Processes and intermediates for preparation of antiviral prodrugs

Abstract

The present invention relates to processes for preparing antiviral prodrugs, co-crystals, solvents, salts or combinations thereof and related synthetic intermediate compounds (I). I

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 523,555, filed June 27, 2023, pursuant to 35 USC § 119(e), which is incorporated herein by reference in its entirety for all purposes. Technical Field

[0002] This invention relates to methods and intermediates for synthesizing antiviral prodrugs, their cocrystals, solvates, salts or combinations thereof, and related synthetic intermediate compounds. Background Technology

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

[0004] Positive single-stranded RNA viruses, including those in the family Retroviridae, include the subfamily Orthoviridiae, which causes many diseases in humans and animals. Orthoretrovirinae ) and alpha retrovirus ( Alpharetrovirus ), β retrovirus ( Betaretrovirus ), γ retrovirus ( Gammaretrovirus ), δ retrovirus ( Deltaretrovirus ε retrovirus ( Epsilon retrovirus ), foam virus ( Spumavirus ) and lentiviruses ( Lentivirus Those belonging to the genus lentivirus. In lentiviruses, HIV-1 infection in humans leads to the depletion of T helper cells and immune dysfunction, resulting in immunodeficiency and susceptibility to opportunistic infections.

[0005] One approach to treating HIV-1 infection is through the administration of NRTTIs. NRTTIs inhibit HIV-1 reverse transcriptase, and since reverse transcriptase function is essential for viral replication and the production of viral proteins, NRTTIs are effective against HIV-1 infection. Curr Opin HIV AIDS. 2018 July; 13(4): 294–299. However, HIV treatment has historically led to the emergence of HIV strains resistant to current therapies. Expert Opin Emerg Drugs. 2018 June; 23(2): 149–157. Therefore, there is a ongoing need to discover new antiretroviral agents and develop methods for the preparation and purification of such new antiretroviral agents.

[0006] U.S. Patent Application No. 17 / 642,552 discloses novel compounds that can be used to treat HIV infection. One specific compound identified in this application is a compound of Formula I: There is a need for improved synthetic methods and intermediates for the preparation of Formula I compounds and their cocrystals, solvates, salts, and combinations thereof. Improved methods for preparing intermediate compounds, which can be used to prepare Formula I compounds and their cocrystals, solvates, salts, and combinations thereof, are also needed. Improved methods and intermediates can reduce the costs, time, and / or waste associated with existing methods for the preparation of Formula I compounds and their cocrystals, solvates, salts, and combinations thereof. The methods disclosed herein meet these and other needs. Summary of the Invention

[0007] This disclosure particularly provides preparation of compounds of formula I: I Or by means of eutectic, solvate, salt or combination thereof, This method involves making a compound of formula XVII: XVII Or its eutectic, solvate, salt, or combination with compounds of formula XVIII: XVIII Where X is selected from halogens, -OCOCH2Ph ​​and OH, and Alkali reaction, To provide a compound of formula I or a eutectic, solvate, salt or combination thereof.

[0008] This disclosure further provides a method for preparing compound of formula I: I Or by means of eutectic, solvate, salt or combination thereof, This method involves making a compound of formula XXII: XXII Or its eutectic, solvate, salt or combination thereof, Where R 6 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyloxy, benzyloxy, or optionally one to five independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl, Compounds of formula XV: XV, Silylating agents and Lewis acid reaction, To provide a compound of formula I or a eutectic, solvate, salt or combination thereof.

[0009] Details of one or more embodiments of the present invention are set forth in the appended description below. Other features, objects, and advantages of the invention will become apparent from the specification, drawings, and claims. Detailed Implementation

[0010] This disclosure provides preparation of compound I: I Methods for the preparation of cocrystals, solvates, salts, or combinations thereof. This compound of formula I is also known as 2-phenylacetic acid (2...). R ,3 S 5 R )-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl ester, and disclosed in U.S. Publication Nos. 20220323476A1 and 20220332751A1, the contents of each of which are incorporated herein by reference in their entirety.

[0011] Compound I is compound XVII (i.e., islatravir, 4′-ethynyl-2-fluoro-2′-deoxyadenosine, or (2 R ,3 S 5 R )-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2-(hydroxymethyl)tetrahydrofuran-3-ol), a prodrug that can be used to treat retroviral infections, including nucleoside reverse transcriptase translocation inhibitors (NRTTIs) caused by HIV.

[0012] XVII 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.

[0013] 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.

[0014] As used herein and in the appended claims, the singular forms “an”, “a”, and “the” include multiple referents unless the context clearly specifies otherwise. Thus, for example, reference to “the compound” includes multiple such compounds, and reference to “the determination” includes reference to one or more determinations, etc.

[0015] 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 rotational plane-polarized light at the wavelength of the sodium D line. 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. All stereochemistry of the compounds described herein is not intended to be limiting.

[0016] 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.

[0017] 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. As used herein, a “non-racemic mixture” is a mixture of stereoisomers in a ratio not equal to 1:1.

[0018] Pharmaceutically acceptable hydrates, solvates, cocrystals, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided.

[0019] The term "hydrate" refers to a complex formed by the combination of a compound of formula I or any of the formulas disclosed herein with water.

[0020] The term "solvent" refers to a complex formed by combining a compound of formula I or any other formula disclosed herein with a solvent or a crystalline solid containing a solvent incorporated into the crystal structure. As used herein, the term "solvent" includes hydrates.

[0021] The term "cocrystal" refers to a crystalline material formed by combining a compound of Formula I or any of the formulas disclosed herein with one or more cocrystal formations (i.e., molecules, ions, or atoms). In certain cases, cocrystals may have improved properties compared to the parent form (i.e., free molecules, zwitterions, etc.) or salts of the parent compound. Improved properties may include increased solubility, increased dissolution rate, increased bioavailability, increased dose response, reduced hygroscopicity, crystalline form of normally amorphous compounds, crystalline form of compounds that are difficult or non-salting, reduced form diversity, more desirable morphology, etc. Methods for preparing and characterizing cocrystals are known to those skilled in the art.

[0022] 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 can 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, 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, and 125I. Various isotopically labeled compounds of this disclosure, such as those incorporating radioactive isotopes such as 3H, 13C, and 14C, are also included. These isotope-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.

[0023] 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 used to prolong 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 a starting material in which one or more hydrogen atoms have been replaced by deuterium.

[0024] The deuterium-labeled or substituted therapeutic compounds of this disclosure 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 requirement. 18F-labeled compounds can be used for PET or SPECT studies. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents in the formulations or procedures disclosed in the examples and formulations described below. Furthermore, substitution with a heavier isotope, especially deuterium (i.e., 2H 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 of the formulas disclosed herein.

[0025] 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.

[0026] 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).

[0027] "Alkyl" is a straight-chain or branched saturated hydrocarbon. For example, an alkyl group may have 1 to 8 carbon atoms (i.e., (C1-C8)alkyl), 1 to 6 carbon atoms (i.e., (C1-C6)alkyl), or 1 to 4 carbon atoms (i.e., (C1-C4)alkyl). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (... n -Pr、 just propyl, -CH2CH2CH3), 2-propyl ( i -Pr、 different propyl, -CH(CH3)2), 1-butyl ( n -Bu、 just Butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl ( i -Bu、 different Butyl, -CH2CH(CH3)2), 2-Butyl ( s -Bu、 Zhong Butyl, -CH(CH3)2CH3), 2-methyl-2-propyl ( t -Bu、 Uncle Butyl, -C(CH3)3), 1-pentyl ( justpentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)) (CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)2CH3), 4-methyl-2-pentyl (-CH(CH3)2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3) and octyl (-(CH2)7CH3).

[0028] As used herein, the term "alkoxy" refers to a group of the formula -O-alkyl. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and tert-butoxy.

[0029] As used in this article, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0030] As used herein, the term "haloalkyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are each independently replaced by a halogen substituent. For example, a (C1-C6)haloalkyl is a (C1-C6)alkyl group in which one or more hydrogen atoms of the (C1-C6)alkyl group have been replaced by a halogen substituent. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0031] As used herein, the term "aryl" refers to a single all-carbon aromatic ring or a polyfused all-carbon ring system, wherein at least one ring is aromatic. For example, in some embodiments, the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl groups include phenyl radicals. Aryl groups also include polyfused ring systems having about 9 to 20 carbon atoms (e.g., ring systems comprising 2, 3, or 4 rings), wherein at least one ring is aromatic, and wherein the other rings may be aromatic or non-aromatic (i.e., carbon rings). Such polyfused ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbon ring portion of the polyfused ring system. When valence requirements permit, the rings of a polyfused ring system may be linked to each other via fusion, spirocyclic, and bridging bonds. It should be understood that the attachment point of a polyfused ring system as defined above can be anywhere in the ring system, including at the aromatic or carbocyclic portion of the ring. It should also be understood that when referring to a range of atomic aryl groups (e.g., 6- to 10-membered aryl groups), the atomic range refers to the total number of ring atoms in that aryl group. For example, a 6-membered aryl group would include a phenyl group, and a 10-membered aryl group would include a naphthyl group and a 1,2,3,4-tetrahydronaphthyl group. Non-limiting examples of aryl groups include, but are not limited to, phenyl (Ph), indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthraceneyl, etc.

[0032] The term "cycloalkyl" refers to cyclic alkyl groups and alkenyl groups. Cycloalkyl groups may have one or more cyclic rings and include fully saturated or partially unsaturated fused and bridging groups. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, methylcyclopropyl (cyclopropylmethyl), ethylcyclopropyl, cyclohexenyl, etc.

[0033] 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... 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.

[0034] In some cases, the methods disclosed herein involve the step of forming a salt of the compounds disclosed herein.

[0035] 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.

[0036] During any method used to prepare the subject compound, it may be necessary and / or desirable to protect sensitive or reactive groups on any molecule of interest. This can be demonstrated in standard works such as TW Greene and PGM Wuts. Protective Groups in Organic Synthesis The protecting group is implemented using conventional protecting groups as described in the 4th edition, Wiley, New York, 2006. The protecting group can be removed at a convenient subsequent stage using methods known in the art.

[0037] 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 operated at a temperature ranging from about -80°C to the reflux temperature of the organic solvent used.

[0038] In some embodiments, this document provides a method for preparing a compound of formula I or a cocrystal thereof, a solvate, a salt, or a combination thereof; said method comprising reacting a compound of formula XVII or a cocrystal thereof, a solvate, a salt, or a combination thereof with a compound of formula XVIII: XVIII Where X is selected from halogens, -OCOCH2Ph ​​and OH, and Alkali reaction, To provide a compound of formula I or a eutectic, solvate, salt or combination thereof.

[0039] In some embodiments, X is a halogen. In some embodiments, X is Cl or Br. In some embodiments, X is Cl.

