represented in its chiral form, it should be understood that the embodiments cover, but are not limited to, specific diastereomeric or enantiomerically enriched forms. When chirality is not specified but is present, it should be understood that the embodiments relate to specific diastereomeric or enantiomerically enriched forms; or racemic or non-racemic mixtures of such compounds.

[0025] The compounds described herein can be in any morphological form, such as, for example, crystalline or amorphous, as well as disordered crystals, liquid crystals, plastic crystals, intermediate phases, or any combination thereof.

[0026] Pharmaceutically acceptable hydrates, solvates, cocrystals, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided.

[0027] Any formula or structure given herein, including Formula I or any formula disclosed herein, is also intended to represent the unlabeled form and isotopically labeled form of the compound. Isotopically labeled compounds have the structure described by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, isotopes of these elements. 2 H (deuterium, D) 3 H (tritium) 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. Various isotope-labeled compounds disclosed herein, such as those doped with radioactive isotopes such as 3 H, 13 C and 14 Compounds of type C can be used to help determine or measure the effectiveness of a compound by characterizing, for example, its site of action or mode of action, or its binding affinity to pharmacologically important sites of action. Such isotopically labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substrates, or for radiation therapy of patients.

[0028] This disclosure also includes compounds of Formula I or any of the formulas disclosed herein, wherein one to "n" hydrogen atoms attached to a carbon atom are replaced by deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for prolonging the half-life of any Formula I compound when administered to mammals. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism". Trends Pharmacol.Sci. 5(12):524-527 (1984). Such compounds are synthesized by methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0029] The deuterium-labeled or substituted therapeutic compounds disclosed herein may have improved DMPK (drug metabolism and pharmacokinetics) properties, which involve distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life and reduced dose requirements. 18 F-labeled compounds can be used in PET or SPECT studies. The isotope-labeled compounds and their prodrugs disclosed herein can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents, as described in the embodiments and formulations below, using the procedures disclosed. Furthermore, heavier isotopes, especially deuterium (i.e.,...), can be used. 2 Substitution with H or D can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dose requirement, or improved therapeutic index. It should be understood that, in this context, deuterium is considered a substituent in compounds of formula I or any formula disclosed herein.

[0030] The concentration of such heavier isotopes (particularly deuterium) can be defined by the isotope enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope means that atom represents any stable isotope. Unless otherwise stated, when a position is specifically designated as “H” or “hydrogen”, that position is understood to be hydrogen having its naturally occurring isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) means that deuterium is represented.

[0031] The modifier “about” used with a quantity includes the value and has the meaning prescribed by the context (e.g., including the degree of error associated with the measurement of a particular quantity).

[0032] As used herein, the term "coupling agent" refers to a reagent used to couple an amine and a carboxylic acid to form an amide. Non-limiting examples of coupling agents include n-propylphosphonic anhydride, oxaloyl chloride, thionyl chloride, phosgene, triphosgene, propanephosphonic anhydride, acetic anhydride, neopentanoic anhydride, benzoic anhydride, 2,4,6-trichlorobenzoyl chloride, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1,1'-carbonyldiimidazole, ethyl chloroformate, isobutyl chloroformate, 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (HATU), O-benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), O-(7-aza-benzotriazole- 1-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate (TATU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU), O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HCTU), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate (PyBOP), (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomonium hexafluorophosphate (COMU), peptide coupling agents, etc.

[0033] "Peptide coupling agents" include, but are not limited to, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (HATU), O-benzotriazol-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), O-(7-aza-benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate (TATU), and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylurea tetrafluoroborate. Salts include TBTU, O-(6-chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (HCTU), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tripyrrolidinylphosphonium hexafluorophosphate (PyBOP), and (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-morpholino-carbomony hexafluorophosphate (COMU), etc.

[0034] "Alkyl" refers to a saturated hydrocarbon chain that is unbranched or branched. As used herein, alkyl groups have 1 to 20 carbon atoms (i.e., C64-C ... 1-20 Alkyl groups, 1 to 12 carbon atoms (i.e., C464) 1-12 Alkyl groups, 1 to 8 carbon atoms (i.e., C464-C ... 1-8 Alkyl groups, 1 to 6 carbon atoms (i.e., C646)1-6 Alkyl groups, 1 to 4 carbon atoms (i.e., C464) 1-4 Alkyl groups, 1 to 3 carbon atoms (i.e., C464) 1-3 Alkyl group or 1 to 2 carbon atoms (i.e., C46) 1-2 Alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue with a specific number of carbons is named by a chemical name or identified by a molecular formula, it may encompass all positional isomers having that number of carbons; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., (CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0035] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) comprising a fused system. As used herein, aryl groups have 6 to 20 ring carbon atoms (i.e., C64 ... 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl group) or 6 to 10 carbon ring atoms (i.e., C46, ​​C56, C6 ... 6-10 Aryl groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthracene.

[0036] The term "halogen" or "halogen" includes fluorine, chlorine, bromine, and iodine.

[0037] "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by a halogen. For example, in cases where the residues are substituted by more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted by two ("di") or three ("tri") halogen groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0038] "Hydroxy group" is used interchangeably and refers to -OH. "Oxy group" refers to a group (=O) or (O). In the presence of tautomerism in a compound, hydroxyl and oxo groups are interchangeable.

[0039] The term "protecting group" refers to a part of a compound that masks or alters the properties of functional groups or the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example, ProtectiveGroups in Organic Chemistry Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often used to mask the reactivity of certain functional groups to contribute to the efficiency of desired chemical reactions, such as the orderly and planned formation and breaking of chemical bonds. The term "deprotection" refers to the removal of a protecting group. The term "deprotecting agent" refers to a reagent that can be used to remove protecting groups from a compound.

[0040] The term "hydroxyl protecting group" refers to a portion that masks or alters the properties of a hydroxyl group. Exemplary hydroxyl protecting groups include, but are not limited to, methyl, tert-butyl, tert-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyl-diphenylsilyl (TBDPS), triphenylsilyl, benzoyl carbamate, acetate, chloroacetate, trichloroacetate, trifluoroacetate, neopentanoate, benzoate, p-phenylbenzoate, 9-fluorenylmethyl carbonate, methanesulfonate, and toluenesulfonate.

[0041] The term "amine protecting group" refers to the portion that masks or alters the properties of an amine group. Exemplary amine protecting groups include, but are not limited to, phthalimide, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), toluenesulfonyl (Ts), saccharin, methoxyphenyl, p-methoxyphenyl, o-methoxyphenyl, acetate, 2,5-dimethylpyrrole, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 2,2-diphenyl, allyl, and triphenylmethyl.

[0042] Abbreviation The abbreviations used in this article have the following corresponding meanings: Methods and Intermediates Unless otherwise stated, the methods and techniques of this disclosure are generally performed according to conventional methods well known in the art and as described in the various general and more specific references cited and discussed throughout this specification. See, for example, Loudon, Organic Chemistry , 5th edition, New York: Oxford University Press, 2009; Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , 7th edition, Wiley-Interscience, 2013.

[0043] In some cases, the methods disclosed herein involve the step of forming a salt of the compounds disclosed herein.

[0044] The compounds described herein can be purified by any means known in the art, including chromatographic methods such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, rapid column chromatography, supercritical fluid chromatography (SFC), and ion-exchange chromatography. Any suitable stationary phase can be used, including normal-phase and reversed-phase, as well as ion exchange resins. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography , 2nd edition, edited by LR Snyder and JJ Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0045] Exemplary chemical entities that can be used to implement the methods will now be described with reference to the general preparation described herein and the illustrative synthetic schemes of specific examples below. Those skilled in the art will recognize that the transformations shown in the following schemes can be performed in any order compatible with the functionality of the particular side groups. In some embodiments, each reaction in the reactions depicted in the general scheme is run at a temperature from about -80°C to the reflux temperature of the organic solvent used.

[0046] The compounds disclosed herein exhibit transisomerism caused by steric hindrance affecting the rate of axial rotation around the single bond. The resulting conformational isomers can be observed as distinct entities using characterization techniques such as NMR and HPLC. The compounds disclosed herein can exist as mixtures of transisomers. However, the detection of transisomers depends on factors such as temperature, solvent, purification conditions, and the timescale of the spectroscopic technique. Interconversion rates at room temperature have half-lives ranging from minutes to hours, hours to days, or days to years. The ratio of transisomers at equilibrium may be inconsistent. The characterization data presented herein may not represent equilibrium states, depending on the separation and characterization conditions, which may include, but are not limited to, the treatment, the solvents used, and the temperature.

[0047] In some embodiments, this disclosure provides methods and intermediates for preparing compounds of formula I and their salts. In other embodiments, this disclosure provides methods for preparing intermediates that can be used to prepare compounds of formula I and their salts.

[0048] This article provides a method for preparing compounds of formula I or salts thereof: I Where R 1 Selected from hydrogen and hydroxyl protecting groups; This method involves making a compound of formula II: II or its salt, It reacts with the first catalyst to give a compound of formula I or a salt thereof.

[0049] In some implementation schemes, R 1 Selected from hydrogen, C 1-4 Alkyl and benzyl. In some embodiments, R 1 It is hydrogen. In some implementations, R 1 It is C 1-4 Alkyl group. In some embodiments, R 1 Selected from hydrogen, methyl, ethyl, and benzyl. In some embodiments, R 1 Selected from methyl, ethyl, and benzyl. In some embodiments, R 1 It is methyl. In some embodiments, R 1 It is ethyl. In some embodiments, R 1 It is benzyl.

[0050] In some embodiments, the compound of formula I or a salt thereof is a compound of formula IA: IA Or its salt.

[0051] In some embodiments, the compound of formula I or a salt thereof is a compound of formula IB: IB Or its salt.

[0052] In some embodiments, the compound of formula II or a salt thereof is a compound of formula II-A: II-A Or its salt.

[0053] In some embodiments, the first catalyst is a metathesis catalyst. In some embodiments, the first catalyst is selected from ruthenium-based catalysts, molybdenum-based catalysts, and tungsten-based catalysts. In some embodiments, the first catalyst is a ruthenium-based catalyst. In some embodiments, the first catalyst is selected from Hoveyda-Grubbs second-generation catalysts, Hoveyda-Grubbs first-generation catalysts, Zhan 1B, nitro Grela, M721, M203, and M730. In some embodiments, the first catalyst is a Hoveyda-Grubbs second-generation catalyst.

[0054] In some embodiments, the molar ratio of the compound of Formula II or a salt thereof to the first catalyst is from about 1:0.001 to about 1:0.05. In some embodiments, the molar ratio of the compound of Formula II or a salt thereof to the first catalyst is from about 1:0.01 to about 1:0.03. In some embodiments, the molar ratio of the compound of Formula II or a salt thereof to the first catalyst is from about 1:0.01 to about 1:0.02. In some embodiments, the molar ratio of the compound of Formula II or a salt thereof to the first catalyst is from about 1:0.015.

[0055] In some embodiments, the reaction of the compound of formula II or its salt is carried out in the presence of a first additive. In some embodiments, the first additive minimizes the amount of impurities (i.e., reaction byproducts) formed during the reaction. In some embodiments, the first additive includes dimethyl maleate, 1,4-benzoquinone, 6-dichloro-1,4-benzoquinone, 2-chloro-1,4-benzoquinone, tetrafluoro-1,4-benzoquinone, 2-methylbenzoquinone, dimethyl fumarate, maleic acid, fumaric acid, maleic anhydride, methyl trans-cinnamate, acetic acid, trifluoroacetic acid, or combinations thereof. In some embodiments, the first additive includes dimethyl maleate.

[0056] In some embodiments, the reaction of the compound of formula II or a salt thereof is carried out in a first solvent. In some embodiments, the first solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, NButylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the first solvent comprises an ester. In some embodiments, the first solvent comprises ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate, or combinations thereof. In some embodiments, the reaction of the compound of formula II or a salt thereof is carried out in a first solvent comprising ethyl acetate.

[0057] In some embodiments, the reaction of the compound of formula II or its salt is carried out in a temperature range of about 20°C to about 120°C. In some embodiments, the reaction of the compound of formula II is carried out in a temperature range of about 50°C to about 100°C. In some embodiments, the reaction of the compound of formula II is carried out in a temperature range of about 70°C to about 90°C. In some embodiments, the reaction of the compound of formula II is carried out at a temperature of about 80°C.

[0058] In some implementation schemes, R 1 It is a hydroxyl protecting group; and the method further includes deprotecting the compound of formula I or its salt; Compounds of formula IA are obtained: IA Or its salt.

[0059] In some embodiments, deprotecting a compound of Formula I or a salt thereof comprises treating the compound of Formula I or a salt thereof with a first deprotecting agent. Any suitable deprotecting agent may be used for the deprotection of compounds of Formula I. In some embodiments, suitable deprotecting agents include metal halide salts (e.g., magnesium bromide, lithium chloride, potassium iodide, sodium iodide, calcium chloride, copper chloride (I), copper chloride (II), zinc chloride), hydrogen halides (e.g., hydrogen chloride, hydrogen bromide, hydrogen iodide), boron reagents (e.g., boron trichloride, boron tribromide), aluminum reagents (e.g., aluminum trichloride, aluminum tribromide), titanium reagents (e.g., titanium tetrachloride, titanium tribromide, titanium tetrabromide), pyridinium halide salts (e.g., pyridinium chloride, pyridinium perbromide, pyridinium iodide), ammonium halides (e.g., ammonium chloride, tetrabutylammonium chloride, tetrabutylammonium iodide), and silyl halides (e.g., trimethylsilyl chloride, trimethylsilyl iodide).

[0060] In some embodiments, the first deprotecting agent is selected from metal halides, hydrogen halides, boron reagents, aluminum reagents, titanium reagents, pyridinium halides, ammonium halides, and silyl halides. In some embodiments, the first deprotecting agent is a metal halide. In some embodiments, the first deprotecting agent includes magnesium bromide, lithium chloride, potassium iodide, sodium iodide, calcium chloride, copper chloride (I), copper chloride (II), zinc chloride, or combinations thereof. In some embodiments, the first deprotecting agent is lithium chloride.

[0061] In some embodiments, the deprotection of a compound of formula I or its salt is performed in a second solvent. In some embodiments, the second solvent includes water, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the second solvent comprises a polar aprotic solvent. In some embodiments, the second solvent comprises... N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N -Butylpyrrolidone (NBP) or combinations thereof. In some embodiments, the deprotection of a compound of formula I or its salt is carried out in a second solvent containing N-methyl-2-pyrrolidone.

[0062] In some embodiments, the deprotection of the compound of formula I or its salts is carried out in a temperature range of about 0°C to about 130°C. In some embodiments, the deprotection of the compound of formula I or its salts is carried out in a temperature range of about 0°C to about 100°C. In some embodiments, the deprotection of the compound of formula I or its salts is carried out in a temperature range of about 70°C to about 90°C. In some embodiments, the deprotection of the compound of formula I or its salts is carried out at a temperature of about 80°C.

[0063] In some embodiments, the method further includes preparing a compound of formula II or a salt thereof by means of the following: Compounds of formula III: III or its salt and Methylene reagent and First acid or first base reaction The compound of formula II or its salt is obtained.

[0064] In some embodiments, the compound of formula III is a compound of formula III-A: III-A Or its salt.

[0065] In some embodiments, the methylene reagent is a formaldehyde reagent or a dihalomethane. In some embodiments, suitable formaldehyde reagents include formaldehyde acetals (e.g., dimethoxymethane, diethoxymethane), formaldehyde solutions, paraformaldehyde, and 1,3,5-trioxane. In some embodiments, suitable methylene reagents include dihalomethanes (e.g., dibromomethane, diiodomethane).

[0066] In some embodiments, the methylene reagent is selected from 1,3,5-trioxane, formaldehyde acetal, formaldehyde, paraformaldehyde, or dihalomethane. In some embodiments, the methylene reagent is a formaldehyde reagent. In some embodiments, the methylene reagent is selected from 1,3,5-trioxane, formaldehyde acetal, formaldehyde, and paraformaldehyde. In some embodiments, the methylene reagent is 1,3,5-trioxane.

[0067] In some embodiments, the compound of formula III or a salt thereof reacts with the first acid. In some embodiments, suitable first acids include carboxylic acids (e.g., oxalic acid, trichloroacetic acid, trifluoroacetic acid), sulfonic acids (e.g., methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid), Lewis acids (e.g., boron trifluoride methyl ether, boron trifluoride dibutyl ether, boron trichloride, boron tribromide, aluminum chloride, aluminum bromide), inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid), or combinations thereof.

[0068] In some embodiments, the first acid includes a carboxylic acid, a sulfonic acid, a Lewis acid, an inorganic acid, or a combination thereof. In some embodiments, the first acid includes a carboxylic acid. In some embodiments, the first acid is selected from oxalic acid, trichloroacetic acid, trifluoroacetic acid, or a combination thereof. In some embodiments, the first acid is trifluoroacetic acid.

[0069] In some embodiments, the compound of formula III or a salt thereof reacts with the first base. In some embodiments, a suitable first base includes an amine (e.g., n-propylamine, triethylamine, ...). N,N-Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring), amidine (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), etc.), guanidine (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate) Metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), amides (e.g., lithium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, lithium diisopropylamino, basic aromatic compounds (e.g., pyridine, 2,6-dimethylpyridine, imidazole) or combinations thereof.

[0070] In some embodiments, the first base includes amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, phosphates, hydroxides, alkoxides, amides, basic aromatic compounds, or combinations thereof.

[0071] In some embodiments, the reaction of the compound of formula III or its salt is carried out in a third solvent. In some embodiments, the third solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., ... N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N The third solvent comprises butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the third solvent comprises a hydrocarbon. In some embodiments, the third solvent comprises toluene, methylcyclohexane, n-heptane, hexane, limonene, or combinations thereof. In some embodiments, the reaction of the compound of formula III or a salt thereof is carried out in a third solvent comprising toluene.

[0072] In some embodiments, the reaction of the compound of formula III or its salt is carried out in a temperature range of about 60°C to about 100°C. In some embodiments, the reaction of the compound of formula III or its salt is carried out in a temperature range of about 75°C to about 85°C. In some embodiments, the reaction of the compound of formula III or its salt is carried out at a temperature of about 80°C.

[0073] In some embodiments, the method further includes preparing a compound of formula III or a salt thereof by means of the following: Compounds of formula IV: IV Or its salt deprotection, wherein R 2 It is an amine protecting group; The compound of formula III or its salt is obtained.

[0074] In some implementation schemes, R 2 It is tert-butyloxycarbonyl (Boc). In some embodiments, R 1 Selected from hydrogen, methyl, ethyl, and benzyl and R 2 It is tert-butyloxycarbonyl. In some embodiments, R 1 It is C 1-4 Alkyl and R 2 It is tert-butyloxycarbonyl. In some embodiments, R 1 Selected from methyl and ethyl and R 2 It is tert-butyloxycarbonyl.

[0075] In some embodiments, the compound of formula IV is the compound of formula IV-A: IV-A Or its salt.

[0076] In some embodiments, deprotecting a compound of formula IV or a salt thereof involves treating the compound of formula IV or a salt thereof with a second acid. Any suitable acid may be used for deprotecting a compound of formula IV or a salt thereof. In some embodiments, suitable second acids include sulfonic acids (e.g., p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid), inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid), organic acids (e.g., trifluoroacetic acid, formic acid, acetic acid, oxalic acid, citric acid), acyl chlorides (e.g., acetyl chloride), and Lewis acids (e.g., aluminum chloride, boron tribromide, lanthanum trifluoromethanesulfonate).

[0077] In some embodiments, the second acid includes sulfonic acid, inorganic acid, organic acid, acyl chloride, Lewis acid, or combinations thereof. In some embodiments, the second acid includes sulfonic acid. In some embodiments, the second acid is selected from p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, or combinations thereof. In some embodiments, the second acid includes methanesulfonic acid.

[0078] In some embodiments, the deprotection of a compound of formula IV or its salt is performed in the absence of an acid.

[0079] In some embodiments, the deprotection of a compound of formula IV or its salt is performed in a fourth solvent. In some embodiments, the fourth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., ... N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N The fourth solvent comprises butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or combinations thereof. In some embodiments, the fourth solvent comprises an ether. In some embodiments, the fourth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the deprotection of a compound of formula IV or its salt is performed in a fourth solvent comprising cyclopentyl methyl ether.

[0080] In some embodiments, the deprotection of the compound of formula IV or its salts is carried out in a temperature range of about 0°C to about 120°C. In some embodiments, the deprotection of the compound of formula IV or its salts is carried out in a temperature range of about 10°C to about 60°C. In some embodiments, the deprotection of the compound of formula IV or its salts is carried out in a temperature range of about 30°C to about 40°C. In some embodiments, the deprotection of the compound of formula IV or its salts is carried out in a temperature range of about 35°C.

[0081] In some embodiments, the method further includes preparing a compound of formula IV or a salt thereof by means of the following: Compounds of formula V: V Or its salt and: Compounds of formula VI: VI Where Y is an anion or salt. Coupling agents and The second base reaction, A compound of formula V or its salt is obtained.

[0082] In some embodiments, the compound of formula V is a compound of formula VA: VA Or its salt.

[0083] In some embodiments, Y is selected from toluenesulfonate, methanesulfonate, and HCl salt. In some embodiments, Y is a toluenesulfonate. In some embodiments, Y is a methanesulfonate. In some embodiments, Y is an HCl salt.

[0084] In some embodiments, the compound of formula VI or a salt thereof is a compound of formula VI-A: .

[0085] In some embodiments, suitable coupling agents include acyl chlorides (e.g., thionyl chloride, oxalyl chloride, phosphoryl(V) chloride), mixed anhydrides (e.g., mixed with reagents such as acetic anhydride, neopentyl chloride, diphenylphosphine anhydride, propanephosphine anhydride, boric acid, isobutyl chloroformate, methanesulfonyl chloride, p-toluenesulfonyl chloride), carbonyl diimidazoles, activated esters, chlorinated 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium, 2-chloro-4,6-dimethoxy-1,3,5-triazine, cyanuric chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b [Pyridinium 3-oxide hexafluorophosphate] and other reagents known to promote the coupling of amines with carboxylic acids.

[0086] In some embodiments, the coupling agent includes 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- bThe coupling agent comprises pyridinium 3-oxide hexafluorophosphate (HATU), acyl chlorides, acid anhydrides, carbonyl diimidazoles, activated esters, or combinations thereof. In some embodiments, the coupling agent includes thionyl chloride, oxalyl chloride, phosphoryl(V) chloride, acetic anhydride, neopentanoyl chloride, diphenylphosphine anhydride, propanephosphine anhydride, boric acid, isobutyl chloroformate, methanesulfonyl chloride, p-toluenesulfonyl chloride, carbonyl diimidazole, activated esters, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine, cyanuryl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate, HATU, or combinations thereof. In some embodiments, the coupling agent is a peptide coupling agent. In some embodiments, the coupling agent is HATU.

[0087] In some embodiments, suitable second bases include amines (e.g., N-methylmorpholine, triethylamine, diisopropylethylamine), amidines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate, etc.), and carbonates (e.g., M(n)H( 2-n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), basic aromatic compounds (e.g., pyridine, 2,6-dimethylpyridine, imidazole, etc.) or combinations thereof.

[0088] In some embodiments, the second base comprises an amine, amidine, guanidine, carboxylate, carbonate, metal hydride, hydroxide, alkoxide, basic aromatic compound, or a combination thereof. In some embodiments, the second base comprises an amine. In some embodiments, the second base comprises N-methylmorpholine, triethylamine, diisopropylethylamine, or a combination thereof. In some embodiments, the second base is N-methylmorpholine.

[0089] In some embodiments, the reaction of the compound of formula V or a salt thereof is carried out in a fifth solvent. In some embodiments, the fifth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide,N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N The fifth solvent comprises butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or combinations thereof. In some embodiments, the fifth solvent comprises an ether. In some embodiments, the fifth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of the compound of formula V or a salt thereof is carried out in a fifth solvent comprising N,N-dimethylacetamide and cyclopentyl methyl ether.

[0090] In some embodiments, the reaction of the compound of formula V or its salt is carried out in a temperature range of about 0°C to about 80°C. In some embodiments, the reaction of the compound of formula V or its salt is carried out in a temperature range of about 10°C to about 30°C. In some embodiments, the reaction of the compound of formula V or its salt is carried out at a temperature of about 20°C.

[0091] In some embodiments, the method further includes preparing a compound of formula V or a salt thereof by means of the following: Compounds of formula VII: VII or its salt, wherein R 3 It is a hydroxyl protecting group; It reacts with the first reagent to give a compound of formula V or a salt thereof.

[0092] In some implementation schemes, R 3 Selected from C 1-4 Alkyl and benzyl. In some embodiments, R 3 Selected from methyl, ethyl, and benzyl. In some embodiments, R 3 C 1-4 Alkyl group. In some embodiments, R 3 Selected from methyl and ethyl. In some embodiments, R 3 It is methyl. In some embodiments, R 3 It is ethyl. In some embodiments, R 3 It is benzyl.

[0093] In some implementation schemes, R 1 Selected from hydrogen, methyl, ethyl, and benzyl and R3 Selected from methyl, ethyl, and benzyl. In some embodiments, R 1 and R 3 Each is C independently 1-4 Alkyl group. In some embodiments, R 1 and R 3 Each is independently selected from methyl and ethyl. In some embodiments, R 1 and R 3 Each is a methyl group.

[0094] In some implementation schemes, R 2 It is tert-butyloxycarbonyl and R 3 Selected from methyl, ethyl, and benzyl. In some embodiments, R 2 It is tert-butyloxycarbonyl and R 3 It is C 1-4 Alkyl group. In some embodiments, R 2 It is tert-butyloxycarbonyl and R 3 Selected from methyl and ethyl. In some embodiments, R 2 It is tert-butyloxycarbonyl and R 3 Selected from methyl.

[0095] In some implementation schemes, R 2 It is tert-butyloxycarbonyl and R 1 and R 3 Each is independently selected from methyl, ethyl, and benzyl. In some embodiments, R 2 It is tert-butyloxycarbonyl and R 1 and R 3 Each is C independently 1-4 Alkyl group. In some embodiments, R 2 It is tert-butyloxycarbonyl and R 1 and R 3 Each is independently selected from methyl and ethyl.

[0096] In some embodiments, the compound of formula VII is the compound of formula VII-B: VII-B In some implementations, the first reagent is selected from a third base and a hydrolase.

[0097] In some embodiments, the first reagent is a third base. In some embodiments, suitable third bases include amines (e.g., n-propylamine, triethylamine, etc.). N,N-Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring), amidine (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), etc.), guanidine (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carbonate (e.g., M(n)H(2-n)CO3, etc.), etc. Sodium carbonate, potassium bicarbonate, cesium carbonate), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), amides (e.g., lithium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, lithium diisopropylamino) or combinations thereof.

[0098] In some embodiments, the third base includes an amine, amidine, guanidine, carbonate, phosphate, hydroxide, alkoxide, amide, or a combination thereof. In some embodiments, the third base includes a hydroxide. In some embodiments, the third base includes an alkali metal hydroxide. In some embodiments, the third base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, or a combination thereof. In some embodiments, the third base is lithium hydroxide.

[0099] In some embodiments, the reaction of the compound of formula VII or its salt is carried out in a sixth solvent. In some embodiments, the sixth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, NThe sixth solvent comprises butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or combinations thereof. In some embodiments, the sixth solvent comprises an ether. In some embodiments, the sixth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the sixth solvent comprises cyclopentyl methyl ether. In some embodiments, the sixth solvent comprises an alcohol. In some embodiments, the sixth solvent comprises methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol, or combinations thereof. In some embodiments, the sixth solvent comprises methanol. In some embodiments, the sixth solvent includes water. In some embodiments, the sixth solvent includes ether, alcohol, and water.

[0100] In some embodiments, the reaction of the compound of formula VII or its salt is carried out in a sixth solvent comprising cyclopentyl methyl ether, methanol, and water. In some embodiments, the reaction of the compound of formula VII or its salt is carried out in a sixth solvent comprising cyclopentyl methyl ether, methanol, and water, wherein the volume ratio of cyclopentyl methyl ether:methanol:water is about 1-3:3-5:1. In some embodiments, the reaction of the compound of formula VII or its salt is carried out in a sixth solvent comprising cyclopentyl methyl ether, methanol, and water, wherein the volume ratio of cyclopentyl methyl ether:methanol:water is about 2:4:1.

[0101] In some embodiments, the reaction of the compound of formula VII or its salt is carried out in a temperature range of about 0°C to about 80°C. In some embodiments, the reaction of the compound of formula VII or its salt is carried out in a temperature range of about 10°C to about 30°C. In some embodiments, the reaction of the compound of formula VII or its salt is carried out at a temperature of about 30°C.

[0102] In some embodiments, the method further includes preparing a compound of formula VII or a salt thereof by means of the following: Compounds of formula VIII: VIII Or its salt and: Compounds of formula IX: IX or its salt, Phosphorus reagents and azodicarbonate reaction, The compound of formula VII or its salt is obtained.

[0103] In some embodiments, the compound of formula VIII is the compound of formula VIII-B: VIII-B Or its salt.

[0104] In some embodiments, suitable phosphorus-based reagents include triarylphosphine (e.g., triphenylphosphine, tri(2-pyridyl)phosphine, tri-(4-methoxyphenyl)phosphine, tri-(dimethylaminophenyl)phosphine, triphenylphosphine acetonitrile), trialkylphosphine (e.g., tricyclohexylphosphine, tributylphosphine), and n-phosphine (e.g., (cyanomethylene)tributyln-phosphine).

[0105] In some embodiments, the phosphorus-based reagent is selected from triarylphosphine, trialkylphosphine, and n-phosphine. In some embodiments, the phosphorus-based reagent is phosphine. In some embodiments, the phosphorus-based reagent is triarylphosphine. In some embodiments, the phosphorus-based reagent is selected from triphenylphosphine, tris(2-pyridyl)phosphine, tris-(4-methoxyphenyl)phosphine, tris-(dimethylaminophenyl)phosphine, and triphenylphosphine acetonitrile. In some embodiments, the phosphorus-based reagent is triphenylphosphine.

[0106] In some embodiments, the azodicarbonate ester is selected from diisopropyl azodicarbonate, di-tert-butyl azodicarbonate, diethyl azodicarbonate, dimethoxy ethyl azodicarbonate, azodicarbonyl dimorpholine, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarbonate. In some embodiments, the azodicarbonate ester is diisopropyl azodicarbonate.

[0107] In some embodiments, the reaction of the compound of formula VIII or a salt thereof is carried out in a seventh solvent. In some embodiments, the seventh solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, NThe seventh solvent comprises butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the seventh solvent comprises an ether. In some embodiments, the seventh solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of the compound of formula VIII or a salt thereof is carried out in a seventh solvent comprising 2-methyltetrahydrofuran.

[0108] In some embodiments, the reaction of the compound of formula VIII or its salt is carried out in a temperature range of about 0°C to about 50°C. In some embodiments, the reaction of the compound of formula VIII or its salt is carried out in a temperature range of about 10°C to about 30°C. In some embodiments, the reaction of the compound of formula VIII or its salt is carried out in a temperature range of about 20°C.

[0109] Alternative methods for preparing compounds of formula VII In some embodiments, the method includes preparing a compound of formula VII or a salt thereof by means of the following: Compounds of formula VIII: VIII Or its salt and: A second reagent containing a crotonyl group or an allyl group Second catalyst and The sixth base reaction, A compound of formula VII or a salt thereof is obtained. In some embodiments, the compound of formula VII is a compound of formula VII-B.

[0110] In some embodiments, the second reagent comprises a crotonyl group (i.e., but-2-en-1-yl). In some embodiments, the second reagent comprises an allyl group (i.e., but-3-en-2-yl).

[0111] In some embodiments, suitable second reagents include crotonyl carbonate (e.g., crotonyl methyl carbonate, crotonyl ethyl carbonate), crotonyl esters (e.g., crotonyl acetate, crotonyl trifluoromethyl acetate), crotonyl halides (e.g., crotonyl chloride, crotonyl bromide), crotonol, 1-methylallyl esters (e.g., 1-methylallyl acetate, 1-methylallyl trifluoroacetate), 1-methylallyl carbonates (e.g., 1-methylallyl methyl carbonate, 1-methylallyl ethyl carbonate), 1-methylallyl halides (e.g., 3-chloro-1-butene, 3-bromo-1-butene), 3-buten-2-ol, or combinations thereof.

[0112] In some embodiments, the second reagent is selected from crotonyl carbonate, crotonyl ester, crotonyl halide, crotonol, 1-methylallyl ester, 1-methylallyl carbonate, 1-methylallyl halide, and 3-buten-2-ol. In some embodiments, the second reagent is selected from crotonyl methyl carbonate, crotonyl ethyl carbonate, or combinations thereof. In some embodiments, the second reagent is crotonyl carbonate. In some embodiments, the second reagent is crotonyl methyl carbonate.

[0113] In some embodiments, the second catalyst is a transition metal catalyst. In some embodiments, the transition metal catalyst is selected from iridium compounds, palladium compounds, cobalt compounds, and rhodium compounds. In some embodiments, the transition metal catalyst is an iridium compound.

[0114] In some embodiments, the second catalyst is formed in situ from a precatalyst and a ligand. In some embodiments, suitable precatalysts include iridium compounds (e.g., bis(1,5-cyclooctadiene)diiridium(I), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer), palladium compounds (e.g., tris(dibenzylacetone)dipalladium(O)[Pd2(dba)3], palladium(II) acetate, allyl palladium(II) chloride dimer), cobalt compounds (e.g., cobalt(II) tetrafluoroborate, cobalt(II) bromide), and rhodium compounds (e.g., chloro(1,5-cyclooctadiene)rhodium(I) dimer, hydroxy(cyclooctadiene)rhodium(I) dimer).

[0115] In some embodiments, the precatalyst is selected from iridium compounds, palladium compounds, cobalt compounds, and rhodium compounds. In some embodiments, the precatalyst is an iridium compound. In some embodiments, the precatalyst is bis(1,5-cyclooctadiene)diiridium(I) dichloride or (1,5-cyclooctadiene)(methoxy)iridium(I) dimer. In some embodiments, the precatalyst is bis(1,5-cyclooctadiene)diiridium(I) dichloride.

[0116] In some embodiments, the molar ratio of the compound of formula VIII or a salt thereof to the precatalyst is from about 1:0.01 to about 1:0.10. In some embodiments, the molar ratio of the compound of formula VIII or a salt thereof to the precatalyst is from about 1:0.01 to about 1:0.07. In some embodiments, the molar ratio of the compound of formula VIII or a salt thereof to the precatalyst is from about 1:0.04.

[0117] In some implementations, suitable ligands include phosphoramidite (e.g., (S,S,S)- (+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a']dinaflav-4-yl)bis(1-phenylethyl)amine, (S)-(+)-N-(3,5-dioxa-4-phosphacyclohepta[2,1-a; 3,4-a']dinaflav-4-yl)-dibenzo[b,f]azacycloheptatriene, (S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a; 3,4-a']dinaflav-4-yl)dimethylamine) and Trost ligands (e.g., ( 1S,2S )-(-)-1,2-Diaminocyclohexane- N,N’ -bis(2-diphenylphosphino)[( S,S )-DACH-phenylTrost ligand], ( 1S, 2S )-(-)-1,2-Diaminocyclohexane- N,N’ -bis(2-diphenylphosphine-1-naphthoyl)[( S,S (-DACH-naphthylTrost ligand). In some embodiments, the ligand is selected from phosphorous amide and Trost ligand. In some embodiments, the ligand is phosphorous amide. In some embodiments, the ligand is selected from... (S,S,S)- (+)-(3,5-dioxa-4-phosphazonyl-heptano[2,1-a:3,4-a']dinaflav-4-yl)bis(1-phenylethyl)amine, (S)-(+)-N-(3,5-dioxa-4-phosphazonyl-heptano[2,1-a; 3,4-a']dinaflav-4-yl)-dibenzo[b,f]azacycloheptatriene, and (S)-(+)-(3,5-dioxa-4-phosphazonyl-heptano[2,1-a; 3,4-a']dinaflav-4-yl)dimethylamine. In some embodiments, the ligand is (S,S,S)- (+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a']dinaphthyl-4-yl)bis(1-phenylethyl)amine.

[0118] In some implementations, suitable sixth bases include amines (e.g., n-propylamine, triethylamine, ... N,N-Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring), amidine (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidine (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium bicarbonate, carbon The sixth base includes cesium hydroxide, metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), amides (e.g., lithium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, lithium diisopropylamino, and basic aromatic compounds (e.g., pyridine, 2,6-dimethylpyridine, imidazole). In some embodiments, the sixth base includes amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, phosphates, hydroxides, alkoxides, amides, and basic aromatic compounds. In some embodiments, the sixth base is an amine. In some embodiments, the sixth base includes n-propylamine, triethylamine, N,N -Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring, or combinations thereof. In some embodiments, the sixth base is n-propylamine.

[0119] In some embodiments, the reaction of the compound of formula VIII or a salt thereof is carried out in a twelfth solvent. In some embodiments, the twelfth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N 1-Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the twelfth solvent comprises a polar aprotic solvent. In some embodiments, the twelfth solvent includes... N,N -Dimethylformamide, N,N -Dimethylacetamide,N 2-Methyl-2-pyrrolidone, N -Butylpyrrolidone (NBP) or combinations thereof. In some embodiments, the reaction of the compounds of formula VIII or their salts is carried out in a twelfth solvent containing N,N-dimethylacetamide.

[0120] In some embodiments, the reaction of the compound of formula VIII or its salt is carried out in a temperature range of about 0°C to about 80°C. In some embodiments, the reaction of the compound of formula VIII or its salt is carried out in a temperature range of about 20°C to about 30°C. In some embodiments, the reaction of the compound of formula VIII or its salt is carried out at a temperature of about 25°C.

[0121] Method for preparing compounds of formula VIII In some embodiments, the method includes preparing a compound of formula VIII or a salt thereof by means of the following: Compounds of formula X: X Or its salt reacts with a compound of formula NH2NHR2 or its salt. A compound of formula VIII or a salt thereof is obtained.

[0122] In some embodiments, the compound of formula X is a compound of formula XB: XB Or its salt.

[0123] In some embodiments, the compound of formula NH2NHR2 or its salt is NH2NHBoc.