[0040] In some embodiments, X is OH, and the reaction is carried out in the presence of an activating agent. In some embodiments, the activating agent comprises a chlorinating agent, 1,1-carbonyldiimidazole, carbodiimide, peptide coupling agent, or a combination thereof. In some embodiments, the chlorinating agent comprises oxalyl chloride, thionyl chloride, phosphoryl chloride, or a combination thereof. In some embodiments, the carbodiimide is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. In some embodiments, the peptide coupling agent comprises HATU, propylphosphonic anhydride, isobutyl chloroformate, or a combination thereof. In some embodiments, the activating agent is selected from the group consisting of oxalyl chloride, thionyl chloride, phosphoryl chloride, 1,1-carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, HATU, propylphosphonic anhydride, and isobutyl chloroformate.

[0041] In some embodiments, the base comprises an aromatic amine, a tertiary alkylamine, a carbonate, or a combination thereof. In some embodiments, the base comprises an aromatic amine. In some embodiments, the aromatic amine comprises pyridine, 2,6-dimethylpyridine, pyridazine, imidazole, pyrimidine, pyrazine, or a combination thereof. In some embodiments, the base is N-methylimidazole. In some embodiments, the tertiary alkylamine comprises triethylamine, diisopropylethylamine, ... N -Methylmorpholine or combinations thereof. In some embodiments, the carbonate is an alkali metal carbonate (e.g., lithium carbonate, sodium carbonate, cesium carbonate).

[0042] In some embodiments, the reaction is carried out in a solvent (e.g., a first solvent) containing a polar aprotic solvent (e.g., acetonitrile, etc.). N , N -Dimethylformamide, N , N -Dimethylacetamide, N 1,2-methyl-2-pyrrolidone), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, diethylene glycol dimethyl ether, dimethyl isosorbide), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene, dichloromethane, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the reaction is carried out in a solvent comprising acetone and acetonitrile (e.g., a first solvent).

[0043] In some embodiments, the reaction is carried out within a temperature range of about -20°C to about 10°C. In some embodiments, the reaction is carried out within a temperature range of about -20°C to about 0°C, such as about -10°C.

[0044] In some embodiments, the reaction is carried out in the presence of a catalyst. In some embodiments, the catalyst is selected from the group consisting of 4-dimethylaminopyridine, imidazole, triphenylphosphine oxide, and 1-hydroxy-7-azabenzotriazole.

[0045] In some embodiments, the method further includes preparing a compound of formula XVII or its eutectic, solvate, salt, or combination thereof by means of: making a compound of formula XVI-A: XVI-A Or its eutectic, solvate, salt or combination thereof, Where P 1 Is it H or (R) 4 )3Si, where each R 4 C is independent 1-6 Alkyl groups, and Deacylation reagents and The second base reaction, To provide compounds of formula XVII or their eutectic, solvate, salt or combination thereof.

[0046] In some implementations, each R 4 Independently for C 1-3 Alkyl group. In some embodiments, P 1 It is trimethylsilyl or triisopropylsilyl. In some embodiments, P 1 It is trimethylsilyl. In some embodiments, P 1 It's H.

[0047] In some embodiments, the compound of formula XVI-A or its eutectic, solvate, salt, or combination thereof is a compound of formula XVI: XVI Or its eutectic, solvate, salt or combination thereof.

[0048] In some implementations, the deacylation agent is C 1-4 Alcohols. In some embodiments, the deacylation agent includes methanol, ethanol, 1-propanol, 2-propanol, or another nucleophilic alcohol (e.g., tert-butanol) or combinations thereof. In some embodiments, the deacylation agent is methanol.

[0049] In some embodiments, the second base comprises a hydroxide, oxide, alkoxide, carbonate, or a combination thereof. For example, the second base is selected from the group consisting of: alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide), alkali metal oxides (e.g., sodium oxide), alkaline earth metal oxides (e.g., calcium oxide, magnesium oxide), alkali metal alkoxides (e.g., sodium methoxide, potassium methoxide, lithium methoxide, potassium tert-butoxide, sodium tert-butoxide), alkali metal carbonates (e.g., sodium carbonate, cesium carbonate, potassium carbonate), or combinations thereof. In some embodiments, the second base comprises an alkali metal alkoxide. In some embodiments, the second base is sodium methoxide.

[0050] In some embodiments, a second base of about 0.02 equivalents to about 0.2 equivalents is used relative to the compound of formula XVI-A or its eutectic, solvate, salt, or combination thereof. In some embodiments, a second base of about 0.02 equivalents to about 0.15 equivalents, about 0.02 equivalents to about 0.10 equivalents, or about 0.02 equivalents to about 0.05 equivalents is used relative to the compound of formula XVI-A or its eutectic, solvate, salt, or combination thereof. In some embodiments, a second base of about 0.03 equivalents is used relative to the compound of formula XVI-A or its eutectic, solvate, salt, or combination thereof.

[0051] In some embodiments, the reaction of the compound of formula XVI-A or its eutectic, solvate, salt, or combination is carried out in a solvent (e.g., a second solvent) containing a polar aprotic solvent (e.g., N , N -Dimethylformamide, N , N -Dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, tert-butylmethyl ether, 1,4-dioxane, diethylene glycol dimethyl ether, dimethyl isosorbide), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene, dichloromethane, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the reaction of the compound of formula XVI-A or its eutectic, solvate, salt, or combination thereof is carried out in a solvent comprising tetrahydrofuran and methanol (e.g., a second solvent).

[0052] In some embodiments, the reaction of the compound of formula XVI-A or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about -20°C to about 20°C. In some embodiments, the reaction of the compound of formula XVI-A or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about -10°C to about 5°C, such as about 0°C.

[0053] In some embodiments, the method further includes preparing a compound of formula XVI-A or its cocrystal, solvate, salt, or combination thereof by means of: making a compound of formula XIV: XIV Or its eutectic, solvate, salt or combination thereof, Where R 1 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyloxy, benzyloxy, or optionally one to five independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl, Compounds of formula XV: XV Or its eutectic, solvate, salt or combination thereof, Silylating agents and Lewis acid reaction, To provide a compound of formula XVI-A or its eutectic, solvate, salt or combination thereof.

[0054] In some implementation schemes, R 1 C 1-4 Alkyl group. In some embodiments, R 1 It is methyl. In some embodiments, R 1 It is ethyl. In some embodiments, R 1 C 1-4 Halogenated alkyl groups. In some embodiments, R 1 It is trifluoromethyl.

[0055] In some implementation schemes, R 1 To be optionally selected from 1 to 5 independently from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl. In some implementations, R 1 It is phenyl. In some embodiments, R 1 It is toluene-based.

[0056] In some embodiments, the Lewis acid is selected from the group consisting of: trimethylsilyl trifluoromethanesulfonate, boron trifluoride diethyl ether, and tin tetrachloride. In some embodiments, the Lewis acid is trimethylsilyl trifluoromethanesulfonate.

[0057] In some embodiments, the silylating agent is selected from the group consisting of bis(trialkylsilyl)acetamide and bis(trialkylsilyl)trifluoroacetamide. In some embodiments, the silylating agent is selected from the group consisting of bis(trimethylsilyl)acetamide and bis(trimethylsilyl)trifluoroacetamide. In some embodiments, the silylating agent is bis(trimethylsilyl)acetamide. In some embodiments, the reaction of the compound of formula XIV or its eutectic, solvate, salt, or combination thereof is carried out in a solvent (e.g., a third solvent) comprising a polar aprotic solvent (e.g., acetonitrile, propionitrile, benzyl nitrile), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, α,α,α-trifluorotoluene), toluene, xylene, anisole, trifluorotoluene, or combinations thereof. In some embodiments, the reaction of the compound of formula XIV or its eutectic, solvate, salt, or combination thereof is carried out in a solvent containing acetonitrile (e.g., a third solvent).

[0058] In some embodiments, the reaction of the compound of formula XIV or its eutectic, solvate, salt, or combination thereof 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 XIV or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about 70°C to about 80°C, such as about 75°C.

[0059] In some embodiments, the method further includes preparing a compound of formula XIV or its cocrystal, solvate, salt, or combination thereof by means of: making a compound of formula XII: XII Or its eutectic, solvate, salt or combination with Select free-form compound XIII-A: XIII-A Compounds in the group consisting of compounds of formula XIII-B: XIII-B, The third alkali and The second catalyst reaction, To provide the compound of formula XIV or its eutectic, solvate, salt or combination thereof.

[0060] In some embodiments, the method includes reacting a compound of formula XII or its eutectic, solvate, salt, or combination thereof with a compound of formula XIII-A. In some embodiments, the compound of formula XIII-A is selected from the group consisting of acetic anhydride, trifluoroacetic anhydride, propionic anhydride, benzoic anhydride, toluene anhydride, and di-tert-butyl dicarbonate (Boc-anhydride). In some embodiments, the compound of formula XIII-A is acetic anhydride.

[0061] In some implementations, the R of formula XIII-A 1 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyloxy, benzyloxy, or optionally one to five independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl. In some embodiments, the R of formula XIII-A 1 C 1-4 Alkyl group. In some embodiments, R of formula XIII-A 1 It is methyl. In some embodiments, R of formula XIII-A 1 It is ethyl. In some embodiments, R of formula XIII-A 1 C 1-4 Halogenated alkyl groups. In some embodiments, the R of formula XIII-A 1 It is trifluoromethyl. In some embodiments, R of formula XIII-A 1 To be optionally selected from 1 to 5 independently from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl. In some embodiments, the R of formula XIII-A 1 It is phenyl. In some embodiments, R of formula XIII-A 1 It is toluene-based.

[0062] In some embodiments, the method includes reacting a compound of formula XII or its eutectic, solvate, salt, or combination thereof with a compound of formula XIII-B. In some embodiments, the compound XIII-B is selected from the group consisting of acetyl chloride, propionyl chloride, benzoyl chloride, tolueneyl chloride, methyl chloroformate, ethyl chloroformate, and benzyl chloroformate.

[0063] In some implementations, the R of formula XIII-B 1 Selected from C 1-4 Alkyl, C 1-4Haloalkyl, C 1-4 Alkyloxy, benzyloxy, or optionally one to five independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl. In some embodiments, the R of formula XIII-B 1 C 1-4 Alkyl group. In some embodiments, the R of formula XIII-B 1 It is methyl. In some embodiments, R of formula XIII-B 1 It is ethyl. In some embodiments, R of formula XIII-B 1 C 1-4 Halogenated alkyl groups. In some embodiments, the R of formula XIII-B 1 It is trifluoromethyl. In some embodiments, R of formula XIII-B 1 To be optionally selected from 1 to 5 independently from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl. In some embodiments, the R of formula XIII-B 1 It is phenyl. In some embodiments, R of formula XIII-B 1 It is toluene-based.