[0124] In some embodiments, the reaction of the compound of formula X or a salt thereof is carried out in the presence of a fourth base. In some embodiments, suitable fourth bases include amines (e.g., triethylamine, ...). N,N-Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring), amidine (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidine (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium bicarbonate, carbonate Cesium), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), amides (e.g., lithium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, lithium diisopropylamino, etc.), basic aromatic compounds (e.g., pyridine, 2,6-dimethylpyridine, imidazole).

[0125] In some embodiments, the fourth base includes amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, phosphates, hydroxides, alkoxides, amides, basic aromatic compounds, or combinations thereof. In some embodiments, the fourth base is a carbonate. In some embodiments, the fourth base is an alkali metal carbonate. In some embodiments, the fourth base includes sodium carbonate, potassium bicarbonate, cesium carbonate, or combinations thereof. In some embodiments, the fourth base is sodium bicarbonate.

[0126] In some implementations, the reaction of the compound of formula X is carried out in the absence of a base.

[0127] In some embodiments, the reaction of the compound of formula X or its salt is carried out in an eighth solvent. In some embodiments, the eighth solvent includes alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or combinations thereof. In some embodiments, the eighth solvent includes alcohols. In some embodiments, the eighth solvent includes methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol, or combinations thereof. In some embodiments, the eighth solvent includes methanol. In some implementations, the eighth solvent includes water.

[0128] In some embodiments, the reaction of the compound of formula X or a salt thereof is carried out in an eighth solvent comprising methanol and water. In some embodiments, the reaction of the compound of formula X or a salt thereof is carried out in an eighth solvent comprising methanol and water, wherein the volume ratio of methanol to water is about 1-10:0.1-1.0. In some embodiments, the reaction of the compound of formula X or a salt thereof is carried out in an eighth solvent comprising methanol and water, wherein the volume ratio of methanol to water is about 6:0.4.

[0129] In some embodiments, the reaction of the compound of formula X or its salt is carried out in a temperature range of about 0°C to about 80°C. In some embodiments, the reaction of the compound of formula X or its salt is carried out in a temperature range of about 35°C to about 55°C. In some embodiments, the reaction of the compound of formula X or its salt is carried out at a temperature of about 45°C.

[0130] In some embodiments, the method further includes preparing a compound of formula X or a salt thereof by means of the following: Compounds of formula XII: XII Or its salt and: Accelerator, Dialkyl oxalate and Fifth base reaction, To obtain a compound of formula X or a salt thereof.

[0131] In some embodiments, the compound of formula XII is the compound of formula XII-A: XII-A In some embodiments, suitable promoters include carboxylic acids (e.g., formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid), sulfonic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid), haloalcohols (e.g., 2,2,2-trichloroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol), Lewis acids (e.g., boron trifluoride methyl ether, boron trifluoride dibutyl ether, boron trichloride, boron tribromide, aluminum chloride, aluminum bromide), and inorganic acids (e.g., hydrochloric acid, sulfuric acid).

[0132] In some embodiments, the accelerator includes carboxylic acids, sulfonic acids, haloalcohols, Lewis acids, inorganic acids, or combinations thereof. In some embodiments, the accelerator includes haloalcohols. In some embodiments, the accelerator includes 2,2,2-trichloroethanol, 1,1,1,3,3,3-hexafluoro-2-propanol, or combinations thereof. In some embodiments, the accelerator is 2,2,2-trifluoroethanol.

[0133] In some embodiments, the reaction of the compound of formula XII or a salt thereof is carried out in the presence of a third acid. In some embodiments, the third acid is an inorganic acid. In some embodiments, the third acid is hydrochloric acid.

[0134] In some embodiments, the dialkyl oxalate is di-C oxalate. 1-4 Alkyl ester. In some embodiments, the dialkyl oxalate is selected from dimethyl oxalate and diethyl oxalate. In some embodiments, the dialkyl oxalate is dimethyl oxalate.

[0135] In some embodiments, a suitable fifth base includes amines (e.g., ethylamine, triethylamine, ...). N,N -Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring), amidine (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidine (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate), metal hydrides (e.g. Lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), alkyl lithium and aryl lithium reagents (e.g., n-butyllithium, phenyl lithium), amides (e.g., bis(trimethylsilyl)aminolithium, bis(trimethylsilyl)aminopotassium, diisopropylaminolithium), and basic aromatic compounds (e.g., pyridine, 2,6-dimethylpyridine, imidazole).

[0136] In some embodiments, the fifth base includes amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, phosphates, hydroxides, alkoxides, alkyllithium reagents, aryllithium reagents, amides, basic aromatic compounds, or combinations thereof. In some embodiments, the fifth base includes metal alkoxides. In some embodiments, the fifth base includes sodium methoxide, sodium ethoxide, potassium tert-butoxide, or combinations thereof. In some embodiments, the fifth base is sodium alkoxide.

[0137] In some embodiments, the reaction of the compound of formula XII or its salt is carried out in a tenth solvent. In some embodiments, the tenth solvent includes alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentane methyl ether, 1,4-dioxane), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g.,N , N -Dimethylformamide, N , N -Dimethylacetamide, N 1-Methyl-2-pyrrolidone, N-butylpyrrolidone (NBP)), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or combinations thereof. In some embodiments, the tenth solvent includes a polar aprotic solvent. In some embodiments, the tenth solvent includes... N , N -Dimethylformamide, N , N -Dimethylacetamide, N -Methyl-2-pyrrolidone, N-butylpyrrolidone (NBP), or combinations thereof. In some embodiments, the reaction of the compound of formula XII or a salt thereof is carried out in a tenth solvent containing N,N-dimethylacetamide.

[0138] In some embodiments, the reaction of the compound of formula XII or its salt is carried out in a temperature range of about -10°C to about 50°C. In some embodiments, the reaction of the compound of formula XII or its salt is carried out in a temperature range of about 0°C to about 20°C. In some embodiments, the reaction of the compound of formula XII or its salt is carried out at a temperature of about 10°C.

[0139] In some embodiments, the method includes preparing a compound of formula X or a salt thereof by means of the following: Compounds of formula XI: XI The compound or its salt reacts with an accelerator to give a compound of formula X or its salt.

[0140] In some embodiments, the accelerator includes carboxylic acids, sulfonic acids, haloalcohols, Lewis acids, inorganic acids, or combinations thereof. In some embodiments, the accelerator includes haloalcohols. In some embodiments, the accelerator is 2,2,2-trifluoroethanol.

[0141] In some embodiments, the reaction of the compound of formula XI or a salt thereof is carried out in the presence of a third acid. In some embodiments, the third acid is an inorganic acid. In some embodiments, the third acid is hydrochloric acid.

[0142] In some embodiments, the reaction of the compound of formula XI or a salt thereof is carried out in a ninth solvent containing dichloromethane.

[0143] In some embodiments, the reaction of the compound of formula XI or its salt is carried out in a temperature range of about -10°C to about 50°C.

[0144] In some embodiments, the compound of formula XI is a compound of formula XI-A: XI-A Or its salt.

[0145] In some embodiments, the reaction of the compound of formula XI or a salt thereof is carried out in the presence of a third acid. In some embodiments, the third acid is an inorganic acid. In some embodiments, the third acid is hydrochloric acid. In some embodiments, the weight ratio of the compound of formula XI to the third acid is about 1:0.01-0.25. In some embodiments, the weight ratio of the compound of formula XI to the third acid is about 1:0.1.

[0146] In some embodiments, the reaction of the compound of formula XI or a salt thereof is carried out in a ninth solvent containing dichloromethane.

[0147] In some embodiments, the reaction of the compound of formula XI or its salt is carried out in a temperature range of about -10°C to about 50°C.

[0148] In some embodiments, the method further includes preparing a compound of formula XI or a salt thereof by means of the following: Compounds of formula XII: XII Or its salt and: Dialkyl oxalate and Fifth base reaction, A compound of formula XI or its salt is obtained.

[0149] In some embodiments, the dialkyl oxalate is selected from dimethyl oxalate and diethyl oxalate. In some embodiments, the dialkyl oxalate is dimethyl oxalate. In some embodiments, the dialkyl oxalate is diethyl oxalate.

[0150] In some embodiments, the fifth base includes amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, phosphates, hydroxides, alkoxides, alkyllithium reagents, aryllithium reagents, amides, basic aromatic compounds, or combinations thereof. In some embodiments, the fifth base includes a metal alkoxide. In some embodiments, the fifth base is a sodium alkoxide.

[0151] In some embodiments, the reaction of the compound of formula XII or a salt thereof is carried out in a tenth solvent containing N,N-dimethylacetamide.

[0152] In some embodiments, the reaction of the compound of formula XII or its salt is carried out in a temperature range of about -10°C to about 50°C.

[0153] In some embodiments, the method further includes preparing a compound of formula XII or a salt thereof by means of the following: Compounds of formula XIII: XIII Or its salt reacts with N,N-dimethylformamide dimethyl acetal. A compound of formula XII or a salt thereof is obtained. The method for preparing a compound of formula XII or a salt thereof is described in WO2015195656, which is incorporated herein by reference.

[0154] In some embodiments, this document provides a method for preparing compounds of formula I or salts thereof: I Where R 1 The method comprises selecting hydrogen and hydroxyl protecting groups, and includes: (a) Compounds of formula VII: VII or its salt, wherein R 2 It is an amine protecting group and R 3 It is a hydroxyl protecting group that reacts with the first reagent to give a compound of formula V: V or its salt; (b) To react with: a compound of formula V or a salt thereof. Compounds of formula VI: VI Where Y is an anion or salt. Coupling agents and The second base reaction, Compounds of formula IV were obtained: IV or its salt; (c) Deprotecting a compound of formula IV or its salt to obtain a compound of formula III: III or its salt; (d) To react with: a compound of formula III or a salt thereof. Methylene reagent and First acid or first base reaction The compound of formula II was obtained: II or its salt; and (e) Reacting a compound of formula II or a salt thereof with a first catalyst to give a compound of formula I or a salt thereof.

[0155] In some embodiments, this document provides a method for preparing a compound of formula IA or a salt thereof: IA The method includes: (a) Compounds of formula VII: VII or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group, and R 2 It is an amine protecting group. The reaction with the first reagent yields a compound of formula V: V or its salt; (b) To react with: a compound of formula V or a salt thereof. Compounds of formula VI: VI Where Y is an anion or salt. Coupling agents and The second base reaction, Compounds of formula IV were obtained: IV or its salt; (c) Deprotecting a compound of formula IV or its salt to obtain a compound of formula III: III or its salt; (d) To react a compound of formula III or a salt thereof with... Methylene reagent and First acid or first base reaction The compound of formula II was obtained: II or its salt; (e) Reacting a compound of formula II or a salt thereof with a first catalyst to give a compound of formula I: I or its salt; and (f) Deprotect a compound of formula I or a salt thereof to obtain a compound of formula IA or a salt thereof.

[0156] In some embodiments, this document provides a method for preparing compounds of formula II or salts thereof: II The method includes: (a) Compounds of formula VII: VII or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group, and R 2 It is an amine protecting group. The reaction with the first reagent yields a compound of formula V: V or its salt; (b) To react with: a compound of formula V or a salt thereof. Compounds of formula VI: VI Where Y is an anion or salt. Coupling agents and The second base reaction, Compounds of formula IV were obtained: IV or its salt; (c) Deprotecting a compound of formula IV or its salt to obtain a compound of formula III: III or its salt; and (d) To react a compound of formula III or a salt thereof with... Methylene reagent and First acid or first base reaction The compound of formula II or its salt is obtained.

[0157] In some embodiments, this document provides a method for preparing compounds of formula III or salts thereof: III The method includes: (a) Compounds of formula VII: VII or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group, and R 2 It is an amine protecting group. The reaction with the first reagent yields a compound of formula V: V or its salt; (b) To react with: a compound of formula V or a salt thereof. Compounds of formula VI: VI Where Y is an anion or salt. Coupling agents and The second base reaction, Compounds of formula IV were obtained: IV or its salt; and (c) Deprotecting a compound of formula IV or a salt thereof to obtain a compound of formula III or a salt thereof.

[0158] In some embodiments, this document provides a method for preparing a compound of formula IV or a salt thereof: IV The method includes: (a) Compounds of formula VII: VII or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group, and R 2 It is an amine protecting group. The reaction with the first reagent yields a compound of formula V: V or its salt; and (b) To react with: a compound of formula V or a salt thereof. Compounds of formula VI: VI Where Y is an anion or salt. Coupling agents and The second base reaction, To obtain a compound of formula IV or a salt thereof.

[0159] In some embodiments, this document provides a method for preparing compounds of formula V or salts thereof: V The method includes: Compounds of formula VII: VII or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group, and R 2 It is an amine protecting group. It reacts with the first reagent to give a compound of formula V or a salt thereof.

[0160] In some embodiments of the methods disclosed herein, compounds of formula VII or salts thereof are prepared by methods comprising: (a) Compounds of formula XIII: XIII or its salt, wherein R 1 It is a hydroxyl protecting group; It reacts with N,N-dimethylformamide dimethyl acetal. Compounds of formula XII were obtained: XII or its salt; (b) To react with: a compound of formula XII or a salt thereof. Accelerator, Dialkyl oxalate and Fifth base reaction, Compounds of formula X are obtained: X or its salt; (c) Reacting a compound of formula X or a salt thereof with a compound of formula NH2NHR2 or a salt thereof. Compounds of formula VIII are obtained: VIII or its salt; and (d) To react with: a compound of formula VIII or a salt thereof. Compounds of formula IX: IX or its salt, Phosphorus reagents and azodicarbonate reaction, The compound of formula VII or its salt is obtained.

[0161] In some embodiments of the methods disclosed herein, compounds of formula VII or salts thereof are prepared by methods comprising: (a) Compounds of formula XIII: XIII or its salt, wherein R 1 It is a hydroxyl protecting group; It reacts with N,N-dimethylformamide dimethyl acetal. Compounds of formula XII were obtained: XII or its salt; (b) To react with: a compound of formula XII or a salt thereof. Accelerator, Dialkyl oxalate and Fifth base reaction, Compounds of formula X are obtained: X or its salt; (c) Reacting a compound of formula X or a salt thereof with a compound of formula NH2NHR2 or a salt thereof. Compounds of formula VIII are obtained: VIII or its salt; and (e) To react with: a compound of formula VIII or a salt thereof. A second reagent containing a crotonyl group or an allyl group Second catalyst and The sixth base reaction, The compound of formula VII or its salt is obtained.

[0162] Alternative methods for preparing compounds of formula III In some embodiments, the method includes preparing a compound of formula III or a salt thereof by means of the following: Compounds of formula VII-A: VII-A Or its salt reacts with the first reagent to hydrolyze the compound of formula VII-A; and The hydrolyzed compound of formula VII-A is reacted with: Compounds of formula VI: VI Where Y is an anion or salt. Coupling agents and The second base reaction, The compound of formula III or its salt is obtained.

[0163] In some implementations, the first reagent is selected from a third base and a hydrolase.

[0164] In some embodiments, the first reagent is a third base. In some embodiments, the third base includes amines, amidines, guanidines, carbonates, phosphates, hydroxides, alkoxides, amides, or combinations thereof. In some embodiments, the third base is lithium hydroxide.

[0165] In some embodiments, Y is selected from toluenesulfonate, methanesulfonate, and HCl salt. In some embodiments, Y is a toluenesulfonate.

[0166] In some embodiments, the coupling agent includes 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b The coupling agent may be pyridinium 3-oxide hexafluorophosphate (HATU), acyl chloride, acid anhydride, carbonyl diimidazole, activated ester, or a combination thereof. In some embodiments, the coupling agent is HATU.

[0167] In some embodiments, the second base includes an amine, amidine, guanidine, carboxylate, carbonate, metal hydride, hydroxide, alkoxide, basic aromatic compound, or a combination thereof. In some embodiments, the second base includes an amine. In some embodiments, the second base is N-methylmorpholine.

[0168] In some embodiments, the method further includes preparing a compound of formula VII-A or a salt thereof by means of the following: Compounds of formula VIII-A: VIII-A Or its salt and: A second reagent containing a crotonyl group or an allyl group Second catalyst and The sixth base reaction, To obtain a compound of formula VII-A or a salt thereof.

[0169] In some embodiments, the second reagent comprises a crotonyl group (i.e., but-2-en-1-yl). In some embodiments, the second reagent comprises an allyl group (i.e., but-3-en-2-yl).

[0170] In some embodiments, suitable second reagents include crotonyl carbonate (e.g., crotonyl methyl carbonate, crotonyl ethyl carbonate), crotonyl esters (e.g., crotonyl acetate, crotonyl trifluoromethyl acetate), crotonyl halides (e.g., crotonyl chloride, crotonyl bromide), crotonol, 1-methylallyl esters (e.g., 1-methylallyl acetate, 1-methylallyl trifluoroacetate), 1-methylallyl carbonates (e.g., 1-methylallyl methyl carbonate, 1-methylallyl ethyl carbonate), 1-methylallyl halides (e.g., 3-chloro-1-butene, 3-bromo-1-butene), 3-buten-2-ol, or combinations thereof.

[0171] In some embodiments, the second reagent is selected from crotonyl carbonate, crotonyl ester, crotonyl halide, crotonol, 1-methylallyl ester, 1-methylallyl carbonate, 1-methylallyl halide, and 3-buten-2-ol. In some embodiments, the second reagent is selected from methyl crotonyl carbonate, ethyl crotonyl carbonate, or combinations thereof. In some embodiments, the second reagent is crotonyl carbonate. In some embodiments, the second reagent is methyl crotonyl carbonate. In some embodiments, the second reagent is methyl crotonyl carbonate, wherein the methyl crotonyl carbonate is a mixture of cis- and trans-methyl crotonyl carbonates.

[0172] In some embodiments, the second catalyst is a transition metal catalyst. In some embodiments, the transition metal catalyst is selected from iridium compounds, palladium compounds, cobalt compounds, and rhodium compounds. In some embodiments, the transition metal catalyst is an iridium compound.

[0173] In some embodiments, the second catalyst is formed in situ from a precatalyst and a ligand. In some embodiments, suitable precatalysts include iridium compounds (e.g., bis(1,5-cyclooctadiene)diiridium(I), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer), palladium compounds (e.g., tris(dibenzylacetone)dipalladium(O)[Pd2(dba)3], palladium(II) acetate, allyl palladium(II) chloride dimer), cobalt compounds (e.g., cobalt(II) tetrafluoroborate, cobalt(II) bromide), and rhodium compounds (e.g., chloro(1,5-cyclooctadiene)rhodium(I) dimer, hydroxy(cyclooctadiene)rhodium(I) dimer).

[0174] In some embodiments, the precatalyst is selected from iridium compounds, palladium compounds, cobalt compounds, and rhodium compounds. In some embodiments, the precatalyst is an iridium compound. In some embodiments, the precatalyst is bis(1,5-cyclooctadiene)diiridium(I) dichloride or (1,5-cyclooctadiene)(methoxy)iridium(I) dimer. In some embodiments, the precatalyst is bis(1,5-cyclooctadiene)diiridium(I) dichloride.

[0175] In some embodiments, the molar ratio of the compound of formula VIII-A or a salt thereof to the precatalyst is from about 1:0.01 to about 1:0.10. In some embodiments, the molar ratio of the compound of formula VIII-A or a salt thereof to the precatalyst is from about 1:0.005 to about 1:0.05. In some embodiments, the molar ratio of the compound of formula VIII-A or a salt thereof to the precatalyst is from about 1:0.01 to about 1:0.03. In some embodiments, the molar ratio of the compound of formula VIII-A or a salt thereof to the precatalyst is from about 1:0.02.

[0176] In some implementations, suitable ligands include phosphoramidite (e.g., (S,S,S)- (+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a']dinaflav-4-yl)bis(1-phenylethyl)amine, (S)-(+)-N-(3,5-dioxa-4-phosphacyclohepta[2,1-a; 3,4-a']dinaflav-4-yl)-dibenzo[b,f]azacycloheptatriene, (S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a; 3,4-a']dinaflav-4-yl)dimethylamine) and Trost ligands (e.g., ( 1S,2S )-(-)-1,2-Diaminocyclohexane- N,N’ -bis(2-diphenylphosphino)[( S,S )-DACH-phenylTrost ligand], ( 1S, 2S )-(-)-1,2-Diaminocyclohexane- N,N’ -bis(2-diphenylphosphine-1-naphthoyl)[( S,S (-DACH-naphthylTrost ligand). In some embodiments, the ligand is selected from phosphorous amide and Trost ligand. In some embodiments, the ligand is phosphorous amide. In some embodiments, the ligand is selected from... (S,S,S)-(+)-(3,5-dioxa-4-phosphazonyl-heptano[2,1-a:3,4-a']dinaflav-4-yl)bis(1-phenylethyl)amine, (S)-(+)-N-(3,5-dioxa-4-phosphazonyl-heptano[2,1-a; 3,4-a']dinaflav-4-yl)-dibenzo[b,f]azacycloheptatriene, and (S)-(+)-(3,5-dioxa-4-phosphazonyl-heptano[2,1-a; 3,4-a']dinaflav-4-yl)dimethylamine. In some embodiments, the ligand is (S,S,S)- (+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a']dinaphthyl-4-yl)bis(1-phenylethyl)amine.

[0177] In some implementations, suitable sixth bases include amines (e.g., n-propylamine, triethylamine, ... N,N -Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring), amidine (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidine (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium bicarbonate, carbon The sixth base includes cesium hydroxide, metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), amides (e.g., lithium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, lithium diisopropylamino, and basic aromatic compounds (e.g., pyridine, 2,6-dimethylpyridine, imidazole). In some embodiments, the sixth base includes amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, phosphates, hydroxides, alkoxides, amides, and basic aromatic compounds. In some embodiments, the sixth base is an amine. In some embodiments, the sixth base includes n-propylamine, triethylamine, N,N -Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring, or combinations thereof. In some embodiments, the sixth base is 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0178] In some embodiments, the reaction of the compound of formula VIII-A or its salt is carried out in a twelfth solvent. In some embodiments, the twelfth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N 1-Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the twelfth solvent comprises a polar aprotic solvent. In some embodiments, the twelfth solvent includes... N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N -Butylpyrrolidone (NBP) or combinations thereof. In some embodiments, the reaction of compounds of formula VIII-A or their salts is carried out in a twelfth solvent containing N,N-dimethylacetamide.

[0179] In some embodiments, the reaction of the compound of formula VIII-A or its salt is carried out in a temperature range of about 0°C to about 80°C. In some embodiments, the reaction of the compound of formula VIII-A or its salt is carried out in a temperature range of about 45°C to about 55°C. In some embodiments, the reaction of the compound of formula VIII-A or its salt is carried out at a temperature of about 50°C.

[0180] Alternative methods for preparing compounds of formula IA In some embodiments, this document provides a method for preparing a compound of formula IA or a salt thereof: IA This method involves making a compound of formula I: I Or its salt deprotection, wherein R 1 It is a hydroxyl protecting group, which yields a compound of formula IA or its salt.

[0181] In some implementation schemes, R 1Selected from C 1-4 Alkyl, benzyl and -COOR 4 ;where R 4 Selected from C 1-4 Alkyl and phenyl. In some embodiments, R 1 The radical is selected from methyl, ethyl, benzyl, acetate, propionate, and benzoate. In some embodiments, R 1 Selected from C 1-4 Alkyl and benzyl. In some embodiments, R 1 It is C 1-4 Alkyl group. In some embodiments, R 1 Selected from methyl, ethyl, and benzyl. In some embodiments, R 1 It is methyl. In some embodiments, R 1 It is ethyl. In some embodiments, R 1 It is benzyl. In some embodiments, R 1 Yes - COOR 4 In some implementations, R 4 C 1-4 Alkyl group. In some embodiments, R 4 It is methyl or ethyl. In some embodiments, R 4 It is a phenyl group.

[0182] In some implementations, the compound of formula I is a compound of formula IB.

[0183] In some embodiments, deprotecting a compound of formula I or a salt thereof includes treating the compound of formula I or a salt thereof with a first deprotecting agent. In some embodiments, suitable first deprotecting agents include metal halide salts (e.g., magnesium bromide, magnesium chloride, lithium chloride, potassium iodide, sodium iodide, calcium chloride, calcium bromide, calcium iodide, copper chloride (I), copper chloride (II), zinc chloride), hydrogen halides (e.g., hydrogen chloride, hydrogen bromide, hydrogen iodide), boron reagents (e.g., boron trichloride, boron tribromide), aluminum reagents (e.g., aluminum trichloride, aluminum tribromide), titanium reagents (e.g., titanium tetrachloride, titanium tribromide, titanium tetrabromide), pyridinium halide salts (e.g., pyridinium chloride, pyridinium perbromide, pyridinium iodide), ammonium halides (e.g., ammonium chloride, tetrabutylammonium chloride, tetrabutylammonium iodide), and silyl halides (e.g., trimethylsilyl chloride, trimethylsilyl iodide).

[0184] In some embodiments, suitable first deprotecting agents include metal halide salts (e.g., magnesium bromide, lithium chloride, potassium iodide, sodium iodide, calcium chloride, copper chloride (I), copper chloride (II), zinc chloride), hydrogen halides (e.g., hydrogen chloride, hydrogen bromide, hydrogen iodide), boron reagents (e.g., boron trichloride, boron tribromide), aluminum reagents (e.g., aluminum trichloride, aluminum tribromide), titanium reagents (e.g., titanium tetrachloride, titanium tribromide, titanium tetrabromide), pyridinium halide salts (e.g., pyridinium chloride, pyridinium perbromide, pyridinium iodide), ammonium halides (e.g., ammonium chloride, tetrabutylammonium chloride, tetrabutylammonium iodide), and silyl halides (e.g., trimethylsilyl chloride, trimethylsilyl iodide).

[0185] In some embodiments, the first deprotecting agent is selected from metal halides, hydrogen halides, boron reagents, aluminum reagents, titanium reagents, pyridinium halides, ammonium halides, and silyl halides. In some embodiments, the first deprotecting agent is a metal halide. In some embodiments, the first deprotecting agent includes magnesium bromide, magnesium chloride, lithium chloride, potassium iodide, sodium iodide, calcium chloride, copper chloride (I), copper chloride (II), zinc chloride, calcium bromide, calcium iodide, or combinations thereof. In some embodiments, the first deprotecting agent includes magnesium bromide, lithium chloride, potassium iodide, sodium iodide, calcium chloride, copper chloride (I), copper chloride (II), zinc chloride, or combinations thereof. In some embodiments, the first deprotecting agent is lithium chloride. In some embodiments, the first deprotecting agent is calcium bromide. In some embodiments, the first deprotecting agent is magnesium chloride.

[0186] In some embodiments, the deprotection of a compound of formula I or its salt is performed in a second solvent. In some embodiments, the second solvent includes water, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the second solvent comprises a polar aprotic solvent. In some embodiments, the second solvent comprises... N,N -Dimethylformamide,N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N -Butylpyrrolidone (NBP) or combinations thereof. In some embodiments, the deprotection of a compound of formula I or its salt is carried out in a second solvent containing N-methyl-2-pyrrolidone.

[0187] In some embodiments, the second solvent comprises an alcohol. In some embodiments, the second solvent comprises methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol, or combinations thereof. In some embodiments, the deprotection of a compound of formula I or its salt is performed in a second solvent comprising 2-propanol.

[0188] In some embodiments, the deprotection of the compound of formula I or its salts is carried out in a temperature range of about 0°C to about 130°C. In some embodiments, the deprotection of the compound of formula I or its salts is carried out in a temperature range of about 0°C to about 100°C. In some embodiments, the deprotection of the compound of formula I or its salts is carried out in a temperature range of about 70°C to about 90°C. In some embodiments, the deprotection of the compound of formula I or its salts is carried out at a temperature of about 80°C.

[0189] In some embodiments, the method further includes preparing a compound of formula I or a salt thereof by means of the following: Compounds of formula A: A or its salt, wherein R 3A It is a hydroxyl protecting group, and: Methylene reagent and First acid or first base reaction The compound of formula I or its salt is obtained.

[0190] In some implementation schemes, R 3A Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and benzyl groups. In some embodiments, R... 3A Selected from methyl, ethyl, isopropyl, trifluoroethyl, and benzyl. In some embodiments, R 3A It is C 1-4 Alkyl group. In some embodiments, R 3A Selected from methyl, ethyl, and isopropyl. In some embodiments, R 3A It is methyl. In some embodiments, R 3A It is C 1-4 Halogenated alkyl groups. In some embodiments, R 3A It is trifluoroethyl. In some embodiments, R 3A It is benzyl.

[0191] In some implementation schemes, R 1 It is C 1-4 Alkyl and R 3A Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and benzyl groups. In some embodiments, R... 1 and R 3A Each is C independently 1-4 Alkyl group. In some embodiments, R 1 and R 3A Each is independently selected from methyl, ethyl, and isopropyl.

[0192] In some embodiments, the compound of formula A is the compound of formula A-1: A-1 Or its salt.

[0193] In some embodiments, the methylene reagent is a formaldehyde reagent or a dihalomethane. In some embodiments, suitable formaldehyde reagents include formaldehyde acetals (e.g., dimethoxymethane, diethoxymethane), formaldehyde solutions, paraformaldehyde, and 1,3,5-trioxane. In some embodiments, suitable methylene reagents include dihalomethanes (e.g., dibromomethane, diiodomethane).

[0194] In some embodiments, the methylene reagent is selected from 1,3,5-trioxane, formaldehyde acetal, formaldehyde, paraformaldehyde, or dihalomethane. In some embodiments, the methylene reagent is a formaldehyde reagent. In some embodiments, the methylene reagent is selected from 1,3,5-trioxane, formaldehyde acetal, formaldehyde, and paraformaldehyde. In some embodiments, the methylene reagent is 1,3,5-trioxane.

[0195] In some embodiments, the compound of formula A or a salt thereof reacts with a first acid. In some embodiments, a suitable first acid includes carboxylic acids (e.g., oxalic acid, trichloroacetic acid, trifluoroacetic acid), sulfonic acids (e.g., methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid), Lewis acids (e.g., boron trifluoride methyl ether, boron trifluoride dibutyl ether, boron trichloride, boron tribromide, aluminum chloride, aluminum bromide), inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid), or combinations thereof.

[0196] In some embodiments, the first acid includes a carboxylic acid, a sulfonic acid, a Lewis acid, an inorganic acid, or a combination thereof. In some embodiments, the first acid includes a carboxylic acid. In some embodiments, the first acid is selected from oxalic acid, trichloroacetic acid, trifluoroacetic acid, or a combination thereof. In some embodiments, the first acid is trifluoroacetic acid.

[0197] In some embodiments, the compound of formula A or a salt thereof reacts with a first base. In some embodiments, a suitable first base includes an amine (e.g., n-propylamine, triethylamine, ...). N,N -Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring), amidine (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), etc.), guanidine (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate) Metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), amides (e.g., lithium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, lithium diisopropylamino, basic aromatic compounds (e.g., pyridine, 2,6-dimethylpyridine, imidazole) or combinations thereof.

[0198] In some embodiments, the first base includes amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, phosphates, hydroxides, alkoxides, amides, basic aromatic compounds, or combinations thereof.

[0199] In some embodiments, the reaction of the compound of formula A or a salt thereof is carried out in a third solvent. In some embodiments, the third solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, NThe third solvent comprises butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the third solvent comprises a hydrocarbon. In some embodiments, the third solvent comprises toluene, methylcyclohexane, n-heptane, hexane, limonene, or combinations thereof. In some embodiments, the reaction of the compound of formula A or a salt thereof is carried out in a third solvent comprising toluene.

[0200] In some embodiments, the reaction of the compound of formula A or a salt thereof is carried out in a temperature range of about 20°C to about 140°C. In some embodiments, the reaction of the compound of formula A or a salt thereof is carried out in a temperature range of about 90°C to about 110°C. In some embodiments, the reaction of the compound of formula III or a salt thereof is carried out at a temperature of about 100°C.

[0201] Alternative methods for preparing compounds of formula I In some embodiments of the method disclosed herein, the method includes preparing a compound of formula I or a salt thereof by means of the following: Compounds of formula R-1: R-1 Or its salt and: Methylene reagent and The eighth acid or the fourteenth base reaction, To obtain a compound of formula I or a salt thereof, wherein R 1 It is a hydroxyl protecting group. In some embodiments, R 1 Selected from C 1-4 Alkyl, benzyl and -COOR 4 ;where R 4 Selected from C 1-4 Alkyl and phenyl groups, as described herein. In some embodiments, compounds of formula I are compounds of formula IB.

[0202] In some embodiments, the compound of formula R-1 or a salt thereof is a compound of formula R-1-A: R-1-A Or its salt.

[0203] In some embodiments, the methylene reagent is a formaldehyde reagent or a dihalomethane. In some embodiments, suitable formaldehyde reagents include formaldehyde acetals (e.g., dimethoxymethane, diethoxymethane), formaldehyde solutions, paraformaldehyde, and 1,3,5-trioxane. In some embodiments, suitable methylene reagents include dihalomethanes (e.g., dibromomethane, diiodomethane).

[0204] In some embodiments, the methylene reagent is selected from 1,3,5-trioxane, formaldehyde acetal, formaldehyde, paraformaldehyde, or dihalomethanes. In some embodiments, the methylene reagent is a formaldehyde reagent. In some embodiments, the methylene reagent is selected from 1,3,5-trioxane, formaldehyde acetal, formaldehyde, and paraformaldehyde. In some embodiments, the methylene reagent is formaldehyde (i.e., formalin). In some embodiments, the methylene reagent is 1,3,5-trioxane.

[0205] In some embodiments, the compound of formula R-1 or a salt thereof reacts with an octet acid. In some embodiments, suitable octet acids include carboxylic acids (e.g., oxalic acid, trichloroacetic acid, trifluoroacetic acid), sulfonic acids (e.g., methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid), Lewis acids (e.g., boron trifluoride methyl ether, boron trifluoride dibutyl ether, boron trichloride, boron tribromide, aluminum chloride, aluminum bromide), inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid), or combinations thereof.

[0206] In some embodiments, the eighth acid includes carboxylic acids, sulfonic acids, Lewis acids, inorganic acids, or combinations thereof. In some embodiments, the eighth acid is a sulfonic acid. In some embodiments, the eighth acid includes methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, or combinations thereof. In some embodiments, the eighth acid is methanesulfonic acid.

[0207] In some embodiments, the eighth acid is an inorganic acid. In some embodiments, the eighth acid includes hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, or combinations thereof. In some embodiments, the eighth acid is phosphoric acid.

[0208] In some embodiments, a compound of formula R-1 or a salt thereof reacts with a fourteenth base. In some embodiments, suitable fourteenth bases include amines (e.g., n-propylamine, triethylamine, etc.). N,N-Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring), amidine (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), etc.), guanidine (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate) Metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), amides (e.g., lithium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, lithium diisopropylamino, basic aromatic compounds (e.g., pyridine, 2,6-dimethylpyridine, imidazole) or combinations thereof.

[0209] In some embodiments, the fourteenth base includes amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, phosphates, hydroxides, alkoxides, amides, basic aromatic compounds, or combinations thereof.

[0210] In some embodiments, the reaction of the compound of formula R-1 or a salt thereof is carried out in an eleventh solvent. In some embodiments, the eleventh solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N 11th solvents include butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the eleventh solvent comprises an ether. In some embodiments, the eleventh solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of the compound of formula R-1 or a salt thereof is carried out in an eleventh solvent containing tetrahydrofuran.

[0211] In some embodiments, the eleventh solvent comprises a hydrocarbon. In some embodiments, the eleventh solvent comprises toluene, methylcyclohexane, n-heptane, hexane, limonene, or combinations thereof. In some embodiments, the reaction of the compound of formula R-1 or a salt thereof is carried out in an eleventh solvent containing toluene.

[0212] In some embodiments, the reaction of the compound of formula R-1 or its salt is carried out in a temperature range of about 20°C to about 100°C. In some embodiments, the reaction of the compound of formula R-1 or its salt is carried out in a temperature range of about 50°C to about 90°C. In some embodiments, the reaction of the compound of formula R-1 or its salt is carried out in a temperature range of about 50°C to about 70°C. In some embodiments, the reaction of the compound of formula R-1 or its salt is carried out at a temperature of about 65°C. In some embodiments, the reaction of the compound of formula R-1 or its salt is carried out at a temperature of about 80°C.

[0213] In some embodiments, the method further includes preparing a compound of formula R-1 or a salt thereof by means of the following: Compounds of formula R-2: R-2 Or its salt and: Coupling agents and The fifteenth base reaction, The compound of formula R-1 or its salt is obtained.

[0214] In some embodiments, the compound of formula R-2 or a salt thereof is a compound of formula R-2-A: R-2-A Or its salt.

[0215] In some embodiments, suitable coupling agents include acyl chlorides (e.g., thionyl chloride, oxalyl chloride, phosphoryl(V) chloride), mixed anhydrides (e.g., mixed with reagents such as acetic anhydride, neopentyl chloride, diphenylphosphine anhydride, propanephosphine anhydride, boric acid, isobutyl chloroformate, methanesulfonyl chloride, p-toluenesulfonyl chloride), carbonyl diimidazoles, activated esters, chlorinated 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium, 2-chloro-4,6-dimethoxy-1,3,5-triazine, cyanuric chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b[Pyridinium 3-oxide hexafluorophosphate] and other reagents known to promote the coupling of amines with carboxylic acids.

[0216] In some embodiments, suitable coupling agents include acyl chlorides (e.g., thionyl chloride, oxalyl chloride, phosphoryl(V) chloride), mixed anhydrides (e.g., mixed with reagents such as acetic anhydride, neopentyl chloride, diphenylphosphine anhydride, propanephosphine anhydride, boric acid, isobutyl chloroformate, methanesulfonyl chloride, p-toluenesulfonyl chloride), organophosphorus compounds (e.g., diphenylphosphine chloride, diphenylphosphine chloride, bis(2-oxo-3-oxazolyl)phosphine chloride), carbonyl chloride, etc. Imidazole, activated ester, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 2-chloro-4,6,-dimethoxy-1,3,5-triazine, cyanuryl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, benzotriazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b Pyridinium 3-oxide hexafluorophosphate, bromo-tripyrrolidinyl-phosphonium hexafluorophosphate) and other reagents known to promote coupling of amines with carboxylic acids.

[0217] In some embodiments, the coupling agent includes 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b The coupling agent comprises pyridinium 3-oxide hexafluorophosphate (HATU), acyl chloride, acid anhydride, carbonyl diimidazole, activated ester, or combinations thereof. In some embodiments, the coupling agent includes 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b The coupling agent comprises pyridinium 3-oxide hexafluorophosphate (HATU), acyl chloride, acid anhydride, carbonyl diimidazole, activated ester, or combinations thereof. In some embodiments, the coupling agent includes thionyl chloride, oxalyl chloride, phosphoryl(V) chloride, acetic anhydride, neopentyl chloride, diphenylphosphine anhydride, propanephosphine anhydride, boric acid, isobutyl chloroformate, methanesulfonyl chloride, p-toluenesulfonyl chloride, carbonyl diimidazole, activated ester, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, 2-chloro-4,6,-dimethoxy-1,3,5-triazine, cyanuryl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, benzotriazol-1-yloxytripyrrolylphosphonium hexafluorophosphate, HATU, or combinations thereof. In some embodiments, the coupling agent is a peptide coupling agent. In some implementations, the coupling agent is HATU.

[0218] In some embodiments, the coupling agent comprises an organophosphorus compound. In some embodiments, the coupling agent comprises diphenylphosphine chloride, diphenylphosphine chloride, bis(2-oxo-3-oxazolidinyl)phosphine chloride, or combinations thereof. In some embodiments, the coupling agent comprises diphenylphosphine chloride.

[0219] In some embodiments, suitable fifteenth bases include amines (e.g., N-methylmorpholine, triethylamine, ... N,N -Diisopropylethylamine), amidines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate, etc.), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, bicarbonate, etc.). Potassium, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), basic aromatic compounds (e.g., pyridine, 2,6-dimethylpyridine, imidazole, etc.) or combinations thereof.

[0220] In some embodiments, the fifteenth base includes amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, hydroxides, alkoxides, basic aromatic compounds, or combinations thereof. In some embodiments, the fifteenth base includes amines. In some embodiments, the fifteenth base includes N-methylmorpholine, triethylamine, etc. N,N -Diisopropylethylamine or combinations thereof. In some embodiments, the fifteenth base is N,N -Diisopropylethylamine.

[0221] In some embodiments, the reaction of the compound of formula R-2 or a salt thereof is carried out in a twenty-eighth solvent. In some embodiments, the twenty-eighth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, Nbutylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or combinations thereof. In some embodiments, the twenty-eighth solvent includes a polar aprotic solvent. In some embodiments, the twenty-eighth solvent includes... N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N -Butylpyrrolidone (NBP) or combinations thereof. In some embodiments, the reaction of the compound of formula R-2 or a salt thereof is carried out in a twenty-eighth solvent containing N,N-dimethylacetamide.

[0222] In some embodiments, the reaction of the compound of formula R-2 or its salt is carried out in a temperature range of about 0°C to about 80°C. In some embodiments, the reaction of the compound of formula R-2 or its salt is carried out in a temperature range of about 20°C to about 30°C. In some embodiments, the reaction of the compound of formula R-2 or its salt is carried out at a temperature of about 20°C.

[0223] In some embodiments, the method further includes preparing a compound of formula R-2 or a salt thereof by means of the following: Compounds of formula A: A or its salt, wherein R 3A It is a hydrogen or hydroxyl protecting group, and is related to: Reagents selected from metal hydroxides, metal halides, and trialkylsilyl halides; A compound of formula R-2 or its salt is obtained.

[0224] In some implementation schemes, R 3A Selected from hydrogen, C 1-4 Alkyl and benzyl. In some embodiments, R 3A Selected from hydrogen, methyl, ethyl, isopropyl, and benzyl. In some embodiments, R 3A It is methyl. In some embodiments, the compound of formula A or a salt thereof is a compound of formula A-1 or a salt thereof.

[0225] In some embodiments, the compound of formula A reacts with a metal hydroxide. In some embodiments, the metal hydroxide is an alkali metal hydroxide. In some embodiments, the metal hydroxide includes sodium hydroxide, lithium hydroxide, potassium hydroxide, cesium hydroxide, or combinations thereof. In some embodiments, the metal hydroxide is sodium hydroxide.

[0226] In some embodiments, the compound of formula A reacts with a metal halide. In some embodiments, the metal halide includes lithium chloride, magnesium bromide, zinc chloride, sodium iodide, or combinations thereof.

[0227] In some embodiments, the compound of formula A reacts with a trialkylsilyl halide. In some embodiments, the trialkylsilyl halide includes trimethylsilyl chloride, trimethylsilyl iodide, or a combination thereof.

[0228] In some embodiments, the reaction of the compound of formula A or a salt thereof is carried out in the second nineteenth solvent. In some embodiments, the second nineteenth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N -Butylpyrrolidone (NBP), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, isoamyl alcohol), water, or combinations thereof. In some embodiments, the twenty-ninth solvent comprises an alcohol. In some embodiments, the twenty-ninth solvent comprises methanol, ethanol, 2-propanol, butanol, isoamyl alcohol, or combinations thereof. In some embodiments, the reaction of the compound of formula A or a salt thereof is carried out in the twenty-ninth solvent containing methanol.

[0229] In some embodiments, the reaction of the compound of formula A or its salt is carried out in a temperature range of about 0°C to about 100°C. In some embodiments, the reaction of the compound of formula A or its salt is carried out in a temperature range of about 20°C to about 70°C. In some embodiments, the reaction of the compound of formula A or its salt is carried out at a temperature of about 65°C.

[0230] Alternative methods for preparing compounds of formula R-1 In some embodiments of the method disclosed herein, the method includes preparing a compound of formula R-1 or a salt thereof by means of the following: Compounds of formula A: A or its salt, wherein R3A It is a hydroxyl protecting group, and: The sixteenth base reaction; The compound of formula R-1 or its salt is obtained.

[0231] In some implementation schemes, R 3A Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and benzyl groups. In some embodiments, R... 3A Selected from methyl, ethyl, isopropyl, trifluoroethyl, and benzyl. In some embodiments, R 3A It is methyl. In some embodiments, the compound of formula A or a salt thereof is a compound of formula A-1 or a salt thereof.

[0232] In some embodiments, suitable sixteenth bases include amines (e.g., N-methylmorpholine, triethylamine, ... N,N -Diisopropylethylamine), amidines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate, etc.), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, bicarbonate, etc.). Potassium, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), basic aromatic compounds (e.g., pyridine, 2,6-dimethylpyridine, imidazole, etc.) or combinations thereof.

[0233] In some embodiments, the sixteenth base includes amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, hydroxides, alkoxides, basic aromatic compounds, or combinations thereof. In some embodiments, the sixteenth base is a guanidine. In some embodiments, the sixteenth base includes 1,5,7-triazabicyclodec-5-ene, 1,1,3,3-tetramethylguanidine, or combinations thereof. In some embodiments, the sixteenth base is 1,5,7-triazabicyclodec-5-ene.

[0234] In some embodiments, the reaction of the compound of formula A or a salt thereof is carried out in a thirtieth solvent. In some embodiments, the thirtieth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g.,N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N The thirtieth solvent comprises butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or combinations thereof. In some embodiments, the thirtieth solvent comprises an ether. In some embodiments, the thirtieth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of the compound of formula A or a salt thereof is carried out in a thirtieth solvent comprising 2-methyltetrahydrofuran.

[0235] In some embodiments, the reaction of the compound of formula A or its salt is carried out in a temperature range of about 20°C to about 110°C. In some embodiments, the reaction of the compound of formula A or its salt is carried out in a temperature range of about 50°C to about 70°C. In some embodiments, the reaction of the compound of formula A or its salt is carried out at a temperature of about 60°C.

[0236] Method for preparing compounds of formula A In some embodiments of the method disclosed herein, the method includes preparing a compound of formula A or a salt thereof by means of a method comprising: Compounds of formula XA: XA Or its salt and: Compounds of formula C: C or its salt and The seventh base reaction, A compound of formula A or its salt is obtained.

[0237] In some embodiments, a compound of formula XA or a salt thereof is a compound of formula XB or a salt thereof.

[0238] In some embodiments, the method includes reacting a compound of formula XA with a salt of a compound of formula C. In some embodiments, the salt of the compound of formula C is a sulfonate. In some embodiments, the salt of the compound of formula C is a methanesulfonate. In some embodiments, the salt of the compound of formula C is a toluenesulfonate.

[0239] In some embodiments, suitable seventh bases include tertiary amines (e.g., N-methylmorpholine, ...). N -Methylpiperidine, 1,4-dimethylpiperazine, triethylamine N,N -Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring), secondary amines (e.g., morpholine, piperidine, pyrrolidine, N,N- Diisopropylamine), bis(triethylsilyl)amine (HMDS), aniline (e.g., N,N -Dimethylaniline, 1,8-bis(dimethylamino)naphthalene (proton sponge)), pyridines (e.g., pyridine, 2,4,6-trimethylpyridine, 2,6-dimethylpyridine), imidazoles, amidines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium carbonate, cesium carbonate), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), and alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide).

[0240] In some embodiments, the seventh base is selected from tertiary amines, secondary amines, aniline, pyridine, imidazole, amidine, guanidine, carbonates, phosphates, hydroxides, alkoxides, or combinations thereof. In some embodiments, the seventh base is an amine. In some embodiments, the seventh base is a tertiary amine. In some embodiments, the seventh base includes N-methylmorpholine, N -Methylpiperidine, 1,4-dimethylpiperazine, triethylamine N,N -Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring, or combinations thereof. In some embodiments, the seventh base is N-methylmorpholine.

[0241] In some embodiments, the reaction of the compound of formula XA or a salt thereof is carried out in a fourteenth solvent. In some embodiments, the fourteenth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, NButylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the fourteenth solvent comprises an alcohol. In some embodiments, the fourteenth solvent comprises methanol, ethanol, 2-propanol, butanol, isoamyl alcohol, or combinations thereof. In some embodiments, the reaction of a compound of formula XA or a salt thereof is carried out in a fourteenth solvent comprising methanol.

[0242] In some embodiments, the reaction of the compound of formula XA or its salt is carried out in a temperature range of about 20°C to about 100°C. In some embodiments, the reaction of the compound of formula XA or its salt is carried out in a temperature range of about 40°C to about 60°C. In some embodiments, the reaction of the compound of formula XA or its salt is carried out at a temperature of about 50°C.

[0243] In some embodiments, the method further includes reacting a compound of formula A with a fourth acid to obtain a salt of the compound of formula A.

[0244] In some embodiments, suitable fourth acids include trifluoroacetic acid, hydrochloric acid, hydrobromic acid, acetic acid, oxalic acid, orotic acid, succinic acid, malonic acid, adipic acid, fumaric acid, benzenesulfonic acid, benzoic acid, citric acid, 1,8-naphthalenedisulfonic acid, tartaric acid (L / D and its common esters, including dibenzoyl tartarate), p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid (S / R), maleic acid, xinafoic acid, and L-pyroglutamic acid.

[0245] In some embodiments, the fourth acid is selected from trifluoroacetic acid, hydrochloric acid, hydrobromic acid, acetic acid, oxalic acid, orotic acid, succinic acid, malonic acid, adipic acid, fumaric acid, benzenesulfonic acid, benzoic acid, citric acid, 1,8-naphthalenedisulfonic acid, tartaric acid or its esters (L / D and their esters such as dibenzoyl tartrate), p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid (S / R), maleic acid, sine, and L-pyroglutamic acid.

[0246] In some embodiments, the fourth acid is oxalic acid. In some embodiments, the reaction yields the oxalate of a compound of formula A.

[0247] In some embodiments, the method further includes preparing a compound of formula C or a salt thereof by means of the following: Compounds of formula D: D Or its salt deprotection, wherein: R 5 Selected from hydrogen and R 9 , where R 9 It is an amine protecting group; and R 7 and R 8 Each is an amine protecting group independently; A compound of formula C or its salt is obtained.

[0248] In some implementation schemes, R 5 It is hydrogen. In some implementations, R 5 It is R 9 In some implementations, R 5 It is an amine protecting group. In some embodiments, R 5 It is tert-butyloxycarbonyl.

[0249] In some implementation schemes, R 7 It is tert-butyloxycarbonyl. In some embodiments, R 8 It is tert-butyloxycarbonyl. In some embodiments, R 7 and R 8 It is tert-butyloxycarbonyl.

[0250] In some embodiments, the compound of formula D or a salt thereof is a compound of formula D-2: D-2 Or its salt.

[0251] In some embodiments, deprotecting a compound of formula D or a salt thereof involves treating the compound of formula D or a salt thereof with a fifth acid. In some embodiments, suitable fifth acids include sulfonic acids (e.g., p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid), sulfuric acid, sulfurous acid, carboxylic acids (e.g., trifluoroacetic acid, trichloroacetic acid, oxalic acid), hydrogen halides (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid), in-situ generated hydrogen halides (e.g., through combinations of acetyl chloride and methanol, trimethylsilyl chloride and methanol, thionyl chloride and methanol), phosphoric acid, and phosphorous acid.

[0252] In some embodiments, the fifth acid is selected from sulfonic acids, sulfuric acids, sulfurous acids, carboxylic acids, hydrogen halides, phosphoric acids, phosphorous acids, or combinations thereof. In some embodiments, the fifth acid is a sulfonic acid. In some embodiments, the fifth acid is selected from p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, or combinations thereof. In some embodiments, the fifth acid includes methanesulfonic acid. In some embodiments, the fifth acid includes p-toluenesulfonic acid.

[0253] In some embodiments, the deprotection of the compound of formula D or its salt is performed in a fifteenth solvent. In some embodiments, the fifteenth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N The fifteenth solvent comprises butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or combinations thereof. In some embodiments, the fifteenth solvent comprises an alcohol. In some embodiments, the fifteenth solvent comprises methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol, or combinations thereof. In some embodiments, the deprotection of a compound of formula D or its salt thereof is performed in a fifteenth solvent comprising methanol. In some embodiments, the deprotection of a compound of formula D or its salt thereof is performed in a fifteenth solvent comprising ethanol.

[0254] In some embodiments, the deprotection of the compound of formula D or its salts is carried out in a temperature range of about 20°C to about 100°C. In some embodiments, the deprotection of the compound of formula D or its salts is carried out in a temperature range of about 40°C to about 60°C. In some embodiments, the deprotection of the compound of formula D or its salts is carried out in a temperature range of about 45°C to about 55°C. In some embodiments, the deprotection of the compound of formula D or its salts is carried out at a temperature of about 50°C.

[0255] In some embodiments, the method further includes preparing a compound of formula D or a salt thereof by means of the following method: wherein the compound of formula D is a compound of formula D-1. D-1 Or its salt, the method comprising: Compounds of formula E: E Or its salt deprotection, wherein: R 9 It is an amine protecting group and R 10 It is hydrogen; or optionally: R9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups; The compound of formula D or its salt is obtained.

[0256] In some implementation schemes, R 7 and R 8 It is tert-butyloxycarbonyl.

[0257] In some implementation schemes, R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups.

[0258] In some implementation schemes, R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form phthalimides. In some embodiments, R 7 and R 8 It is tert-butyloxycarbonyl, and R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form phthalimides.

[0259] In some implementation schemes, R 9 It is tert-butyloxycarbonyl.

[0260] In some embodiments, deprotecting a compound of formula E or a salt thereof includes treating the compound of formula E or a salt thereof with a second deprotecting agent. In some embodiments, suitable second deprotecting agents include hydrazine (e.g., hydrazine, methylhydrazine, phenylhydrazine), amines (e.g., ethanolamine, 1,3-diaminopropane, methylamine, ethylamine, propylamine, hydroxylamine), alkoxides (e.g., potassium methoxide, lithium isopropoxide), thiols (e.g., decanethiol, sodium sulfide), and hydrolases (e.g., phthalamides, dihydropyrimidines, hydantoinase, imidase, lipase).

[0261] In some embodiments, deprotecting a compound of formula E or a salt thereof includes treating the compound of formula E or a salt thereof with a second deprotecting agent. In some embodiments, suitable second deprotecting agents include hydrazine (e.g., hydrazine, methylhydrazine, phenylhydrazine), amines (e.g., ethanolamine, 1,3-diaminopropane, methylamine, ethylamine, propylamine, hydroxylamine), alkoxides (e.g., potassium methoxide, lithium isopropoxide), thiols (e.g., decanethiol, sodium sulfide), hydrolases (e.g., phthalamides, dihydropyrimidines, hydantoinase, imidases, lipases), and hydrides (e.g., sodium borohydride, sodium acetoxyborohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum hydride).

[0262] In some embodiments, the second deprotecting agent is selected from hydrazine, amine, alkoxide, thiol, hydrolase, hydride, or combinations thereof. In some embodiments, the second deprotecting agent is an amine. In some embodiments, the second deprotecting agent includes ethanolamine, 1,3-diaminopropane, methylamine, ethylamine, propylamine, hydroxylamine, or combinations thereof. In some embodiments, the second deprotecting agent is ethylenediamine. In some embodiments, the second deprotecting agent is a hydride. In some embodiments, the second deprotecting agent includes sodium borohydride, sodium acetoxyborohydride, sodium cyanoborohydride, lithium borohydride, lithium aluminum hydride, or combinations thereof. In some embodiments, the second deprotecting agent is sodium borohydride.

[0263] In some embodiments, the deprotection of a compound of formula E or its salt is further performed in the presence of a ninth acid. In some embodiments, suitable ninth acids include carboxylic acids (e.g., acetic acid, neopentanoic acid, formic acid) and strong acids (e.g., methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid). In some embodiments, the ninth acid includes carboxylic acids, strong acids, or combinations thereof. In some embodiments, the deprotection of a compound of formula E or its salt is performed in the absence of an acid.

[0264] In some embodiments, the deprotection of the compound of formula E or its salt is performed in a sixteenth solvent. In some embodiments, the second solvent includes water, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the sixteenth solvent comprises an alcohol. In some embodiments, the sixteenth solvent comprises methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol, or combinations thereof. In some embodiments, the deprotection of a compound of formula E or its salt is performed in a sixteenth solvent comprising methanol.

[0265] In some embodiments, the deprotection of the compound of formula E or its salts is carried out in a temperature range of about 0°C to about 100°C. In some embodiments, the deprotection of the compound of formula E or its salts is carried out in a temperature range of about 40°C to about 60°C. In some embodiments, the deprotection of the compound of formula E or its salts is carried out at a temperature of about 50°C.

[0266] Alternative methods for preparing compounds of formula A In some embodiments of the method disclosed herein, the method includes preparing a compound of formula A or a salt thereof by means of a method comprising: Compounds of formula Q-1: Q-1 or its salt, Reaction with reagents selected from hydrazine, amine, alkoxide and hydrolase; A compound of formula A or its salt is obtained.

[0267] In some embodiments, the compound of formula Q-1 or a salt thereof is a compound of formula Q-1-A: Q-1-A Or its salt.

[0268] In some embodiments, the method includes reacting a compound of formula Q-1 with hydrazine. In some embodiments, the hydrazine is selected from hydrazine, methylhydrazine, phenylhydrazine, or combinations thereof. In some embodiments, the method includes reacting a compound of formula Q-1 with hydrazine hydrate. In some embodiments, the method includes reacting a compound of formula Q-1 with hydrazine hydrate.

[0269] In some embodiments, the method includes reacting a compound of formula Q-1 with an amine. In some embodiments, the amine is selected from ethanolamine, 1,3-diaminopropane, methylamine, ethylamine, propylamine, hydroxylamine, or combinations thereof.

[0270] In some embodiments, the method includes reacting a compound of formula Q-1 with an alkoxide. In some embodiments, the alkoxide is selected from potassium methoxide, lithium isopropoxide, or combinations thereof.

[0271] In some embodiments, the method includes reacting a compound of formula Q-1 with a hydrolase. In some embodiments, the hydrolase is selected from phthalamides, dihydropyrimidines, hydantoinases, imidases, lipases, or combinations thereof.

[0272] In some embodiments, the reaction of the compound of formula Q-1 or a salt thereof is carried out in a thirty-first solvent. In some embodiments, the thirty-first solvent includes water, ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N The solvent comprises butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the thirty-first solvent comprises hydrocarbons. In some embodiments, the thirty-first solvent comprises toluene, methylcyclohexane, n-heptane, hexane, limonene, or combinations thereof. In some embodiments, the reaction of the compound of formula Q-1 or a salt thereof is carried out in a thirty-first solvent comprising toluene.

[0273] In some embodiments, the reaction of the compound of formula Q-1 or its salt is carried out in a temperature range of about 0°C to about 100°C. In some embodiments, the reaction of the compound of formula Q-1 or its salt is carried out in a temperature range of about 75°C to about 95°C. In some embodiments, the reaction of the compound of formula Q-1 or its salt is carried out at a temperature of about 100°C.

[0274] In some embodiments, the method further includes preparing a compound of formula Q-1 or a salt thereof by means of the following: Compounds of formula Q-2: Q-2 Or its salt and: Compounds of formula XA: XA or its salt and Thirteenth base reaction; A compound of formula Q-1 or a salt thereof is obtained. In some embodiments, a compound of formula XA or a salt thereof is a compound of formula XB or a salt thereof.

[0275] In some implementations, suitable thirteenth bases include tertiary amines (e.g., N-methylmorpholine, ...).N -Methylpiperidine, 1,4-dimethylpiperazine, triethylamine N,N -Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring), secondary amines (e.g., morpholine, piperidine, pyrrolidine, N,N- Diisopropylamine), bis(triethylsilyl)amine (HMDS), aniline (e.g., N,N -Dimethylaniline, 1,8-bis(dimethylamino)naphthalene (proton sponge)), pyridines (e.g., pyridine, 2,4,6-trimethylpyridine, 2,6-dimethylpyridine), imidazoles, amidines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium carbonate, cesium carbonate), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), and alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide).

[0276] In some embodiments, the thirteenth base is selected from tertiary amines, secondary amines, aniline, pyridine, imidazole, amidine, guanidine, carbonates, phosphates, hydroxides, alkoxides, or combinations thereof. In some embodiments, the seventh base is an amine. In some embodiments, the seventh base is a tertiary amine. In some embodiments, the thirteenth base includes N-methylmorpholine, N -Methylpiperidine, 1,4-dimethylpiperazine, triethylamine N,N -Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring, or combinations thereof. In some embodiments, the thirteenth base is N-methylmorpholine.

[0277] In some embodiments, the reaction of the compound of formula Q-2 or a salt thereof is carried out in a thirty-second solvent. In some embodiments, the thirty-second solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, NButylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the thirty-second solvent comprises an alcohol. In some embodiments, the thirty-second solvent comprises methanol, ethanol, 2-propanol, butanol, isoamyl alcohol, or combinations thereof. In some embodiments, the reaction of the compound of formula Q-2 or a salt thereof is carried out in a thirty-second solvent containing methanol.

[0278] In some embodiments, the reaction of the compound of formula Q-2 or its salt is carried out in a temperature range of about 20°C to about 100°C. In some embodiments, the reaction of the compound of formula Q-2 or its salt is carried out in a temperature range of about 40°C to about 60°C. In some embodiments, the reaction of the compound of formula Q-2 or its salt is carried out at a temperature of about 50°C.

[0279] Method for preparing compounds of formula E In some embodiments of the method disclosed herein, the method includes preparing a compound of formula E or a salt thereof by means of a method comprising: Compounds of formula F: F Or its salt and: Phosphine reagent azodicarbonate and Formula R 7 -NH-NH-R 8 The reaction of compounds; The compound of formula E or its salt is obtained.

[0280] In some embodiments of the compound of formula F, R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form phthalimides.

[0281] In some implementation schemes, formula R 7 -NH-NH-R 8 The compound is .

[0282] In some embodiments, suitable phosphine agents include triarylphosphine (e.g., triphenylphosphine, tri(2-pyridyl)phosphine, tri-(4-methoxyphenyl)phosphine), trialkylphosphine (e.g., tricyclohexylphosphine, tributylphosphine, trimethylphosphine), tri-(dimethylaminophenyl)phosphine, (triphenylphosphine)acetonitrile, and n-phosphine (e.g., (cyanomethylene)tributyln-n-phosphine).

[0283] In some embodiments, the phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine. In some embodiments, the phosphine reagent is triarylphosphine. In some embodiments, the phosphine reagent includes triphenylphosphine, tris(2-pyridyl)phosphine, tris(4-methoxyphenyl)phosphine, or combinations thereof. In some embodiments, the phosphine reagent is triphenylphosphine.

[0284] In some embodiments, the azodicarbonate ester is selected from di-tert-butyl azodicarbonate, diisopropyl azodicarbonate, diethyl azodicarbonate, dimethoxy ethyl azodicarbonate, azodicarbonyl dimorpholine, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarbonate. In some embodiments, the azodicarbonate ester is di-tert-butyl azodicarbonate.

[0285] In some embodiments, the reaction of the compound of formula F or a salt thereof is carried out in a seventeenth solvent. In some embodiments, the seventeenth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N The seventeenth solvent comprises butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the seventeenth solvent comprises an ether. In some embodiments, the seventeenth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of a compound of formula F or a salt thereof is carried out in a seventeenth solvent comprising 2-methyltetrahydrofuran. In some embodiments, the seventeenth solvent comprises an ester. In some embodiments, the seventeenth solvent comprises isopropyl acetate.

[0286] In some embodiments, the reaction of the compound of formula F or its salt is carried out in a temperature range of about -20°C to about 50°C. In some embodiments, the reaction of the compound of formula F or its salt is carried out in a temperature range of about 0°C to about 22°C.

[0287] In some embodiments, the method further includes preparing a compound of formula F or a salt thereof by means of the following: Compounds of formula G: G Or its salt and: The third catalyst, and Hydrogen source reaction; To obtain a compound of formula F or a salt thereof.

[0288] In some embodiments, the method includes preparing a compound of formula F or a salt thereof by reacting a compound of formula G or a salt thereof with a third catalyst and hydrogen gas to obtain a compound of formula F or a salt thereof.

[0289] In some embodiments of the compound of formula G, R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form phthalimides.

[0290] In some embodiments, suitable third catalysts include palladium catalysts (e.g., 5 wt% palladium supported on carbon, 10 wt% palladium supported on carbon, 1 wt% palladium supported on carbon, 5 wt% palladium supported on calcium carbonate, 5 wt% palladium supported on alumina, palladium hydroxide, palladium acetate, palladium acetate / manganese, palladium chloride, palladium trifluoroacetate, palladium propionate, palladium neopentanoate, tris(dibenzylacetone)dipalladium, palladium bromide, bis(acetylacetone)palladium(II), bis(benzonitrile)dichloride, 20 wt% palladium supported on carbon, lead poisoned palladium supported on, for example, barium sulfate or calcium carbonate), bimetallic catalysts (e.g., 4 wt% palladium and 1 wt% platinum supported on carbon, 9 wt% palladium and 1 wt% copper supported on carbon, 4 wt% palladium and 1 wt% copper supported on carbon), and platinum catalysts (e.g., platinum supported on carbon, platinum oxide).

[0291] In some embodiments, suitable third catalysts include palladium catalysts (e.g., 5 wt% palladium supported on carbon, 10 wt% palladium supported on carbon, 1 wt% palladium supported on carbon, 5 wt% palladium supported on calcium carbonate, 5 wt% palladium supported on alumina, 20 wt% palladium hydroxide supported on carbon, lead poisoned palladium), bimetallic catalysts (e.g., 4 wt% palladium and 1 wt% platinum supported on carbon, 9 wt% palladium and 1 wt% copper supported on carbon, 4 wt% palladium and 1 wt% copper supported on carbon), and platinum catalysts (e.g., platinum supported on carbon, platinum oxide).

[0292] In some embodiments, the third catalyst is selected from palladium catalysts, platinum catalysts, and bimetallic catalysts, wherein the bimetallic catalyst comprises two metals selected from palladium, platinum, and copper.

[0293] In some embodiments, the third catalyst is a palladium catalyst. In some embodiments, the third catalyst comprises palladium supported on carbon, palladium supported on calcium carbonate, or palladium supported on alumina. In some embodiments, the third catalyst is selected from 5 wt% palladium supported on carbon, 10 wt% palladium supported on carbon, 1 wt% palladium supported on carbon, 5 wt% palladium supported on calcium carbonate, 5 wt% palladium supported on alumina, 20 wt% palladium supported on carbon, and lead-poisoned palladium.

[0294] In some embodiments, the third catalyst is a Lindlar catalyst. In some embodiments, the third catalyst comprises 5% by weight palladium supported on lead-poisoned calcium carbonate.

[0295] In some embodiments, the molar ratio of the compound of formula G or a salt thereof to the third catalyst is from about 1:0.001 to about 1:0.05. In some embodiments, the molar ratio of the compound of formula G or a salt thereof to the third catalyst is from about 1:0.001 to about 1:0.005. In some embodiments, the molar ratio of the compound of formula G or a salt thereof to the third catalyst is from about 1:0.002.

[0296] In some embodiments, the hydrogen source includes hydrogen, formic acid, water, or combinations thereof. In some embodiments, the hydrogen source comprises a mixture of hydrogen, formic acid, and potassium carbonate, water, or combinations thereof. In some embodiments, the hydrogen source is hydrogen gas.

[0297] In some embodiments, the reaction of the compound of formula G or a salt thereof is carried out in the presence of a second additive. In some embodiments, suitable second additives include quinoline, pyridine, triethylamine, carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, potassium carbonate), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium bicarbonate), phosphates (e.g., trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), 1,8-diazabicyclo[5.4.0]undec-7-ene, formates (e.g., potassium formate, sodium formate, ammonium formate), acetates (e.g., potassium acetate, sodium acetate, cesium acetate), alkoxides (e.g., potassium tert-butoxide, sodium tert-butoxide), halides (e.g., potassium iodide, lithium chloride, sodium chloride, calcium chloride), and hydroxides (e.g., potassium hydroxide). In some embodiments, the second additive includes quinoline, pyridine, triethylamine, carbonate, bicarbonate, phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, potassium formate, sodium formate, ammonium formate, potassium hydroxide, potassium acetate, sodium acetate, cesium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium iodide, lithium chloride, sodium chloride, calcium chloride, or combinations thereof.

[0298] In some embodiments, the reaction of the compound of formula G or a salt thereof is carried out at a pressure of about 1 psi to about 100 psi. In some embodiments, the reaction of the compound of formula G or a salt thereof is carried out at a pressure of about 25 psi to about 75 psi. In some embodiments, the reaction of the compound of formula G or a salt thereof is carried out at a pressure of about 50 psi.

[0299] In some embodiments, the reaction of the compound of formula G or a salt thereof is carried out in an eighteenth solvent. In some embodiments, the eighteenth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, isoamyl alcohol, tert-amyl alcohol), glycols (e.g., polyethylene glycol 400), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the eighteenth solvent comprises a polar aprotic solvent. In some embodiments, the eighteenth solvent comprises...N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N -Butylpyrrolidone (NBP) or combinations thereof. In some embodiments, the reaction of the compound of formula G or a salt thereof is carried out in an eighteenth solvent containing N,N-dimethylformamide.

[0300] In some embodiments, the reaction of the compound of formula G or a salt thereof is carried out in an eighteenth solvent. In some embodiments, the eighteenth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene, anisole), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N 1-Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, isoamyl alcohol, tert-amyl alcohol, 1-butanol), diols (e.g., polyethylene glycol 400), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof.

[0301] In some embodiments, the reaction of the compound of formula G or its salt is carried out in a temperature range of about 0°C to about 100°C. In some embodiments, the reaction of the compound of formula G or its salt is carried out in a temperature range of about 10°C to about 30°C. In some embodiments, the reaction of the compound of formula G or its salt is carried out at a temperature of about 20°C.

[0302] In some embodiments, the method further includes preparing a compound of formula G or a salt thereof by means of the following: Compounds of formula H: H or its salt, wherein R 11 Selected from C 1-20 Alkyl, phenyl, and -CH2NH2; Reaction with the sixth acid or the eighth base A compound of formula G or its salt is obtained.

[0303] In some implementation schemes, R 11The radical is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, pentadecyl, phenyl, and -CH2NH2. In some embodiments, R 11 C 1-20 Alkyl group. In some embodiments, R 11 The compound is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, and pentadecyl. In some embodiments, R 11 It is methyl. In some embodiments, R 11 It is phenyl. In some embodiments, R 11 It is -CH2NH2.

[0304] In some embodiments, the compound of formula H or a salt thereof is a compound of formula H-2: H-2 Or its salt.

[0305] In some embodiments, a compound of formula H or a salt thereof reacts with a sixth acid. In some embodiments, suitable sixth acids include mineral acids (e.g., concentrated hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid), trifluoroacetic acid, and sulfonic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid).

[0306] In some embodiments, the sixth acid is selected from mineral acids, trifluoroacetic acid, sulfonic acids, or combinations thereof. In some embodiments, the sixth acid is a sulfonic acid. In some embodiments, the sixth acid includes methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, or combinations thereof. In some embodiments, the sixth acid is p-toluenesulfonic acid.

[0307] In some embodiments, a compound of formula H or a salt thereof reacts with an eighth base. In some embodiments, suitable eighth bases include carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, potassium carbonate), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium bicarbonate), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide), and amines (e.g., methylamine, diethylamine, isopropylamine, diisopropylethylamine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, bis(trimethylsilyl)amine).

[0308] In some embodiments, a compound of formula H or a salt thereof reacts with an eighth base. In some embodiments, suitable eighth bases include carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, potassium carbonate), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium bicarbonate), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide), and amines (e.g., methylamine, diethylamine, isopropylamine, diisopropylethylamine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, bis(trimethylsilyl)amine, 1,1,3,3,-tetramethylguanidine, triazabicyclodecene (TBD)).

[0309] In some embodiments, the eighth base is selected from guanidine, carbonate, bicarbonate, metal alkoxide, amine, or combinations thereof.

[0310] In some embodiments, the reaction of the compound of formula H or its salt is carried out in a thirty-fourth solvent. In some embodiments, the thirty-fourth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), and polar aprotic solvents (e.g., ... N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the thirty-fourth solvent comprises an alcohol. In some embodiments, the thirty-fourth solvent comprises methanol, ethanol, 2-propanol, butanol, isoamyl alcohol, or combinations thereof. In some embodiments, the reaction of a compound of formula H or a salt thereof is carried out in a thirty-fourth solvent containing methanol.

[0311] In some embodiments, the reaction of the compound of formula H or its salt is carried out in a temperature range of about 0°C to about 70°C. In some embodiments, the reaction of the compound of formula H or its salt is carried out in a temperature range of about 10°C to about 30°C. In some embodiments, the reaction of the compound of formula H or its salt is carried out at a temperature of about 20°C.

[0312] Alternative methods for preparing compounds of formula F In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula F or a salt thereof by means of the following: Compounds of formula W: W Or its salt and: The sixth catalyst and Reducing agent reaction; To obtain a compound of formula F or a salt thereof.

[0313] In some embodiments of compounds of formula W or salts thereof, R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups.

[0314] In some embodiments, the compound of formula W or a salt thereof is a compound of formula W-1: W-1 Or its salt.

[0315] In some embodiments of compounds of formula F or salts thereof, R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups.

[0316] In some embodiments, the compound of formula F or a salt thereof is a compound of formula F-2: F-2 Or its salt.

[0317] In some embodiments, suitable sixth catalysts include Corey-Bakshi-Shibata (CBS) catalysts and transition metal catalysts (e.g., ruthenium catalysts). In some embodiments, the sixth catalyst is selected from (…). R )-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazoborazole), ( R (R)-nBu-CBS, any other derivatives of CBS, and RuCl[(R,R)-TSDPEN] (trimethylbenzene). In some embodiments, the sixth catalyst is selected from ( R )-(+)-2-methyl-CBS-oxazolium borane and RuCl [(R,R)-TSDPEN] (mestrimethylbenzene). In some embodiments, the sixth catalyst is a CBS catalyst. In some embodiments, the sixth catalyst is selected from ( R(R)-nBu-CBS and any other derivatives of CBS. In some embodiments, the sixth catalyst is ( R )-(+)-2-methyl-CBS-oxazolborane. In some embodiments, the sixth catalyst ( R )-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazoborazole.

[0318] In some embodiments, suitable reducing agents include formic acid / triethylamine, NaBH4, LiBH4, CeCl3∙7H2O with NaBH4, LiAlH4, MgBu2 with HBpin, Red-Al, LiAlH(OtBu)3, BH3∙SMe2, catecholborane, or combinations thereof. In some embodiments, the reducing agent includes formic acid and triethylamine, NaBH4, LiBH4, CeCl3∙7H2O with NaBH4, LiAlH4, MgBu2 with HBpin, Red-Al, LiAlH(OtBu)3, BH3∙SMe2, catecholborane, or combinations thereof. In some embodiments, the reducing agent includes catecholborane.

[0319] In some embodiments, the reaction of the compound of formula W or its salt is carried out in a 43rd solvent. In some embodiments, the 43rd solvent comprises ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), chlorinated solvents (e.g., dichloromethane, CHCl3, CCl4, chlorobenzene), or combinations thereof. In some embodiments, the 43rd solvent comprises a chlorinated solvent. In some embodiments, the 43rd solvent comprises dichloromethane, CHCl3, CCl4, chlorobenzene, or combinations thereof. In some embodiments, the reaction of the compound of formula W or its salt is carried out in a 43rd solvent containing dichloromethane.

[0320] In some embodiments, the reaction of the compound of formula W or its salt is carried out in a temperature range of about -78°C to about 30°C. In some embodiments, the reaction of the compound of formula W or its salt is carried out in a temperature range of about -30°C to about 10°C. In some embodiments, the reaction of the compound of formula W or its salt is carried out at a temperature of about -10°C.

[0321] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula W or a salt thereof by a method comprising the following steps: Compounds of formula S: S Or its salt and: Compounds of formula T: T or its salt, Where R 15 Selected from phenyl and C 1-4 Haloalkyl, wherein the phenyl group is optionally surrounded by one to four C16 atoms. 1-4 Alkyl, halogen, C 1-4 Substitution of alkyl and cyano groups; The seventeenth base and Fourth additive reaction; A compound of formula W or its salt is obtained.

[0322] In some embodiments of compounds of formula W or salts thereof, R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups. In some embodiments, the compound of formula W or a salt thereof is a compound of formula W-1 or a salt thereof.

[0323] In some embodiments of compounds of formula S or salts thereof, R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups.

[0324] In some embodiments, the compound of formula S or a salt thereof is a compound of formula S-1: S-1 Or its salt.

[0325] In some implementation schemes, R 15 The derivative is selected from trifluoroethyl, hexafluoroisopropyl, trichloroethyl, phenyl, chlorophenyl (e.g., 4-chlorophenyl), fluorophenyl (e.g., 2-fluorophenyl), trifluoromethylphenyl (e.g., 2-trifluoromethylphenyl), cyanophenyl (e.g., 3-cyanophenyl), and methylphenyl (e.g., 2-methylphenyl). In some embodiments, R 15 Selected from phenyl and C 1-4 Haloalkyl, wherein the phenyl group is optionally substituted with a halogen group. In some embodiments, R 15 Selected from trifluoroethyl, trichloroethyl, phenyl, and chlorophenyl (e.g., 4-chlorophenyl). In some embodiments, R 15 It is a phenyl group.