[0064] In some embodiments, the third base comprises an aromatic amine, a tertiary alkylamine, a carbonate, or a combination thereof. In some embodiments, the aromatic amine comprises pyridine, 2,6-dimethylpyridine, pyridazine, imidazole, pyrimidine, pyrazine, or a combination thereof. In some embodiments, the tertiary alkylamine comprises triethylamine, diisopropylethylamine, ... N -Methylmorpholine or combinations thereof. In some embodiments, the carbonate includes alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate).

[0065] In some embodiments, the third base comprises a tertiary alkylamine. In some embodiments, the third base is triethylamine.

[0066] In some embodiments, the second catalyst is selected from the group consisting of 4-dimethylaminopyridine, imidazole, triphenylphosphine oxide, and 1-hydroxy-7-azabenzotriazole. In some embodiments, the second catalyst is 4-dimethylaminopyridine.

[0067] In some embodiments, the reaction of the compound of formula XII or its eutectic, solvate, salt, or combination thereof is carried out in a solvent (e.g., a fourth solvent) comprising hydrocarbons (e.g., toluene, xylene), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, diethylene glycol dimethyl ether, dimethyl isosorbide), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene, dichloromethane, α,α,α-trifluorotoluene), and polar aprotic solvents (e.g., N , N -Dimethylformamide, N , N -Dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile), esters (e.g., ethyl acetate, isopropyl acetate), or combinations thereof. In some embodiments, the reaction of the compound of formula XII or its eutectic, solvate, salt, or combination thereof is carried out in a solvent containing toluene (e.g., a fourth solvent).

[0068] In some embodiments, the reaction of the compound of formula XII or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about -50°C to about 50°C. In some embodiments, the reaction of the compound of formula XII or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about -5°C to about 15°C, such as about 5°C.

[0069] In some embodiments, the method further includes preparing a compound of formula XII or its eutectic, solvate, salt, or combination thereof by means of reducing a compound of formula XI with a reducing agent: XI Or its eutectic, solvate, salt or combination thereof, To provide a compound of formula XII or its eutectic, solvate, salt or combination thereof.

[0070] In some embodiments, the reducing agent is selected from the group consisting of: diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, lithium aluminum hydride, lithium borohydride, and lithium tri-tert-butoxyaluminum hydride. In some embodiments, the reducing agent is diisobutylaluminum hydride.

[0071] In some embodiments, the reduction is performed in a solvent (e.g., a fifth solvent) containing ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, dimethyl isosorbide), hydrocarbons (e.g., toluene, xylene), or combinations thereof. In some embodiments, the reduction is performed in a solvent (e.g., a fifth solvent) containing 1,2-dimethoxyethane.

[0072] In some embodiments, reduction is carried out in a temperature range of about -80°C to about -30°C. In some embodiments, reduction is carried out in a temperature range of about -78°C to about -30°C, or about -60°C to about -40°C, such as about -50°C.

[0073] In some embodiments, the method further includes preparing a compound of formula XI or its eutectic, solvate, salt, or combination thereof by means of: Compound X: X Or its eutectic, solvate, salt or combination thereof Fourth base, The third catalyst, and Esterification is performed using acylation reagents. To provide a compound of formula XI or its eutectic, solvate, salt or combination thereof.

[0074] In some implementations, the fourth base is an organic or inorganic base.

[0075] In some embodiments, the organic base is selected from the group consisting of: N-methylimidazole, triethylamine, Wrenning's base, pyridine, imidazole, DABCO, and DBU. In some embodiments, the fourth base is N-methylimidazole.

[0076] In some embodiments, the inorganic base includes alkali metal carbonates, alkaline earth metal carbonates, or alkali metal hydroxides. In some embodiments, the inorganic base is selected from the group consisting of: Na₂CO₃, Cs₂CO₃, K₂CO₃, NaOH, and KOH.

[0077] In some embodiments, the third catalyst comprises an aromatic base. In some embodiments, the third catalyst is selected from the group consisting of 4-dimethylaminopyridine, pyridine, imidazole, and 4-pyrrolylpyridine. In some embodiments, the third catalyst is 4-dimethylaminopyridine.

[0078] In some embodiments, the acylation agent is selected from the group consisting of toluene halides and toluene carboxylic acid. In some embodiments, the acylation agent is toluene chloride and toluene carboxylic acid. In some embodiments, the acylation agent is toluene chloride.

[0079] In some embodiments, the acylation agent is toluene, and the esterification is performed in the presence of a carboxylic acid activator. In some embodiments, the carboxylic acid activator is selected from the group consisting of 1,1'-carbonyldiimidazole, thionyl chloride, and oxalyl chloride.

[0080] In some embodiments, esterification is performed in a solvent containing a polar aprotic solvent (e.g., a sixth solvent). For example, the polar aprotic solvent contains N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, ethyl acetate, THF, 1,2-dimethoxyethane, acetonitrile, dichloromethane, or combinations thereof. In some embodiments, esterification is performed in a solvent containing 1,2-dimethoxyethane and acetonitrile (e.g., a sixth solvent).

[0081] In some embodiments, esterification is carried out in a temperature range of about -20°C to about 40°C. In some embodiments, esterification is carried out in a temperature range of about -20°C to about 0°C.

[0082] In some embodiments, this document provides a method for preparing compound I: I Or by means of eutectic, solvate, salt or combination thereof, This method involves making a compound of formula XXII: XXII Or its eutectic, solvate, salt or combination thereof, Where R 6 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyloxy, benzyloxy, or optionally one to five independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl, Compounds of formula XV: XV, Silylating agents and Lewis acid reaction, To provide a compound of formula I or a eutectic, solvate, salt or combination thereof.

[0083] In some implementation schemes, R 6 C 1-4 Alkyl group. In some embodiments, R 6 It is methyl. In some embodiments, R 6 It is ethyl. In some embodiments, R 6 C 1-4 Halogenated alkyl groups. In some embodiments, R 6 It is trifluoromethyl.

[0084] In some implementation schemes, R 6 To be optionally selected from 1 to 5 independently from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl. In some implementations, R 6 It is phenyl. In some embodiments, R 6 It is toluene-based.

[0085] In some embodiments, the Lewis acid is selected from the group consisting of: trimethylsilyl trifluoromethanesulfonate, boron trifluoride diethyl ether, and tin tetrachloride. In some embodiments, the Lewis acid is trimethylsilyl trifluoromethanesulfonate.

[0086] In some embodiments, the silylating agent is selected from the group consisting of bis(trialkylsilyl)acetamide and bis(trialkylsilyl)trifluoroacetamide. In some embodiments, the silylating agent is selected from the group consisting of bis(trimethylsilyl)acetamide and bis(trimethylsilyl)trifluoroacetamide. In some embodiments, the silylating agent is bis(trimethylsilyl)acetamide. In some embodiments, the reaction is carried out in a solvent (e.g., a first solvent) comprising a polar aprotic solvent (e.g., acetonitrile, propionitrile, benzyl nitrile), a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, α,α,α-trifluorotoluene), toluene, xylene, anisole, trifluorotoluene, or combinations thereof. In some embodiments, the reaction is carried out in a solvent containing acetonitrile (e.g., the first solvent).

[0087] In some embodiments, the reaction is carried out in a temperature range of about 60°C to about 100°C. In some embodiments, the reaction is carried out in a temperature range of about 70°C to about 80°C, such as about 75°C.

[0088] In some embodiments, the method further includes preparing a compound of formula XXII or its cocrystal, solvate, salt, or combination thereof by means of the following: Compounds with formula XX: XX Or its eutectic, solvate, salt or combination with Select free XXI-A compounds: XXI-A Compounds in the group consisting of compounds of formula XXI-B: XXI-B alkali and Catalytic reaction, To provide a compound of formula XXII or its eutectic, solvate, salt or combination thereof.

[0089] In some embodiments, the method includes reacting a compound of formula XX or its eutectic, solvate, salt, or combination thereof with a compound of formula XXI-A. In some embodiments, the compound of formula XXI-A is selected from the group consisting of acetic anhydride, trifluoroacetic anhydride, propionic anhydride, benzoic anhydride, toluene anhydride, and di-tert-butyl dicarbonate (Boc-anhydride). In some embodiments, the compound of formula XXI-A is acetic anhydride.

[0090] In some implementations, the R of formula XXI-A 6 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyloxy, benzyloxy, or optionally one to five independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl. In some embodiments, the R of formula XXI-A 6 C 1-4 Alkyl group. In some embodiments, the R of formula XXI-A 6 It is methyl. In some embodiments, the R of formula XXI-A 6 It is ethyl. In some embodiments, the R of formula XXI-A 6 C 1-4 Halogenated alkyl groups. In some embodiments, the R of formula XXI-A... 6 It is trifluoromethyl. In some embodiments, R of formula XXI-A 6 To be optionally selected from 1 to 5 independently from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl. In some embodiments, the R of formula XXI-A 6 It is a phenyl group. In some embodiments, the R of formula XXI-A is... 6 It is toluene-based.

[0091] In some embodiments, the method includes reacting a compound of formula XX or its cocrystal, solvate, salt, or combination thereof with a compound of formula XXI-B. In some embodiments, the compound XXI-B is selected from the group consisting of acetyl chloride, propionyl chloride, benzoyl chloride, tolueneyl chloride, methyl chloroformate, ethyl chloroformate, and benzyl chloroformate.

[0092] In some implementations, the R of formula XXI-B 6 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyloxy, benzyloxy, or optionally one to five independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl. In some embodiments, the R of formula XXI-B 6 C 1-4 Alkyl group. In some embodiments, the R of formula XXI-B 6 It is methyl. In some embodiments, R of formula XXI-B 6 It is ethyl. In some embodiments, R of formula XXI-B 6 C 1-4 Halogenated alkyl groups. In some embodiments, the R of formula XXI-B 6 It is trifluoromethyl. In some embodiments, R of formula XXI-B 6 To be optionally selected from 1 to 5 independently from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl. In some embodiments, the R of formula XXI-B 6 It is a phenyl group. In some embodiments, R of formula XXI-B 6 It is toluene-based.

[0093] In some embodiments, the base includes aromatic amines, tertiary alkylamines, carbonates, or combinations thereof. In some embodiments, the aromatic amine includes pyridine, 2,6-dimethylpyridine, pyridazine, imidazole, pyrimidine, pyrazine, or combinations thereof. In some embodiments, the tertiary alkylamine includes triethylamine, diisopropylethylamine, ... N -Methylmorpholine or combinations thereof. In some embodiments, the carbonate includes alkali metal carbonates (e.g., lithium carbonate, sodium carbonate, cesium carbonate).

[0094] In some embodiments, the base includes tertiary alkylamines. In some embodiments, the base is triethylamine.

[0095] In some embodiments, the catalyst is selected from the group consisting of 4-dimethylaminopyridine, imidazole, triphenylphosphine oxide, and 1-hydroxy-7-azabenzotriazole. In some embodiments, the catalyst is 4-dimethylaminopyridine.

[0096] In some embodiments, the reaction of the compound of formula XX or its cocrystal, solvate, salt, or combination thereof is carried out in a solvent (e.g., a second solvent) comprising hydrocarbons (e.g., toluene, xylene), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, diethylene glycol dimethyl ether, dimethyl isosorbide), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene, dichloromethane, α,α,α-trifluorotoluene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile), esters (e.g., ethyl acetate, isopropyl acetate), or combinations thereof. In some embodiments, the reaction of the compound of formula XX or its cocrystal, solvate, salt, or combination thereof is carried out in a solvent containing toluene (e.g., a second solvent).

[0097] In some embodiments, the reaction of the compound of formula XX or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about -50°C to about 50°C. In some embodiments, the reaction of the compound of formula XX or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about -5°C to about 15°C, such as about 5°C.

[0098] In some embodiments, the method further includes preparing a compound of formula XX or its cocrystal, solvate, salt, or combination thereof by means of: Reduce compound XIX with a reducing agent: XIX Or its eutectic, solvate, salt or combination thereof, To provide a compound of formula XX or its eutectic, solvate, salt or combination thereof.

[0099] In some embodiments, the reducing agent is selected from the group consisting of: diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, lithium aluminum hydride, lithium borohydride, and lithium tri-tert-butoxyaluminum hydride. In some embodiments, the reducing agent is diisobutylaluminum hydride.

[0100] In some embodiments, the reduction is performed in a solvent (e.g., a third solvent) comprising ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, dimethyl isosorbide), hydrocarbons (e.g., toluene, xylene), or combinations thereof. In some embodiments, the reduction is performed in a solvent (e.g., a third solvent) comprising 1,2-dimethoxyethane.

[0101] In some embodiments, reduction is carried out in a temperature range of about -80°C to about -30°C. In some embodiments, reduction is carried out in a temperature range of about -78°C to about -30°C, or about -60°C to about -40°C, such as about -50°C.

[0102] In some embodiments, the method further includes preparing a compound of formula XIX or its cocrystal, solvate, salt, or combination thereof by means of the following: Compound X: X Or its eutectic, solvate, salt or combination thereof Second alkali, and The second catalyst is used for esterification. To provide a compound of formula XIX or its eutectic, solvate, salt or combination thereof.

[0103] In some implementations, the fourth base is an organic or inorganic base.

[0104] In some embodiments, the organic base is selected from the group consisting of: N-methylimidazole, triethylamine, Wrenning's base, pyridine, imidazole, DABCO, and DBU. In some embodiments, the fourth base is N-methylimidazole.

[0105] In some embodiments, the inorganic base includes alkali metal carbonates, alkaline earth metal carbonates, or alkali metal hydroxides. In some embodiments, the inorganic base is selected from the group consisting of: Na₂CO₃, Cs₂CO₃, K₂CO₃, NaOH, and KOH.

[0106] In some embodiments, the second catalyst comprises an aromatic base. In some embodiments, the second catalyst is selected from the group consisting of 4-dimethylaminopyridine, pyridine, imidazole, and 4-pyrrolylpyridine. In some embodiments, the third catalyst is 4-dimethylaminopyridine.

[0107] In some embodiments, esterification is performed in a solvent containing a polar aprotic solvent (e.g., a fourth solvent). For example, the polar aprotic solvent includes N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, ethyl acetate, THF, 1,2-dimethoxyethane, acetonitrile, dichloromethane, or combinations thereof. In some embodiments, esterification is performed in a solvent containing 1,2-dimethoxyethane and acetonitrile (e.g., a fourth solvent).

[0108] In some embodiments, esterification is carried out in a temperature range of about -20°C to about 40°C. In some embodiments, esterification is carried out in a temperature range of about -20°C to about 0°C.

[0109] In some embodiments, the method further includes preparing a compound of formula X or its cocrystal, solvate, salt, or combination thereof by means of: Compounds of formula IX: IX Or its eutectic, solvate, salt or combination with Acid reaction, To provide a compound of formula X or its eutectic, solvate, salt or combination thereof.

[0110] In some embodiments, the acid is a strong protic acid (e.g., HCl, sulfuric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid) or a strong Lewis acid (e.g., boron tribromide, boron trichloride, boron trifluoride, aluminum trichloride). In some embodiments, the acid is a strong protic acid. In some embodiments, the acid is HCl.

[0111] In some embodiments, the reaction of the compound of formula IX or its cocrystal, solvate, salt, or combination thereof is carried out in a solvent (e.g., the seventh solvent) comprising ethers (e.g., dioxane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, tert-butylmethyl ether, diethylene glycol dimethyl ether, dimethyl isosorbide), halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene, α,α,α-trifluorotoluene), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone), protic solvents (e.g., water, propionic acid, acetic acid), or combinations thereof. In some embodiments, the reaction of the compound of formula IX or its cocrystal, solvate, salt, or combination thereof is carried out in a solvent containing 1,2-dimethoxyethane (e.g., the seventh solvent).

[0112] In some embodiments, the reaction of the formula IX compound or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about 30°C to about 60°C. In some embodiments, the reaction of the formula IX compound or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about 40°C to about 50°C, such as about 45°C.

[0113] In some embodiments, the method further includes preparing a compound of formula IX or its cocrystal, solvate, salt, or combination thereof by means of: a compound of formula VIII-A: VIII-A Where P 2 Yes (R) 5 )3Si, where each R 5 C is independent 1-6 alkyl; Or its eutectic, solvate, salt or combination thereof The fluoride source undergoes desilylation. To provide a compound of formula IX or its eutectic, solvate, salt or combination thereof.

[0114] In some implementations, each R 5 Independently for C 1-3 Alkyl group. In some embodiments, P 2 It is triisopropylsilyl or trimethylsilyl. In some embodiments, P 2 It is trimethylsilyl.

[0115] In some embodiments, the compound of formula VIII-A or its eutectic, solvate, salt, or combination thereof is a compound of formula VIII: VIII Or its eutectic, solvate, salt or combination thereof.

[0116] In some embodiments, the fluoride source is selected from the group consisting of alkali metal fluorides (e.g., NaF, CsF), alkaline earth metal fluorides (e.g., CaF2), hydrofluoric acid, pyridine trihydrofluoride, tetrabutylammonium fluoride, and their hydrates. In some embodiments, the fluoride source is tetrabutylammonium fluoride trihydrate.

[0117] In some embodiments, desilylation is performed in a solvent (e.g., solvent eight) comprising ethers (e.g., dioxane, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, tert-butylmethyl ether, diethylene glycol dimethyl ether, dimethyl isosorbide), polar aprotic solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone), or combinations thereof. In some embodiments, desilylation is performed in a solvent containing tetrahydrofuran (e.g., solvent eight).

[0118] In some embodiments, desilylation is carried out in a temperature range of about -10°C to about 35°C. In some embodiments, desilylation is carried out in a temperature range of about 5°C to about 15°C, such as about 10°C.

[0119] In some embodiments, the method further includes preparing a compound of formula VIII-A or its eutectic, solvate, salt, or combination thereof by means of: making a compound of formula VII-A: VII-A Or its eutectic, solvate, salt or combination with hydrogen source, and The fourth catalyst reaction, To provide a compound of formula VIII-A or its eutectic, solvate, salt or combination thereof.

[0120] In some implementations, P of formula VII-A 2 For (R) 5 )3Si, where each R 5 Independently for C 1-6 Alkyl group. In some embodiments, each R 5 Independently for C 1-3 Alkyl group. In some embodiments, P of formula VII-A 2 It is triisopropylsilyl or trimethylsilyl. In some embodiments, P of formula VII-A 2 It is a triisopropylsilyl group.

[0121] In some embodiments, the compound of formula VII-A or its eutectic, solvate, salt, or combination thereof is a compound of formula VII: VII Or its eutectic, solvate, salt or combination thereof.

[0122] In some embodiments, the hydrogen source is selected from the group consisting of formic acid, formate, aqueous sodium formate solution, secondary alcohols (e.g., glycerol, 2-propanol), or hemisyl ester. In some embodiments, the hydrogen source may be a formate. In some embodiments, the hydrogen source is a trimethylamine formate complex.

[0123] In some embodiments, the fourth catalyst is a transition metal catalyst. In some embodiments, the fourth catalyst comprises ruthenium, iron, osmium, cobalt, rhodium, iridium, nickel, palladium, gold, or combinations thereof. In some embodiments, the fourth catalyst is a transition metal catalyst having an N-heterocyclic carbene ligand. In some embodiments, the fourth catalyst is a ruthenium catalyst. In some embodiments, the fourth catalyst is N-[(1S,2S)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)-ethyl]-4-methylbenzenesulfonamide(chloro)ruthenium(II), also known as (S,S)-Ts-DENEB. ® .

[0124] In some embodiments, the reaction of a compound of formula VII-A or its eutectic, solvate, salt, or combination thereof is carried out in a solvent (e.g., the ninth solvent) containing a polar aprotic solvent (e.g., N , N -Dimethylformamide, N , N -Dimethylacetamide, N-methyl-2-pyrrolidone), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, tert-butylmethyl ether, 1,4-dioxane, diethylene glycol dimethyl ether, dimethyl isosorbide), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene, dichloromethane, α,α,α-trifluorotoluene), or combinations thereof. In some embodiments, the reaction of a compound of formula VII-A or its eutectic, solvate, salt, or combination thereof is carried out in a solvent containing tetrahydrofuran (e.g., solvent IX).

[0125] In some embodiments, the reaction of the compound of formula VII-A or its eutectic, solvate, salt, or combination thereof 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 VII-A or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about 30°C to about 40°C, such as about 35°C.

[0126] In some embodiments, reacting a compound of formula VII-A or its eutectic, solvate, salt, or combination thereof includes: Prepare a first mixture comprising a compound of formula VII-A or its eutectic, solvate, or combination thereof with a fourth catalyst; Preparation of a second mixture containing a hydrogen source; and The first mixture and the second mixture are combined to provide a compound of formula VIII-A or its eutectic, solvate, salt or combination thereof.

[0127] In some embodiments, the method further includes preparing a compound of formula VII-A or its cocrystal, solvate, salt, or combination thereof by means of the following: Compounds of formula VI-A: VI-A Or its eutectic, solvate, salt or combination thereof, Where R 2 and R 3 Independently selected from C3-C7 cycloalkyl, C 1-6 Alkyl and benzyl, with Second acid, Second activating agent, monomalonate, and Fifth base reaction, To provide compounds of formula VII-A or their eutectic, solvate, salt or combination thereof.