[0326] In some embodiments, suitable seventeenth bases include amides (e.g., lithium hexamethyldisilamide, sodium hexamethyldisilamide, or potassium hexamethyldisilamide), amine bases (e.g., N-methylmorpholine, triethylamine, diisopropylethylamine), amidines (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)), guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carbonates (e.g., sodium carbonate, potassium carbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., trisodium phosphate, tripotassium phosphate), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide), basic aromatic compounds (e.g., pyridine, 2,6-dimethylpyridine, imidazole), or combinations thereof.

[0327] In some embodiments, the seventeenth base is selected from amides, amine bases, amidines, guanidines, carbonates, metal hydrides, phosphates, alkoxides, basic aromatic compounds, and combinations thereof. In some embodiments, the seventeenth base is an amide. In some embodiments, the seventeenth base is potassium hexamethyldisilamide.

[0328] In some embodiments, a suitable fourth additive includes ethers (e.g., 18-crown ether-6, bis(2-methoxyethyl) ether), metal salts (e.g., lithium chloride, magnesium chloride, zinc bromide), or combinations thereof. In some embodiments, the fourth additive is selected from ethers, metal salts, or combinations thereof. In some embodiments, the fourth additive is selected from ethers, metal halides, or combinations thereof. In some embodiments, the fourth additive is an ether. In some embodiments, the fourth additive is 18-crown ether-6.

[0329] In some embodiments, the reaction of the compound of formula S or its salt is carried out in a forty-fourth solvent. In some embodiments, the forty-fourth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N , N -Dimethylformamide, N,N-Dimethylacetamide, N-methyl-2-pyrrolidone, N-butylpyrrolidone (NBP), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or combinations thereof. In some embodiments, the forty-fourth solvent comprises an ether. In some embodiments, the forty-fourth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of a compound of formula S or a salt thereof is carried out in the forty-fourth solvent containing tetrahydrofuran.

[0330] In some embodiments, the reaction of the compound of formula S or its salt is carried out in a temperature range of about -100°C to about 25°C. In some embodiments, the reaction of the compound of formula S or its salt is carried out in a temperature range of about -80°C to about -50°C. In some embodiments, the reaction of the compound of formula S or its salt is carried out at a temperature of about -60°C.

[0331] Second alternative method for preparing compounds of formula F In some embodiments of the method disclosed herein, the method includes preparing a compound of formula F or a salt thereof by means of the following: Compounds of formula W: W Or its salt and: The second enzyme reacts in the presence of the second buffer solution; To obtain a compound of formula F or a salt thereof.

[0332] In some embodiments of compounds of formula F or salts thereof, R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups. In some embodiments, the compound of formula F or a salt thereof is a compound of formula F-2 or a salt thereof.

[0333] In some embodiments of compounds of formula W or salts thereof, R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups. In some embodiments, the compound of formula W or a salt thereof is a compound of formula W-1 or a salt thereof.

[0334] In some embodiments, suitable second enzymes include ketone reductases, alcohol oxidases, and P450. In some embodiments, the second enzyme is selected from ketone reductases, alcohol oxidases, or P450. In some embodiments, the second enzyme is a ketone reductase. In some embodiments, the second enzyme is KRED NADH 101 (Codexis). ® ).

[0335] In some embodiments, suitable second buffers include citrate buffer, phosphate buffer, tris(hydroxymethyl)aminomethane (Tris), and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) (HEPES). In some embodiments, the second buffer is selected from citrate buffer, phosphate buffer, tris(hydroxymethyl)aminomethane, and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) (HEPES). In some embodiments, the second buffer is a phosphate buffer. In some embodiments, the second buffer is a sodium phosphate buffer.

[0336] In some embodiments, the reaction of the compound of formula W or its salt is carried out in a co-solvent. In some embodiments, the co-solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N Butylpyrrolidone (NBP), dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the co-solvent includes a polar protic solvent. In some embodiments, the co-solvent includes... N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N - Butylpyrrolidone (NBP), dimethyl sulfoxide, or combinations thereof. In some embodiments, the reaction of the compound of formula W or its salt is carried out in a cosolvent containing dimethyl sulfoxide.

[0337] In some embodiments, the reaction of the compound of formula W or its salt is carried out in a temperature range of about 5°C to about 100°C. In some embodiments, the reaction of the compound of formula W or its salt is carried out in a temperature range of about 10°C to about 30°C. In some embodiments, the reaction of the compound of formula W or its salt is carried out at a temperature of about 20°C.

[0338] In some embodiments, the method further includes preparing a compound of formula W or a salt thereof according to the method described herein.

[0339] A third alternative method for preparing compounds of formula F In some embodiments of the methods disclosed herein, compounds of formula F or salts thereof are prepared by methods comprising: Compounds of formula G: G Or its salt and: Third reducing agent and Activator reaction; To obtain a compound of formula F or a salt thereof.

[0340] In some embodiments, the compound of formula F or a salt thereof is a compound of formula F-1: F-1 Or its salts. In some embodiments of the compound of formula F-1, R 9 It is tert-butyloxycarbonyl.

[0341] In some embodiments, the compound of formula G or a salt thereof is a compound of formula G-1: G-1 Or its salt. In some embodiments of the compound of formula G-1, R 9 It is tert-butyloxycarbonyl.

[0342] In some embodiments of compounds of formula F or salts thereof, R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups. In some embodiments of compounds of formula F or their salts, R 9 and R 10 Together with the nitrogen atom to which they are attached, they form phthalimides or saccharin. In some embodiments, the compound of formula F or a salt thereof is a compound of formula F-2 or a salt thereof.

[0343] In some embodiments of compounds of formula G or salts thereof, R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups. In some embodiments of compounds of formula G or their salts, R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form phthalimides or saccharin.

[0344] In some embodiments, suitable third reducing agents include zinc (e.g., zinc powder, graphite-supported zinc, Rieke zinc), metals (e.g., iron, manganese), diimides (e.g., o-nitrobenzenesulfonyl hydrazine), copper / bis(pinacol)diboron, imidazoline onion salts (e.g., 1,3-bis-(2,6-diisopropylphenyl)imidazoline onion chloride, 1,3-bis(2,4,6-trimethylphenyl)imidazoline onion chloride, 1,3-bis(2,6-diisopropylphenyl)imidazoline onion chloride, 1,3-bis(2,4,6-trimethylphenyl)imidazoline onion chloride, 1,3-bis(2,6-diisopropylphenyl)imidazoline onion chloride, 1,3-bis(2,4,6-trimethylphenyl)imidazoline onion chloride) or combinations thereof.

[0345] In some embodiments, the third reducing agent includes zinc, a metal, a diimide, copper, and bis(pinacol)diboron, an imidazoline onion salt, or a combination thereof. In some embodiments, the third reducing agent includes zinc. In some embodiments, the third reducing agent includes zinc powder, graphite-supported zinc, or Rieke zinc. In some embodiments, the third reducing agent includes zinc powder.

[0346] Any suitable activator (e.g., an entrainer) can be used to activate the third reducing agent. In some embodiments, the activator activates the third reducing agent, wherein the third reducing agent comprises zinc (e.g., by removing zinc oxide from a zinc surface). In some embodiments, suitable activators include organosilicon compounds, organobromine compounds, strong acids, hydrides, or combinations thereof. In some embodiments, the activator is selected from trimethylchlorosilane, dibromoethane, hydrochloric acid, and diisobutylaluminum hydride. In some embodiments, the activator is trimethylchlorosilane.

[0347] In some embodiments, the reaction of the compound of formula G or a salt thereof is carried out in a forty-fifth solvent. In some embodiments, the forty-fifth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, NButylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, isoamyl alcohol, tert-amyl alcohol), glycols (e.g., polyethylene glycol 400), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the forty-fifth solvent comprises an alcohol. In some embodiments, the forty-fifth solvent comprises methanol, ethanol, 2-propanol, butanol, isoamyl alcohol, tert-amyl alcohol, or combinations thereof. In some embodiments, the reaction of a compound of formula G or a salt thereof is carried out in a forty-fifth solvent containing ethanol.

[0348] In some embodiments, the reaction of the compound of formula G or its salt is carried out in a temperature range of about 0°C to about 100°C. In some embodiments, the reaction of the compound of formula G or its salt is carried out in a temperature range of about 10°C to about 30°C. In some embodiments, the reaction of the compound of formula G or its salt is carried out at a temperature of about 20°C.

[0349] Method for preparing compounds of formula D In some embodiments of the method disclosed herein, the method includes preparing a compound of formula D or a salt thereof by a method comprising the following: wherein R 5 It is R 9 : Compounds of formula F-1: F-1 or its salt, wherein R 9 It is an amine protecting group, and: Phosphine reagent azodicarbonate and Formula R 7 -NH-NH-R 8 The reaction of compounds; The compound of formula D or its salt is obtained.

[0350] In some embodiments of the compound of formula F-1 or a salt thereof, wherein R 9 It is tert-butyloxycarbonyl.

[0351] In some implementation schemes, formula R 7 -NH-NH-R 8 The compound is .

[0352] In some embodiments, suitable phosphine agents include triarylphosphine (e.g., triphenylphosphine, tri(2-pyridyl)phosphine, tri-(4-methoxyphenyl)phosphine), trialkylphosphine (e.g., tricyclohexylphosphine, tributylphosphine, trimethylphosphine), tri-(dimethylaminophenyl)phosphine, (triphenylphosphine)acetonitrile, and n-phosphine (e.g., (cyanomethylene)tributyln-n-phosphine).

[0353] In some embodiments, the phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine. In some embodiments, the phosphine reagent is triarylphosphine. In some embodiments, the phosphine reagent includes triphenylphosphine, tris(2-pyridyl)phosphine, tris(4-methoxyphenyl)phosphine, or combinations thereof. In some embodiments, the phosphine reagent is triphenylphosphine.

[0354] In some embodiments, the azodicarbonate ester is selected from di-tert-butyl azodicarbonate, diisopropyl azodicarbonate, diethyl azodicarbonate, dimethoxy ethyl azodicarbonate, azodicarbonyl dimorpholine, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarbonate. In some embodiments, the azodicarbonate ester is di-tert-butyl azodicarbonate.

[0355] In some embodiments, the reaction of the compound of formula F-1 or its salt is carried out in a thirty-fifth solvent. In some embodiments, the thirty-fifth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., ... N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N 1-Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the thirty-fifth solvent comprises an ether. In some embodiments, the thirty-fifth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of the compound of formula F-1 or a salt thereof is carried out in a thirty-fifth solvent containing 2-methyltetrahydrofuran.

[0356] In some embodiments, the reaction of the compound of formula F-1 or its salt is carried out in a temperature range of about -20°C to about 50°C. In some embodiments, the reaction of the compound of formula F-1 or its salt is carried out in a temperature range of about 15°C to about 30°C. In some embodiments, the reaction of the compound of formula F-1 or its salt is carried out in a temperature range of about 22°C.

[0357] In some embodiments, the method further includes preparing a compound of formula F-1 or a salt thereof by means of the following: Compounds of formula G-1: G-1 Or its salt and: Third catalyst Aromatic amines or sulfur-containing reagents; and Hydrogen reaction; The compound of formula F-1 or its salt is obtained.

[0358] In some embodiments of the compound of formula G-1, R 9 It is tert-butyloxycarbonyl.

[0359] In some embodiments, suitable third catalysts include palladium catalysts (e.g., 5 wt% palladium supported on carbon, 10 wt% palladium supported on carbon, 1 wt% palladium supported on carbon, 5 wt% palladium supported on calcium carbonate, 5 wt% palladium supported on alumina, 20 wt% palladium hydroxide supported on carbon, lead poisoned palladium), bimetallic catalysts (e.g., 4 wt% palladium and 1 wt% platinum supported on carbon, 9 wt% palladium and 1 wt% copper supported on carbon, 4 wt% palladium and 1 wt% copper supported on carbon), and platinum catalysts (e.g., platinum supported on carbon, platinum oxide).

[0360] In some embodiments, the third catalyst is selected from palladium catalysts, platinum catalysts, and bimetallic catalysts, wherein the bimetallic catalyst comprises two metals selected from palladium, platinum, and copper.

[0361] In some embodiments, the third catalyst is a palladium catalyst. In some embodiments, the third catalyst comprises palladium supported on carbon, palladium supported on calcium carbonate, or palladium supported on alumina. In some embodiments, the third catalyst is selected from 5 wt% palladium supported on carbon, 10 wt% palladium supported on carbon, 1 wt% palladium supported on carbon, 5 wt% palladium supported on calcium carbonate, 5 wt% palladium supported on alumina, 20 wt% palladium supported on carbon, and lead-poisoned palladium.

[0362] In some embodiments, the third catalyst is a Lindela catalyst. In some embodiments, the third catalyst comprises 5% by weight palladium supported on lead-poisoned calcium carbonate.

[0363] In some embodiments, the molar ratio of the compound of formula G-1 or a salt thereof to the third catalyst is from about 1:0.001 to about 1:0.05. In some embodiments, the molar ratio of the compound of formula G-1 or a salt thereof to the third catalyst is from about 1:0.001 to about 1:0.005. In some embodiments, the molar ratio of the compound of formula G-1 or a salt thereof to the third catalyst is from about 1:0.002.

[0364] In some embodiments, the reaction of the compound of formula G-1 or its salt is carried out at a pressure of about 1 psi to about 100 psi. In some embodiments, the reaction of the compound of formula G-1 or its salt is carried out at a pressure of about 1 psi to about 40 psi. In some embodiments, the reaction of the compound of formula G-1 or its salt is carried out at a pressure of about 22 psi.

[0365] In some embodiments, the compound of formula G-1 or a salt thereof reacts with an aromatic amine. In some embodiments, the compound of formula G-1 or a salt thereof reacts with an aromatic amine selected from quinoline and pyridine. In some embodiments, the aromatic amine is a quinoline.

[0366] In some embodiments, the compound of formula G-1 or a salt thereof reacts with a sulfur-containing compound. In some embodiments, the compound of formula G-1 or a salt thereof reacts with a sulfur-containing compound selected from thiols and sulfides.

[0367] In some embodiments, the reaction of the compound of formula G-1 or its salt is carried out in a thirty-sixth solvent. In some embodiments, the thirty-sixth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, isoamyl alcohol, tert-amyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the thirty-sixth solvent includes polar aprotic solvents. In some embodiments, the thirty-sixth solvent includes... N,N -Dimethylformamide, N,N -Dimethylacetamide,N 2-Methyl-2-pyrrolidone, N -Butylpyrrolidone (NBP) or combinations thereof. In some embodiments, the reaction of the compound of formula G-1 or its salt is carried out in a 36th solvent containing N,N-dimethylformamide.

[0368] In some embodiments, the reaction of the compound of formula G-1 or its salt is carried out in a temperature range of about 20°C to about 100°C. In some embodiments, the reaction of the compound of formula G-1 or its salt is carried out in a temperature range of about 10°C to about 30°C. In some embodiments, the reaction of the compound of formula G-1 or its salt is carried out at a temperature of about 22°C.

[0369] In some embodiments, the method further includes preparing a compound of formula G-1 or a salt thereof by means of the following: Compounds of formula H having formula H-1: H-1 or its salt, wherein R 11 Selected from C 1-20 Alkyl, phenyl, and -CH2NH2; Reaction with the twelfth base, A compound of formula G-1 or its salt is obtained.

[0370] In some implementation schemes, R 11 The radical is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, pentadecyl, phenyl, and -CH2NH2. In some embodiments, R 11 C 1-20 Alkyl group. In some embodiments, R 11 The compound is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, and pentadecyl. In some embodiments, R 11 It is methyl. In some embodiments, R 11 It is phenyl. In some embodiments, R 11 It is -CH2NH2.

[0371] In some embodiments, the compound of formula H-1 or a salt thereof is a compound of formula H-1-A: H-1-A Or its salt.

[0372] In some embodiments, the compound of formula H-1 or a salt thereof reacts with a twelfth base. In some embodiments, suitable twelfth bases include guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, potassium carbonate), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium bicarbonate), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide), and amines (e.g., methylamine, diethylamine, isopropylamine, diisopropylethylamine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, bis(trimethylsilyl)amine).

[0373] In some embodiments, the twelfth base is selected from guanidine, carbonate, bicarbonate, metal alkoxide, amine, or combinations thereof. In some embodiments, the twelfth base includes triazabicyclodecene, tetramethylguanidine, or combinations thereof. In some embodiments, the twelfth base is tetramethylguanidine.

[0374] In some embodiments, the reaction of the compound of formula H-1 or a salt thereof is carried out in a thirty-seventh solvent. In some embodiments, the thirty-seventh solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), and polar aprotic solvents (e.g., N, N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the thirty-seventh solvent comprises an alcohol. In some embodiments, the thirty-seventh solvent comprises methanol, ethanol, 2-propanol, butanol, isoamyl alcohol, or combinations thereof. In some embodiments, the reaction of a compound of formula H-1 or a salt thereof is carried out in a thirty-seventh solvent containing methanol.

[0375] In some embodiments, the reaction of the compound of formula H-1 or its salt is carried out in a temperature range of about 0°C to about 30°C. In some embodiments, the reaction of the compound of formula H-1 or its salt is carried out in a temperature range of about 10°C to about 20°C. In some embodiments, the reaction of the compound of formula H-1 or its salt is carried out at a temperature of about 20°C.

[0376] Alternative methods for preparing compounds of formula G-1 In some embodiments of the methods disclosed herein, compounds of formula G-1 or salts thereof are prepared by methods comprising: Compounds of formula U-1: U-1 The compound or its salt reacts with a reagent containing a second amine protecting group to give a compound of formula G-1 or its salt.

[0377] In some embodiments of the compound of formula G-1 or a salt thereof, R 9 It is tert-butyloxycarbonyl.

[0378] In some implementations, the second amine protecting group reagent is di-tert-butyl dicarbonate.

[0379] In some embodiments, the reaction of the compound of formula U-1 or a salt thereof is carried out in a forty-sixth solvent. In some embodiments, the forty-sixth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, isoamyl alcohol, tert-amyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the forty-sixth solvent comprises an ether. In some embodiments, the forty-sixth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of the compound of formula U-1 or a salt thereof is carried out in a forty-sixth solvent containing 2-methyltetrahydrofuran.

[0380] In some embodiments, the reaction of the compound of formula U-1 or its salt is carried out in a temperature range of about 5°C to about 100°C. In some embodiments, the reaction of the compound of formula U-1 or its salt is carried out in a temperature range of about 10°C to about 30°C. In some embodiments, the reaction of the compound of formula U-1 or its salt is carried out at a temperature of about 20°C.

[0381] In some embodiments, the method further includes preparing a compound of formula U-1 or a salt thereof by means of the following: Compounds of formula U-2: U-2 Or its salt and: The third enzyme reacts in the presence of the third buffer solution; A compound of formula U-1 or its salt is obtained.

[0382] In some implementations, a suitable third enzyme includes a transaminase (e.g., from Codexis). ® The third enzyme is selected from transaminases, aminohydrogenases, and imine reductases. In some embodiments, the third enzyme is selected from transaminases, aminohydrogenases, imine reductases, and combinations thereof. In some embodiments, the third enzyme is a transaminase. In some embodiments, the third enzyme is ATA-238, ATA-P1-G05, or ATA-P1-BO2.

[0383] In some embodiments, suitable third buffers include citrate buffer, phosphate buffer, tris(hydroxymethyl)aminomethane (Tris), and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) (HEPES). In some embodiments, the third buffer is selected from citrate buffer, phosphate buffer, tris(hydroxymethyl)aminomethane (Tris) buffer, and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) (HEPES). In some embodiments, the third buffer is Tris buffer.

[0384] In some embodiments, the reaction of the compound of formula U-2 or its salt is further performed in the presence of a coenzyme. In some embodiments, the coenzyme is pyridoxal phosphate. In some embodiments, the third enzyme is a transaminase and the coenzyme is pyridoxal phosphate.

[0385] In some embodiments, the reaction of the compound of formula U-2 or a salt thereof is carried out in a second cosolvent. In some embodiments, the second cosolvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, isoamyl alcohol, tert-amyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the second cosolvent comprises a polar aprotic solvent. In some embodiments, the second cosolvent comprises DMSO, N , N -Dimethylacetamide, N -Methyl-2-pyrrolidone, N-butylpyrrolidone (NBP), limonene, or combinations thereof. In some embodiments, the reaction of the compound of formula U-2 or a salt thereof is carried out in a second cosolvent containing dimethyl sulfoxide.

[0386] In some embodiments, the reaction of the compound of formula U-2 or its salt is carried out in a temperature range of about 5°C to about 100°C. In some embodiments, the reaction of the compound of formula U-2 or its salt is carried out in a temperature range of about 10°C to about 30°C. In some embodiments, the reaction of the compound of formula U-2 or its salt is carried out at a temperature of about 20°C.

[0387] In some embodiments, the method further includes preparing a compound of formula U-2 or a salt thereof by means of the following: Compounds of formula L: L Or its salt and: The fourth enzyme reacts in the presence of the fourth buffer solution; A compound of formula U-2 or its salt is obtained.

[0388] In some implementations, a suitable fourth enzyme includes a ketone reductase (e.g., from Codexis). ®The fourth enzyme is selected from ketone reductase, alcohol oxidase, and P450. In some embodiments, the fourth enzyme is selected from ketone reductase, alcohol oxidase, P450, and combinations thereof. In some embodiments, the fourth enzyme is ketone reductase. In some embodiments, the fourth enzyme is KRED-476.

[0389] In some embodiments, suitable fourth buffers include citrate buffer, phosphate buffer, tris(hydroxymethyl)aminomethane (Tris), and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) (HEPES). In some embodiments, the fourth buffer is selected from citrate buffer, phosphate buffer, tris(hydroxymethyl)aminomethane, and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) (HEPES). In some embodiments, the fourth buffer is Tris buffer.

[0390] In some embodiments, the reaction of a compound of formula L or a salt thereof involves reacting a compound of formula L with a second reducing agent. In some embodiments, the reducing agent is sodium β-nicotinamide adenine dinucleotide.

[0391] In some embodiments, the reaction of the compound of formula L or a salt thereof is carried out in a third cosolvent. In some embodiments, the third cosolvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N -Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, isoamyl alcohol, tert-amyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the third cosolvent comprises a polar aprotic solvent. In some embodiments, the second cosolvent comprises DMSO, N , N -Dimethylacetamide, N -Methyl-2-pyrrolidone, N-butylpyrrolidone (NBP), limonene, or combinations thereof. In some embodiments, the reaction of a compound of formula L or a salt thereof is carried out in a third cosolvent containing dimethyl sulfoxide.

[0392] In some embodiments, the reaction of the compound of formula L or its salt is carried out in a temperature range of about 5°C to about 100°C. In some embodiments, the reaction of the compound of formula L or its salt is carried out in a temperature range of about 10°C to about 30°C. In some embodiments, the reaction of the compound of formula L or its salt is carried out at a temperature of about 20°C.

[0393] Methods for preparing compounds of formula H In some embodiments of the method disclosed herein, the method includes preparing a compound of formula H or a salt thereof by means of the following: Compounds of formula J: J Or its salt and: Second phosphine reagent, Second azodicarbonate and Amine protecting group reagent reaction; To obtain a compound of formula H or a salt thereof.

[0394] In some embodiments of the compound of formula J, R 11 It is a methyl group.

[0395] In some embodiments, suitable second phosphine agents include triarylphosphine (e.g., triphenylphosphine, tri(2-pyridyl)phosphine, tri-(4-methoxyphenyl)phosphine), trialkylphosphine (e.g., tricyclohexylphosphine, tributylphosphine, trimethylphosphine), tri-(dimethylaminophenyl)phosphine, (triphenylphosphine)acetonitrile, and n-phosphine (e.g., (cyanomethylene)tributyln-n-phosphine).

[0396] In some embodiments, the second phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine. In some embodiments, the second phosphine reagent is triarylphosphine. In some embodiments, the second phosphine reagent includes triphenylphosphine, tris(2-pyridyl)phosphine, tris(4-methoxyphenyl)phosphine, or combinations thereof. In some embodiments, the second phosphine reagent is triphenylphosphine.

[0397] In some embodiments, the second azodicarbonate ester is selected from di-tert-butyl azodicarbonate, diisopropyl azodicarbonate, diethyl azodicarbonate, dimethoxyethyl azodicarbonate, azodicarbonyl dimorpholine, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarbonate. In some embodiments, the second azodicarbonate ester is diisopropyl azodicarbonate.

[0398] In some embodiments, the amine protecting group reagent is an imide. In some embodiments, the amine protecting group reagent is an imide selected from phthalimide, tert-butyl methyl iminocarbamate, and di-tert-butyl iminocarbamate. In some embodiments, the amine protecting group reagent is phthalimide.

[0399] In some embodiments, the reaction of the compound of formula J or a salt thereof is carried out in a thirty-eighth solvent. In some embodiments, the thirty-eighth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N 1-Butylpyrrolidone (NBP), dimethyl sulfoxide), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the 38th solvent comprises an ether. In some embodiments, the 38th solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of the compound of formula J or a salt thereof is carried out in a 38th solvent comprising 2-methyltetrahydrofuran.

[0400] In some embodiments, the reaction of the compound of formula J or its salt is carried out in a temperature range of about -20°C to about 50°C. In some embodiments, the reaction of the compound of formula J or its salt is carried out in a temperature range of about -5°C to about 15°C. In some embodiments, the reaction of the compound of formula J or its salt is carried out in a temperature range of about 5°C.

[0401] Alternative methods for preparing compounds of formula H In some embodiments of the method disclosed herein, the method includes preparing a compound of formula H or a salt thereof by means of the following: Compounds of formula N: N Or its salt, wherein: R 12 It is -S(O)3R 13 or -OC(=N)R 14 ; R 13 Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and optionally C 1-4 Alkyl-substituted phenyl; and R 14 It is C 1-4 Halogenated alkyl groups; Reaction with amine protecting group reagents, To obtain a compound of formula H or a salt thereof.

[0402] In some implementation schemes, R 12 It is -S(O)3R 13 In some implementations, R 13 Selected from toluene, methyl, and trifluoromethyl. In some embodiments, R 13 It is C 1-4 Alkyl group. In some embodiments, R 13 It is methyl. In some embodiments, R 13 It is toluene-based.

[0403] In some implementation schemes, R 12 It is -OC(=N)R 14 In some implementations, R 14 Selected from trichloromethyl and tribromomethyl.

[0404] In some embodiments, the amine protecting group reagent is selected from phthalimide, p-methoxyaniline, 2,4-dimethoxyaniline, acetamide, 2,5-dimethylpyrrole, 4-methoxybenzylamine, 2,4-dimethoxybenzylamine, 2,2-diphenylamine, allylamine, triphenylmethylamine, di-tert-butyl iminodiacetate, tert-butyl carbamate, or salts thereof. In some embodiments, the amine protecting group reagent is selected from phthalimide, p-methoxyaniline, o-dimethoxyaniline, p-dimethoxyaniline, acetamide, 2,5-dimethylpyrrole, 4-methoxybenzylamine, 2,4-dimethoxybenzylamine, 2,2-diphenylamine, allylamine, triphenylmethylamine, or salts thereof. In some embodiments, the amine protecting group reagent is phthalimide or a salt thereof. In some embodiments, the amine protecting group reagent is a salt of phthalimide. In some embodiments, the amine protecting group reagent is potassium phthalimide.

[0405] In some embodiments, the reaction of the compound of formula N or a salt thereof is further carried out in the presence of a third additive. In some embodiments, suitable third additives include 18-crown ether-6, tetrabutylammonium salts (e.g., chlorides, bromides, sulfates, iodides), hexamethylphosphoramide, and water. In some embodiments, the third additive comprises 18-crown ether-6, tetrabutylammonium salts, hexamethylphosphoramide, water, or combinations thereof. In some embodiments, the third additive comprises 18-crown ether-6. In some embodiments, the reaction of the compound of formula N is carried out in the absence of a third additive.

[0406] In some embodiments, the reaction of the compound of formula N or its salt is carried out in the presence of a tenth base. In some embodiments, a suitable tenth base includes an amine (e.g., n-propylamine, triethylamine, ...). N,N -Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring), amidine (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), etc.), guanidine (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2 -n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate), metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), basic aromatic compounds (e.g., pyridine, 2,6-dimethylpyridine, imidazole) or combinations thereof. In some embodiments, the tenth base is selected from amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, phosphates, hydroxides, alkoxides, and basic aromatic compounds.

[0407] In some embodiments, the reaction of the compound of formula N or a salt thereof is carried out in a twentieth solvent. In some embodiments, the twentieth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N1,2-Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or combinations thereof. In some embodiments, the twentieth solvent comprises a polar aprotic solvent. In some embodiments, the twentieth solvent is... N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N -Butylpyrrolidone (NBP) or combinations thereof. In some embodiments, the reaction of a compound of formula N or a salt thereof is carried out in a twentieth solvent containing N,N-dimethylacetamide.

[0408] In some embodiments, the reaction of the compound of formula N or a salt thereof is carried out in a twentieth solvent. In some embodiments, the twentieth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N Butylpyrrolidone (NBP), dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), water, or combinations thereof. In some embodiments, the twentieth solvent comprises a polar aprotic solvent. In some embodiments, the twentieth solvent comprises... N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N - Butylpyrrolidone (NBP), limonene, dimethyl sulfoxide, or combinations thereof.

[0409] In some embodiments, the reaction of the compound of formula N or its salt is carried out in a temperature range of about 20°C to about 100°C. In some embodiments, the reaction of the compound of formula N or its salt is carried out in a temperature range of about 10°C to about 30°C.

[0410] In some embodiments, the method further includes preparing a compound of formula N or a salt thereof by means of the following: Compounds of formula J: J Or its salt and: The eleventh base and The third reagent reaction, wherein the third reagent is selected from sulfonyl chloride, sulfonic anhydride, halonitrile, imine chloride or acyl halide; A compound of formula N or its salt is obtained.

[0411] In some embodiments, the method further includes preparing a compound of formula N or a salt thereof by reacting a compound of formula J or a salt thereof with an eleventh base and a third reagent selected from sulfonyl chloride, sulfonic anhydride, halonitrile or imine chloride; to obtain a compound of formula N or a salt thereof.

[0412] In some embodiments, the third reagent is a sulfonyl chloride. In some embodiments, the third reagent is selected from methanesulfonyl chloride and 4-toluenesulfonyl chloride. In some embodiments, the third reagent is methanesulfonyl chloride. In some embodiments, the third reagent is benzenesulfonyl chloride, toluenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, triisopropylbenzenesulfonyl chloride, trimethylbenzenesulfonyl chloride, naphthalenesulfonyl chloride, 2-chlorobenzenesulfonyl chloride, 2,4-dichlorobenzenesulfonyl chloride, or methanesulfonyl chloride.

[0413] In some embodiments, the third reagent is a sulfonic anhydride. In some embodiments, the sulfonic anhydride is selected from methanesulfonic anhydride and trifluoromethanesulfonic anhydride. In some embodiments, the third reagent is a sulfonic anhydride (e.g., hexanoic anhydride, isobutyric anhydride, benzoic anhydride, propionic anhydride, octanoic anhydride, decanoic anhydride).

[0414] In some embodiments, the third reagent is a halonitrile. In some embodiments, the halonitrile is selected from trichloroacetonitrile and trifluoroacetonitrile.

[0415] In some embodiments, the third reagent is an imine chloride. In some embodiments, the imine chloride is (N-phenyl)trifluoroiminoacetyl chloride.

[0416] In some embodiments, the third reagent is an acyl halide. In some embodiments, the acyl halide is selected from acetyl chloride, acetyl bromide, and benzoyl chloride.

[0417] In some embodiments, suitable eleventh bases include amines (e.g., triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,1,3,3-tetramethylguanidine, 2,2,6,6-tetramethylpiperidine, pyridine, 2,6-dimethylpyridine, etc.). N , N -Diisopropylethylamine, quinine ring, diisopropylamine, N , N -Diisopropylethylamine, tributylamine), carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, potassium carbonate), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium bicarbonate), and metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide).

[0418] In some embodiments, the eleventh base is an amine. In some embodiments, the eleventh base includes triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,1,3,3-tetramethylguanidine, 2,2,6,6-tetramethylpiperidine, pyridine, 2,6-dimethylpyridine, N , N -Diisopropylethylamine, quinine ring, diisopropylamine, N , N -Diisopropylethylamine, tributylamine, or combinations thereof. In some embodiments, the eleventh base is triethylamine.

[0419] In some embodiments, the reaction of the compound of formula J or a salt thereof is carried out in a second-first solvent. In some embodiments, the second-first solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the twenty-first solvent comprises a polar aprotic solvent. In some embodiments, the twenty-first solvent includes...N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N -Butylpyrrolidone (NBP) or combinations thereof. In some embodiments, the reaction of the compound of formula J or a salt thereof is carried out in a twentieth solvent containing N,N-dimethylacetamide.

[0420] In some embodiments, the reaction of the compound of formula J or its salt is carried out in a temperature range of about -15°C to about 60°C. In some embodiments, the reaction of the compound of formula J or its salt is carried out in a temperature range of about -10°C to about 10°C. In some embodiments, the reaction of the compound of formula J or its salt is carried out at a temperature of about 0°C.

[0421] Alternative methods for preparing compounds of formula H-1 In some embodiments of the method disclosed herein, the method includes preparing a compound of formula H-1 or a salt thereof by means of the following: Compounds of formula P-1: P-1 The compound or its salt reacts with an amine protecting group reagent to give a compound of formula H-1 or a salt thereof. In some embodiments of the compound of formula P-1 or a salt thereof, R 11 It is a methyl group.

[0422] In some implementations, the amine protecting group reagent is di-tert-butyl dicarbonate.

[0423] In some embodiments, the method further includes preparing a compound of formula P-1 or a salt thereof by means of the following: Compounds of formula N: N Or its salt, wherein: R 12 It is -S(O)3R 13 ;and R 13 Selected from C 1-4 Alkyl groups and optionally C 1-4 Alkyl-substituted phenyl; and: azides and Tertiary phosphine reagent reaction; A compound of formula P-1 or its salt is obtained.

[0424] In some embodiments, the azide is selected from sodium azide, diphenyl azidophosphate, and trimethyl azidosilane. In some embodiments, the azide is sodium azide.

[0425] In some embodiments, suitable third phosphine agents include triarylphosphine (e.g., triphenylphosphine, tri(2-pyridyl)phosphine, tri-(4-methoxyphenyl)phosphine), trialkylphosphine (e.g., tricyclohexylphosphine, tributylphosphine, trimethylphosphine), tri-(dimethylaminophenyl)phosphine, (triphenylphosphine)acetonitrile, and n-phosphine (e.g., (cyanomethylene)tributyln-n-phosphine).

[0426] In some embodiments, the third phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine. In some embodiments, the third phosphine reagent is triarylphosphine. In some embodiments, the third phosphine reagent includes triphenylphosphine, tris(2-pyridyl)phosphine, tris(4-methoxyphenyl)phosphine, or combinations thereof. In some embodiments, the third phosphine reagent is triphenylphosphine.

[0427] In some embodiments, the reaction of the compound of formula N or a salt thereof is carried out in a second seventeenth solvent. In some embodiments, the second seventeenth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the twenty-seventh solvent comprises a polar aprotic solvent. In some embodiments, the twenty-seventh solvent includes... N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N -Butylpyrrolidone (NBP) or combinations thereof. In some embodiments, the reaction of a compound of formula N or a salt thereof is carried out in a 27th solvent containing N,N-dimethylformamide.

[0428] In some embodiments, the reaction of the compound of formula N or its salt is carried out in a temperature range of about -20°C to about 50°C. In some embodiments, the reaction of the compound of formula N or its salt is carried out in a temperature range of about 10°C to about 30°C.

[0429] Alternative methods for preparing compounds of formula H-1 In some embodiments of the method disclosed herein, the method includes preparing a compound of formula H-1 or a salt thereof by means of the following: Compounds of formula P-2: P-2 Or its salt and: Phosphine reagent; and Amine protecting group reagent reaction; A compound of formula H-1 or a salt thereof is obtained. In some embodiments of a compound of formula P-2 or a salt thereof, R 11 It is a methyl group.

[0430] In some embodiments, suitable fourth phosphine agents include triarylphosphine (e.g., triphenylphosphine, tri(2-pyridyl)phosphine, tri-(4-methoxyphenyl)phosphine), trialkylphosphine (e.g., tricyclohexylphosphine, tributylphosphine, trimethylphosphine), tri-(dimethylaminophenyl)phosphine, (triphenylphosphine)acetonitrile, and n-phosphine (e.g., (cyanomethylene)tributyln-n-phosphine).

[0431] In some embodiments, the fourth phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine. In some embodiments, the fourth phosphine reagent is triarylphosphine. In some embodiments, the fourth phosphine reagent includes triphenylphosphine, tris(2-pyridyl)phosphine, tris(4-methoxyphenyl)phosphine, or combinations thereof. In some embodiments, the fourth phosphine reagent is triphenylphosphine.

[0432] In some implementations, the amine protecting group reagent is di-tert-butyl dicarbonate.

[0433] In some embodiments, the method further includes preparing a compound of formula P-2 or a salt thereof by means of the following: Compounds of formula J: J Or its salt and: azides, Tertiary phosphine reagent and Third azodicarbonate reaction; A compound of formula P-2 or its salt is obtained.

[0434] In some embodiments, the azide is selected from sodium azide, diphenyl azidophosphate, and trimethyl azidosilane. In some embodiments, the azide is sodium azide.

[0435] In some embodiments, suitable third phosphine agents include triarylphosphine (e.g., triphenylphosphine, tri(2-pyridyl)phosphine, tri-(4-methoxyphenyl)phosphine), trialkylphosphine (e.g., tricyclohexylphosphine, tributylphosphine, trimethylphosphine), tri-(dimethylaminophenyl)phosphine, (triphenylphosphine)acetonitrile, and n-phosphine (e.g., (cyanomethylene)tributyln-n-phosphine).

[0436] In some embodiments, the third phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine. In some embodiments, the third phosphine reagent is triarylphosphine. In some embodiments, the third phosphine reagent includes triphenylphosphine, tris(2-pyridyl)phosphine, tris(4-methoxyphenyl)phosphine, or combinations thereof. In some embodiments, the third phosphine reagent is triphenylphosphine.