[0128] In some implementations, the P of formula VI-A 2 For (R) 5 )3Si, where each R 5 Independently for C 1-6 Alkyl group. In some embodiments, each R 5 Independently for C 1-3 Alkyl group. In some embodiments, P of formula VI-A 2 It is triisopropylsilyl or trimethylsilyl. In some embodiments, P of formula VI-A 2 It is a triisopropylsilyl group.

[0129] In some embodiments, the compound of formula VI-A or its eutectic, solvate, salt, or combination thereof is a compound of formula VI: VI Or its eutectic, solvate, salt or combination thereof.

[0130] In some implementation schemes, R 2 and R 3 Independently, it is a C3-C7 cycloalkyl group. In some embodiments, R 2 and R 3 It is cyclohexyl. In some implementations, R 2 and R 3 Independently, it is a C1-C6 alkyl group. In some embodiments, R 2and R 3 It is isopropyl. In some embodiments, R 2 and R 3 It is tert-butyl. In some implementations, R 2 and R 3 It is benzyl. In some embodiments, R 2 and R 3 same.

[0131] In some embodiments, the second acid is a protic acid. In some embodiments, the second acid is selected from the group consisting of citric acid, acetic acid, and hydrochloric acid. In some embodiments, the second acid is citric acid.

[0132] In some embodiments, the second activator is a carbonyl transfer agent. In some embodiments, the second activator is selected from the group consisting of 1,1'-carbonyldiimidazole, phosgene, triphosgene, and thionyl chloride. In some embodiments, the second activator is 1,1'-carbonyldiimidazole.

[0133] In some embodiments, the malonic acid monoester is selected from the group consisting of tert-butyl malonate and monomethyl malonate. In some embodiments, the malonic acid monoester is tert-butyl malonate.

[0134] In some embodiments, the fifth base is a Grignard reagent. In some embodiments, the Grignard reagent comprises alkyl magnesium halide or aryl magnesium halide. For example, the fifth base includes isopropyl magnesium chloride, isopropyl magnesium bromide, phenyl magnesium chloride, or phenyl magnesium bromide. In some embodiments, the fifth base is isopropyl magnesium chloride.

[0135] In some embodiments, reacting a compound of formula VI-A or its eutectic, solvate, salt, or combination thereof includes: Prepare a first mixture comprising the second acid and the second activator; Prepare a second mixture comprising the malonate monoester and the fifth base; and The first mixture and the second mixture are combined to provide a compound of formula VII-A or its eutectic, solvate, salt or combination thereof.

[0136] In some embodiments, the reaction of the compound of formula VI-A or its cocrystal, solvate, salt, or combination thereof is carried out in a solvent (e.g., the tenth solvent) containing an ether (e.g., methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethylene glycol dimethyl ether, dimethyl isosorbide). In some embodiments, the reaction of the compound of formula VI-A or its cocrystal, solvate, salt, or combination thereof is carried out in a solvent (e.g., the tenth solvent) containing methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof.

[0137] In some embodiments, the reaction of the compound of formula VI-A or its eutectic, solvate, salt, or combination thereof 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 VI-A or its eutectic, solvate, salt, or combination thereof is carried out at a temperature of about 20°C.

[0138] In some embodiments, the method further includes preparing a compound of formula VI-A or its cocrystal, solvate, salt, or combination thereof by means of: a compound of formula VA: VA Or its eutectic, solvate, salt or combination thereof Oxidizing reagents Fifth catalyst The sixth base, and Oxidation of salt-forming reagents To provide a compound of formula VI-A or its eutectic, solvate, salt or combination thereof.

[0139] In some implementations, the P of formula VA 2 For (R) 5 )3Si, where each R 5 Independently for C 1-6 Alkyl group. In some embodiments, each R 5 Independently for C 1-3 Alkyl group. In some embodiments, the P of formula VA 2 It is triisopropylsilyl or trimethylsilyl. In some embodiments, P of formula VA 2 It is a triisopropylsilyl group.

[0140] In some embodiments, the compound of formula VA, or its eutectic, solvate, salt, or combination thereof, is a compound of formula V: V Or its eutectic, solvate, salt or combination thereof.

[0141] In some embodiments, the oxidizing agent is selected from the group consisting of: hypervalent iodine reagents, activated DMSO (e.g., DMSO activated by oxalyl chloride, carbodiimide, sulfur trioxide pyridine, or acetic anhydride), copper reagents (e.g., copper chloride, copper iodide, or copper bromide), and sulfur reagents (e.g., potassium peroxymonosulfate). In some embodiments, the oxidizing agent is a hypervalent iodine reagent. In some embodiments, the hypervalent iodine reagent is (diacetoxyiodo)benzene (DAIB), Desmond-Martin periodoline, iodophenyl iodide, or Koser reagent. In some embodiments, the oxidizing agent is (diacetoxyiodo)benzene (DAIB).

[0142] In some embodiments, the fifth catalyst is selected from the group consisting of nitrogen oxides, organic peroxides (e.g., benzoyl peroxide, di-tert-butyl peroxide), and azo radical initiators (e.g., azobisisobutyronitrile, 1,1'-azobis-(cyclohexanecarboxynitrile)). In some embodiments, the fifth catalyst is a nitrogen oxide. In some embodiments, the nitrogen oxide is selected from the group consisting of (2,2,6,6-tetramethylpiperidin-1-yl)oxy radical (TEMPO), 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxy, and trimethylamine N-oxide. In some embodiments, the fifth catalyst is (2,2,6,6-tetramethylpiperidin-1-yl)oxy radical (TEMPO).

[0143] In some embodiments, the sixth base comprises a phosphate or a carbonate. In some embodiments, the sixth base comprises an alkali metal phosphate (e.g., monosodium phosphate, trisodium phosphate), an alkali metal hydrogen phosphate (e.g., disodium hydrogen phosphate), an alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, cesium carbonate), or a combination thereof. In some embodiments, the sixth base is disodium hydrogen phosphate.

[0144] In some implementations, the salt-forming reagent is of formula R 2 R 3 NH secondary amine, of which R 2 and R 3 As defined herein. In some embodiments, the salt-forming agent is selected from the group consisting of: dicyclohexylamine, diisopropylamine, dibenzylamine, and di-tert-butylamine. In some embodiments, the salt-forming agent is dicyclohexylamine.

[0145] In some embodiments, oxidation is performed in a solvent (e.g., an eleventh solvent) that contains a polar aprotic solvent (e.g., N , N -Dimethylformamide, N , N -Dimethylacetamide, N 2-methyl-2-pyrrolidone, acetonitrile), ethers (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, tert-butylmethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, diethylene glycol dimethyl ether, dimethyl isosorbide), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone), halogenated solvents (e.g., 1,2-dichloroethane, chloroform, chlorobenzene, dichloromethane, α,α,α-trifluorotoluene), water, or combinations thereof. In some embodiments, oxidation is performed in a solvent comprising acetonitrile and water (e.g., eleventh solvent).

[0146] In some embodiments, oxidation is carried out in a temperature range of about 0°C to about 50°C. In some embodiments, oxidation is carried out in a temperature range of about 10°C to about 30°C, such as 20°C.

[0147] In some embodiments, the method further includes preparing a VA compound or its cocrystal, solvate, salt, or combination thereof by means of: Compounds of formula IV-A: IV-A Or its eutectic, solvate, salt or combination with acid catalysts 1,2-Diol protecting reagent, and The seventh base reaction, To provide a VA compound or its eutectic, solvate, salt or combination thereof.

[0148] In some implementations, the P of formula IV-A 2 For (R) 5 )3Si, where each R 5 Independently for C 1-6 Alkyl group. In some embodiments, each R 5 Independently for C 1-3 Alkyl group. In some embodiments, P of formula IV-A 2 It is triisopropylsilyl or trimethylsilyl. In some embodiments, P of formula IV-A 2 It is a triisopropylsilyl group.

[0149] In some embodiments, the compound of formula IV-A or its eutectic, solvate, salt, or combination thereof is a compound of formula IV: IV Or its eutectic, solvate, salt or combination thereof.

[0150] In some embodiments, the acid catalyst is a weak acid with a pKa in the range of about 4 to about 6. In some embodiments, the acid catalyst is a weak acid with a pKa in the range of about 5. In some embodiments, the acid catalyst is selected from the group consisting of: pyridinium p-toluenesulfonate (PPTS), acetic acid, zirconium chloride (IV), and iodine. In some embodiments, the acid catalyst is pyridinium p-toluenesulfonate (PPTS).

[0151] In some embodiments, the 1,2-diol protecting agent is selected from the group consisting of 2,2-dimethoxypropane, acetone, and isopropyl acetate. In some embodiments, the 1,2-diol protecting agent is 2,2-dimethoxypropane.

[0152] In some embodiments, the seventh base comprises an alkoxide or a hydroxide. For example, the seventh base comprises an alkali metal alkoxide (e.g., sodium methoxide, sodium ethoxide), an alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide), an alkaline earth metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide, barium hydroxide), or a combination thereof. In some embodiments, the seventh base comprises an alkali metal alkoxide. In some embodiments, the seventh base comprises sodium methoxide.

[0153] In some embodiments, the reaction of the compound of formula IV-A or its cocrystal, solvate, salt, or combination thereof is carried out in a solvent (e.g., a twelfth solvent) comprising ethers (e.g., methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, diisopropyl ether, di-n-butyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, 1,4-dioxane, diethylene glycol dimethyl ether, dimethyl isosorbide), nitriles (e.g., acetonitrile, propionitrile, butyronitrile, benzyl nitrile), halogenated solvents (e.g., dichloromethane, 1,2-dichloroethane, chloroform, chlorobenzene, α,α,α-trifluorotoluene) or combinations thereof. In some embodiments, the reaction of the compound of formula IV-A or its cocrystal, solvate, salt, or combination thereof is carried out in a solvent comprising methyl tert-butyl ether and acetonitrile (e.g., a twelfth solvent).

[0154] In some embodiments, the reaction of the compound of formula IV-A or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about 20°C to about 80°C. In some embodiments, the reaction of the compound of formula IV-A or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about 40°C to about 60°C, such as about 50°C.

[0155] In some embodiments, the method further includes preparing a compound of formula IV-A or its cocrystal, solvate, salt, or combination thereof by means of: Compounds of formula III-A: III-A Or its eutectic, solvate, salt or combination with Eighth base, and Enzyme reaction, To provide a compound of formula IV-A or its eutectic, solvate, salt or combination thereof.

[0156] In some implementations, P of Formula III-A 2 For (R) 5 )3Si, where each R 5 Independently for C 1-6 Alkyl group. In some embodiments, each R5 Independently for C 1-3 Alkyl group. In some embodiments, P of formula III-A 2 It is triisopropylsilyl or trimethylsilyl. In some embodiments, P of formula III-A 2 It is a triisopropylsilyl group.