[0437] In some embodiments, the third azodicarbonate ester is selected from di-tert-butyl azodicarbonate, diisopropyl azodicarbonate, diethyl azodicarbonate, dimethoxyethyl azodicarbonate, azodicarbonyl dimorpholine, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarbonate. In some embodiments, the third azodicarbonate ester is diisopropyl azodicarbonate.

[0438] In some embodiments, the reaction of the compound of formula J or a salt thereof is carried out in a thirty-ninth solvent. In some embodiments, the thirty-ninth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N-Butylpyrrolidone (NBP), dimethyl sulfoxide), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the thirty-eighth solvent comprises an ether. In some embodiments, the thirty-ninth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of the compound of formula J or a salt thereof is carried out in the thirty-ninth solvent containing tetrahydrofuran.

[0439] In some embodiments, the reaction of the compound of formula J or its salt is carried out in a temperature range of about -20°C to about 50°C. In some embodiments, the reaction of the compound of formula J or its salt is carried out in a temperature range of about 10°C to about 30°C.

[0440] Method for preparing compounds of formula J In some embodiments of the method disclosed herein, the method includes preparing a compound of formula J or a salt thereof by means of the following: Compounds of formula K: K Or its salt and: enzymes and Buffer reaction; A compound of formula J or its salt is obtained.

[0441] In some embodiments of compounds of formula K or salts thereof, R 11 Selected from C 1-20 Alkyl and phenyl. In some embodiments of compounds of formula K or their salts, R 11 Selected from methyl, hexyl, isopropyl, and benzyl. In some embodiments of compounds of formula K or salts thereof, R 11 It is a methyl group.

[0442] In some implementations, suitable enzymes include hydrolases (such as Candida antarcticus). Candida antarctica Lipases A and B, lipase AK, lipase PS, and Candida albicans ( candida rugosa (Lipase, L-092, etc.), Prozomix 4, Prozomix 5, Prozomix 25, Prozomix 26 and Novozyme 435.

[0443] In some embodiments, the enzyme is selected from hydrolases, Prozomix 4, Prozomix 5, Prozomix 25, Prozomix 26, and Novozyme 435. In some embodiments, the enzyme is a hydrolase. In some embodiments, the enzyme is selected from L-092, Candida antarcticis lipases A and B, lipase AK, lipase PS, and Candida pleurisy lipase. In some embodiments, the enzyme is L-092 hydrolases.

[0444] In some embodiments, the molar ratio of the enzyme to the compound of formula K or a salt thereof is from about 0.00001:1 to about 2:1. In some embodiments, the molar ratio of the enzyme to the compound of formula K or a salt thereof is from about 0.00001:1 to about 0.01:1. In some embodiments, the molar ratio of the enzyme to the compound of formula K or a salt thereof is from about 0.001:1 to about 0.01:1. In some embodiments, the molar ratio of the enzyme to the compound of formula K or a salt thereof is from about 0.001:1 to about 0.005:1.

[0445] In some embodiments, suitable buffers include citrate buffer, phosphate buffer (e.g., potassium phosphate, citrate phosphate), tris(hydroxymethyl)aminomethane (Tris), and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) (HEPES). In some embodiments, the buffer is selected from citrate buffer, phosphate buffer, tris(hydroxymethyl)aminomethane, and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) (HEPES). In some embodiments, the buffer is selected from phosphate buffer, tris(hydroxymethyl)aminomethane, and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) (HEPES). In some embodiments, the buffer is a phosphate buffer. In some embodiments, the buffer is a potassium phosphate buffer. In some embodiments, the buffer has a concentration of about 0.1 M to about 1.5 M.

[0446] In some embodiments, the method includes adjusting the pH of the reaction mixture containing a compound of formula K or a salt thereof to a range of approximately pH 8 to pH 12. In some embodiments, the method includes adjusting the pH of the reaction mixture containing a compound of formula K or a salt thereof to approximately pH 10.

[0447] In some embodiments, the reaction of the compound of formula K or its salt is carried out at a pH of about 5 to about 10. In some embodiments, the reaction of the compound of formula K or its salt is carried out at a pH of about 7 to about 10. In some embodiments, the reaction of the compound of formula K or its salt is carried out at a pH of about 6 to about 8. In some embodiments, the reaction of the compound of formula K or its salt is carried out at a pH of about 7. In some embodiments, the reaction of the compound of formula K or its salt is carried out at a pH of about 10.

[0448] In some embodiments, the reaction of the compound of formula K or its salt is carried out in the presence of a metal ion. In some embodiments, the metal ion is an ion of zinc, nickel, calcium, iron, magnesium, or manganese. In some embodiments, the reaction of the compound of formula K or its salt is carried out in the presence of a metal halide. In some embodiments, the metal ion or metal halide includes zinc, nickel, calcium, iron, magnesium, or manganese. In some embodiments, the metal halide is a metal chloride. In some embodiments, the metal halide includes zinc chloride, nickel(II) chloride, calcium chloride, ferric chloride(II), ferric chloride(III), magnesium chloride, manganese(II) chloride, or combinations thereof.

[0449] In some embodiments, the reaction of the compound of formula K or its salt is carried out in the presence of a surfactant. In some embodiments, the surfactant is selected from sodium dodecyl sulfate, polypropylene glycol, and polyoxyethylene fatty ethers. In some embodiments, the surfactant is selected from sodium dodecyl sulfate, polypropylene glycol 2000, and Brij surfactants (e.g., L23, 58, S20, O20, L4, O10, S10, C10).

[0450] In some embodiments, the reaction of the compound of formula K or a salt thereof is carried out in a fortieth solvent. In some embodiments, the fortieth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, Nbutylpyrrolidone (NBP), dimethyl sulfoxide (DMSO), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the fortieth solvent includes dimethyl sulfoxide, tert-butyl methyl ether, heptane, cyclopentyl methyl ether, toluene, 2-methylhydrofuran, or combinations thereof.

[0451] In some embodiments, the 40th solvent comprises an ether. In some embodiments, the 40th solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of the compound of formula K or a salt thereof is carried out in the 40th solvent comprising tert-butyl methyl ether.

[0452] In some embodiments, the reaction of the compound of formula K or its salt is carried out in a temperature range of about 0°C to about 70°C. In some embodiments, the reaction of the compound of formula K or its salt is carried out in a temperature range of about 30°C to about 50°C. In some embodiments, the reaction of the compound of formula K or its salt is carried out in a temperature range of about 20°C to about 40°C. In some embodiments, the reaction of the compound of formula K or its salt is carried out at a temperature of about 30°C.

[0453] In some embodiments, this document provides a method for preparing a compound of formula J or a salt thereof by comprising the following steps: React the compound of formula K or its salt with an enzyme and a buffer solution; A compound of formula J or its salt is obtained.

[0454] In some embodiments, this document provides a method for preparing a compound of formula I or a salt thereof by means of the following: Compounds of formula J or their salts may be prepared by methods including the following: React the compound of formula K or its salt with an enzyme and a buffer solution; A compound of formula J or its salt is obtained.

[0455] In some embodiments, the method further includes preparing a compound of formula K or a salt thereof by means of the following: Compounds of formula L: L or its salt; with: Ninth Alkali Fourth catalyst and Reactions of compounds of formula M-1 or M-2: M-1 ; M-2 Where X is a halide; A compound of formula K or its salt is obtained.

[0456] In some embodiments, a compound of formula L or a salt thereof reacts with a compound of formula M-1. In some embodiments, the compound of formula M-1 is selected from acetic anhydride, hexanoic anhydride, isobutyric anhydride, benzoic anhydride, propionic anhydride, octanoic anhydride, and decanoic anhydride. In some embodiments, the compound of formula M-1 is acetic anhydride (i.e., R...). 11 (It is methyl).

[0457] In some embodiments, the compound of formula L or a salt thereof reacts with the compound of formula M-2. In some embodiments, the halide is a chloride or a bromide. In some embodiments, the compound of formula M-2 is selected from acetyl chloride, acetyl bromide, and benzoyl chloride.

[0458] In some embodiments, suitable ninth bases include carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate), metal alkoxides (e.g., sodium methoxide, sodium tert-butoxide, lithium tert-butoxide), amines (e.g., diethylamine, triethylamine, isopropylamine, diisopropylethylamine, N-methylmorpholine, 1,4-diazabicyclo[2.2.2]octane, diazabicycloundecene, bis(trimethylsilyl)amine), and metal hydroxides (e.g., sodium hydroxide).

[0459] In some embodiments, the ninth base is selected from carbonates, metal alkoxides, amines, metal hydroxides, or combinations thereof. In some embodiments, the ninth base is an amine. In some embodiments, the ninth base includes diethylamine, triethylamine, isopropylamine, diisopropylethylamine, N-methylmorpholine, 1,4-diazabicyclo[2.2.2]octane, dizabicycloundecene, bis(trimethylsilyl)amine, or combinations thereof. In some embodiments, the ninth base is triethylamine.

[0460] In some embodiments, the fourth catalyst is an aromatic amine. In some embodiments, the fourth catalyst is selected from 4-dimethylaminopyridine, N-methylimidazole, and pyridine. In some embodiments, the fourth catalyst is 4-dimethylaminopyridine.

[0461] In some embodiments, the reaction of the compound of formula L or a salt thereof is carried out in a forty-first solvent. In some embodiments, the forty-first solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N butylpyrrolidone (NBP), dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the forty-first solvent comprises an ether. In some embodiments, the forty-first solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of a compound of formula L or a salt thereof is carried out in a forty-first solvent comprising tert-butyl methyl ether.

[0462] In some embodiments, the reaction of the compound of formula L or its salt is carried out in a temperature range of about 0°C to about 100°C. In some embodiments, the reaction of the compound of formula L or its salt is carried out in a temperature range of about 15°C to about 25°C. In some embodiments, the reaction of the compound of formula L or its salt is carried out at a temperature of about 20°C.

[0463] Alternative methods for preparing compounds of formula E In some embodiments of the method disclosed herein, the method includes preparing a compound of formula E or a salt thereof by means of a method comprising: Compounds of formula O-1: O-1 Or its salt and: Amine protecting group reagents Phosphine reagents and azodicarbonate reaction, The compound of formula E or its salt is obtained.

[0464] In some embodiments of the compound of formula O-1, R 7 and R 8 It is tert-butyloxycarbonyl.

[0465] In some embodiments, the amine protecting group reagent is selected from phthalimide, di-tert-butyl iminodicarboxylate, ethyl 2-((tert-butoxycarbonyl)amino)-2-oxoacetate, methyl 2-((tert-butoxycarbonyl)amino)-2-oxoacetate, tert-butyl methyl iminodiacarbonate, and dimethyl iminodiacarbonate. In some embodiments, the amine protecting group reagent is phthalimide.

[0466] In some embodiments, suitable phosphine agents include triarylphosphine (e.g., triphenylphosphine, tri(2-pyridyl)phosphine, tri-(4-methoxyphenyl)phosphine), trialkylphosphine (e.g., tricyclohexylphosphine, tributylphosphine, trimethylphosphine), tri-(dimethylaminophenyl)phosphine, (triphenylphosphine)acetonitrile, and n-phosphine (e.g., (cyanomethylene)tributyln-n-phosphine).

[0467] In some embodiments, the phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine. In some embodiments, the phosphine reagent is triarylphosphine. In some embodiments, the phosphine reagent includes triphenylphosphine, tris(2-pyridyl)phosphine, tris(4-methoxyphenyl)phosphine, or combinations thereof. In some embodiments, the phosphine reagent is triphenylphosphine.

[0468] In some embodiments, the azodicarbonate ester is selected from di-tert-butyl azodicarbonate, diisopropyl azodicarbonate, diethyl azodicarbonate, dimethoxy ethyl azodicarbonate, azodicarbonyl dimorpholine, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarbonate. In some embodiments, the azodicarbonate ester is di-tert-butyl azodicarbonate.

[0469] In some embodiments, the reaction of the compound of formula O-1 or a salt thereof is carried out in a second second solvent. In some embodiments, the second second solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N22 solvents include butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the 22 solvent comprises an ether. In some embodiments, the 22 solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of the compound of formula O-1 or a salt thereof is carried out in a 22 solvent containing 2-methyltetrahydrofuran.

[0470] In some embodiments, the reaction of the compound of formula O-1 or its salt is carried out in a temperature range of about -20°C to about 50°C. In some embodiments, the reaction of the compound of formula O-1 or its salt is carried out in a temperature range of about 0°C to about 22°C.

[0471] In some embodiments, the method further includes preparing a compound of formula O-1 or a salt thereof by means of the following: Compounds of formula O-2: O-2 Or its salt and: Fifth catalyst and Hydrogen reaction; A compound of formula O-1 or its salt is obtained.

[0472] In some embodiments, suitable fifth catalysts include palladium catalysts (e.g., 5 wt% palladium supported on carbon, 10 wt% palladium supported on carbon, 1 wt% palladium supported on carbon, 5 wt% palladium supported on calcium carbonate, 5 wt% palladium supported on alumina, 20 wt% palladium hydroxide supported on carbon, lead poisoned palladium), bimetallic catalysts (e.g., 4 wt% palladium and 1 wt% platinum supported on carbon, 9 wt% palladium and 1 wt% copper supported on carbon, 4 wt% palladium and 1 wt% copper supported on carbon), and platinum catalysts (e.g., platinum supported on carbon, platinum oxide).

[0473] In some embodiments, suitable fifth catalysts include palladium catalysts (e.g., 5 wt% palladium supported on carbon, 10 wt% palladium supported on carbon, 1 wt% palladium supported on carbon, 5 wt% palladium supported on calcium carbonate, 5 wt% palladium supported on alumina, palladium hydroxide, palladium acetate, palladium acetate / manganese, palladium chloride, palladium trifluoroacetate, palladium propionate, palladium neopentanoate, tris(dibenzylacetone)dipalladium, palladium bromide, bis(acetylacetone)palladium(II), bis(benzonitrile)dichloride, 20 wt% palladium supported on carbon, lead poisoned palladium supported on barium sulfate or calcium carbonate), bimetallic catalysts (e.g., 4 wt% palladium and 1 wt% platinum supported on carbon, 9 wt% palladium and 1 wt% copper supported on carbon, 4 wt% palladium and 1 wt% copper supported on carbon), and platinum catalysts (e.g., platinum supported on carbon, platinum oxide).

[0474] In some embodiments, the fifth catalyst is selected from palladium catalysts, platinum catalysts, and bimetallic catalysts, wherein the bimetallic catalyst comprises two metals selected from palladium, platinum, and copper.

[0475] In some embodiments, the fifth catalyst is a palladium catalyst. In some embodiments, the fifth catalyst comprises palladium supported on carbon, palladium supported on calcium carbonate, or palladium supported on alumina. In some embodiments, the fifth catalyst is selected from 5 wt% palladium supported on carbon, 10 wt% palladium supported on carbon, 1 wt% palladium supported on carbon, 5 wt% palladium supported on calcium carbonate, 5 wt% palladium supported on alumina, 20 wt% palladium supported on carbon, and lead-poisoned palladium.

[0476] In some embodiments, the fifth catalyst is a Lindela catalyst. In some embodiments, the fifth catalyst comprises 5% by weight palladium supported on lead-poisoned calcium carbonate.

[0477] In some embodiments, the hydrogen is derived from a hydrogen source. In some embodiments, the hydrogen source is hydrogen gas or a combination of formic acid, potassium carbonate, and water. In some embodiments, the hydrogen source is hydrogen gas. In some embodiments, the hydrogen source may be a combination of formic acid, potassium carbonate, and water.

[0478] In some embodiments, the preparation of the compound of formula O-1 is further carried out in the presence of an additive by a method comprising reacting a compound of formula O-2 or a salt thereof with a fifth catalyst and hydrogen. In some embodiments, the additive is selected from quinoline, pyridine, triethylamine, carbonates (such as lithium carbonate, sodium carbonate, cesium carbonate, potassium carbonate), bicarbonates (such as lithium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium bicarbonate), phosphates M(n)H(3-n)PO4 (such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, etc.), 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, potassium formate, sodium formate, ammonium formate, potassium hydroxide, potassium acetate, sodium acetate, cesium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium iodide, lithium chloride, sodium chloride, calcium chloride, triethylamine, and potassium hydroxide.

[0479] In some embodiments, the molar ratio of the compound of formula O-2 or a salt thereof to the fifth catalyst is from about 1:0.001 to about 1:0.05. In some embodiments, the molar ratio of the compound of formula O-2 or a salt thereof to the third catalyst is from about 1:0.001 to about 1:0.005. In some embodiments, the molar ratio of the compound of formula O-2 or a salt thereof to the third catalyst is from about 1:0.003.

[0480] In some embodiments, the reaction of the compound of formula O-2 or its salt is carried out at a pressure of about 1 psi to about 100 psi. In some embodiments, the reaction of the compound of formula O-2 or its salt is carried out at a pressure of about 25 psi to about 75 psi. In some embodiments, the reaction of the compound of formula O-2 or its salt is carried out at a pressure of about 50 psi.

[0481] In some embodiments, the reaction of the compound of formula O-2 or a salt thereof is carried out in the second third solvent. In some embodiments, the second third solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, NButylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, isoamyl alcohol, tert-amyl alcohol), glycols (e.g., polyethylene glycol 400), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the twenty-third solvent includes a polar aprotic solvent. In some embodiments, the twenty-third solvent includes... N,N -Dimethylformamide, N, N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N -Butylpyrrolidone (NBP) or combinations thereof. In some embodiments, the reaction of the compound of formula O-2 or its salt is carried out in a 23rd solvent containing N,N-dimethylformamide.

[0482] In some embodiments, the twenty-third solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene, anisole), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N 1-Butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol (e.g., 1-butanol), isoamyl alcohol, tert-amyl alcohol), glycols (e.g., polyethylene glycol 400), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof.

[0483] In some embodiments, the reaction of the compound of formula O-2 or its salt is carried out in a temperature range of about 0°C to about 100°C. In some embodiments, the reaction of the compound of formula O-2 or its salt is carried out in a temperature range of about 15°C to about 30°C. In some embodiments, the reaction of the compound of formula O-2 or its salt is carried out at a temperature of about 22°C.

[0484] In some embodiments, the method further includes preparing a compound of formula O-2 or a salt thereof by means of the following: Compounds of formula O-3: O-3 or its salt, wherein R 11 Selected from C 1-20 Alkyl, phenyl and -CH2NH2; with: The twelfth base reaction; A compound of formula O-2 or its salt is obtained.

[0485] In some embodiments of the compound of formula O-3 or its salt, R 11 Selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, pentadecyl, phenyl, and -CH2NH2. In some embodiments of compounds of formula O-3 or salts thereof, R 11 It is a methyl group.

[0486] In some embodiments, suitable twelfth bases include guanidines (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate, potassium carbonate), bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, cesium bicarbonate, potassium bicarbonate), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide), amines (e.g., methylamine, diethylamine, isopropylamine, diisopropylethylamine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, bis(trimethylsilyl)amine), and metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide).

[0487] In some embodiments, the twelfth base is guanidine. In some embodiments, the twelfth base is selected from triazabicyclodecene and tetramethylguanidine. In some embodiments, the twelfth base is tetramethylguanidine.

[0488] In some embodiments, the reaction of the compound of formula O-3 or a salt thereof is carried out in a second fourteenth solvent. In some embodiments, the second fourteenth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), and polar aprotic solvents (e.g., ... N, N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, Nbutylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol, tert-amyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the twenty-fourth solvent comprises an alcohol. In some embodiments, the twenty-fourth solvent comprises methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol, tert-amyl alcohol, or combinations thereof. In some embodiments, the reaction of the compound of formula O-3 or a salt thereof is carried out in the twenty-fourth solvent containing methanol.

[0489] In some embodiments, the reaction of the compound of formula O-3 or its salt is carried out in a temperature range of about -10°C to about 80°C. In some embodiments, the reaction of the compound of formula O-3 or its salt is carried out in a temperature range of about 10°C to about 30°C. In some embodiments, the reaction of the compound of formula O-3 or its salt is carried out at a temperature of about 20°C.

[0490] In some embodiments, the method further includes preparing a compound of formula O-3 or a salt thereof by means of the following: Compounds of formula O-4: O-4 Or its salt and: Second phosphine reagent, Second azodicarbonate and Formula R 7 -NH-NH-R 8 Reacts with compounds or (1,3-dioxoisoindoline-2-yl)carbamate; A compound of formula O-3 or its salt is obtained.

[0491] In some embodiments, suitable second phosphine agents include triarylphosphine (e.g., triphenylphosphine, tri(2-pyridyl)phosphine, tri-(4-methoxyphenyl)phosphine), trialkylphosphine (e.g., tricyclohexylphosphine, tributylphosphine, trimethylphosphine), tri-(dimethylaminophenyl)phosphine, (triphenylphosphine)acetonitrile, and n-phosphine (e.g., (cyanomethylene)tributyln-n-phosphine).

[0492] In some embodiments, the second phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine. In some embodiments, the second phosphine reagent is triarylphosphine. In some embodiments, the second phosphine reagent includes triphenylphosphine, tris(2-pyridyl)phosphine, tris(4-methoxyphenyl)phosphine, or combinations thereof. In some embodiments, the second phosphine reagent is triphenylphosphine.

[0493] In some embodiments, the second azodicarbonate ester is selected from di-tert-butyl azodicarbonate, diisopropyl azodicarbonate, diethyl azodicarbonate, dimethoxy ethyl azodicarbonate, azodicarbonyl dimorpholine, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarbonate. In some embodiments, the second azodicarbonate ester is di-tert-butyl azodicarbonate.

[0494] In some implementation schemes, formula R 7 -NH-NH-R 8 The compound is .

[0495] In some embodiments, the reaction of the compound of formula O-4 or a salt thereof is carried out in a second fifth solvent. In some embodiments, the second fifth solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N butylpyrrolidone (NBP), dimethyl sulfoxide, esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the twenty-fifth solvent comprises an ether. In some embodiments, the twenty-fifth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of the compound of formula O-4 or a salt thereof is carried out in a twenty-fifth solvent containing 2-methyltetrahydrofuran.

[0496] In some embodiments, the reaction of the compound of formula O-4 or its salt is carried out in a temperature range of about -20°C to about 50°C. In some embodiments, the reaction of the compound of formula O-4 or its salt is carried out in a temperature range of about 0°C to about 22°C.

[0497] In some embodiments, the method further includes preparing a compound of formula O-4 or a salt thereof by means of the following: Compounds of formula L: L Or its salt and: Alkyl esters, alkenyl esters, or oxime esters; and Enzyme reaction, A compound of formula O-4 or its salt is obtained.

[0498] In some embodiments, a compound of formula L or a salt thereof reacts with an alkenyl ester. In some embodiments, a compound of formula L or a salt thereof reacts with an alkenyl ester selected from vinyl acetate, isopropylene acetate, and vinyl butyrate. In some embodiments, the alkenyl ester is isopropylene acetate.

[0499] In some embodiments, a compound of formula L or a salt thereof reacts with an alkyl ester. In some embodiments, a compound of formula L or a salt thereof reacts with an alkyl ester selected from ethyl acetate, methyl acetate, isopropyl acetate, and methyl butyrate.

[0500] In some embodiments, a compound of formula L or a salt thereof reacts with an oxime ester. In some embodiments, a compound of formula L or a salt thereof reacts with an oxime ester selected from propion-2-one O-acetyl oxime and propion-2-one O-butyryl oxime.

[0501] In some embodiments, suitable enzymes include hydrolases (e.g., Candida antarcticis lipases A and B, lipase AK, lipase PS, Candida rhombiformis lipase, etc.), Prozomix 4, Prozomix 5, Prozomix 25, Prozomix 26, and Novozyme 435. In some embodiments, the enzyme is selected from hydrolases, Prozomix 4, Prozomix 5, Prozomix 25, Prozomix 26, and Novozyme 435. In some embodiments, the enzyme is a hydrolases. In some embodiments, the enzyme is lipase AK.

[0502] In some embodiments, the reaction of the compound of formula L or a salt thereof is carried out in a second sixteenth solvent. In some embodiments, the second sixteenth solvent comprises ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane), hydrocarbons (e.g., toluene, n-heptane), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol, tert-amyl alcohol), or combinations thereof. In some embodiments, the second sixteenth solvent comprises ethers. In some embodiments, the second sixteenth solvent comprises tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof. In some embodiments, the reaction of the compound of formula L or a salt thereof is carried out in a second sixteenth solvent containing tert-butyl methyl ether.

[0503] In some embodiments, the reaction of the compound of formula L or its salt is carried out in a temperature range of about 10°C to about 70°C. In some embodiments, the reaction of the compound of formula L or its salt is carried out in a temperature range of about 30°C to about 60°C. In some embodiments, the reaction of the compound of formula L or its salt is carried out at a temperature of about 50°C.

[0504] In some embodiments, this document provides a method for preparing a compound of formula IA or a salt thereof: IA The method includes: (a) Compounds of formula A: A or its salt, wherein R 3A It is a hydroxyl protecting group, and: Methylene reagent and First acid or first base reaction The compound of formula I was obtained: I or its salt, wherein R 1 It is a hydroxyl protecting group; and (b) Deprotecting a compound of formula I or a salt thereof to obtain a compound of formula IA or a salt thereof.

[0505] In some embodiments, this document provides a method for preparing a compound of formula IA or a salt thereof: IA The method includes: (a) Compounds of formula R-1: R-1 Or its salt and: Methylene reagent and The eighth acid or the fourteenth base reaction, The compound of formula I was obtained: I or its salt, wherein R 1 It is a hydroxyl protecting group; and (b) Deprotecting a compound of formula I or a salt thereof to obtain a compound of formula IA or a salt thereof.

[0506] In some embodiments of the methods disclosed herein, the compound of formula R-1 or a salt thereof is prepared by a method comprising the following: (c) Compounds of formula A: A or its salt, wherein R 3A It is a hydrogen or hydroxyl protecting group, and is related to: Reagents selected from metal hydroxides, metal halides, and trialkylsilyl halides; The compound of formula R-2 is obtained: R-2 or its salt; and (d) To react with: a compound of formula R-2 or a salt thereof. Coupling agents and The fifteenth base reaction, The compound of formula R-1 or its salt is obtained.

[0507] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula R-1 or a salt thereof by means of the following: Compounds of formula A: A or its salt, wherein R 3A It is a hydroxyl protecting group, and: The sixteenth base reaction; The compound of formula R-1 or its salt is obtained.

[0508] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula A or a salt thereof by a method comprising the following steps: (e) Compounds of formula D: D Or its salt deprotection, wherein R 5 Is it hydrogen or R? 9 , where R 9 It is an amine protecting group, and R 7 and R 8 Each is an amine protecting group independently; The compound of formula C is obtained: C or its salt; and (f) Compounds of formula XA: XA Or its salt and: Compounds of formula C or their salts, and The seventh base reaction; A compound of formula A or its salt is obtained.

[0509] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula D or a salt thereof by a method comprising the following steps: (g) Compounds of formula E: E Or its salt deprotection, wherein: R 7 and R 8 Each is an amine protecting group independently; and R 9 It is an amine protecting group and R 10 It is hydrogen; or optionally: R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups; To obtain a compound of formula D or a salt thereof, having formula D-1: D-1 Or its salt.

[0510] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula A by a method comprising the following steps: (e) Compounds of formula E: E or its salt, wherein R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form phthalimides; It reacts with the seventh acid to give a compound of formula Q-2: Q-2 or its salt; (f) To react with: a compound of formula Q-2 or a salt thereof. Compounds of formula XA: XA or its salt and Thirteenth base reaction; The compound of formula Q-1 was obtained: Q-1 or its salt; and (g) Reacting a compound of formula Q-1 or a salt thereof with a reagent selected from hydrazine, alkoxide and hydrolase; A compound of formula A or its salt is obtained.

[0511] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula E by a method comprising the following steps: (h) Compounds of formula H: H or its salt, wherein R 11 Selected from C 1-20 Alkyl, phenyl, and -CH2NH2; Reaction with the sixth acid or the eighth base Compounds of formula G are obtained: G or its salt; (i) To react with: a compound of formula G or a salt thereof. The third catalyst, and Hydrogen reaction; Compounds of formula F are obtained: F or its salt; and (j) To make a compound of formula F or a salt thereof react with: Phosphine reagent azodicarbonate and Formula R 7 -NH-NH-R 8 The reaction of compounds; The compound of formula E or its salt is obtained.

[0512] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula E by a method comprising the following steps: (h) Compounds of formula F: F Or its salt and: Phosphine reagent azodicarbonate and Formula R 7 -NH-NH-R 8 The reaction of compounds; The compound of formula E or its salt is obtained.

[0513] In some embodiments of the method disclosed herein, the method further includes preparing compounds of formula F by means of the following: (i) Compounds of formula S: S Or its salt and: Compounds of formula T: T or its salt, Where R 15 Selected from phenyl and C 1-4 Haloalkyl, wherein the phenyl group is optionally surrounded by one to four C16 atoms. 1-4 Alkyl, halogen, C 1-4 Substitution of alkyl and cyano groups; The seventeenth base and Fourth additive reaction; Compounds of formula W were obtained: W or its salt; and (j) To make a compound of formula W or a salt thereof react with: The sixth catalyst and Reducing agent reaction; To obtain a compound of formula F or a salt thereof.

[0514] In some embodiments of the method disclosed herein, the method further includes preparing compounds of formula F by means of the following: (i) Compounds of formula W: W Or its salt and: The second enzyme reacts in the presence of the second buffer solution; To obtain a compound of formula F or a salt thereof.

[0515] In some embodiments of the method disclosed herein, the method further includes preparing compounds of formula F by means of the following: (i) Compounds of formula S: S Or its salt and: Compounds of formula T: T or its salt, Where R 15 Selected from phenyl and C 1-4 Haloalkyl, wherein the phenyl group is optionally surrounded by one to four C16 atoms. 1-4 Alkyl, halogen, C 1-4 Substitution of alkyl and cyano groups; The seventeenth base and Fourth additive reaction; Compounds of formula W were obtained: W or its salt; and (j) To make a compound of formula W or a salt thereof react with: The sixth catalyst and Reducing agent reaction; To obtain a compound of formula F or a salt thereof.

[0516] In some embodiments of the method disclosed herein, the method further includes preparing compounds of formula F by means of the following: (i) Compounds of formula G: G Or its salt and: Third reducing agent and Activator reaction; To obtain a compound of formula F or a salt thereof.

[0517] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula D or a salt thereof by a method comprising the following steps: (g) To make compounds of formula H having formula H-1: H-1 Or its salt, wherein: R 9 It is an amine protecting group; and R 11 Selected from C1-20 Alkyl, phenyl, and -CH2NH2; Reaction with the twelfth base, The compound of formula G-1 was obtained: G-1 or its salt; (h) To react with: a compound of formula G-1 or a salt thereof. Third catalyst Aromatic amines or sulfur-containing reagents; and Hydrogen reaction; The compound of formula F-1 was obtained: F-1 or its salt; and (i) To react with: a compound of formula F-1 or a salt thereof. Phosphine reagent azodicarbonate and Formula R 7 -NH-NH-R 8 The reaction of compounds; The compound of formula D or its salt is obtained.

[0518] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula D or a salt thereof by a method comprising the following steps: (g) Compounds of formula G-1: G-1 Or its salt and: Third catalyst Aromatic amines or sulfur-containing reagents; and Hydrogen reaction; The compound of formula F-1 was obtained: F-1 or its salt; and (h) To react with: a compound of formula F-1 or a salt thereof. Phosphine reagent azodicarbonate and Formula R 7 -NH-NH-R 8 The reaction of compounds; The compound of formula D or its salt is obtained.

[0519] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula G or a salt thereof by a method comprising the following: wherein the compound of formula G or a salt thereof is a compound of formula G-1 or a salt thereof: (j) Compounds of formula L: L Or its salt and: The fourth enzyme reacts in the presence of the fourth buffer solution; Compounds of formula U-2 were obtained: U-2 or its salt; (k) To react with: a compound of formula U-2 or a salt thereof. The third enzyme reacts in the presence of the third buffer solution; Compounds of formula U-1 were obtained: U-1 or its salt; and (l) To react with: a compound of formula U-1 or a salt thereof. The second amine protecting group reacts with a reagent to give a compound of formula G-1 or its salt.

[0520] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula H or a salt thereof by means of the following: (k) Compounds of formula J: J Or its salt and: Second phosphine reagent, Second azodicarbonate and Amine protecting group reagent reaction; To obtain a compound of formula H or a salt thereof.

[0521] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula H or a salt thereof by means of the following: (k) Compounds of formula J: J Or its salt, wherein: R 12 It is -S(O)3R 13 or -OC(=N)R 14 ; R 13 Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and optionally C 1-4 Alkyl-substituted phenyl; and R 14 It is C1-4 Halogenated alkyl groups; and: The eleventh base and The third reagent reaction, wherein the third reagent is selected from methanesulfonyl chloride, acid anhydride or acyl halide; Compounds of formula N are obtained: N or its salt; and (l) Reacting a compound of formula N or its salt with an amine protecting group reagent. To obtain a compound of formula H or a salt thereof.

[0522] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula H-1 or a salt thereof by means of the following: (k) Compounds of formula N: N Or its salt, wherein: R 12 It is -S(O)3R 13 or -OC(=N)R 14 ;and R 13 Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and optionally C 1-4 Alkyl-substituted phenyl; and: azides and Tertiary phosphine reagent reaction; The compound of formula P-1 was obtained: P-1 or its salt; and (l) React a compound of formula P-1 or its salt with an amine protecting group reagent to obtain a compound of formula H-1 or its salt.

[0523] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula H-1 or a salt thereof by means of the following: (k) Compounds of formula J: J Or its salt and: azides, Tertiary phosphine reagent and Third azodicarbonate reaction; Compounds of formula P-2 were obtained: P-2 or its salt; and (l) To react with: a compound of formula P-2 or a salt thereof. Phosphine reagent; and Amine protecting group reagent reaction; A compound of formula H-1 or its salt is obtained.

[0524] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula J or a salt thereof by a method comprising the following: (m) Compounds of formula L: L or its salt; with: Ninth Alkali Fourth catalyst and Reactions of compounds of formula M-1 or M-2: M-1 ; M-2 Where X is a halide; Compounds of formula K were obtained: K or its salt; and (n) Make a compound of formula K or a salt thereof react with: enzymes and Buffer reaction; A compound of formula J or its salt is obtained.

[0525] In some embodiments of the method disclosed herein, the method further includes preparing a compound of formula E by a method comprising the following steps: (h) Compounds of formula L: L Or its salt and: Alkyl esters, alkenyl esters, or oxime esters; and Enzyme reaction, Compounds of formula O-4 were obtained: O-4 or its salt; (i) To react with: a compound of formula O-4 or a salt thereof. Second phosphine reagent, Second azodicarbonate and Formula R7 -NH-NH-R 8 Reacts with compounds or (1,3-dioxoisoindoline-2-yl)carbamate; Compounds of formula O-3 were obtained: O-3 or its salt; (j) making a compound of formula O-3 or a salt thereof, wherein R 11 Selected from C 1-20 Alkyl, phenyl and -CH2NH2; with: The twelfth base reaction; Compounds of formula O-2 were obtained: O-2 or its salt; (k) To react with: a compound of formula O-2 or a salt thereof. Fifth catalyst and Hydrogen reaction; The compound of formula O-1 is obtained: O-1 or its salt; and (l) To react with: a compound of formula O-1 or a salt thereof. Amine protecting group reagents Phosphine reagents and azodicarbonate reaction, The compound of formula E or its salt is obtained.

[0526] Alternative Method for Preparing the Compound of Formula I In some embodiments, this document provides a method comprising preparing a compound of formula I or a salt thereof: I Where R 1 The method comprises: (selected from hydrogen and hydroxyl protecting groups) Compounds of formula R-1: R-1 Or its salt and: Methylene reagent and The eighth acid or the fourteenth base reaction, The compound of formula I or its salt is obtained.

[0527] In some embodiments, the methylene reagent is a formaldehyde reagent or a dihalomethane. In some embodiments, suitable formaldehyde reagents include formaldehyde acetals (e.g., dimethoxymethane, diethoxymethane), formaldehyde solutions, paraformaldehyde, and 1,3,5-trioxane. In some embodiments, suitable methylene reagents include dihalomethanes (e.g., dibromomethane, diiodomethane).

[0528] In some embodiments, the methylene reagent is selected from 1,3,5-trioxane, formaldehyde acetal, formaldehyde, paraformaldehyde, or dihalomethane. In some embodiments, the methylene reagent is a formaldehyde reagent. In some embodiments, the methylene reagent is selected from 1,3,5-trioxane, formaldehyde acetal, formaldehyde, and paraformaldehyde. In some embodiments, the methylene reagent is formaldehyde.

[0529] In some embodiments, the compound of formula R-1 or a salt thereof reacts with an octet acid. In some embodiments, suitable octet acids include carboxylic acids (e.g., oxalic acid, trichloroacetic acid, trifluoroacetic acid), sulfonic acids (e.g., methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid), Lewis acids (e.g., boron trifluoride methyl ether, boron trifluoride dibutyl ether, boron trichloride, boron tribromide, aluminum chloride, aluminum bromide), inorganic acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid), or combinations thereof.

[0530] In some embodiments, the eighth acid includes carboxylic acids, sulfonic acids, Lewis acids, inorganic acids, or combinations thereof. In some embodiments, the eighth acid includes sulfonic acids. In some embodiments, the eighth acid includes methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, or combinations thereof. In some embodiments, the eighth acid is methanesulfonic acid.

[0531] In some embodiments, a compound of formula R-1 or a salt thereof reacts with a fourteenth base. In some embodiments, suitable fourteenth bases include amines (e.g., n-propylamine, triethylamine, etc.). N,N-Diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), quinine ring), amidine (e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), etc.), guanidine (e.g., triazabicyclodecene (TBD), 1,1,3,3-tetramethylguanidine), carboxylates (e.g., sodium acetate, potassium acetate, sodium propionate), carbonates (e.g., M(n)H(2-n)CO3 such as sodium carbonate, potassium bicarbonate, cesium carbonate) Metal hydrides (e.g., lithium hydride, sodium hydride, potassium hydride), phosphates (e.g., M(n)H(3-n)PO4 such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate), hydroxides (e.g., sodium hydroxide, potassium hydroxide, cesium hydroxide), alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.), amides (e.g., lithium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, lithium diisopropylamino, basic aromatic compounds (e.g., pyridine, 2,6-dimethylpyridine, imidazole) or combinations thereof.

[0532] In some embodiments, the fourteenth base includes amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, phosphates, hydroxides, alkoxides, amides, basic aromatic compounds, or combinations thereof.

[0533] In some embodiments, the reaction of the compound of formula R-1 or a salt thereof is carried out in a forty-second solvent. In some embodiments, the forty-second solvent includes ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxane, cyclopentyl methyl ether, 1,4-dioxane), nitriles (e.g., acetonitrile, propionitrile, butyronitrile), hydrocarbons (e.g., toluene, methylcyclohexane, n-heptane, hexane, limonene), and polar aprotic solvents (e.g., N,N -Dimethylformamide, N,N -Dimethylacetamide, N 2-Methyl-2-pyrrolidone, N butylpyrrolidone (NBP), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, dimethyl-2-methylglutarate, propylene carbonate), ketones (e.g., acetone, 2-butanone, 4-methyl-2-pentanone), alcohols (e.g., methanol, ethanol, 2-propanol, butanol, glycerol, isoamyl alcohol), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chlorobenzene, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the forty-second solvent includes ethers. In some embodiments, the forty-second solvent includes tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, 1,3-dioxolane, cyclopentyl methyl ether, 1,4-dioxane, or combinations thereof.

[0534] In some embodiments, the reaction of the compound of formula R-1 or its salt is carried out in a temperature range of about 20°C to about 100°C. In some embodiments, the reaction of the compound of formula R-1 or its salt is carried out in a temperature range of about 50°C to about 70°C. In some embodiments, the reaction of the compound of formula R-1 or its salt is carried out at a temperature of about 65°C.

[0535] In some embodiments, the method further includes preparing a compound of formula R-1 or a salt thereof by reacting a compound of formula R-2 or a salt thereof with a coupling agent and a fifteenth base to obtain a compound of formula R-1 or a salt thereof, as described herein.

[0536] In some embodiments, the method further includes preparing a compound of formula R-2 or a salt thereof by reacting a compound of formula A or a salt thereof with a reagent selected from metal hydroxides, metal halides and trialkylsilyl halides to obtain a compound of formula R-2 or a salt thereof, as described herein.

[0537] In some embodiments, this document provides a method for preparing compounds of formula I or salts thereof: I Where R 1 The method comprises: (selected from hydrogen and hydroxyl protecting groups) (a) Compounds of formula A: A or its salt, wherein R 3A It is a hydrogen or hydroxyl protecting group, and is related to: Reagents selected from metal hydroxides, metal halides, and trialkylsilyl halides; The compound of formula R-2 is obtained: R-2 or its salt; (b) To react with: a compound of formula R-2 or a salt thereof. Coupling agents and The fifteenth base reaction, The compound of formula R-1 was obtained: R-1 or its salt; and (c) To react with: a compound of formula R-1 or a salt thereof. Methylene reagent and The eighth acid or the fourteenth base reaction, The compound of formula I or its salt is obtained.

[0538] Intermediate In some embodiments, this document provides intermediates for forming compounds of formula I (e.g., compounds of formula IA) or salts thereof.

[0539] Therefore, in some embodiments, compounds of formula I are provided: I or its salt, wherein R 1 It is a hydroxyl protecting group.

[0540] In some embodiments, the compound of formula I or a salt thereof is a compound of formula IB: IB Or its salt.

[0541] In some implementations, compounds of formula II are provided: II or its salt, wherein R 1 It is a hydroxyl protecting group.

[0542] In some embodiments, the compound of formula II or a salt thereof is a compound of formula II-A: II-A Or its salt.

[0543] In some implementations, compounds of formula III are provided: III or its salt, wherein R 1 It is a hydroxyl protecting group.

[0544] In some embodiments, the compound of formula III or a salt thereof is a compound of formula III-A: III-A Or its salt.

[0545] In some implementations, compounds of formula IV are provided: IV or its salt, wherein R 1 It is a hydroxyl protecting group and R 2 It is an amine protecting group.

[0546] In some embodiments, the compound of formula IV or a salt thereof is a compound of formula IV-A: IV-A Or its salt.

[0547] In some implementations, compounds of formula V are provided: V or its salt, wherein R 1 It is a hydroxyl protecting group and R 2 It is an amine protecting group.

[0548] In some embodiments, the compound of formula V or a salt thereof is a compound of formula VA: VA Or its salt.

[0549] In some implementations, compounds of formula VII are provided: VII or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group and R 2 It is a hydrogen or amine protecting group.

[0550] In some embodiments, the compound of formula VII or a salt thereof is a compound of formula VII-A: VII-A Or its salt.

[0551] In some embodiments, the compound of formula VII or a salt thereof is a compound of formula VII-B: VII-B Or its salt.

[0552] In some implementations, compounds of formula VIII are provided: VIII or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group and R 2 It is a hydrogen or amine protecting group.

[0553] In some embodiments, the compound of formula VIII or a salt thereof is a compound of formula VIII-A: VIII-A Or its salt.

[0554] In some embodiments, the compound of formula VIII or a salt thereof is a compound of formula VIII-B: VIII-B Or its salt.

[0555] In some implementations, compounds of formula X are provided: X or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group and R 2 It is a hydrogen or amine protecting group.

[0556] In some embodiments, the compound of formula X or a salt thereof is a compound of formula XA: XA Or its salt.

[0557] In some embodiments, the compound of formula X or a salt thereof is a compound of formula XB: XB Or its salt.

[0558] In some implementations, compounds of formula XI are provided: XI or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group.

[0559] In some embodiments, the compound of formula XI or a salt thereof is a compound of formula XI-A: XI-A Or its salt.

[0560] In some embodiments, compounds of formula XII are provided: XII or its salt, wherein R 1 It is a hydroxyl protecting group.

[0561] In some embodiments, the compound of formula XII or a salt thereof is a compound of formula XII-A: XII-A Or its salt.

[0562] In some implementations, a compound of formula A is provided: A or its salt, wherein R 1 and R 3A It is independently selected from hydrogen and hydroxyl protecting groups.

[0563] In some embodiments, the compound of formula A or a salt thereof is a compound of formula A-1: A-1 Or its salt.

[0564] In some implementations, a compound of formula R-1 is provided: R-1 or its salt, wherein R 1 Selected from hydrogen and hydroxyl protecting groups.

[0565] In some embodiments, the compound of formula R-1 or a salt thereof is a compound of formula R-1-A: R-1-A Or its salt.

[0566] In some embodiments, compounds of formula R-2 are provided herein: R-2 or its salt, wherein R 1 Selected from hydrogen and hydroxyl protecting groups.

[0567] In some embodiments, the compound of formula R-2 or a salt thereof is a compound of formula R-2-A: R-2-A Or its salt.

[0568] In some implementations, a compound of formula Q-1 is provided: Q-1 or its salt, wherein R 1 and R 3AEach has a hydroxyl protecting group.

[0569] In some embodiments, the compound of formula Q-1 or a salt thereof is a compound of formula Q-1-A: Q-1-A Or its salt.

[0570] In some implementations, a compound of formula Q-2 is provided: Q-2 Or its salt.

[0571] In some implementations, compounds of formula C are provided: C Or its salt.

[0572] In some implementations, compounds of formula D are provided: D Or its salt, wherein: R 5 Selected from hydrogen and R 9 , where R 9 It is an amine protecting group; and R 7 and R 8 Each is an amine protecting group.

[0573] In some embodiments, the compound of formula D or a salt thereof is a compound of formula D-1: D-1 Or its salt.

[0574] In some embodiments, the compound of formula D or a salt thereof is a compound of formula D-2: D-2 Or its salt.

[0575] In some implementations, compounds of formula E are provided: E Or its salt, wherein: R 9 It is an amine protecting group and R 10 It is hydrogen; or optionally: R 9 and R 10Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups.

[0576] In some implementations, compounds of formula F are provided: F Or its salt, wherein: R 9 It is an amine protecting group and R 10 It is hydrogen; or optionally: R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups.

[0577] In some embodiments, the compound of formula F or a salt thereof is a compound of formula F-1: F-1 Or its salt.

[0578] In some embodiments, the compound of formula F is a compound of formula F-2: F-2 Or its salt.

[0579] In some implementations, compounds of formula G are provided: G Or its salt, wherein: R 9 It is an amine protecting group and R 10 It is hydrogen; or optionally: R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups.

[0580] In some embodiments, the compound of formula G or a salt thereof is a compound of formula G-1: G-1 Or its salt.

[0581] In some implementations, compounds of formula H are provided: H Or its salt, wherein: R 9 It is an amine protecting group and R 10 It is hydrogen; or optionally: R 9 and R10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups; and R 11 Selected from C 1-20 Alkyl, phenyl and -CH2NH2.

[0582] In some embodiments, the compound of formula H or a salt thereof is a compound of formula H-1: H-1 Or its salt.

[0583] In some embodiments, the compound of formula H-1 or a salt thereof is a compound of formula H-1-A: H-1-A Or its salt.

[0584] In some embodiments, the compound of formula H or a salt thereof is a compound of formula H-2: H-2 Or its salt.

[0585] In some implementations, compounds of formula J are provided: J or its salt, wherein R 11 Selected from C 1-20 Alkyl, phenyl and -CH2NH2.

[0586] In some implementations, compounds of formula N are provided: N Or its salt, wherein: R 11 Selected from C 1-20 Alkyl, phenyl and -CH2NH2 R 12 It is -S(O)3R 13 or -OC(=N)R 14 ; R 13 Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and optionally C 1-4 Alkyl-substituted phenyl; and R 14 It is C 1-4 Halogenated alkyl groups.

[0587] In some implementations, compounds of formula P-1 are provided: P-1 Or its salt, wherein: R 11 Selected from C 1-20 Alkyl, phenyl and -CH2NH2.

[0588] In some implementations, compounds of formula P-2 are provided: P-2 Or its salt, wherein: R 11 Selected from C 1-20 Alkyl, phenyl and -CH2NH2.

[0589] In some implementations, compounds of formula K are provided: K Or its salt.

[0590] In some implementations, compounds of formula O-1 are provided: O-1 or its salt, wherein R 7 and R 8 Each is an amine protecting group.

[0591] In some implementations, compounds of formula O-2 are provided: O-2 or its salt, wherein R 7 and R 8 Each is an amine protecting group.

[0592] In some implementations, compounds of formula O-3 are provided: O-3 Or its salt, wherein: R 7 and R 8 Each is an amine protecting group independently; and R 11 Selected from C 1-20 Alkyl, phenyl and -CH2NH2.

[0593] In some implementations, compounds of formula O-4 are provided: O-4 or its salt, wherein R 11 Selected from C 1-20 Alkyl, phenyl and -CH2NH2.

[0594] In some implementations, compounds of formula W are provided: W Or its salt, wherein: R 9 It is an amine protecting group and R 10 It is hydrogen; or optionally: R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups.

[0595] In some embodiments, the compound of formula W or a salt thereof is a compound of formula W-1: W-1 Or its salt.

[0596] In some embodiments of the methods and compounds disclosed herein, R 1 Selected from C 1-4 Alkyl, benzyl and -COOR 4 ;where R 4 Selected from C 1-4 Alkyl and phenyl. In some embodiments, R 1 The radical is selected from methyl, ethyl, benzyl, acetate, propionate, and benzoate. In some embodiments, R 1 Selected from C 1-4 Alkyl and benzyl. In some embodiments, R 1 It is C 1-4 Alkyl group. In some embodiments, R 1 Selected from methyl, ethyl, and benzyl. In some embodiments, R 1 It is methyl. In some embodiments, R 1 It is ethyl. In some embodiments, R 1 It is benzyl. In some embodiments, R 1 Yes - COOR 4 In some implementations, R 4 C 1-4 Alkyl group. In some embodiments, R 4 It is methyl or ethyl. In some embodiments, R 4 It is a phenyl group.

[0597] In some embodiments of the methods and compounds disclosed herein, R1 Selected from hydrogen, C 1-4 Alkyl and benzyl. In some embodiments, R 1 It is hydrogen. In some implementations, R 1 It is C 1-4 Alkyl group. In some embodiments, R 1 Selected from hydrogen, methyl, ethyl and benzyl.

[0598] In some embodiments of the methods and compounds disclosed herein, R 2 It is tert-butyloxycarbonyl.

[0599] In some embodiments of the compounds disclosed herein, R 3 Selected from C 1-4 Alkyl and benzyl. In some embodiments, R 3 Selected from methyl, ethyl, and benzyl. In some embodiments, R 3 C 1-4 Alkyl group. In some embodiments, R 3 Selected from methyl and ethyl. In some embodiments, R 3 It is methyl. In some embodiments, R 3 It is ethyl. In some embodiments, R 3 It is benzyl.

[0600] In some embodiments of the methods and compounds disclosed herein, R 3A Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and benzyl groups. In some embodiments, R... 3A Selected from methyl, ethyl, isopropyl, trifluoroethyl, and benzyl. In some embodiments, R 3A It is C 1-4 Alkyl group. In some embodiments, R 3A Selected from methyl, ethyl, and isopropyl. In some embodiments, R 3A It is methyl. In some embodiments, R 3A It is C 1-4 Halogenated alkyl groups. In some embodiments, R 3A It is trifluoroethyl. In some embodiments, R 3A It is benzyl.

[0601] In some embodiments of the methods an...

Claims

1. A method for preparing a compound of formula I or a salt thereof: I Where R 1 Selected from hydrogen and hydroxyl protecting groups; The method includes using a compound of formula II: II or its salt, The compound of formula I or its salt is reacted with a first catalyst to obtain the compound of formula I or its salt.

2. The method according to claim 1, wherein R 1 Selected from hydrogen, C 1-4 Alkyl and benzyl.

3. The method according to claim 1 or 2, wherein R 1 Selected from hydrogen, methyl, ethyl and benzyl.

4. The method according to any one of claims 1 to 3, wherein R 1 It is a methyl group.

5. The method according to any one of claims 1 to 4, wherein the first catalyst is a metathesis catalyst.

6. The method according to any one of claims 1 to 5, wherein the first catalyst is selected from ruthenium-based catalysts, molybdenum-based catalysts, and tungsten-based catalysts.

7. The method according to any one of claims 1 to 6, wherein the first catalyst is a ruthenium-based catalyst.

8. The method according to any one of claims 1 to 7, wherein the first catalyst is selected from Hoveyda-Grubbs second-generation catalyst, Hoveyda-Grubbs first-generation catalyst, Zhan 1B, nitro Grela, M721, M203 and M730.

9. The method according to any one of claims 1 to 8, wherein the first catalyst is a Hoveyda-Grubbs second-generation catalyst.

10. The method according to any one of claims 1 to 9, wherein the molar ratio of the compound of formula II or a salt thereof to the first catalyst is from about 1:0.001 to about 1:0.

05.

11. The method according to any one of claims 1 to 10, wherein the reaction is performed in the presence of the first additive.

12. The method according to any one of claims 1 to 11, wherein the first additive comprises dimethyl maleate, 1,4-benzoquinone, 6-dichloro-1,4-benzoquinone, 2-chloro-1,4-benzoquinone, tetrafluoro-1,4-benzoquinone, 2-methylbenzoquinone, dimethyl fumarate, maleic acid, fumaric acid, maleic anhydride, methyl trans-cinnamate, acetic acid, trifluoroacetic acid, or combinations thereof.

13. The method according to any one of claims 1 to 12, wherein the first additive comprises dimethyl maleate.

14. The method according to any one of claims 1 to 13, wherein the reaction is carried out in a first solvent comprising ethyl acetate.

15. The method according to any one of claims 1 to 14, wherein the reaction is carried out in a temperature range of about 20°C to about 120°C.

16. The method according to any one of claims 1 to 15, wherein R 1 It is a hydroxyl protecting group; and the method further includes deprotecting the compound of formula I or a salt thereof; Compounds of formula IA are obtained: IA Or its salt.

17. The method of claim 16, wherein deprotecting the compound of formula I or a salt thereof comprises treating the compound of formula I or a salt thereof with a first deprotecting agent.

18. The method of claim 17, wherein the first deprotecting agent is selected from metal halides, hydrogen halides, boron reagents, aluminum reagents, titanium reagents, pyridinium halides, ammonium halides, and silyl halides.

19. The method according to claim 17 or 18, wherein the first deprotecting agent is a metal halide.

20. The method according to any one of claims 17 to 19, wherein the first deprotecting agent is lithium chloride.

21. The method according to any one of claims 17 to 20, wherein the deprotection of the compound of formula I or its salt is performed in a second solvent comprising N-methyl-2-pyrrolidone.

22. The method according to any one of claims 17 to 21, wherein the deprotection of the compound of formula I or its salt is carried out in a temperature range of about 0°C to about 130°C.

23. The method according to any one of claims 1 to 22, further comprising preparing a compound of formula II or a salt thereof by a method comprising: Compounds of formula III: III or its salt and Methylene reagent and First acid or first base reaction The compound of formula II or its salt is obtained.

24. The method of claim 23, wherein the methylene reagent is a formaldehyde reagent or a dihalomethane.

25. The method according to claim 23 or 24, wherein the methylene reagent is selected from 1,3,5-trioxane, formaldehyde acetal, formaldehyde, paraformaldehyde, or dihalomethane.

26. The method according to any one of claims 23 to 25, wherein the methylene reagent is 1,3,5-trioxane.

27. The method according to any one of claims 23 to 26, wherein the compound of formula III or a salt thereof is reacted with the first acid.

28. The method according to any one of claims 23 to 27, wherein the first acid comprises a carboxylic acid, a sulfonic acid, a Lewis acid, an inorganic acid, or a combination thereof.

29. The method according to any one of claims 23 to 28, wherein the first acid is trifluoroacetic acid.

30. The method according to any one of claims 23 to 26, wherein the compound of formula III or a salt thereof is reacted with the first base.

31. The method according to any one of claims 23 to 26 and 30, wherein the first base comprises an amine, amidine, guanidine, carboxylate, carbonate, metal hydride, phosphate, hydroxide, alkoxide, amide, basic aromatic compound, or a combination thereof.

32. The method according to any one of claims 23 to 31, wherein the reaction of the compound of formula III or a salt thereof is carried out in a third solvent comprising toluene.

33. The method according to any one of claims 23 to 32, wherein the reaction of the compound of formula III or a salt thereof is carried out in a temperature range of about 60°C to about 100°C.

34. The method according to any one of claims 23 to 33, further comprising preparing a compound of formula III or a salt thereof by a method comprising: Compounds of formula IV: IV Or its salt deprotection, wherein R 2 It is an amine protecting group; The compound of formula III or its salt is obtained.

35. The method of claim 34, wherein R 2 It is tert-butyloxycarbonyl.

36. The method according to claim 34 or 35, wherein deprotecting the compound of formula IV or a salt thereof comprises treating the compound of formula IV or a salt thereof with a second acid.

37. The method of claim 36, wherein the second acid comprises sulfonic acid, inorganic acid, organic acid, acyl chloride, Lewis acid, or a combination thereof.

38. The method according to claim 36 or 37, wherein the second acid comprises methanesulfonic acid.

39. The method according to any one of claims 34 to 38, wherein the deprotection of the compound of formula IV or its salt is performed in a fourth solvent comprising cyclopentyl methyl ether.

40. The method according to any one of claims 34 to 39, wherein the deprotection of the compound of formula IV or its salt is carried out in a temperature range of about 0°C to about 120°C.

41. The method according to any one of claims 34 to 40, further comprising preparing a compound of formula IV or a salt thereof by a method comprising: Compounds of formula V: V Or its salt and: Compounds of formula VI: VI Where Y is an anion or salt. Coupling agents and The second base reaction, The compound of formula V or its salt is obtained.

42. The method of claim 41, wherein Y is selected from toluenesulfonate, methanesulfonate and HCl salt.

43. The method according to claim 41 or 42, wherein Y is a toluenesulfonate.

44. The method according to any one of claims 41 to 43, wherein the coupling agent comprises 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b Pyridinium 3-oxide hexafluorophosphate (HATU), acyl chloride, acid anhydride, carbonyl diimidazole, activated ester or a combination thereof.

45. The method according to any one of claims 41 to 44, wherein the coupling agent is HATU.

46. ​​The method according to any one of claims 41 to 45, wherein the second base comprises an amine, amidine, guanidine, carboxylate, carbonate, metal hydride, hydroxide, alkoxide, basic aromatic compound, or a combination thereof.

47. The method according to any one of claims 41 to 46, wherein the second base comprises an amine.

48. The method according to any one of claims 41 to 47, wherein the second base is N-methylmorpholine.

49. The method according to any one of claims 41 to 48, wherein the reaction of the compound of formula V or a salt thereof is carried out in a fifth solvent comprising N,N-dimethylacetamide and cyclopentyl methyl ether.

50. The method according to any one of claims 41 to 49, wherein the reaction of the compound of formula V or a salt thereof is carried out in a temperature range of about 0°C to about 80°C.

51. The method according to any one of claims 41 to 50, further comprising preparing a compound of formula V or a salt thereof by a method comprising: Compounds of formula VII: VII or its salt, wherein R 3 It is a hydroxyl protecting group; The compound of formula V or its salt is obtained by reacting with the first reagent.

52. The method of claim 51, wherein R 3 Selected from C 1-4 Alkyl and benzyl.

53. The method according to claim 51 or 52, wherein R 3 Selected from methyl, ethyl and benzyl.

54. The method according to any one of claims 51 to 53, wherein R 3 It is a methyl group.

55. The method according to any one of claims 51 to 54, wherein the first reagent is selected from a third base and a hydrolase.

56. The method according to any one of claims 51 to 55, wherein the first reagent is the third base.

57. The method according to any one of claims 51 to 56, wherein the third base comprises an amine, amidine, guanidine, carbonate, phosphate, hydroxide, alkoxide, amide, or a combination thereof.

58. The method according to any one of claims 51 to 57, wherein the third alkali is lithium hydroxide.

59. The method according to any one of claims 51 to 58, wherein the reaction of the compound of formula VII or a salt thereof is carried out in a sixth solvent comprising cyclopentyl methyl ether, methanol and water.

60. The method according to any one of claims 51 to 59, wherein the reaction of the compound of formula VII or a salt thereof is carried out in a temperature range of about 0°C to about 80°C.

61. The method according to any one of claims 51 to 60, further comprising preparing a compound of formula VII or a salt thereof by a method comprising: Compounds of formula VIII: VIII Or its salt and: Compounds of formula IX: IX or its salt, Phosphorus reagents and azodicarbonate reaction, The compound of formula VII or its salt is obtained.

62. The method according to claim 61, wherein the phosphorus-based reagent is selected from triarylphosphine, trialkylphosphine, and n-phosphine.

63. The method according to claim 61 or 62, wherein the phosphorus-based reagent is triphenylphosphine.

64. The method according to any one of claims 61 to 63, wherein the azodicarboxylate is selected from diisopropyl azodicarboxylate, ditert-butyl azodicarboxylate, diethyl azodicarboxylate, dimethoxy ethyl azodicarboxylate, azodicarbonyl dimorpholine, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzoic acid azodicarboxylate.

65. The method according to any one of claims 61 to 64, wherein the azodicarbonate is diisopropyl azodicarbonate.

66. The method according to any one of claims 61 to 65, wherein the reaction of the compound of formula VIII or a salt thereof is carried out in a seventh solvent comprising 2-methyltetrahydrofuran.

67. The method according to any one of claims 61 to 66, wherein the reaction of the compound of formula VIII or a salt thereof is carried out in a temperature range of about 0°C to about 50°C.

68. The method according to any one of claims 51 to 60, further comprising preparing a compound of formula VII or a salt thereof by a method comprising: Compounds of formula VIII: VIII Or its salt and: A second reagent containing a crotonyl group or an allyl group Second catalyst and The sixth base reaction, The compound of formula VII or its salt is obtained.

69. The method according to claim 68, wherein the second reagent is selected from crotonyl carbonate, crotonyl ester, crotonyl halide, crotonol, 1-methyl allyl ester, 1-methyl allyl carbonate, 1-methyl allyl halide and 3-buten-2-ol.

70. The method according to claim 68 or 69, wherein the second reagent is crotonyl carbonate.

71. The method according to any one of claims 68 to 70, wherein the second reagent is crotonyl methyl carbonate.

72. The method according to any one of claims 68 to 71, wherein the second catalyst is a transition metal catalyst.

73. The method according to any one of claims 68 to 72, wherein the second catalyst is formed in situ from a precatalyst and a ligand.

74. The method of claim 73, wherein the precatalyst is selected from iridium compounds, palladium compounds, cobalt compounds, and rhodium compounds.

75. The method according to claim 73 or 74, wherein the precatalyst is bis(1,5-cyclooctadiene)diiridium(I) dichloride.

76. The method according to any one of claims 73 to 75, wherein the molar ratio of the compound of formula VIII or a salt thereof to the precatalyst is from about 1:0.01 to about 1:0.

10.

77. The method according to any one of claims 73 to 76, wherein the ligand is selected from phosphoramidite and Trost ligand.

78. The method according to any one of claims 73 to 77, wherein the ligand is ( S,S,S)- (+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a']dinaphth-4-yl)bis(1-phenylethyl)amine.

79. The method according to any one of claims 68 to 78, wherein the sixth base comprises an amine, amidine, guanidine, carboxylate, carbonate, metal hydride, phosphate, hydroxide, alkoxide, amide, or basic aromatic compound.

80. The method according to any one of claims 68 to 79, wherein the sixth base is an amine.

81. The method according to any one of claims 68 to 80, wherein the sixth base is n-propylamine.

82. The method according to any one of claims 68 to 81, wherein the reaction of the compound of formula VIII or a salt thereof is carried out in a twelfth solvent containing N,N-dimethylacetamide.

83. The method according to any one of claims 68 to 82, wherein the reaction of the compound of formula VIII or a salt thereof is carried out in a temperature range of about 0°C to about 80°C.

84. The method according to any one of claims 61 to 83, further comprising preparing a compound of formula VIII or a salt thereof by a method comprising: Compounds of formula X: X Or its salt reacts with a compound of formula NH2NHR2 or its salt. The compound of formula VIII or its salt is obtained.

85. The method according to claim 84, wherein the reaction of the compound of formula X or a salt thereof is carried out in the presence of a fourth base.

86. The method according to claim 84 or 85, wherein the fourth base comprises an amine, amidine, guanidine, carboxylate, carbonate, metal hydride, phosphate, hydroxide, alkoxide, amide, basic aromatic compound, or a combination thereof.

87. The method according to any one of claims 84 to 86, wherein the fourth base is sodium bicarbonate.

88. The method according to any one of claims 84 to 87, wherein the reaction of the compound of formula X or a salt thereof is carried out in an eighth solvent comprising methanol and water.

89. The method according to any one of claims 84 to 88, wherein the reaction of the compound of formula X or a salt thereof is carried out in a temperature range of about 0°C to about 80°C.

90. The method according to any one of claims 84 to 89, further comprising preparing a compound of formula X or a salt thereof by a method comprising: Compounds of formula XII: XII Or its salt and: Accelerator, Dialkyl oxalate and Fifth base reaction, A compound of formula X or a salt thereof is obtained.

91. The method of claim 90, wherein the accelerator comprises a carboxylic acid, a sulfonic acid, a haloalcohol, a Lewis acid, an inorganic acid, or a combination thereof.

92. The method according to claim 90 or 91, wherein the promoter comprises a haloalcohol.

93. The method according to any one of claims 90 to 92, wherein the accelerator is 2,2,2-trifluoroethanol.

94. The method according to any one of claims 90 to 93, wherein the reaction of the compound of formula XII or a salt thereof is carried out in the presence of a third acid.

95. The method according to claim 94, wherein the third acid is an inorganic acid.

96. The method according to claim 94 or 95, wherein the third acid is hydrochloric acid.

97. The method according to any one of claims 90 to 96, wherein the dialkyl oxalate is selected from dimethyl oxalate and diethyl oxalate.

98. The method according to any one of claims 90 to 97, wherein the dialkyl oxalate is dimethyl oxalate.

99. The method according to any one of claims 90 to 98, wherein the fifth base comprises an amine, amidine, guanidine, carboxylate, carbonate, metal hydride, phosphate, hydroxide, alkoxide, alkyllithium reagent, aryllithium reagent, amide, basic aromatic compound, or a combination thereof.

100. The method according to any one of claims 90 to 99, wherein the fifth base comprises a metal alkoxide.

101. The method according to any one of claims 90 to 100, wherein the fifth base is sodium alkoxide.

102. The method according to any one of claims 90 to 101, wherein the reaction of the compound of formula XII or a salt thereof is carried out in a tenth solvent comprising N,N-dimethylacetamide.

103. The method according to any one of claims 90 to 102, wherein the reaction of the compound of formula XII or a salt thereof is carried out in a temperature range of about -10°C to about 50°C.

104. The method according to any one of claims 90 to 103, further comprising preparing a compound of formula XII or a salt thereof by a method comprising: Compounds of formula XIII: XIII Or its salt reacts with N,N-dimethylformamide dimethyl acetal. A compound of formula XII or a salt thereof is obtained.

105. A method for preparing a compound of formula I or a salt thereof: I Where R 1 The method, selected from hydrogen and hydroxyl protecting groups, includes: (a) Compounds of formula VII: VII or its salt, wherein R 2 It is an amine protecting group and R 3 It is a hydroxyl protecting group that reacts with the first reagent to give a compound of formula V: V or its salt; (b) To react the compound of formula V or a salt thereof with: Compounds of formula VI: VI Where Y is an anion or salt. Coupling agents and The second base reaction, Compounds of formula IV were obtained: IV or its salt; (c) Deprotecting the compound of formula IV or its salt to obtain the compound of formula III: III or its salt; (d) Mixing the compound of formula III or a salt thereof with: Methylene reagent and The first acid or first base reaction yields the compound of formula II: II or its salt; as well as (e) To make the compound of formula II or a salt thereof The compound of formula I or its salt is reacted with a first catalyst to obtain the compound of formula I or its salt.

106. A method for preparing a compound of formula IA or a salt thereof: IA The method includes: (a) Compounds of formula VII: VII or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group, and R 2 It is an amine protecting group. The reaction with the first reagent yields a compound of formula V: V or its salt; (b) To react the compound of formula V or a salt thereof with: Compounds of formula VI: VI Where Y is an anion or salt. Coupling agents and The second base reaction, Compounds of formula IV were obtained: IV or its salt; (c) Deprotecting the compound of formula IV or its salt to obtain the compound of formula III: III or its salt; (d) Mixing the compound of formula III or a salt thereof with: Methylene reagent and The first acid or first base reaction yields the compound of formula II: II or its salt; (e) To make the compound of formula II or a salt thereof The reaction with the first catalyst yields the compound of formula I: I or its salt; as well as (f) Deprotect the compound of formula I or its salt; A compound of formula IA or a salt thereof is obtained.

107. A method for preparing a compound of formula II or a salt thereof: II The method includes: (a) Compounds of formula VII: VII or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group, and R 2 It is an amine protecting group. The reaction with the first reagent yields a compound of formula V: V or its salt; (b) To react the compound of formula V or a salt thereof with: Compounds of formula VI: VI Where Y is an anion or salt. Coupling agents and The second base reaction, Compounds of formula IV were obtained: IV or its salt; (c) Deprotecting the compound of formula IV or its salt to obtain the compound of formula III: III or its salt; as well as (d) Mixing the compound of formula III or a salt thereof with: Methylene reagent and The compound of Formula II or its salt is obtained by reacting with a first acid or a first base.

108. A method for preparing a compound of formula III or a salt thereof: III The method includes: (a) Compounds of formula VII: VII or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group, and R 2 It is an amine protecting group. The reaction with the first reagent yields a compound of formula V: V or its salt; (b) To react the compound of formula V or a salt thereof with: Compounds of formula VI: VI Where Y is an anion or salt. Coupling agents and The second base reaction, Compounds of formula IV were obtained: IV or its salt; as well as (c) Deprotect the compound of formula IV or its salt to obtain the compound of formula III or its salt.

109. A method for preparing a compound of formula IV or a salt thereof: IV The method includes: (a) Compounds of formula VII: VII or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group, and R 2 It is an amine protecting group. The reaction with the first reagent yields a compound of formula V: V or its salt; as well as (b) To react the compound of formula V or a salt thereof with: Compounds of formula VI: VI Where Y is an anion or salt. Coupling agents and The second base reaction, The compound of formula IV or its salt is obtained.

110. A method for preparing a compound of formula V or a salt thereof: V The method includes: Compounds of formula VII: VII or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group, and R 2 It is an amine protecting group. The compound of formula V or its salt is obtained by reacting with the first reagent.

111. The method according to any one of claims 106 to 110, wherein the compound of formula VII or a salt thereof is prepared by a method comprising: (a) Compounds of formula XIII: XIII or its salt, wherein R 1 It is a hydroxyl protecting group; It reacts with N,N-dimethylformamide dimethyl acetal. Compounds of formula XII were obtained: XII or its salt; (b) To react a compound of formula XII or a salt thereof with: Accelerator, Dialkyl oxalate and Fifth base reaction, The compound of formula X is obtained: X or its salt; (c) Reacting a compound of formula X or a salt thereof with a compound of formula NH2NHR2 or a salt thereof. Compounds of formula VIII are obtained: VIII or its salt; (d) Mixing the compound of formula VIII or a salt thereof with: Compounds of formula IX: IX or its salt, Phosphorus reagents and azodicarbonate reaction, The compound of formula VII or its salt is obtained.

112. The method according to any one of claims 106 to 110, wherein the compound of formula VII or a salt thereof is prepared by a method comprising: (a) Compounds of formula XIII: XIII or its salt, wherein R 1 It is a hydroxyl protecting group; It reacts with N,N-dimethylformamide dimethyl acetal. Compounds of formula XII were obtained: XII or its salt; (b) To react a compound of formula XII or a salt thereof with: Accelerator, Dialkyl oxalate and Fifth base reaction, The compound of formula X is obtained: X or its salt; (c) Reacting a compound of formula X or a salt thereof with a compound of formula NH2NHR2 or a salt thereof. Compounds of formula VIII are obtained: VIII or its salt; as well as (d) Mixing the compound of formula VIII or a salt thereof with: A second reagent containing a crotonyl group or an allyl group Second catalyst and The sixth base reaction, The compound of formula VII or its salt is obtained.

113. A compound of formula I: I or its salt, wherein R 1 It is a hydroxyl protecting group.

114. A compound of formula II: II or its salt, wherein R 1 It is a hydroxyl protecting group.

115. A compound of formula III: III or its salt, wherein R 1 It is a hydroxyl protecting group.

116. A compound of formula IV: IV or its salt, wherein R 1 It is a hydroxyl protecting group and R 2 It is an amine protecting group.

117. A compound of formula V: V or its salt, wherein R 1 It is a hydroxyl protecting group and R 2 It is an amine protecting group.

118. A compound of formula VII: VII or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group and R 2 It is a hydrogen or amine protecting group.

119. A compound of formula VIII: VIII or its salt, wherein R 1 and R 3 Each is an independent hydroxyl protecting group and R 2 It is a hydrogen or amine protecting group.

120. The compound according to any one of claims 113 to 119, wherein R 1 Selected from C 1-4 Alkyl and benzyl.

121. The compound according to any one of claims 113 to 120, wherein R 1 It is a methyl group.

122. The compound according to any one of claims 116 to 119, wherein R 2 It is tert-butyloxycarbonyl.

123. The compound according to claim 118 or 119, wherein R 3 Selected from C 1-4 Alkyl and benzyl.

124. The compound according to any one of claims 118, 119 and 123, wherein R 3 It is a methyl group.

125. The method according to any one of claims 23 to 33, further comprising preparing a compound of formula III or a salt thereof by a method comprising: Compounds of formula VII-A: VII-A Or its salt reacts with the first reagent to hydrolyze the compound of formula VII-A; and The hydrolyzed compound of formula VII-A is reacted with: Compounds of formula VI: VI Where Y is an anion or salt. Coupling agents and The second base reaction, The compound of formula III or its salt is obtained.

126. The method according to claim 125, wherein the first reagent is selected from a third base and a hydrolase.

127. The method according to claim 126, wherein the first reagent is the third base.

128. The method according to claim 126 or 127, wherein the third base comprises an amine, amidine, guanidine, carbonate, phosphate, hydroxide, alkoxide, amide, or a combination thereof.

129. The method according to any one of claims 126 to 128, wherein the third base is lithium hydroxide.

130. The method according to any one of claims 125 to 129, wherein Y is selected from toluenesulfonate, methanesulfonate and HCl salt.

131. The method according to any one of claims 125 to 130, wherein Y is a toluenesulfonate.

132. The method according to any one of claims 125 to 131, wherein the coupling agent comprises 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b Pyridinium 3-oxide hexafluorophosphate (HATU), acyl chloride, acid anhydride, carbonyl diimidazole, activated ester or a combination thereof.

133. The method according to any one of claims 125 to 132, wherein the coupling agent is HATU.

134. The method according to any one of claims 125 to 133, wherein the second base comprises an amine, amidine, guanidine, carboxylate, carbonate, metal hydride, hydroxide, alkoxide, basic aromatic compound, or a combination thereof.

135. The method according to any one of claims 125 to 134, wherein the second base comprises an amine.

136. The method according to any one of claims 125 to 135, wherein the second base is N-methylmorpholine.

137. The method according to any one of claims 125 to 136, further comprising preparing a compound of formula VII-A or a salt thereof by a method comprising: Compounds of formula VIII-A: VIII-A Or its salt and: A second reagent containing a crotonyl group or an allyl group Second catalyst and The sixth base reaction, The compound of formula VII-A or its salt is obtained.

138. The method according to claim 137, wherein the second reagent is selected from crotonyl carbonate, crotonyl ester, crotonyl halide, crotonol, 1-methylallyl ester, 1-methylallyl carbonate, 1-methylallyl halide and 3-buten-2-ol.

139. The method according to claim 137 or 138, wherein the second reagent is crotonyl carbonate.

140. The method according to any one of claims 137 to 139, wherein the second reagent is crotonyl methyl carbonate.

141. The method according to any one of claims 137 to 140, wherein the second catalyst is a transition metal catalyst.

142. The method according to any one of claims 137 to 141, wherein the second catalyst is formed in situ from a precatalyst and a ligand.

143. The method of claim 142, wherein the precatalyst is selected from iridium compounds, palladium compounds, cobalt compounds, and rhodium compounds.

144. The method according to claim 142 or 143, wherein the precatalyst is bis(1,5-cyclooctadiene)diiridium(I) dichloride.