[0157] In some embodiments, the compound of formula III-A or its eutectic, solvate, salt, or combination thereof is a compound of formula III: III Or its eutectic, solvate, salt or combination thereof.

[0158] In some embodiments, the eighth base comprises an alkali metal hydroxide and an alkali metal buffer. In some embodiments, the eighth base comprises an alkali metal hydroxide (e.g., NaOH, KOH) and an alkali metal phosphate monohydric aqueous buffer (e.g., KH₂PO₄, NaH₂PO₄). In some embodiments, the eighth base comprises potassium hydroxide and an aqueous KH₂PO₄ buffer.

[0159] In some embodiments, the reaction of the compound of formula III-A or its cocrystal, solvate, salt, or combination thereof is carried out at a pH in the range of about 5 to about 7. In some embodiments, the reaction of the compound of formula III-A or its cocrystal, solvate, salt, or combination thereof is carried out at a pH in the range of about 5 to about 5.8.

[0160] In some implementations, the enzyme is selected from the group consisting of: Candida antarcticis lipase A (CALA) enzyme (e.g., NovoCor). ® ADL), Candida antarcticis lipase A immobilized on Immobead 150, recombinant enzyme derived from Aspergillus oryzae, Palatase ® 20000 L, Novozym ® 51032 and Lipozyme ® TL 100 L, Lipozyme ® CALB L. In some implementations, the enzyme includes Candida antarcticis lipase A (CALA).

[0161] In some embodiments, the reaction of the compound of formula III-A or its eutectic, solvate, salt, or combination thereof is carried out in a solvent containing alcohol (e.g., methanol, ethanol, 1-propanol, 1-butanol, 2-butanol, tert-butanol), water, or combinations thereof (e.g., a thirteenth solvent). In some embodiments, the reaction of the compound of formula III-A or its eutectic, solvate, salt, or combination thereof is carried out in a solvent containing methanol (e.g., a thirteenth solvent).

[0162] In some embodiments, the reaction of the compound of formula III-A or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about 5°C to about 65°C. In some embodiments, the reaction of the compound of formula III-A or its eutectic, solvate, salt, or combination thereof is carried out in a temperature range of about 20°C to about 40°C, such as about 30°C.

[0163] In some embodiments, the method further includes preparing a compound of formula III-A or its cocrystal, solvate, salt, or combination thereof by means of: Compound of formula II: II Or its eutectic, solvate, salt or combination with Formula P 2 - Acetylene compounds, and The ninth base reaction, To provide a compound of formula III-A or its eutectic, solvate, salt or combination thereof.

[0164] In some implementation schemes, formula P 2 - The acetylene compound is (trimethylsilyl)acetylene or (triisopropylsilyl)acetylene. In some embodiments, formula P 2 -The acetylene compound is (triisopropylsilyl)acetylene.

[0165] In some embodiments, the ninth base comprises alkyllithium (e.g., methyllithium, sec-butyllithium, isopropyllithium, tert-butyllithium), aryllithium (e.g., phenyllithium), Grignard reagents (e.g., alkyl magnesium halides, aryl magnesium halides), diisopropylaminolithium, hexamethyldisilazanelithium, hexamethyldisilazanesodium, hexamethyldisilazanepotassium, aminolithium, aminosodium, metal hydrides (e.g., sodium hydride, potassium hydride), alkoxides (e.g., tert-butoxidelithium, tert-butoxidesodium, tert-butoxidepotassium), or combinations thereof. In some embodiments, the ninth base comprises alkyllithium. In some embodiments, the ninth base comprises n-butyllithium.

[0166] In some embodiments, the reaction of the compound of formula II or its cocrystal, solvate, salt, or combination thereof is carried out in a solvent (e.g., the fourteenth solvent) comprising ethers (e.g., methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, cyclopentylmethyl ether, diisopropyl ether, di-n-butyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, 1,4-dioxane, diethylene glycol dimethyl ether, dimethyl isosorbide), hydrocarbons (e.g., toluene, n-hexane, hexane derivatives, n-heptane, heptane derivatives), or combinations thereof. In some embodiments, the reaction of the compound of formula II or its cocrystal, solvate, salt, or combination thereof is carried out in a solvent containing tetrahydrofuran (e.g., the fourteenth solvent).

[0167] In some embodiments, the reaction of the compound of formula II or its eutectic, solvate, salt or combination thereof is carried out in a temperature range of about -100°C to about -40°C.

[0168] In some embodiments, reacting the compound of formula II or its eutectic, solvate, salt, or combination thereof includes: Make the ninth base react with formula P 2 - Acetylene compounds react to form a mixture; and The mixture is combined with a compound of formula II to provide a compound of formula III-A or its eutectic, solvate, salt or combination thereof.

[0169] In some implementations, the ninth base is reacted with formula P 2 The reaction of the acetylene compound is carried out in a temperature range of about -60°C to about -40°C, such as about -50°C. In some embodiments, the mixture is combined with the compound of formula II in a temperature range of about -70°C to about -50°C, such as about -60°C.

[0170] In some embodiments, compounds of formula III-A are provided: III-A Or its eutectic, solvate, salt or combination thereof.

[0171] In some implementations, compounds of formula IV-A are provided: IV-A Or its eutectic, solvate, salt or combination thereof.

[0172] In some implementations, a compound of formula VA is provided: VA Or its eutectic, solvate, salt or combination thereof.

[0173] In some implementations, compounds of formula VI-A are provided: VI-A Or its eutectic, solvate, salt or combination thereof.

[0174] In some embodiments, compounds of formula VII-A are provided: VII-A Or its eutectic, solvate, salt or combination thereof.

[0175] In some embodiments, compounds of formula VIII-A are provided: VIII-A Or its eutectic, solvate, salt or combination thereof.

[0176] In some implementations, compounds of formula IX are provided: IX Or its eutectic, solvate, salt or combination thereof.

[0177] In some implementations, a compound of formula X is provided: X Or its eutectic, solvate, salt or combination thereof.

[0178] In some implementations, compounds of formula XI are provided: XI Or its eutectic, solvate, salt or combination thereof.

[0179] In some implementations, compounds of formula XII are provided: XII Or its eutectic, solvate, salt or combination thereof.

[0180] In some implementations, compounds of formula XIV are provided: XIV Or its eutectic, solvate, salt or combination thereof.

[0181] In some implementations, compounds of formula XVI-A are provided: XVI-A Or its eutectic, solvate, salt or combination thereof.

[0182] In some implementations, compounds of formula XIX are provided: XIX Or its eutectic, solvate, salt or combination thereof.

[0183] In some implementations, compounds of formula XX are provided: XX Or its eutectic, solvate, salt or combination thereof.

[0184] In some implementations, compounds of formula XXII are provided: XXII Or its eutectic, solvate, salt or combination thereof.

[0185] In some embodiments, this document provides a method for preparing compound I: I A method comprising: or a eutectic, solvate, salt, or combination thereof, the method comprising: (a) Compound X: X Or its eutectic, solvate, salt or combination thereof Fourth base, The third catalyst, and Esterification is performed using acylation reagents. To provide compounds of formula XI: XI Or its eutectic, solvate, salt or combination thereof.

[0186] (b) Reduction of compound XI or its eutectic, solvate, salt or combination thereof with a reducing agent. To provide compound of formula XII: XII Or its eutectic, solvate, salt or combination thereof; (c) Mixing the compound of formula XII or its eutectic, solvate, salt or combination with... Select free-form compound XIII-A: XIII-A Compounds in the group consisting of compounds of formula XIII-B: XIII-B Where R 1 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyloxy, benzyloxy, or optionally one to five independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl, The third alkali and The second catalyst reaction, Provided as a compound of formula XIV: XIV Or its eutectic, solvate, salt or combination thereof; (d) To mix a compound of formula XIV or its eutectic, solvate, salt or combination with a compound of formula XV: XV Or its eutectic, solvate, salt or combination thereof, Silylating agents and Lewis acid reaction, To provide a compound of formula XVI-A: XVI-A Or its eutectic, solvate, salt or combination thereof, Where P 1 Is it H or (R) 4 )3Si, where each R 4 C is independent 1-6 alkyl; (e) To mix a compound of formula XVI or its eutectic, solvate, salt or combination thereof with: Deacylation reagents and The second base reaction, To provide compounds of formula XVII: XVII or its eutectic, solvate, salt or combination thereof; and (f) To mix a compound of formula XVII or its eutectic, solvate, salt or combination with: Compound XVIII: XVIII Where X is selected from halogens, acid anhydrides, and OH, and Alkali reaction, To provide a compound of formula I or a eutectic, solvate, salt or combination thereof.

[0187] In some embodiments, this document provides a method for preparing compound I: I A method comprising: or a eutectic, solvate, salt, or combination thereof, the method comprising: (a) Compound X: X Or its eutectic, solvate, salt or combination thereof Second alkali, and The second catalyst is used for esterification. Provided as a compound of formula XIX: XIX Or its eutectic, solvate, salt or combination thereof; (b) Reduction of compound XIX or its eutectic, solvate, salt or combination thereof with a reducing agent. Provide compound of formula XX: XX Or its eutectic, solvate, salt or combination thereof; (c) To mix a compound of formula XX or its eutectic, solvate, salt or combination with... Select free XXI-A compounds: XXI-A Compounds in the group consisting of compounds of formula XXI-B: XXI-B, Where R 6 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyloxy, benzyloxy, or optionally one to five independently selected from C 1-4 Alkyl, C 1-4Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl, alkali and Catalytic reaction, To provide compound of formula XXII: XXII or its eutectic, solvate, salt or combination thereof; and (d) To make a compound of formula XXII or its eutectic, solvate, salt or combination thereof, Compounds of formula XV: XV, Silylating agents and Lewis acid reaction, To provide a compound of formula I or a eutectic, solvate, salt or combination thereof.

[0188] The methods disclosed herein include alternative pathways, for example, for the synthesis of compound I or its cocrystals, solvates, salts, or combinations thereof. Compound X or its cocrystals, solvates, salts, or combinations thereof may be used as intermediates in any of the synthetic pathways provided herein.

[0189] In some embodiments, the compound of formula X or its eutectic, solvate, salt, or combination thereof is prepared by a method comprising the following: (a) Make compound II: II Or its eutectic, solvate, salt or combination with Formula P 2 - Acetylene compounds, where P 2 Yes (R) 4 )3Si, where each R 4 C is independent 1-6 Alkyl groups, and The ninth base reaction, To provide compounds of formula III-A: III-A Or its eutectic, solvate, salt or combination thereof; (b) To mix a compound of formula III-A or its eutectic, solvate, salt or combination with... Eighth base, and Enzyme reaction, To provide compounds of formula IV-A: IV-A Or its eutectic, solvate, salt or combination thereof; (c) To mix a compound of formula IV-A or its eutectic, solvate, salt or combination with... acid catalysts 1,2-Diol protecting reagent, and The seventh base reaction, Provided VA compound: VA Or its eutectic, solvate, salt or combination thereof; (d) Using a compound of formula VA or its eutectic, solvate, salt or combination thereof... Oxidizing reagents Fifth catalyst The sixth base, and Oxidation of salt-forming reagents To provide a compound of formula VI-A: VI-A Or its eutectic, solvate, salt or combination thereof, Where R 2 and R 3 Independently selected from C3-C7 cycloalkyl, C 1-6 Alkyl and benzyl; (e) To mix a compound of formula VI-A or its eutectic, solvate, salt or combination with... Second acid, Second activating agent, monomalonate, and Fifth base reaction, To provide compounds of formula VII-A: VII-A Or its eutectic, solvate, salt or combination thereof; (f) To mix a compound of formula VII-A or its eutectic, solvate, salt or combination with: hydrogen source, and The fourth catalyst reaction, To provide compounds of formula VIII-A: VIII-A Or its eutectic, solvate, salt or combination thereof; (g) Using a compound of formula VIII-A or its eutectic, solvate, salt or combination thereof... The fluoride source undergoes desilylation. To provide compounds of formula IX: IX or its eutectic, solvate, salt or combination thereof; and (h) To mix a compound of formula IX or its eutectic, solvate, salt or combination with... Acid reaction, To provide a compound of formula X or its eutectic, solvate, salt or combination thereof.

[0190] In some embodiments, this disclosure relates to the use of a compound of formula I for treating infections caused by retroviral viruses, including infections caused by HIV, the use of which includes administering a therapeutically effective amount of the compound of formula I to a subject in need.

[0191] Example The absolute stereochemistry of compounds XI and XVII was determined. All other stereochemistry shown throughout the examples was based on extrapolation and specified according to literature priority.

[0192] Example 1.(4) S 5 R )-5-ethynyl-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3 H Preparation of )-ketone (X) step 1. diacetic acid 2- hydroxyl -2-(( Triisopropylsilyl ) Acetylene ) propane -1,3- Dimethyl ester ( III )of preparation : Diacetoxyacetone (II, 1.0 equivalent, scaling factor) was charged into a container containing tetrahydrofuran (8 volumes) and cooled to approximately -60°C. TIPS-acetylene (TIPS-acetylene, 1.03 equivalent) and tetrahydrofuran (6 volumes) were charged into another container and cooled to approximately -60°C. Then, n-butyllithium (1.0 equivalent, 2.5 M hexane solution) was added over approximately 2 hours, maintaining the temperature below -40°C. The resulting reaction mixture was transferred to a reactor containing solution II over approximately 2 hours, maintaining the temperature below -50°C. The reaction was aged at approximately -60°C for approximately 30 minutes, then quenched by the slow addition of acetic acid (1.2 equivalent), maintaining the temperature below -40°C. Tert-butyl methyl ether (4 volumes) was added to the quenched reaction mixture, and the mixture was warmed to approximately 20°C. The reaction mixture was washed sequentially with 5% by weight potassium bicarbonate aqueous solution (5 volumes) and 10% by weight sodium chloride aqueous solution (5 volumes). The organic layer was concentrated under vacuum to approximately 4 volumes, then methanol (15 volumes) was added, and the mixture was concentrated under vacuum to approximately 4 volumes. The concentrate was diluted with methanol (5 volumes) and filtered to obtain a solution of III in methanol for use in the next step (Step 2).

[0193] step 2. Acetic acid (R)-2- hydroxyl -2-( hydroxymethyl )-4-( Triisopropylsilyl ) Man -3- acetylene -1- ester( IV Preparation of ) : A phosphate buffer solution (0.1 M, pH 7.5, 1.8 volume) containing aqueous solutions of potassium dihydrogen phosphate and potassium hydroxide was added to the reactor and warmed to approximately 30°C. Then, NovoCor was added. ® AD L enzyme (1.2 g / g). Adjust the pH of the mixture to approximately 5.8 with phosphoric acid, then add a methanol solution of III (1.0 equivalent, scaling factor). Adjust the pH of the mixture to approximately 5.4 and stir at approximately 30°C for approximately 15 hours. Add methyl tert-butyl ether (4 volumes) and stir the mixture for approximately 30 minutes. Add 15% by weight sodium chloride aqueous solution (4 volumes), stir for approximately 30 minutes, and then allow to settle for at least 30 minutes. Discard the bottom aqueous layer. Filter the organic layer to remove the emulsion and wash with tert-butyl methyl ether (1 volume). Wash the filtrate with 15% by weight sodium chloride aqueous solution (4 volumes) to obtain the organic layer, which is a solution of IV in tert-butyl methyl ether.

[0194] step 3.(S)-(2,2- dimethyl -4-(( Triisopropylsilyl ) Acetylene )-1,3- Dioxolane -4- base ) Methanol ( V Preparation of ) : A solution of IV in tert-butyl methyl ether (1.0 equivalent, proportion factor) was charged into a reactor, concentrated under vacuum to approximately 4 volumes, and diluted with acetonitrile (10 volumes). The resulting mixture was concentrated to approximately 4 volumes and adjusted to approximately 20°C. 2,2-Dimethoxypropane (4 equivalents), tert-butyl methyl ether (5 volumes), and pyridine p-toluenesulfonic acid (PPTS, 0.1 equivalents) were charged into the reactor, and the contents were stirred at approximately 50°C for approximately 2 hours, then cooled to approximately 20°C. A methanol solution of sodium methoxide (25 wt%, 0.4 equivalents) was charged, and the contents were stirred at approximately 20°C for approximately 15 minutes. The reaction mixture was washed sequentially with 10 wt% aqueous citric acid solution (5 volumes), 15 wt% aqueous sodium chloride solution (5 volumes), and water (2.5 volumes). The organic layer was concentrated under vacuum to approximately 4 volumes, diluted with acetonitrile (10 volumes), and then concentrated under vacuum to approximately 4 volumes to obtain a solution of V in acetonitrile.

[0195] step 4. Dicyclohexylammonium (R)-2,2- dimethyl -4-(( Triisopropylsilyl ) Acetylene )-1,3- Dioxide Pentocyclohexane -4- Formate ( VI-1 Preparation of ) : A solution of acetonitrile (V = 1 equivalent, proportionality factor) was added to a reactor containing a solution of disodium hydrogen phosphate (3.1 equivalents) in water (4.0 volumes) and diacetoxyiodobenzene (DAIB, 2.4 equivalents). Then, (2,2,6,6-tetramethylpiperidin-1-yl)oxy radicals (TEMPO, 0.2 equivalents) were added batchwise to the reactor at a rate used to maintain the internal temperature below 40°C. The internal reactor temperature was then adjusted to approximately 20°C, and the reactor contents were agitated for approximately 2 hours. Next, an aqueous solution of sodium sulfite (1.5 equivalents, a solution of sodium sulfate in 3.4 volumes of water) was added to the reactor to quench the reaction, and the quenched reactor contents were allowed to settle after agitation for approximately 30 minutes. The bottom water layer was discarded, and dicyclohexylamine (1.55 equivalents) was added to the reactor over a period of approximately 1 hour, and the reactor contents were agitated for approximately 2 hours. The resulting slurry was filtered, and the solids were washed with water (5.0 to 10 volumes) and heptane (4.0 volumes). The filter cake was then dried under vacuum at a jacket temperature of about 60°C for about 18 hours to obtain VI-1.

[0196] 1 H NMR (400MHz, chloroform-d) δ 4.33 (d, J = 8.0Hz, 1H), 4.24 (d, J = 8.0Hz, 1H), 2.97 (tt, J = 11.7, 3.8Hz, 2H), 2.09 – 1.94 (m, 4H), 1.77 (d, J = 9.9Hz, 5H), 1.66 – 1.47 (m, 9H), 1.42 (s, 3H), 1.28 – 1.13 (m, 6H), 1.06 (d, J =3.8Hz, 21H).

[0197] This method was found to be reproducible and suitable for scale-up. Dicyclohexylamine salt VI-1 was identified as a separable, stable compound. Furthermore, the method disclosed herein provides compound VI-1 with good purity and stereochemical control.

[0198] step 5.(R)-3-(2,2- dimethyl -4-(( Triisopropylsilyl ) Acetylene )-1,3- Dioxolane -4- base )-3- tert-butyl oxypropionate ( VII Preparation of ) : VI-1 (1.0 equivalent, scaling factor), tert-butyl methyl ether (5 volumes), and 15% wt% aqueous citric acid solution (5 volumes) were charged into the reactor, and the contents were agitated for about 15 minutes, then allowed to settle for about 15 minutes. The bottom aqueous layer was discarded. The organic layer was washed with 15% wt% aqueous citric acid solution (5 volumes), and then washed with 10% wt% aqueous sodium chloride solution (5 volumes). The organic layer was concentrated under vacuum at about 40°C to about 2 volumes, and then diluted with 2-methyltetrahydrofuran (5 volumes). The reactor contents were concentrated under vacuum at about 40°C to about 2 volumes, mixed with 2-methyltetrahydrofuran (2.5 volumes), and cooled at about 20°C. N,N-carbonyldiimidazole (1.2 equivalent) was charged into the reactor, and the reaction mixture was agitated at about 20°C for about 3 hours.

[0199] 2-Methyltetrahydrofuran (2.5 volumes) and mono-tert-butyl malonate (1.4 equivalents) were charged into another reactor, and the resulting solution was cooled to approximately 0°C. A 2.0 M THF solution of magnesium isopropyl chloride (2.8 equivalents) was then charged into the reactor, maintaining the reactor contents at approximately 15°C. The temperature was then adjusted to approximately 20°C, and the reaction mixture was stirred for approximately 3 hours.

[0200] The contents of the first reactor were cooled to approximately 0°C, and the contents of the second reactor were transferred to the first reactor, maintaining the temperature at approximately 15°C. The resulting reaction mixture was adjusted to approximately 20°C and aged for approximately 12 hours. The reaction was then quenched by adding 10% by weight of an aqueous citric acid solution (10 volumes), and the mixture was stirred at approximately 20°C for approximately 30 minutes, then allowed to settle for phase separation. The bottom aqueous layer was discarded. The organic layer was washed with 5% by weight of an aqueous NaHCO3 solution (5 volumes), followed by washing with 10% by weight of an aqueous NaCl solution (10 volumes). The organic layer was concentrated under vacuum at approximately 40°C to approximately 2 volumes, diluted with tetrahydrofuran (10 volumes), and concentrated under vacuum again to obtain a solution of VII in tetrahydrofuran.

[0201] The decarboxylation Claisen procedure described in this paper was found to offer good scalability, yield, and product quality.