145. The method according to any one of claims 142 to 144, wherein the molar ratio of the compound of formula VIII-A or a salt thereof to the precatalyst is from about 1:0.01 to about 1:0.

10.

146. The method according to any one of claims 142 to 145, wherein the ligand is selected from phosphoramidite and Trost ligand.

147. The method according to any one of claims 142 to 146, wherein the ligand is ( S,S,S)- (+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a:3,4-a']dinaphth-4-yl)bis(1-phenylethyl)amine.

148. The method according to any one of claims 137 to 147, wherein the sixth base comprises an amine, amidine, guanidine, carboxylate, carbonate, metal hydride, phosphate, hydroxide, alkoxide, amide, or basic aromatic compound.

149. The method according to any one of claims 137 to 148, wherein the sixth base is an amine.

150. The method according to any one of claims 137 to 149, wherein the sixth base is 1,4-diazabicyclo[2.2.2]octane (DABCO).

151. The method according to any one of claims 137 to 150, wherein the reaction of the compound of formula VIII-A or a salt thereof is carried out in a twelfth solvent containing N,N-dimethylacetamide.

152. The method according to any one of claims 137 to 151, wherein the reaction of the compound of formula VIII-A or a salt thereof is carried out in a temperature range of about 0°C to about 80°C.

153. A method for preparing a compound of formula IA or a salt thereof: IA The method includes using a compound of formula I: I Or its salt deprotection, wherein R 1 It is a hydroxyl protecting group, which yields a compound of formula IA or a salt thereof.

154. The method of claim 153, wherein R 1 Selected from C 1-4 Alkyl, benzyl and -COOR 4 ; Where R 4 Selected from C 1-4 Alkyl and phenyl.

155. The method according to claim 153 or 154, wherein R 1 It is selected from methyl, ethyl, benzyl, acetate, propionate and benzoate.

156. The method according to any one of claims 153 to 155, wherein R 1 Selected from C 1-4 Alkyl and benzyl.

157. The method according to any one of claims 153 to 156, wherein R 1 Selected from methyl, ethyl and benzyl.

158. The method according to any one of claims 153 to 157, wherein R 1 It is a methyl group.

159. The method according to any one of claims 153 to 158, wherein deprotecting the compound of formula I or a salt thereof comprises treating the compound of formula I or a salt thereof with a first deprotecting agent.

160. The method of claim 159, wherein the first deprotecting agent is selected from metal halides, hydrogen halides, boron reagents, aluminum reagents, titanium reagents, pyridinium halides, ammonium halides, and silyl halides.

161. The method according to claim 159 or 160, wherein the first deprotecting agent is a metal halide.

162. The method according to any one of claims 159 to 161, wherein the first deprotecting agent is lithium chloride.

163. The method according to any one of claims 159 to 161, wherein the first deprotecting agent is calcium bromide.

164. The method according to any one of claims 153 to 163, wherein the deprotection of the compound of formula I or its salt is performed in a second solvent comprising N-methyl-2-pyrrolidone.

165. The method according to any one of claims 153 to 164, wherein the deprotection of the compound of formula I or its salt is carried out in a temperature range of about 0°C to about 130°C.

166. The method according to any one of claims 153 to 165, further comprising preparing a compound of formula I or a salt thereof by a method comprising: Compounds of formula A: A or its salt, wherein R 3A It is a hydroxyl protecting group. and: Methylene reagent and First acid or first base reaction The compound of formula I or its salt is obtained.

167. The method of claim 166, wherein R 3A Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and benzyl groups.

168. The method according to claim 166 or 167, wherein R 3A It is selected from methyl, ethyl, isopropyl, trifluoroethyl and benzyl.

169. The method according to any one of claims 166 to 168, wherein R 3A It is a methyl group.

170. The method according to any one of claims 166 to 169, wherein the methylene reagent is a formaldehyde reagent or a dihalomethane.

171. The method according to any one of claims 166 to 170, wherein the methylene reagent is selected from 1,3,5-trioxane, formaldehyde acetal, formaldehyde, paraformaldehyde, or dihalomethane.

172. The method according to any one of claims 166 to 171, wherein the methylene reagent is 1,3,5-trioxane.

173. The method according to any one of claims 166 to 172, wherein the compound of formula A or a salt thereof is reacted with the first acid.

174. The method according to any one of claims 166 to 173, wherein the first acid comprises a carboxylic acid, a sulfonic acid, a Lewis acid, an inorganic acid, or a combination thereof.

175. The method according to any one of claims 166 to 174, wherein the first acid comprises a carboxylic acid.

176. The method according to any one of claims 166 to 175, wherein the first acid is trifluoroacetic acid.

177. The method according to any one of claims 166 to 173, wherein the compound of formula A or a salt thereof is reacted with the first base.

178. The method according to any one of claims 166 to 173 and 177, wherein the first base comprises an amine, amidine, guanidine, carboxylate, carbonate, metal hydride, phosphate, hydroxide, alkoxide, amide, basic aromatic compound, or a combination thereof.

179. The method according to any one of claims 166 to 178, wherein the reaction of the compound of formula A or a salt thereof is carried out in a thirteenth solvent comprising toluene.

180. The method according to any one of claims 166 to 179, wherein the reaction of the compound of formula A or a salt thereof is carried out in a temperature range of about 20°C to about 140°C.

181. The method according to any one of claims 153 to 165, further comprising preparing a compound of formula I or a salt thereof by a method comprising: Compounds of formula R-1: R-1 Or its salt and: Methylene reagent and The eighth acid or the fourteenth base reaction, The compound of formula I or its salt is obtained.

182. The method according to claim 181, wherein the methylene reagent is a formaldehyde reagent or a dihalomethane.

183. The method according to claim 181 or 182, wherein the methylene reagent is selected from 1,3,5-trioxane, formaldehyde acetal, formaldehyde, paraformaldehyde, or dihalomethane.

184. The method according to any one of claims 181 to 183, wherein the methylene reagent is formaldehyde.

185. The method according to any one of claims 181 to 183, wherein the methylene reagent is 1,3,5-trioxane.

186. The method according to any one of claims 181 to 185, wherein the compound of formula R-1 or a salt thereof is reacted with the eighth acid.

187. The method according to any one of claims 181 to 186, wherein the eighth acid comprises a carboxylic acid, a sulfonic acid, a Lewis acid, an inorganic acid, or a combination thereof.

188. The method according to any one of claims 181 to 187, wherein the eighth acid is a sulfonic acid.

189. The method according to any one of claims 181 to 188, wherein the eighth acid is methanesulfonic acid.

190. The method according to any one of claims 181 to 187, wherein the eighth acid is an inorganic acid.

191. The method according to any one of claims 181 to 187 and 190, wherein the eighth acid is phosphoric acid.

192. The method according to any one of claims 181 to 185, wherein the compound of formula R-1 or a salt thereof is reacted with the fourteenth base.

193. The method according to any one of claims 181 to 185 and 192, wherein the fourteenth base comprises an amine, amidine, guanidine, carboxylate, carbonate, metal hydride, phosphate, hydroxide, alkoxide, amide, basic aromatic compound, or a combination thereof.

194. The method according to any one of claims 181 to 193, wherein the reaction of the compound of formula R-1 or a salt thereof is carried out in an eleventh solvent containing tetrahydrofuran.

195. The method according to any one of claims 181 to 194, wherein the reaction of the compound of formula R-1 or a salt thereof is carried out in a temperature range of about 20°C to about 100°C.

196. The method according to any one of claims 181 to 195, further comprising preparing a compound of formula R-1 or a salt thereof by a method comprising: Compounds of formula R-2: R-2 Or its salt and: Coupling agents and The fifteenth base reaction, The compound of formula R-1 or its salt is obtained.

197. The method of claim 196, wherein the coupling agent comprises 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b Pyridinium 3-oxide hexafluorophosphate (HATU), acyl chloride, acid anhydride, carbonyl diimidazole, activated ester, organophosphorus compound, or combinations thereof.

198. The method of claim 197, wherein the coupling agent comprises 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b Pyridinium 3-oxide hexafluorophosphate (HATU), acyl chloride, acid anhydride, carbonyl diimidazole, activated ester or a combination thereof.

199. The method according to any one of claims 197 or 198, wherein the coupling agent is HATU.

200. The method according to any one of claims 197 to 199, wherein the coupling agent is diphenylphosphoyl chloride.

201. The method according to any one of claims 197 to 200, wherein the fifteenth base is selected from amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, phosphates, hydroxides, alkoxides, basic aromatic compounds, or combinations thereof.

202. The method according to any one of claims 197 to 201, wherein the fifteenth alkali is an amine.

203. The method according to any one of claims 197 to 202, wherein the fifteenth base is N,N-diisopropylethylamine.

204. The method according to any one of claims 197 to 203, wherein the reaction of the compound of formula R-2 or a salt thereof is carried out in a twenty-eighth solvent containing N,N-dimethylacetamide.

205. The method according to any one of claims 197 to 204, wherein the reaction of the compound of formula R-2 or a salt thereof is carried out in a temperature range of about 0°C to about 80°C.

206. The method according to any one of claims 197 to 205, further comprising preparing a compound of formula R-2 or a salt thereof by a method comprising: Compounds of formula A: A or its salt, wherein R 3A It is a hydrogen or hydroxyl protecting group, and is related to: Reagents selected from metal hydroxides, metal halides, and trialkylsilyl halides; The compound of formula R-2 or its salt is obtained.

207. The method of claim 206, wherein R 3A Selected from hydrogen, C 1-4 Alkyl and benzyl.

208. The method according to claim 206 or 207, wherein R 3A It is selected from hydrogen, methyl, ethyl, isopropyl and benzyl.

209. The method according to any one of claims 206 to 208, wherein R 3A It is a methyl group.

210. The method according to any one of claims 206 to 209, wherein the compound of formula A is reacted with a metal hydroxide.

211. The method according to any one of claims 206 to 210, wherein the metal hydroxide is sodium hydroxide.

212. The method according to any one of claims 206 to 211, wherein the reaction of the compound of formula A or a salt thereof is carried out in a twenty-ninth solvent comprising methanol.

213. The method according to any one of claims 206 to 212, wherein the reaction of the compound of formula A or a salt thereof is carried out in a temperature range of about 0°C to about 100°C.

214. The method according to any one of claims 181 to 195, further comprising preparing a compound of formula R-1 or a salt thereof by a method comprising: Compounds of formula A: A or its salt, wherein R 3A It is a hydroxyl protecting group, and: The sixteenth base reaction; The compound of formula R-1 or its salt is obtained.

215. The method of claim 214, wherein R 3A Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and benzyl groups.

216. The method according to claim 214 or 215, wherein R 3A It is selected from methyl, ethyl, isopropyl, trifluoroethyl and benzyl.

217. The method according to any one of claims 214 to 216, wherein R 3A It is a methyl group.

218. The method according to any one of claims 214 to 217, wherein the sixteenth base is selected from amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, phosphates, hydroxides, amides, basic aromatic compounds, or combinations thereof.

219. The method according to any one of claims 214 to 218, wherein the sixteenth alkaloid is guanidine.

220. The method according to any one of claims 214 to 219, wherein the sixteenth base is 1,5,7-triazabicyclodec-5-ene.

221. The method according to any one of claims 214 to 220, wherein the reaction of the compound of formula A or a salt thereof is carried out in a thirtieth solvent containing 2-methyltetrahydrofuran.

222. The method according to any one of claims 214 to 221, wherein the reaction of the compound of formula A or a salt thereof is carried out in a temperature range of about 20°C to about 110°C.

223. The method according to any one of claims 166 to 180 and 206 to 222, the method further comprising preparing a compound of formula A or a salt thereof by a method comprising: Compounds of formula XA: XA Or its salt and: Compounds of formula C: C or its salt, The seventh base reaction, The compound of formula A or its salt is obtained.

224. The method of claim 223, wherein the method comprises reacting a compound of formula XA with a salt of a compound of formula C.

225. The method according to claim 223 or 224, wherein the salt of the compound of formula C is a methanesulfonate.

226. The method according to claim 223 or 224, wherein the salt of the compound of formula C is a toluenesulfonate.

227. The method according to any one of claims 223 to 226, wherein the seventh base is selected from tertiary amines, secondary amines, aniline, pyridine, imidazole, amidine, guanidine, carbonates, phosphates, hydroxides, alkoxides, or combinations thereof.

228. The method according to any one of claims 223 to 227, wherein the seventh base is N-methylmorpholine.

229. The method according to any one of claims 223 to 228, wherein the reaction of the compound of formula XA or a salt thereof is carried out in a fourteenth solvent comprising methanol.

230. The method according to any one of claims 223 to 229, wherein the reaction of the compound of formula XA or a salt thereof is carried out in a temperature range of about 20°C to about 100°C.

231. The method according to any one of claims 223 to 230, the method further comprising reacting the compound of formula A with a fourth acid to obtain a salt of the compound of formula A.

232. The method according to claim 231, wherein the fourth acid is selected from trifluoroacetic acid, hydrochloric acid, hydrobromic acid, acetic acid, oxalic acid, orotic acid, succinic acid, malonic acid, adipic acid, fumaric acid, benzenesulfonic acid, benzoic acid, citric acid, 1,8-naphthalenedisulfonic acid, tartaric acid or its esters, p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, maleic acid, sine, and L-pyroglutamic acid.

233. The method according to claim 231 or 232, wherein the fourth acid is oxalic acid.

234. The method according to any one of claims 223 to 233, further comprising preparing a compound of formula C or a salt thereof by a method comprising: Compounds of formula D: D Or its salt deprotection, wherein: R 5 Selected from hydrogen and R 9 , where R 9 It is an amine protecting group; and R 7 and R 8 Each is an amine protecting group independently; The compound of formula C or its salt is obtained.

235. The method of claim 234, wherein R 5 It is hydrogen.

236. The method of claim 234, wherein R 5 It is R 9 And R 9 It is an amine protecting group.

237. The method according to claim 234 or 236, wherein R 5 It is tert-butyloxycarbonyl.

238. The method according to any one of claims 234 to 237, wherein R 7 and R 8 It is tert-butyloxycarbonyl.

239. The method according to any one of claims 234 to 238, wherein deprotecting the compound of formula D or its salt comprises treating the compound of formula D or its salt with a fifth acid.

240. The method of claim 239, wherein the fifth acid is selected from sulfonic acid, sulfuric acid, sulfurous acid, carboxylic acid, hydrogen halide, phosphoric acid, phosphorous acid, or combinations thereof.

241. The method according to claim 239 or 240, wherein the fifth acid is a sulfonic acid.

242. The method according to any one of claims 239 to 241, wherein the fifth acid is methanesulfonic acid.

243. The method according to any one of claims 239 to 241, wherein the fifth acid is p-toluenesulfonic acid.

244. The method according to any one of claims 234 to 243, wherein the deprotection of the compound of formula D or its salt is performed in a fifteenth solvent comprising methanol.

245. The method according to any one of claims 234 to 244, wherein the deprotection of the compound of formula D or its salt is carried out in a temperature range of about 20°C to about 100°C.

246. The method according to any one of claims 234 to 245, further comprising preparing a compound of formula D or a salt thereof by a method comprising: D-1 Or a salt thereof, the method comprising: Compounds of formula E: E Or its salt deprotection, wherein: R 9 It is an amine protecting group and R 10 It is hydrogen; or optionally: R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups; The compound of formula D or its salt is obtained.

247. The method of claim 246, wherein R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups.

248. The method according to claim 246 or 247, wherein R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form phthalimides.

249. The method of claim 246, wherein R 9 It is tert-butyloxycarbonyl.

250. The method according to any one of claims 246 to 249, wherein deprotecting the compound of formula E or a salt thereof comprises treating the compound of formula E or a salt thereof with a second deprotecting agent.

251. The method of claim 250, wherein the second deprotecting agent is selected from hydrazine, amine, alkoxide, thiol, hydrolase, hydride, or a combination thereof.

252. The method according to claim 250 or 251, wherein the second deprotecting agent is selected from hydrazine, amine, alkoxide, thiol, hydrolase, or a combination thereof.

253. The method according to any one of claims 250 to 252, wherein the second deprotecting agent is an amine.

254. The method according to any one of claims 250 to 253, wherein the second deprotecting agent is ethylenediamine.

255. The method according to claim 250 or 251, wherein the second deprotecting agent is a hydride.

256. The method according to any one of claims 250, 251 and 255, wherein the second deprotecting agent is sodium borohydride.

257. The method according to any one of claims 250 to 256, wherein the deprotection of the compound of formula E or its salt is performed in the presence of a ninth acid.

258. The method of claim 257, wherein the ninth acid comprises a carboxylic acid, a strong acid, or a combination thereof.

259. The method according to any one of claims 246 to 258, wherein the deprotection of the compound of formula E or its salt is performed in a sixteenth solvent comprising methanol.

260. The method according to any one of claims 246 to 259, wherein the deprotection of the compound of formula E or its salt is carried out in a temperature range of about 0°C to about 100°C.

261. The method according to any one of claims 166 to 180 and 206 to 222, the method further comprising preparing a compound of formula A or a salt thereof by a method comprising: Compounds of formula Q-1: Q-1 Or its salt reacts with a reagent selected from hydrazine, amine, alkoxide and hydrolase; The compound of formula A or its salt is obtained.

262. The method of claim 261, wherein the method comprises reacting the compound of formula Q-1 with hydrazine.

263. The method according to claim 261 or 262, wherein the method comprises reacting the compound of formula Q-1 with hydrazine hydrate.

264. The method according to any one of claims 261 to 263, wherein the reaction of the compound of formula Q-1 or a salt thereof is carried out in a thirty-first solvent comprising toluene.

265. The method according to any one of claims 261 to 264, wherein the reaction of the compound of formula Q-1 or a salt thereof is carried out in a temperature range of about 0°C to about 100°C.

266. The method according to any one of claims 261 to 265, further comprising preparing a compound of formula Q-1 or a salt thereof by a method comprising: Compounds of formula Q-2: Q-2 Or its salt and: Compounds of formula XA: XA or its salt and Thirteenth base reaction; The compound of formula Q-1 or its salt is obtained.

267. The method of claim 266, wherein the thirteenth base is selected from tertiary amines, secondary amines, aniline, pyridine, imidazole, amidine, guanidine, carbonates, phosphates, hydroxides, alkoxides, or combinations thereof.

268. The method according to claim 266 or 267, wherein the thirteenth base is a tertiary amine.

269. The method according to any one of claims 266 to 268, wherein the thirteenth base is N-methylmorpholine.

270. The method according to any one of claims 266 to 269, wherein the reaction of the compound of formula Q-2 or a salt thereof is carried out in a thirtieth-second solvent containing methanol.

271. The method according to any one of claims 266 to 270, wherein the reaction of the compound of formula Q-2 or a salt thereof is carried out in a temperature range of about 20°C to about 100°C.

272. The method according to any one of claims 266 to 271, further comprising preparing a compound of formula Q-2 or a salt thereof by a method comprising: Compounds of formula E: E or its salt, wherein R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form phthalimides; It reacts with the seventh acid to give the compound of formula Q-2 or its salt.

273. The method according to claim 272, wherein the seventh acid is selected from sulfonic acid, sulfuric acid, sulfurous acid, carboxylic acid, hydrogen halide, in-situ generated hydrogen halide, phosphoric acid, phosphorous acid, or combinations thereof.

274. The method according to claim 272 or 273, wherein the seventh acid is a sulfonic acid.

275. The method according to any one of claims 272 to 274, wherein the seventh acid is p-toluenesulfonic acid.

276. The method according to any one of claims 272 to 275, wherein the reaction of the compound of formula E or a salt thereof is carried out in a thirty-third solvent containing methanol.

277. The method according to any one of claims 272 to 276, wherein the reaction of the compound of formula E or a salt thereof is carried out in a temperature range of about 20°C to about 100°C.

278. The method according to any one of claims 246 to 260 and 272 to 277, the method further comprising preparing a compound of formula E or a salt thereof by a method comprising: Compounds of formula F: F Or its salt and: Phosphine reagent azodicarbonate and Formula R 7 -NH-NH-R 8 The reaction of compounds; The compound of formula E or its salt is obtained.

279. The method according to claim 278, wherein the phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine.

280. The method according to claim 278 or 279, wherein the phosphine reagent is a triarylphosphine.

281. The method according to any one of claims 278 to 280, wherein the phosphine reagent is triphenylphosphine.

282. The method according to any one of claims 278 to 281, wherein the azodicarbonate is selected from di-tert-butyl azodicarbonate, diisopropyl azodicarbonate, diethyl azodicarbonate, dimethoxy ethyl azodicarbonate, azodicarbonyl dimorpholine, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzoic acid azodicarbonate.

283. The method according to any one of claims 278 to 282, wherein the azodicarbonate is di-tert-butyl azodicarbonate.

284. The method according to any one of claims 278 to 283, wherein the formula R 7 -NH-NH-R 8 The compound is .

285. The method according to any one of claims 278 to 284, wherein the reaction of the compound of formula F or a salt thereof is carried out in a seventeenth solvent comprising 2-methyltetrahydrofuran.

286. The method according to any one of claims 278 to 285, wherein the reaction of the compound of formula F or a salt thereof is carried out in a temperature range of about -20°C to about 50°C.

287. The method according to any one of claims 278 to 286, further comprising preparing a compound of formula F or a salt thereof by a method comprising: Compounds of formula G: G Or its salt and: The third catalyst, and Hydrogen source reaction; To obtain a compound of formula F or a salt thereof.

288. The method of claim 287, wherein the third catalyst is selected from palladium catalysts, platinum catalysts, and bimetallic catalysts, wherein the bimetallic catalyst comprises two metals selected from palladium, platinum, and copper.

289. The method according to claim 287 or 288, wherein the third catalyst is a palladium catalyst.

290. The method according to any one of claims 287 to 289, wherein the third catalyst is a lindra catalyst.

291. The method according to any one of claims 287 to 290, wherein the third catalyst comprises 5% by weight palladium supported on lead-poisoned calcium carbonate.

292. The method according to any one of claims 287 to 291, wherein the molar ratio of the compound of formula G or a salt thereof to the third catalyst is from about 1:0.001 to about 1:0.

05.

293. The method according to any one of claims 287 to 292, wherein the hydrogen source comprises hydrogen, formic acid, water, or a combination thereof.

294. The method according to any one of claims 287 to 293, wherein the hydrogen source is hydrogen.

295. The method according to any one of claims 287 to 294, wherein the reaction of the compound of formula G or a salt thereof is carried out in the presence of a second additive.

296. The method according to claim 295, wherein the second additive comprises quinoline, pyridine, triethylamine, carbonate, bicarbonate, phosphate, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, potassium formate, sodium formate, ammonium formate, potassium hydroxide, potassium acetate, sodium acetate, cesium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium iodide, lithium chloride, sodium chloride, calcium chloride, or combinations thereof.

297. The method according to any one of claims 287 to 296, wherein the reaction of the compound of formula G or a salt thereof is carried out at a pressure of about 1 psi to about 100 psi.

298. The method according to any one of claims 287 to 297, wherein the reaction of the compound of formula G or a salt thereof is carried out at a pressure of about 50 psi.

299. The method according to any one of claims 287 to 298, wherein the reaction of the compound of formula G or a salt thereof is carried out in an eighteenth solvent containing N,N-dimethylformamide.

300. The method according to any one of claims 287 to 299, wherein the reaction of the compound of formula G or a salt thereof is carried out in a temperature range of about 0°C to about 100°C.

301. The method according to any one of claims 287 to 300, the method further comprising preparing a compound of formula G or a salt thereof by a method comprising: Compounds of formula H: H or its salt, wherein R 11 Selected from C 1-20 Alkyl, phenyl, and -CH2NH2; Reaction with the sixth acid or the eighth base A compound of formula G or a salt thereof is obtained.

302. The method of claim 301, wherein R 11 It is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, pentadecyl, phenyl and -CH2NH2.

303. The method according to claim 301 or 302, wherein R 11 It is a methyl group.

304. The method according to any one of claims 301 to 303, wherein the compound of formula H or a salt thereof is reacted with the sixth acid.

305. The method according to any one of claims 301 to 304, wherein the sixth acid is selected from mineral acids, trifluoroacetic acid, sulfonic acid, or combinations thereof.

306. The method according to any one of claims 301 to 305, wherein the sixth acid is a sulfonic acid.

307. The method according to any one of claims 301 to 306, wherein the sixth acid is p-toluenesulfonic acid.

308. The method according to any one of claims 301 to 303, wherein the compound of formula H or a salt thereof is reacted with the eighth base.

309. The method according to any one of claims 301 to 303 and 308, wherein the eighth base is selected from guanidine, carbonate, bicarbonate, metal alkoxide, amine or a combination thereof.

310. The method according to any one of claims 301 to 309, wherein the reaction of the compound of formula H or a salt thereof is carried out in a thirty-fourth solvent comprising methanol.

311. The method according to any one of claims 301 to 310, wherein the reaction of the compound of formula H or a salt thereof is carried out in a temperature range of about 0°C to about 70°C.

312. The method according to any one of claims 278 to 286, further comprising preparing a compound of formula F or a salt thereof by a method comprising: Compounds of formula W: W Or its salt and: The sixth catalyst and Reducing agent reaction; To obtain a compound of formula F or a salt thereof.

313. The method of claim 312, wherein R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups.

314. The method according to claim 312 or 313, wherein the compound of formula W or a salt thereof is a compound of formula W-1: W-1 Or its salt.

315. The method according to any one of claims 312 to 314, wherein the compound of formula F or a salt thereof is a compound of formula F-2: F-2 Or its salt.

316. The method according to any one of claims 312 to 315, wherein the sixth catalyst is a CBS catalyst or a ruthenium catalyst.

317. The method according to any one of claims 312 to 316, wherein the sixth catalyst is a CBS catalyst.

318. The method according to any one of claims 312 to 317, wherein the sixth catalyst is ( R )-(+)-2-methyl-CBS-oxazolborane.

319. The method according to any one of claims 312 to 318, wherein the reducing agent comprises formic acid and triethylamine, NaBH4, LiBH4, CeCl3∙7H2O and NaBH4, LiAlH4, MgBu2 and HBpin, Red-Al, LiAlH(OtBu)3, BH3∙SMe2, catecholborane or combinations thereof.

320. The method according to any one of claims 312 to 319, wherein the reducing agent comprises catecholborane.

321. The method according to any one of claims 312 to 320, wherein the reaction of the compound of formula W or a salt thereof is carried out in a forty-third solvent comprising dichloromethane.

322. The method according to any one of claims 312 to 321, wherein the reaction of the compound of formula W or a salt thereof is carried out in a temperature range of about -78°C to about 30°C.

323. The method according to any one of claims 312 to 322, further comprising preparing a compound of formula W or a salt thereof by a method comprising: Compounds of formula S: S Or its salt and: Compounds of formula T: T or its salt, Where R 15 Selected from phenyl and C 1-4 Halogenated alkyl group, wherein the phenyl group is optionally composed of 1 to 4 C6 atoms. 1-4 Alkyl, halogen, C 1-4 Substitution of alkyl and cyano groups; The seventeenth base and Fourth additive reaction; A compound of formula W or its salt is obtained.

324. The method according to claim 323, wherein the compound of formula S or a salt thereof is a compound of formula S-1: S-1 Or its salt.

325. The method according to claim 323 or 324, wherein R 15 Selected from phenyl, trifluoroethyl, trichloroethyl, phenyl and chlorophenyl.

326. The method according to any one of claims 323 to 325, wherein R 15 It is phenyl.

327. The method according to any one of claims 323 to 326, wherein the seventeenth base is selected from amides, amine bases, amidines, guanidines, carbonates, metal hydrides, phosphates, alkoxides, basic aromatic compounds, and combinations thereof.

328. The method according to any one of claims 323 to 327, wherein the seventeenth base is an amide.

329. The method according to any one of claims 323 to 328, wherein the seventeenth base is potassium hexamethyldisilamide.

330. The method according to any one of claims 323 to 329, wherein the fourth additive is selected from ethers, metal salts, or combinations thereof.

331. The method according to any one of claims 323 to 330, wherein the fourth additive is an ether.

332. The method according to any one of claims 323 to 331, wherein the fourth additive is 18-crown ether-6.

333. The method according to any one of claims 323 to 332, wherein the reaction of the compound of formula S or a salt thereof is carried out in a forty-fourth solvent containing tetrahydrofuran.

334. The method according to any one of claims 323 to 333, wherein the reaction of the compound of formula S or a salt thereof is carried out in a temperature range of about -100°C to about 25°C.

335. The method according to any one of claims 278 to 286, further comprising preparing a compound of formula F or a salt thereof by a method comprising: Compounds of formula W: W Or its salt and: The second enzyme reacts in the presence of the second buffer solution; To obtain a compound of formula F or a salt thereof.

336. The method of claim 335, wherein R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups.

337. The method according to claim 335 or 336, wherein the compound of formula W or a salt thereof is a compound of formula W-1: W-1 Or its salt.

338. The method according to any one of claims 335 to 337, wherein the compound of formula F or a salt thereof is a compound of formula F-2: F-2 Or its salt.

339. The method according to any one of claims 335 to 338, wherein the second enzyme is selected from ketone reductase, alcohol oxidase or P450.

340. The method according to any one of claims 335 to 339, wherein the second enzyme is a ketone reductase.

341. The method according to any one of claims 335 to 340, wherein the second buffer is selected from citrate buffer, phosphate buffer, tris(hydroxymethyl)aminomethane and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) (HEPES).

342. The method according to any one of claims 335 to 341, wherein the second buffer is a phosphate buffer.

343. The method according to any one of claims 335 to 342, wherein the reaction of the compound of formula W or a salt thereof is carried out in a cosolvent containing dimethyl sulfoxide.

344. The method according to any one of claims 335 to 343, wherein the reaction of the compound of formula W or its salt is carried out in a temperature range of about 5°C to about 100°C.

345. The method according to any one of claims 278 to 286, further comprising preparing a compound of formula F or a salt thereof by a method comprising: Compounds of formula G: G Or its salt and: Third reducing agent and Activator reaction; To obtain a compound of formula F or a salt thereof.

346. The method of claim 345, wherein the compound of formula F or a salt thereof is a compound of formula F-1: F-1 Or its salt.

347. The method according to claim 345 or 346, wherein R 9 It is tert-butyloxycarbonyl.

348. The method according to any one of claims 345 to 347, wherein the compound of formula G or a salt thereof is a compound of formula G-1: G-1 Or its salt.

349. The method of claim 345, wherein R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups.

350. The method according to claim 345 or 349, wherein R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form phthalimides or saccharin.

351. The method according to any one of claims 345 to 350, wherein the third reducing agent comprises zinc, a metal, a diimide, copper, and bis(pinacol)diboron, imidazoline onion salt, or a combination thereof.

352. The method according to any one of claims 345 to 351, wherein the third reducing agent comprises zinc.

353. The method according to any one of claims 345 to 352, wherein the activator is selected from trimethylchlorosilane, dibromoethane, hydrochloric acid and diisobutylaluminum hydride.

354. The method according to any one of claims 345 to 353, wherein the activator is trimethylchlorosilane.

355. The method according to any one of claims 345 to 354, wherein the reaction of the compound of formula G or a salt thereof is carried out in a forty-fifth solvent comprising ethanol.

356. The method according to any one of claims 345 to 355, wherein the reaction of the compound of formula G or a salt thereof is carried out in a temperature range of about 0°C to about 100°C.

357. The method according to any one of claims 234 to 245, further comprising preparing a compound of formula D or a salt thereof by a method comprising the following, wherein R 5 For R 9 : Compounds of formula F-1: F-1 or its salt, wherein R 9 It is an amine protecting group, and: Phosphine reagent azodicarbonate and Formula R 7 -NH-NH-R 8 The reaction of compounds; The compound of formula D or its salt is obtained.

358. The method of claim 357, wherein R 9 It is tert-butyloxycarbonyl.

359. The method according to claim 357 or 358, wherein the phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine.

360. The method according to any one of claims 357 to 359, wherein the phosphine reagent is triarylphosphine.

361. The method according to any one of claims 357 to 360, wherein the phosphine reagent is triphenylphosphine.

362. The method according to any one of claims 357 to 361, wherein the azodicarbonate is selected from di-tert-butyl azodicarbonate, diisopropyl azodicarbonate, diethyl azodicarbonate, dimethoxy ethyl azodicarbonate, azodicarbonyl dimorpholine, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzoic acid azodicarbonate.

363. The method according to any one of claims 357 to 362, wherein the azodicarbonate is di-tert-butyl azodicarbonate.

364. The method according to any one of claims 357 to 363, wherein formula R 7 -NH-NH-R 8 The compound is .

365. The method according to any one of claims 357 to 364, wherein the reaction of the compound of formula F-1 or a salt thereof is carried out in a thirty-fifth solvent comprising 2-methyltetrahydrofuran.

366. The method according to any one of claims 357 to 365, wherein the reaction of the compound of formula F-1 or a salt thereof is carried out in a temperature range of about -20°C to about 50°C.

367. The method according to any one of claims 357 to 366, further comprising preparing a compound of formula F-1 or a salt thereof by a method comprising: Compounds of formula G-1: G-1 Or its salt and: Third catalyst Aromatic amines or sulfur-containing reagents; and Hydrogen reaction; The compound of formula F-1 or its salt is obtained.

368. The method of claim 367, wherein the third catalyst is selected from palladium catalysts, platinum catalysts, and bimetallic catalysts, wherein the bimetallic catalyst comprises two metals selected from palladium, platinum, and copper.

369. The method according to claim 367 or 368, wherein the third catalyst is a palladium catalyst.

370. The method according to any one of claims 367 to 369, wherein the third catalyst is a lindra catalyst.

371. The method according to any one of claims 367 to 370, wherein the third catalyst comprises 5% by weight palladium supported on lead-poisoned calcium carbonate.

372. The method according to any one of claims 367 to 371, wherein the molar ratio of the compound of formula G-1 or a salt thereof to the third catalyst is from about 1:0.001 to about 1:0.

05.

373. The method according to any one of claims 367 to 372, wherein the compound of formula G-1 is reacted with an aromatic amine selected from quinoline and pyridine.

374. The method according to any one of claims 367 to 373, wherein the aromatic amine is quinoline.

375. The method according to any one of claims 367 to 374, wherein the compound of formula G-1 is reacted with a sulfur-containing compound selected from thiols and sulfides.

376. The method according to any one of claims 367 to 375, wherein the reaction of the compound of formula G-1 or a salt thereof is carried out at a pressure of about 1 psi to about 100 psi.

377. The method according to any one of claims 367 to 376, wherein the reaction of the compound of formula G-1 or a salt thereof is carried out at a pressure of about 20 psi.

378. The method according to any one of claims 367 to 377, wherein the reaction of the compound of formula G-1 or a salt thereof is carried out in a thirty-sixth solvent containing N,N-dimethylformamide.

379. The method according to any one of claims 367 to 378, wherein the reaction of the compound of formula G-1 or a salt thereof is carried out in a temperature range of about 20°C to about 100°C.

380. The method according to any one of claims 367 to 379, further comprising preparing a compound of formula G-1 or a salt thereof by a method comprising: Compounds of formula H having formula H-1: H-1 or its salt, wherein R 11 Selected from C 1-20 Alkyl, phenyl, and -CH2NH2; Reaction with the twelfth base, The compound of formula G-1 or its salt is obtained.

381. The method of claim 380, wherein R 11 It is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, pentadecyl, phenyl and -CH2NH2.

382. The method according to claim 380 or 381, wherein R 11 It is a methyl group.

383. The method according to any one of claims 380 to 382, ​​wherein the twelfth alkali is selected from guanidine, carbonate, bicarbonate, metal alkoxide, amine or a combination thereof.

384. The method according to any one of claims 380 to 383, wherein the twelfth alkaloid is guanidine.

385. The method according to any one of claims 380 to 384, wherein the twelfth base is tetramethylguanidine.

386. The method according to any one of claims 380 to 385, wherein the reaction of the compound of formula H-1 or a salt thereof is carried out in a thirty-seventh solvent containing methanol.

387. The method according to any one of claims 380 to 386, wherein the reaction of the compound of formula H-1 or a salt thereof is carried out in a temperature range of about 0°C to about 30°C.

388. The method according to any one of claims 380 to 387, further comprising preparing a compound of formula G-1 or a salt thereof by a method comprising: Compounds of formula U-1: U-1 The compound of formula G-1 or its salt is reacted with a reagent containing a second amine protecting group to obtain the compound of formula G-1 or its salt.

389. The method according to claim 388, wherein the compound of formula G-1 or a salt thereof has R 9 It is tert-butyloxycarbonyl.

390. The method according to claim 388 or 389, wherein the second amine protecting group is ditert-butyl dicarbonate.

391. The method according to any one of claims 388 to 390, wherein the reaction of the compound of formula U-1 or a salt thereof is carried out in a forty-sixth solvent containing 2-methyltetrahydrofuran.

392. The method according to any one of claims 388 to 391, wherein the reaction of the compound of formula U-1 or a salt thereof is carried out in a temperature range of about 5°C to about 100°C.

393. The method according to any one of claims 388 to 392, further comprising preparing a compound of formula U-1 or a salt thereof by a method comprising: Compounds of formula U-2: U-2 Or its salt and: The third enzyme reacts in the presence of the third buffer solution; The compound of formula U-1 or its salt is obtained.

394. The method of claim 393, wherein the third enzyme is selected from transaminases, hydrogenases, imine reductases, and combinations thereof.

395. The method according to claim 393 or 394, wherein the third enzyme is a transaminase.

396. The method according to any one of claims 393 to 395, wherein the third buffer is selected from citrate buffer, phosphate buffer, tris(hydroxymethyl)aminomethane (Tris) buffer and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) (HEPES).

397. The method according to any one of claims 393 to 396, wherein the third buffer is a Tris buffer.

398. The method according to any one of claims 393 to 397, wherein the reaction of the compound of formula U-2 or a salt thereof is carried out in a second cosolvent containing dimethyl sulfoxide.

399. The method according to any one of claims 393 to 398, wherein the reaction of the compound of formula U-2 or a salt thereof is carried out in a temperature range of about 5°C to about 100°C.

400. The method according to any one of claims 393 to 399, further comprising preparing a compound of formula U-2 or a salt thereof by a method comprising: Compounds of formula L: L Or its salt and: The fourth enzyme reacts in the presence of the fourth buffer solution; The compound of formula U-2 or its salt is obtained.

401. The method of claim 400, wherein the fourth enzyme is selected from ketone reductase, alcohol oxidase, P450, and combinations thereof.

402. The method according to claim 400 or 401, wherein the fourth enzyme is a ketone reductase.

403. The method according to any one of claims 400 to 402, wherein the fourth buffer is selected from citrate buffer, phosphate buffer, tris(hydroxymethyl)aminomethane (Tris) buffer and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) (HEPES).

404. The method according to any one of claims 400 to 403, wherein the fourth buffer is a Tris buffer.

405. The method according to any one of claims 400 to 404, wherein the reaction of the compound of formula L or a salt thereof is carried out in a third cosolvent comprising dimethyl sulfoxide.

406. The method according to any one of claims 400 to 405, wherein the reaction of the compound of formula L or a salt thereof is carried out in a temperature range of about 5°C to about 100°C.

407. The method according to any one of claims 301 to 311 and 380 to 387, the method further comprising preparing a compound of formula H or a salt thereof by a method comprising: Compounds of formula J: J Or its salt and: Second phosphine reagent, Second azodicarbonate and Amine protecting group reagent reaction; To obtain a compound of formula H or a salt thereof.

408. The method according to claim 407, wherein the second phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine.

409. The method according to claim 407 or 408, wherein the second phosphine reagent is triarylphosphine.

410. The method according to any one of claims 407 to 409, wherein the second phosphine reagent is triphenylphosphine.

411. The method according to any one of claims 407 to 410, wherein the second azodicarbonate is selected from di-tert-butyl azodicarbonate, diisopropyl azodicarbonate, diethyl azodicarbonate, dimethoxy ethyl azodicarbonate, azodicarbonyl dimorpholine, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzyl azodicarbonate.

412. The method according to any one of claims 407 to 411, wherein the second azodicarbonate is diisopropyl azodicarbonate.

413. The method according to any one of claims 407 to 412, wherein the amine protecting group reagent is an imide.

414. The method according to any one of claims 407 to 413, wherein the amine protecting group reagent is an imide selected from phthalimide, tert-butyl methyl iminocarbamate and di-tert-butyl iminocarbamate.

415. The method according to any one of claims 407 to 414, wherein the amine protecting group reagent is phthalimide.

416. The method according to any one of claims 407 to 415, wherein the reaction of the compound of formula J or a salt thereof is carried out in a thirty-eighth solvent comprising 2-methyltetrahydrofuran.

417. The method according to any one of claims 407 to 416, wherein the reaction of the compound of formula J or a salt thereof is carried out in a temperature range of about -20°C to about 50°C.

418. The method according to any one of claims 301 to 311 and 380 to 387, the method further comprising preparing a compound of formula H or a salt thereof by a method comprising: Compounds of formula N: N or its salt, wherein: R 12 It is -S(O)3R 13 or -OC(=N)R 14 ; R 13 Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and optionally C 1-4 Alkyl-substituted phenyl; and R 14 It is C 1-4 Halogenated alkyl groups; Reaction with amine protecting group reagents, To obtain a compound of formula H or a salt thereof.

419. The method of claim 418, wherein R 12 It is -S(O)3R 13 .

420. The method according to claim 418 or 419, wherein R 13 Selected from toluene, methyl and trifluoromethyl.

421. The method according to any one of claims 418 to 420, wherein R 13 It is a methyl group.

422. The method according to any one of claims 418 to 420, wherein R 13 It is toluene-based.

423. The method of claim 418, wherein R 12 It is -OC(=N)R 14 .

424. The method according to any one of claims 418 and 423, wherein R 14 Selected from trichloromethyl and tribromomethyl.

425. The method according to any one of claims 418 to 424, wherein the amine protecting group reagent is selected from phthalimide, p-methoxyaniline, 2,4-dimethoxyaniline, acetamide, 2,5-dimethylpyrrole, 4-methoxybenzylamine, 2,4-dimethoxybenzylamine, 2,2-diphenylamine, allylamine, triphenylmethylamine, di-tert-butyl iminodiacarbonate, tert-butyl carbamate, or salts thereof.

426. The method according to any one of claims 418 to 425, wherein the amine protecting group reagent is a salt of phthalimide.

427. The method according to any one of claims 418 to 426, wherein the amine protecting group reagent is potassium phthalimide.

428. The method according to any one of claims 418 to 427, wherein the reaction of the compound of formula N or a salt thereof is carried out in the presence of a third additive.

429. The method of claim 428, wherein the third additive comprises 18-crown ether-6, tetrabutylammonium salt, hexamethylphosphoramide, water, or a combination thereof.

430. The method according to claim 428 or 429, wherein the third additive comprises 18-crown ether-6.

431. The method according to any one of claims 418 to 430, wherein the reaction of the compound of formula N or a salt thereof is carried out in the presence of a tenth base.

432. The method according to claim 431, wherein the tenth base is selected from amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, phosphates, hydroxides, alkoxides, and basic aromatic compounds.

433. The method according to any one of claims 418 to 432, wherein the reaction of the compound of formula N or a salt thereof is carried out in a twentieth solvent containing N,N-dimethylacetamide.

434. The method according to any one of claims 418 to 433, wherein the reaction of the compound of formula N or a salt thereof is carried out in a temperature range of about 20°C to about 100°C.

435. The method according to any one of claims 418 to 434, further comprising preparing a compound of formula N or a salt thereof by a method comprising: Compounds of formula J: J Or its salt and: The eleventh base and The third reagent reaction, wherein the third reagent is selected from sulfonyl chloride, sulfonic anhydride, halonitrile, imine chloride or acyl halide; A compound of formula N or a salt thereof is obtained.

436. The method of claim 435, wherein the third reagent is selected from sulfonyl chloride, sulfonic anhydride, halonitrile or imine chloride.

437. The method according to claim 435 or 436, wherein the third reagent is sulfonyl chloride.

438. The method of claim 437, wherein the sulfonyl chloride is selected from methanesulfonyl chloride and 4-toluenesulfonyl chloride.

439. The method according to any one of claims 435 to 438, wherein the third reagent is methanesulfonyl chloride.

440. The method according to claim 435 or 436, wherein the third reagent is sulfonic anhydride.

441. The method according to any one of claims 435, 436 and 440, wherein the sulfonic anhydride is selected from methanesulfonic anhydride and trifluoromethanesulfonic anhydride.

442. The method according to claim 435 or 436, wherein the third reagent is a halonitrile.

443. The method according to any one of claims 435, 436 and 442, wherein the halonitrile is selected from trichloroacetonitrile and trifluoroacetonitrile.

444. The method according to claim 435 or 436, wherein the third reagent is imine chloride.

445. The method according to any one of claims 435, 446 and 444, wherein the imine chloride is (N-phenyl)trifluoroiminoacetyl chloride.

446. The method of claim 435, wherein the third reagent is an acyl halide.

447. The method according to claim 435 or 446, wherein the acyl halide is selected from acetyl chloride, acetyl bromide and benzoyl chloride.

448. The method according to any one of claims 435 to 447, wherein the eleventh base is selected from amines, carbonates, bicarbonates, metal alkoxides, or combinations thereof.

449. The method according to any one of claims 435 to 448, wherein the eleventh base is an amine.

450. The method according to any one of claims 435 to 449, wherein the eleventh base is triethylamine.

451. The method according to any one of claims 435 to 450, wherein the reaction of the compound of formula J or a salt thereof is carried out in a twenty-first solvent containing N,N-dimethylacetamide.

452. The method according to any one of claims 435 to 451, wherein the reaction of the compound of formula J or a salt thereof is carried out in a temperature range of about -15°C to about 60°C.

453. The method according to any one of claims 380 to 387, further comprising preparing a compound of formula H-1 or a salt thereof by a method comprising: Compounds of formula P-1: P-1 The compound of formula H-1 or its salt reacts with an amine protecting group reagent to obtain the compound of formula H-1 or its salt.

454. The method according to claim 453, wherein the amine protecting group reagent is di-tert-butyl dicarbonate.

455. The method according to claim 453 or 454, further comprising preparing a compound of formula P-1 or a salt thereof by a method comprising: Compounds of formula N: N or its salt, wherein: R 12 It is -S(O)3R 13 ;and R 13 Selected from C 1-4 Alkyl groups and optionally C 1-4 Alkyl-substituted phenyl; and: azides and Tertiary phosphine reagent reaction; The compound of formula P-1 or its salt is obtained.

456. The method of claim 455, wherein the azide is selected from sodium azide, diphenyl azidophosphate, and trimethyl azidosilane.

457. The method according to claim 455 or 456, wherein the azide is sodium azide.

458. The method according to any one of claims 455 to 457, wherein the third phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine.

459. The method according to any one of claims 455 to 458, wherein the third phosphine reagent is a triarylphosphine.

460. The method according to any one of claims 455 to 459, wherein the third phosphine reagent is triphenylphosphine.

461. The method according to any one of claims 455 to 460, wherein the reaction of the compound of formula N or a salt thereof is carried out in a twenty-seventh solvent containing N,N-dimethylformamide.

462. The method according to any one of claims 455 to 461, wherein the reaction of the compound of formula N or a salt thereof is carried out in a temperature range of about -20°C to about 50°C.

463. The method according to any one of claims 380 to 387, further comprising preparing a compound of formula H-1 or a salt thereof by a method comprising: Compounds of formula P-2: P-2 Or its salt and: Phosphine reagent; and Amine protecting group reagent reaction; The compound of formula H-1 or its salt is obtained.

464. The method according to claim 463, wherein the fourth phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine.

465. The method according to claim 463 or 464, wherein the fourth phosphine reagent is a triarylphosphine.

466. The method according to any one of claims 463 to 465, wherein the fourth phosphine reagent is triphenylphosphine.

467. The method according to any one of claims 463 to 466, wherein the amine protecting group reagent is di-tert-butyl dicarbonate.

468. The method according to any one of claims 463 to 467, further comprising preparing a compound of formula P-2 or a salt thereof by a method comprising: Compounds of formula J: J Or its salt and: azides, Tertiary phosphine reagent and Third azodicarbonate reaction; The compound of formula P-2 or its salt is obtained.

469. The method of claim 468, wherein the azide is selected from sodium azide, diphenyl azidophosphate, and trimethyl azidosilane.

470. The method according to claim 468 or 469, wherein the azide is sodium azide.

471. The method according to any one of claims 468 to 470, wherein the third phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine.

472. The method according to any one of claims 468 to 471, wherein the third phosphine reagent is a triarylphosphine.

473. The method according to any one of claims 468 to 472, wherein the third phosphine reagent is triphenylphosphine.

474. The method according to any one of claims 468 to 473, wherein the third azodicarbonate is selected from di-tert-butyl azodicarbonate, diisopropyl azodicarbonate, diethyl azodicarbonate, dimethoxy ethyl azodicarbonate, azodicarbonyl dimorpholine, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzoic acid azodicarbonate.

475. The method according to any one of claims 468 to 474, wherein the third azodicarbonate is diisopropyl diazodicarbonate.

476. The method according to any one of claims 468 to 475, wherein the reaction of the compound of formula J or a salt thereof is carried out in a thirty-ninth solvent containing tetrahydrofuran.

477. The method according to any one of claims 468 to 476, wherein the reaction of the compound of formula J or a salt thereof is carried out in a temperature range of about -20°C to about 50°C.

478. The method according to any one of claims 407 to 417, 345 to 355, and 468 to 477, further comprising preparing a compound of formula J or a salt thereof by a method comprising: Compounds of formula K: K Or its salt and: enzymes and Buffer reaction; The compound of formula J or its salt is obtained.

479. The method of claim 478, wherein the enzyme is selected from hydrolases, Prozomix 4, Prozomix 5, Prozomix 25, Prozomix 26 and Novozyme 435.

480. The method according to claim 478 or 479, wherein the enzyme is a hydrolase.

481. The method according to any one of claims 478 to 480, wherein the enzyme is L-092 hydrolase.

482. The method according to any one of claims 478 to 481, wherein the molar ratio of the enzyme to the compound of formula K or a salt thereof is from about 0.00001:1 to about 0.01:

1.

483. The method according to any one of claims 478 to 482, wherein the buffer is selected from citrate buffer, phosphate buffer, tris(hydroxymethyl)aminomethane and (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) (HEPES).

484. The method according to any one of claims 478 to 483, wherein the buffer solution is a potassium phosphate buffer.

485. The method according to any one of claims 478 to 484, wherein the reaction of the compound of formula K or a salt thereof is carried out in the presence of a metal halide.

486. The method of claim 485, wherein the metal halide comprises zinc, nickel, calcium, iron, magnesium, or manganese.

487. The method according to any one of claims 478 to 486, wherein the reaction of the compound of formula K or a salt thereof is carried out in the presence of a surfactant.

488. The method of claim 487, wherein the surfactant is selected from sodium dodecyl sulfate, polypropylene glycol, and polyoxyethylene fatty ethers.

489. The method according to any one of claims 478 to 488, wherein the reaction of the compound of formula K or a salt thereof is carried out in a fortieth solvent containing tert-butyl methyl ether.

490. The method according to any one of claims 478 to 489, wherein the reaction of the compound of formula K or a salt thereof is carried out in a temperature range of about 0°C to about 70°C.

491. The method according to any one of claims 478 to 490, further comprising preparing a compound of formula K or a salt thereof by a method comprising: Compounds of formula L: L or its salt; and: Ninth Alkali Fourth catalyst and Reactions of compounds of formula M-1 or M-2: M-1 ； M-2 Where X is a halide; A compound of formula K or its salt is obtained.

492. The method according to claim 491, wherein the ninth base is selected from carbonates, metal alkoxides, amines, metal hydroxides, or combinations thereof.

493. The method according to claim 491 or 492, wherein the ninth base is an amine.

494. The method according to any one of claims 491 to 493, wherein the ninth base is triethylamine.

495. The method according to any one of claims 491 to 494, wherein the fourth catalyst is an aromatic amine.

496. The method according to any one of claims 491 to 495, wherein the fourth catalyst is selected from 4-dimethylaminopyridine, N-methylimidazolium and pyridine.

497. The method according to any one of claims 491 to 496, wherein the reaction of the compound of formula L or a salt thereof is carried out in a forty-first solvent comprising tert-butyl methyl ether.

498. The method according to any one of claims 491 to 497, wherein the reaction of the compound of formula L or a salt thereof is carried out in a temperature range of about 0°C to about 100°C.

499. The method according to any one of claims 246 to 260 and 272 to 277, the method further comprising preparing a compound of formula E or a salt thereof by a method comprising: Compounds of formula O-1: O-1 Or its salt and: Amine protecting group reagents Phosphine reagents and azodicarbonate reaction, The compound of formula E or its salt is obtained.

500. The method according to claim 499, wherein the amine protecting group reagent is selected from phthalimide, di-tert-butyl iminodicarboxylate, ethyl 2-((tert-butoxycarbonyl)amino)-2-oxoacetate, methyl 2-((tert-butoxycarbonyl)amino)-2-oxoacetate, tert-butyl methyl iminodicarbonate, and dimethyl iminodicarbonate.

501. The method according to claim 499 or 500, wherein the amine protecting group reagent is phthalimide.

502. The method according to any one of claims 499 to 501, wherein the phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine.

503. The method according to any one of claims 499 to 502, wherein the phosphine reagent is triarylphosphine.

504. The method according to any one of claims 499 to 503, wherein the phosphine reagent is triphenylphosphine.

505. The method according to any one of claims 499 to 504, wherein the azodicarbonate is selected from di-tert-butyl azodicarbonate, diisopropyl azodicarbonate, diethyl azodicarbonate, dimethoxy ethyl azodicarbonate, azodicarbonyl dimorpholine, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzoic acid azodicarbonate.

506. The method according to any one of claims 499 to 505, wherein the azodicarbonate is diisopropyl azodicarbonate.

507. The method according to any one of claims 499 to 506, wherein the reaction of the compound of formula O-1 or a salt thereof is carried out in a second-twelfth solvent containing 2-methyltetrahydrofuran.

508. The method according to any one of claims 499 to 507, wherein the reaction of the compound of formula O-1 or a salt thereof is carried out in a temperature range of about -20°C to about 50°C.

509. The method according to any one of claims 499 to 508, further comprising preparing a compound of formula O-1 or a salt thereof by a method comprising: Compounds of formula O-2: O-2 Or its salt and: Fifth catalyst and Hydrogen reaction; The compound of formula O-1 or its salt is obtained.

510. The method of claim 509, wherein the fifth catalyst is selected from palladium catalysts, platinum catalysts, and bimetallic catalysts, wherein the bimetallic catalyst comprises two metals selected from palladium, platinum, and copper.

511. The method according to claim 509 or 510, wherein the fifth catalyst is a palladium catalyst.

512. The method according to any one of claims 509 to 511, wherein the fifth catalyst is a lindra catalyst.

513. The method according to any one of claims 509 to 512, wherein the fifth catalyst comprises 5% by weight palladium supported on lead-poisoned calcium carbonate.

514. The method according to any one of claims 509 to 513, wherein the molar ratio of the compound of formula O-2 or a salt thereof to the fifth catalyst is from about 1:0.001 to about 1:0.

05.

515. The method according to any one of claims 509 to 514, wherein the reaction of the compound of formula O-2 or a salt thereof is carried out at a pressure of about 1 psi to about 100 psi.

516. The method according to any one of claims 509 to 515, wherein the reaction of the compound of formula O-2 or a salt thereof is carried out at a pressure of about 50 psi.

517. The method according to any one of claims 509 to 516, wherein the reaction of the compound of formula O-2 or a salt thereof is carried out in a twenty-third solvent containing N,N-dimethylformamide.

518. The method according to any one of claims 509 to 517, wherein the reaction of the compound of formula O-2 or a salt thereof is carried out in a temperature range of about 0°C to about 100°C.

519. The method according to any one of claims 509 to 518, further comprising preparing a compound of formula O-2 or a salt thereof by a method comprising: Compounds of formula O-3: O-3 or its salt, wherein R 11 Selected from C 1-20 Alkyl, phenyl and -CH2NH2; with: The twelfth base reaction; The compound of formula O-2 or its salt is obtained.

520. The method of claim 519, wherein R 11 It is selected from methyl, ethyl, isopropyl, pentyl, heptyl, nonyl, pentadecyl, phenyl and -CH2NH2.

521. The method according to claim 519 or 520, wherein R 11 It is a methyl group.

522. The method according to any one of claims 519 to 521, wherein the twelfth base is selected from guanidine, carbonate, bicarbonate, metal alkoxide, amine, hydroxide, or a combination thereof.

523. The method according to any one of claims 519 to 522, wherein the twelfth alkaloid is guanidine.

524. The method according to any one of claims 519 to 523, wherein the twelfth base is tetramethylguanidine.

525. The method according to any one of claims 519 to 524, wherein the reaction of the compound of formula O-3 or a salt thereof is carried out in a twenty-fourth solvent containing methanol.

526. The method according to any one of claims 519 to 525, wherein the reaction of the compound of formula O-3 or a salt thereof is carried out in a temperature range of about -10°C to about 80°C.

527. The method according to any one of claims 519 to 526, further comprising preparing the compound of formula O-3 or a salt thereof by a method comprising: Compounds of formula O-4: O-4 Or its salt and: Second phosphine reagent, Second azodicarbonate and Formula R 7 -NH-NH-R 8 Reacts with compounds or (1,3-dioxoisoindoline-2-yl)carbamate; The compound of formula O-3 or its salt is obtained.

528. The method of claim 527, wherein the second phosphine reagent is selected from trialkylphosphine, triarylphosphine, (triphenylphosphine)acetonitrile, and n-phosphine.

529. The method according to claim 527 or 528, wherein the second phosphine reagent is a triarylphosphine.

530. The method according to any one of claims 527 to 529, wherein the second phosphine reagent is triphenylphosphine.

531. The method according to any one of claims 527 to 530, wherein the second azodicarbonate is selected from di-tert-butyl azodicarbonate, diisopropyl azodicarbonate, diethyl azodicarbonate, dimethoxy ethyl azodicarbonate, azodicarbonyl dimorpholine, 1,1-azodicarbonyl dipiperidine, and di-4-chlorobenzoic acid azodicarbonate.

532. The method according to any one of claims 527 to 531, wherein the second azodicarbonate is di-tert-butyl azodicarbonate.

533. The method according to any one of claims 527 to 532, wherein the formula R 7 -NH-NH-R 8 The compound is .

534. The method according to any one of claims 527 to 533, wherein the reaction of the compound of formula O-4 or a salt thereof is carried out in a twenty-fifth solvent containing 2-methyltetrahydrofuran.

535. The method according to any one of claims 527 to 534, wherein the reaction of the compound of formula O-4 or a salt thereof is carried out in a temperature range of about -20°C to about 50°C.

536. The method according to any one of claims 527 to 535, further comprising preparing a compound of formula O-4 or a salt thereof by a method comprising: Compounds of formula L: L Or its salt and: Alkyl esters, alkenyl esters, or oxime esters; and Enzyme reaction, The compound of formula O-4 or its salt is obtained.

537. The method of claim 536, wherein the compound of formula L or a salt thereof is reacted with an alkenyl ester selected from vinyl acetate, isopropylene acetate and vinyl butyrate.

538. The method according to claim 536 or 537, wherein the alkenyl ester is isopropyl acetate.

539. The method according to any one of claims 536 to 538, wherein the compound of formula L or a salt thereof is reacted with an alkyl ester selected from ethyl acetate, methyl acetate, isopropyl acetate and methyl butyrate.

540. The method according to any one of claims 536 to 539, wherein the compound of formula L or a salt thereof is reacted with an oxime ester selected from propion-2-one O-acetyl oxime and propion-2-one O-butyryl oxime.

541. The method according to any one of claims 536 to 540, wherein the enzyme is selected from hydrolases, Prozomix 4, Prozomix 5, Prozomix 25, Prozomix 26 and Novozyme 435.

542. The method according to any one of claims 536 to 541, wherein the enzyme is a hydrolase.

543. The method according to any one of claims 536 to 542, wherein the enzyme is lipase AK.

544. The method according to any one of claims 536 to 543, wherein the reaction of the compound of formula L or a salt thereof is carried out in a second sixteenth solvent comprising tert-butyl methyl ether.

545. The method according to any one of claims 536 to 544, wherein the reaction of the compound of formula L or a salt thereof is carried out in a temperature range of about 10°C to about 70°C.

546. A method for preparing a compound of formula IA or a salt thereof: IA The method includes: (a) Compounds of formula A: A or its salt, wherein R 3A It is a hydroxyl protecting group, and: Methylene reagent and First acid or first base reaction The compound of formula I was obtained: I or its salt, wherein R 1 It is a hydroxyl protecting group; and (b) Deprotect the compound of formula I or a salt thereof to obtain the compound of formula IA or a salt thereof.

547. A method for preparing a compound of formula IA or a salt thereof: IA The method includes: (a) Compounds of formula R-1: R-1 Or its salt and: Methylene reagent and The eighth acid or the fourteenth base reaction, The compound of formula I was obtained: I or its salt, wherein R 1 It is a hydroxyl protecting group; and (b) Deprotect the compound of formula I or a salt thereof to obtain the compound of formula IA or a salt thereof.

548. The method of claim 547, further comprising preparing a compound of formula R-1 or a salt thereof by a method comprising: (c) Compounds of formula A: A or its salt, wherein R 3A It is a hydrogen or hydroxyl protecting group, and is related to: Reagents selected from metal hydroxides, metal halides, and trialkylsilyl halides; The compound of formula R-2 is obtained: R-2 or its salt; and (d) Mixing the compound of formula R-2 or a salt thereof with: Coupling agents and The fifteenth base reaction, The compound of formula R-1 or its salt is obtained.

549. The method of claim 547, further comprising preparing a compound of formula R-1 or a salt thereof by a method comprising: (c) Compounds of formula A: A or its salt, wherein R 3A It is a hydroxyl protecting group, and: The sixteenth base reaction; The compound of formula R-1 or its salt is obtained.

550. The method according to any one of claims 546 to 549, further comprising preparing a compound of formula A or a salt thereof by a method comprising: (e) Compounds of formula D: D Or its salt deprotection, wherein R 5 Is it hydrogen or R? 9 , where R 9 It is an amine protecting group, and R 7 and R 8 Each is an amine protecting group independently; Compounds of formula C are obtained: C or its salt; and (f) Compounds of formula XA: XA Or its salt and: The compound of formula C or a salt thereof, and The seventh base reaction; The compound of formula A or its salt is obtained.

551. The method of claim 550, further comprising preparing a compound of formula D or a salt thereof by a method comprising: (g) Compounds of formula E: E Or its salt deprotection, wherein: R 7 and R 8 Each is an amine protecting group independently; and R 9 It is an amine protecting group and R 10 It is hydrogen; or optionally: R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form heterocyclic protecting groups; A compound of formula D or a salt thereof is obtained, having formula D-1: D-1 Or its salt.

552. The method according to any one of claims 546 and 548 to 551, further comprising preparing the compound of formula A by a method comprising: (e) Compounds of formula E: E or its salt, wherein R 9 and R 10 Together with the nitrogen atoms to which they are attached, they form phthalimides; It reacts with the seventh acid to give a compound of formula Q-2: Q-2 or its salt; (f) Mixing the compound of formula Q-2 or a salt thereof with: Compounds of formula XA: XA or its salt and Thirteenth base reaction; The compound of formula Q-1 was obtained: Q-1 or its salt; and (g) Reacting the compound of formula Q-1 or a salt thereof with a reagent selected from hydrazine, alkoxide and hydrolase; The compound of formula A or its salt is obtained.

553. The method according to claim 551 or 552, further comprising preparing the compound of formula E by a method comprising: (h) Compounds of formula H: H or its salt, wherein R 11 Selected from C 1-20 Alkyl, phenyl, and -CH2NH2; Reaction with the sixth acid or the eighth base Compounds of formula G are obtained: G or its salt; (i) To react the compound of formula G or a salt thereof with: The third catalyst, and Hydrogen reaction; Compounds of formula F are obtained: F or its salt; and (j) Mixing a compound of formula F or a salt thereof with: Phosphine reagent azodicarbonate and Formula R 7 -NH-NH-R 8 The reaction of compounds; The compound of formula E or its salt is obtained.

554. The method according to claim 551 or 552, further comprising preparing the compound of formula E by a method comprising: (h) Compounds of formula F: F Or its salt and: Phosphine reagent azodicarbonate and Formula R 7 -NH-NH-R 8 The reaction of compounds; The compound of formula E or its salt is obtained.

555. The method of claim 554, further comprising preparing a compound of formula F by means of: (i) Compounds of formula S: S Or its salt and: Compounds of formula T: T or its salt, Where R 15 Selected from phenyl and C 1-4 Halogenated alkyl group, wherein the phenyl group is optionally composed of 1 to 4 C6 atoms. 1-4 Alkyl, halogen, C 1-4 Substitution of alkyl and cyano groups; The seventeenth base and Fourth additive reaction; Compounds of formula W were obtained: W or its salt; and (j) Mixing a compound of formula W or a salt thereof with: The sixth catalyst and Reducing agent reaction; To obtain a compound of formula F or a salt thereof.

556. The method of claim 554, further comprising preparing a compound of formula F by means of: (i) Compounds of formula W: W Or its salt and: The second enzyme reacts in the presence of the second buffer solution; To obtain a compound of formula F or a salt thereof.

557. The method of claim 554, further comprising preparing a compound of formula F by means of: (i) Compounds of formula G: G Or its salt and: Third reducing agent and Activator reaction; To obtain a compound of formula F or a salt thereof.

558. The method according to claim 550 or 551, further comprising preparing a compound of formula D or a salt thereof by a method comprising: (g) To make compounds of formula H having formula H-1: H-1 or its salt, wherein: R 9 It is an amine protecting group; and R 11 Selected from C 1-20 Alkyl, phenyl, and -CH2NH2; Reaction with the twelfth base, The compound of formula G-1 was obtained: G-1 or its salt; (h) Mix the compound of formula G-1 or a salt thereof with: Third catalyst Aromatic amines or sulfur-containing reagents; and Hydrogen reaction; The compound of formula F-1 was obtained: F-1 or its salt; as well as (i) To react the compound of formula F-1 or a salt thereof with: Phosphine reagent azodicarbonate and Formula R 7 -NH-NH-R 8 The reaction of compounds; The compound of formula D or its salt is obtained.

559. The method according to claim 550 or 551, further comprising preparing a compound of formula D or a salt thereof by a method comprising: (g) Compounds of formula G-1: G-1 Or its salt and: Third catalyst Aromatic amines or sulfur-containing reagents; and Hydrogen reaction; The compound of formula F-1 was obtained: F-1 or its salt; and (h) Mix the compound of formula F-1 or a salt thereof with: Phosphine reagent azodicarbonate and Formula R 7 -NH-NH-R 8 The reaction of compounds; The compound of formula D or its salt is obtained.

560. The method according to claim 557 or 559, further comprising preparing a compound of formula G or a salt thereof by a method comprising: wherein the compound of formula G or a salt thereof is a compound of formula G-1 or a salt thereof: (j) Compounds of formula L: L Or its salt and: The fourth enzyme reacts in the presence of the fourth buffer solution; Compounds of formula U-2 were obtained: U-2 or its salt; (k) Mix the compound of formula U-2 or a salt thereof with: The third enzyme reacts in the presence of the third buffer solution; Compounds of formula U-1 were obtained: U-1 or its salt; and (l) Mixing the compound of formula U-1 or a salt thereof with: The second amine protecting group reacts with a reagent to give the compound of formula G-1 or its salt.

561. The method according to claim 553 or 558, further comprising preparing a compound of formula H or a salt thereof by a method comprising: (k) Compounds of formula J: J Or its salt and: Second phosphine reagent, Second azodicarbonate and Amine protecting group reagent reaction; To obtain a compound of formula H or a salt thereof.

562. The method according to claim 553 or 558, further comprising preparing a compound of formula H or a salt thereof by a method comprising: (k) Compounds of formula J: J or its salt, wherein: R 12 It is -S(O)3R 13 or -OC(=N)R 14 ; R 13 Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and optionally C 1-4 Alkyl-substituted phenyl; and R 14 It is C 1-4 Halogenated alkyl groups; and: The eleventh base and The third reagent reaction, wherein the third reagent is selected from methanesulfonyl chloride, acid anhydride or acyl halide; Compounds of formula N are obtained: N or its salt; as well as (l) Reacting a compound of formula N or a salt thereof with an amine protecting group reagent, To obtain a compound of formula H or a salt thereof.

563. The method of claim 558, further comprising preparing a compound of formula H-1 or a salt thereof by a method comprising: (k) Compounds of formula N: N or its salt, wherein: R 12 It is -S(O)3R 13 or -OC(=N)R 14 ;and R 13 Selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups and optionally C 1-4 Alkyl-substituted phenyl; and: azides and Tertiary phosphine reagent reaction; The compound of formula P-1 was obtained: P-1 or its salt; as well as (l) React the compound of formula P-1 or its salt with an amine protecting group reagent to obtain the compound of formula H-1 or its salt.

564. The method of claim 558, further comprising preparing a compound of formula H-1 or a salt thereof by a method comprising: (k) Compounds of formula J: J Or its salt and: azides, Tertiary phosphine reagent and Third azodicarbonate reaction; Compounds of formula P-2 were obtained: P-2 or its salt; and (l) Mixing the compound of formula P-2 or a salt thereof with: Phosphine reagent; and Amine protecting group reagent reaction; The compound of formula H-1 or its salt is obtained.

565. The method according to any one of claims 561, 562, and 564, further comprising preparing a compound of formula J or a salt thereof by a method comprising: (m) Compounds of formula L: L or its salt; and: Ninth Alkali Fourth catalyst and Reactions of compounds of formula M-1 or M-2: M-1 ； M-2 Where X is a halide; Compounds of formula K are obtained: K or its salt; as well as (n) Mix the compound of formula K or a salt thereof with: enzymes and Buffer reaction; The compound of formula J or its salt is obtained.

566. The method according to claim 551 or 552, further comprising preparing the compound of formula E by a method comprising: (h) Compounds of formula L: L Or its salt and: Alkyl esters, alkenyl esters, or oxime esters; and Enzyme reaction, Compounds of formula O-4 were obtained: O-4 or its salt; (i) To react the compound of formula O-4 or a salt thereof with: Second phosphine reagent, Second azodicarbonate and Formula R 7 -NH-NH-R 8 Reacts with compounds or (1,3-dioxoisoindoline-2-yl)carbamate; Compounds of formula O-3 were obtained: O-3 or its salt; (j) Make a compound of formula O-3 or a salt thereof, wherein R 11 Selected from C 1-20 Alkyl, phenyl and -CH2NH2; with: The twelfth base reaction; Compounds of formula O-2 were obtained: O-2 or its salt; (k) Mix the compound of formula O-2 or a salt thereof with: Fifth catalyst and Hydrogen reaction; The compound of formula O-1 is obtained: O-1 or its salt; and (l) Mixing the compound of formula O-1 or a salt thereof with: Amine protecting group reagents Phosphine reagents and azodicarbonate reaction, The compound of formula E or its salt is obtained.

567. A method for preparing a compound of formula I or a salt thereof: I Where R 1 Selected from hydrogen and hydroxyl protecting groups; the method includes: Compounds of formula R-1: R-1 Or its salt and: Methylene reagent and The eighth acid or the fourteenth base reaction, The compound of formula I or its salt is obtained.

568. The method according to claim 567, wherein the methylene reagent is a formaldehyde reagent or a dihalomethane.

569. The method according to claim 567 or 568, wherein the methylene reagent is selected from 1,3,5-trioxane, formaldehyde acetal, formaldehyde, paraformaldehyde, or dihalomethane.

570. The method according to any one of claims 567 to 569, wherein the methylene reagent is formaldehyde.

571. The method according to any one of claims 567 to 570, wherein the compound of formula R-1 or a salt thereof is reacted with the eighth acid.

572. The method according to any one of claims 567 to 571, wherein the eighth acid comprises a carboxylic acid, a sulfonic acid, a Lewis acid, an inorganic acid, or a combination thereof.

573. The method according to any one of claims 567 to 572, wherein the eighth acid is a sulfonic acid.

574. The method according to any one of claims 567 to 573, wherein the eighth acid is methanesulfonic acid.

575. The method according to claims 567 to 570, wherein the compound of formula R-1 or a salt thereof is reacted with the fourteenth base.

576. The method according to any one of claims 567 to 570 and 575, wherein the fourteenth base comprises an amine, amidine, guanidine, carboxylate, carbonate, metal hydride, phosphate, hydroxide, alkoxide, amide, basic aromatic compound, or a combination thereof.

577. The method according to any one of claims 567 to 576, wherein the reaction of the compound of formula R-1 or a salt thereof is carried out in a forty-second solvent containing tetrahydrofuran.

578. The method according to any one of claims 567 to 577, wherein the reaction of the compound of formula R-1 or a salt thereof is carried out in a temperature range of about 20°C to about 100°C.

579. The method according to any one of claims 567 to 578, further comprising preparing a compound of formula R-1 or a salt thereof by a method comprising: Compounds of formula R-2: R-2 Or its salt and: Coupling agents and The fifteenth base reaction, The compound of formula R-1 or its salt is obtained.

580. The method of claim 579, wherein the coupling agent comprises 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b Pyridinium 3-oxide hexafluorophosphate (HATU), acyl chloride, acid anhydride, carbonyl diimidazole, activated ester or a combination thereof.

581. The method according to claim 579 or 580, wherein the coupling agent is HATU.

582. The method according to any one of claims 579 to 581, wherein the fifteenth base is selected from amines, amidines, guanidines, carboxylates, carbonates, metal hydrides, phosphates, hydroxides, alkoxides, basic aromatic compounds, or combinations thereof.

583. The method according to any one of claims 579 to 582, wherein the fifteenth alkali is an amine.

584. The method according to any one of claims 579 to 583, wherein the fifteenth base is N,N-diisopropylethylamine.

585. The method according to any one of claims 579 to 584, wherein the reaction of the compound of formula R-2 or a salt thereof is carried out in a twenty-eighth solvent containing N,N-dimethylacetamide.

586. The method according to any one of claims 579 to 585, wherein the reaction of the compound of formula R-2 or a salt thereof is carried out in a temperature range of about 0°C to about 80°C.

587. The method according to any one of claims 579 to 586, further comprising preparing a compound of formula R-2 or a salt thereof by a method comprising: Compounds of formula A: A or its salt, wherein R 3A It is a hydrogen or hydroxyl protecting group, and is related to: Reagents selected from metal hydroxides, metal halides, and trialkylsilyl halides; The compound of formula R-2 or its salt is obtained.

588. The method of claim 587, wherein R 3A Selected from hydrogen, C 1-4 Alkyl and benzyl.

589. The method according to claim 587 or 588, wherein R 3A It is selected from hydrogen, methyl, ethyl, isopropyl and benzyl.

590. The method according to any one of claims 587 to 589, wherein R 3A It is a methyl group.

591. The method according to any one of claims 587 to 590, wherein the compound of formula A is reacted with a metal hydroxide.

592. The method according to any one of claims 587 to 591, wherein the metal hydroxide is sodium hydroxide.

593. The method according to any one of claims 587 to 592, wherein the reaction of the compound of formula A or a salt thereof is carried out in a forty-fourth solvent containing methanol.

594. The method according to any one of claims 587 to 593, wherein the reaction of the compound of formula A or a salt thereof is carried out in a temperature range of about 0°C to about 100°C.

595. A method for preparing a compound of formula I or a salt thereof: I Where R 1 Selected from hydrogen and hydroxyl protecting groups; the method includes: (a) Compounds of formula A: A or its salt, wherein R 3A It is a hydrogen or hydroxyl protecting group, and is related to: Reagents selected from metal hydroxides, metal halides, and trialkylsilyl halides; The compound of formula R-2 is obtained: R-2 or its salt; (b) Mixing the compound of formula R-2 or a salt thereof with: Coupling agents and The fifteenth base reaction, The compound of formula R-1 was obtained: R-1 or its salt; as well as (c) Mixing the compound of formula R-1 or a salt thereof with: Methylene reagent and The eighth acid or the fourteenth base reaction, The compound of formula I or its salt is obtained.

596. A compound of formula A: A or its salt, wherein R 1 and R 3A It is independently selected from hydrogen and hydroxyl protecting groups.

597. A compound of formula R-1: R-1 or its salt, wherein R 1 Selected from hydrogen and hydroxyl protecting groups.

598. A compound of formula R-2: R-2 or its salt, wherein R 1 Selected from hydrogen and hydroxyl protecting groups.

599. A compound of formula Q-1: Q-1 or its salt, wherein R 1 and R 3A Each has a hydroxyl protecting group.

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