[0202] step 6.(S)-3-((R)-2,2- dimethyl -4-(( Triisopropylsilyl ) Acetylene )-1,3- Dioxane ring -4- base )-3- tert-butyl hydroxypropionate ( VIII Preparation of ) : Add VII (1.0 equivalent, scaling factor), tetrahydrofuran (9.0 volume), and then ( S,S)-Ts-DENEB (0.005 equivalents) was charged into the reactor. The reactor contents were stirred and cooled to about 15°C. Tetrahydrofuran (1.0 volume) and triethylamine (1.0 equivalents) were charged into another reactor, the mixture was cooled to about 0°C, and then formic acid (2.5 equivalents) was charged, maintaining the reactor contents at about 0°C. Subsequently, the contents of the second reactor were transferred to the first reactor containing VII, maintaining the reaction mixture at about 15°C. The resulting mixture was heated to about 35°C and stirred for about 18 hours. The reaction mixture was then cooled to about 10°C, and tert-butyl methyl ether (10 volumes) and 10% by weight aqueous citric acid solution (7.0 volumes) were charged into the reactor. The two-phase mixture was stirred for about 30 minutes, and then allowed to settle for phase separation. The lower aqueous phase was discarded. The organic phase was washed with 10% by weight aqueous potassium bicarbonate solution (5.0 volumes), and then washed with 10% by weight aqueous sodium chloride solution (7.0 volumes). Activated carbon (Darco, 0.25 wt / wt) was added and the resulting mixture was stirred at about 10°C for about 1 hour. The reactor contents were then filtered, and the filter cake was washed with tert-butyl methyl ether (2.0 volume). The combined organic phases were concentrated under vacuum to obtain VIII.

[0203] step 7.(S)-3-((R)-4- Acetylene -2,2- dimethyl -1,3- Dioxolane -4- base )-3- Tertiary hydroxypropionic acid Butyl ester ( IX Preparation of ) : Tetrahydrofuran (5.0 volumes) was charged into reactor VIII (1.0 equivalent, scale factor), and the contents were cooled to approximately 10°C. A solution of 1.0 M tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (1.1 equivalents) was added, and the reaction mixture was aged at approximately 10°C for approximately 1 hour. The discovery that this reaction is insensitive to water content allowed for the preparation of a TBAF solution by dissolving readily available TBAF trihydrate in tetrahydrofuran. The reaction mixture was diluted with tert-butyl methyl ether (10 volumes) and washed twice with water (5.0 volumes each time). The organic phase was filtered and concentrated under reduced pressure to give IX.

[0204] step 8.(4S,5R)-5- Acetylene -4- hydroxyl -5-( hydroxymethyl ) dihydrofuran -2(3H)- ketone( X ) : 1,2-Dimethoxyethane (6.0 volumes) was charged into reactor IX (1.0 equivalent, scaling factor). Then, concentrated hydrochloric acid (5.0 volumes) was charged into the reactor over a period of approximately 30 minutes, and the reactor contents were heated to approximately 45°C and aged for approximately 2 hours. The reaction mixture was cooled to approximately 20°C and concentrated to approximately 2 volumes. Acetonitrile (10 volumes) was added, and the mixture was then concentrated to approximately 2 volumes. Subsequently, another portion of acetonitrile (10 volumes) was charged, and the mixture was concentrated to approximately 1.5 volumes to obtain X.

[0205] 1 H NMR (400MHz, DMSO-d6): 5.86 (s, 1H), 5.59 (s, 1H), 4.41-4.38 (m,1H), 3.77 (s, 1H), 3.64-3.67 (m, 2H), 2.94 (dd, J = 16Hz, 8Hz, 1H), 2.41 (dd, J =16Hz, 4Hz, 1H).

[0206] Example 2.2-Phenylacetic acid (2 R ,3 S 5 R )-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2- Preparation of ((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl ester (I) step 1. preparation 4- Methylbenzoic acid (2R,3S)-2- Acetylene -2-(((4- Methylbenzoyl ) Oxygen ) First base )-5- oxotetrahydrofuran -3- esters ( XI Preparation of ) : X (1.0 equivalent, scaling factor) was mixed with 1,2-dimethoxyethane (8.0 volumes) and acetonitrile (1.0 volumes) in a reactor, and the resulting solution was cooled to approximately -20°C. Then, 4-dimethylaminopyridine (0.05 equivalents) was added to the reactor, followed by 1-methylimidazole (2.8 equivalents). Subsequently, 4-methylbenzoyl chloride (2.2 equivalents) was added over a period of approximately 30 minutes, maintaining the reactor contents below 0°C. The resulting mixture was then aged at approximately 0°C for approximately 18 hours. Water (6.0 volumes) and ethyl acetate (10 volumes) were then added to the reactor, and the two-phase mixture was stirred at approximately 20°C for approximately 30 minutes, followed by sedimentation for phase separation. The bottom layer (aqueous phase) was discarded. The organic phase was concentrated under vacuum to approximately 3 volumes and then diluted with 2-propanol (10 volumes). The resulting mixture was stirred at about 40°C for about 3 hours, then slowly cooled to about 10°C over about 3 hours, and aged at about 10°C for about 18 hours. The resulting slurry was filtered, the filter cake was washed with a 9:1 mixture of heptane and isopropyl acetate (2 volumes), and vacuum dried at about 40°C for about 24 hours to obtain XI.

[0207] 1 H NMR (400MHz, DMSO-d6): δ 7.99-7.92 ( m , 4H), 7.42-7.39 ( m , 4H), 5.91 ( dd , J = 8Hz, 4Hz, 1H), 4.72 ( m , 2H), 4.01 ( s , 1H), 3.44 ( dd , J= 20Hz, 8Hz, 1H), 3.09 ( dd (J = 16Hz, 4Hz, 1H), 2.43 ( s , 6H).

[0208] step 2.4- Methylbenzoic acid (2R,3S)-2- Acetylene -5- hydroxyl -2-(((4- Methylbenzoyl ) Oxygen ) First base ) Tetrahydrofuran -3- esters ( XII Preparation of ) : XI (1.0 equivalent, scaling factor) and 1,2-dimethoxyethane (DME, 8.0 volume) were charged into the reactor. The resulting solution was cooled to approximately -55°C. A toluene solution of diisobutylaluminum hydride (DIBAL) (1.90 equivalent) was slowly charged into the reactor, maintaining the reactor contents below approximately -45°C. The resulting reaction mixture was diluted with pre-cooled (approximately -55°C) toluene (8.0 volume), and then quenched by the slow addition of acetic acid (5 equivalent), maintaining the reactor contents below approximately -20°C. The reaction mixture was washed with 1M aqueous H₂SO₄ (7.0 volume) and 10% by weight NaCl aqueous solution (7.0 volume), and then concentrated under vacuum to approximately 3 volumes. Toluene (7.0 volume) was charged. The resulting mixture was then cooled to approximately 5°C and stirred overnight. The resulting slurry was filtered and washed with toluene (1.5 volume). The solution of XII in toluene was reused in the next step (Step 3).

[0209] The method described in this paper was found to achieve the desired selective reduction to lactol XII in a reproducible manner.

[0210] step 3.4- Methylbenzoic acid (2R,3S)-5- Acetoxy -2- Acetylene -2-(((4- Methylbenzoyl ) oxygen base ) methyl ) Tetrahydrofuran -3- esters ( XIV-1 Preparation of ) : 4-Dimethylaminopyridine (DMAP, 0.05 equivalents) and triethylamine (1.25 equivalents) were added to a cooled solution of XII (approximately 0°C) in toluene, followed by the slow addition of acetic anhydride (1.25 equivalents), maintaining the reactor contents below approximately 5°C. The reaction mixture was then quenched with water (0.4 volumes) and washed sequentially with 10% wt% aqueous citric acid solution (5.0 volumes), 5% wt% aqueous NaHCO3 solution (5.0 volumes), and water (5.0 volumes). The organic layer was concentrated under vacuum to approximately 2 volumes. Acetonitrile (7.0 volumes) was then added. The solution of XIV-1 in acetonitrile was reused in the next step.

[0211] step 4.4- Methylbenzoic acid (2R,3S,5R)-2- Acetylene -5-(2- fluorine -6-(( Trimethylsilyl ) ammonia base )-9H- purine -9- base )-2-(((4- Methylbenzoyl ) Oxygen ) methyl ) Tetrahydrofuran -3- esters ( XVI Preparation of ) : 2-Fluoroadenine (XV, 1.1 equivalents), acetonitrile (10.0 volumes), and bis(trimethylsilyl)acetamide (BSA, 3.0 equivalents) were charged into a reactor. The reaction mixture was heated to about 72°C and maintained at that temperature for at least 1 hour. The reaction mixture was then cooled to about 20°C, and trimethylsilyl trifluoromethanesulfonate (TMSOTf, 1.1 equivalents) was charged. The reaction mixture was heated to about 72°C, and a solution of XIV-1 (1.0 equivalents, proportioning factor) in acetonitrile was slowly added to the reaction mixture over about 1 hour, maintaining the reactor contents above 70°C. Additional BSA (1.0 equivalents) was added, and the reaction mixture was concentrated under vacuum to about 11 volumes, maintaining the reactor contents above 60°C. XVI (0.0007 equivalents) crystals were then seeded into the mixture, stirred at about 60°C for about 1 hour, and then slowly cooled to about 5°C with stirring. The resulting slurry was filtered, and the filter cake was washed with MTBE (2 × 1.5 volumes) and vacuum dried at 50°C to obtain XVI.

[0212] 1 H NMR (400MHz, DMSO-d6): δ 8.36 (s, 1H), 7.90 (br, 2H), 7.97 (m, 2H), 7.83 (m, 2H), 7.38 (m, 2H), 7.28 (m, 2H), 6.53 (dd, 6.7Hz, 1H), 6.09 (dd, 5.3 and 6.9Hz, 1H), 4.70 (d, 11.5Hz, 1H), 4.56 (d, 11.5Hz, 1H), 3.80 (s, 1H), 3.35 (ddd, 14.1Hz, 7.1Hz, 6.9Hz, 1H), 2.84 (ddd, 14.1Hz, 7.0Hz, 5.5Hz, 1H), 2.41 (s, 3H), 2.37 (s, 3H). 13 C NMR (126MHz, DMSO-d6): δ 165.0, 164.7, 158.6, 157.7,150.2, 144.2, 143.9, 140.2, 129.5, 129.4, 129.2, 126.4, 126.3, 117.7, 82.8,81.2, 80.0, 78.4, 73.6, 65.7, 34.5, 21.21, 21.20 step 5.4'- Acetylene -2- fluorine -2'- Deoxyadenosine ( islatravir , XVII Preparation of ) : XVI (1 equivalent, scaling factor) and THF (10.0 volume) were charged into the reactor. The reactor contents were stirred to produce a clear solution, which was then cooled to approximately 0°C. A dilute methanol solution of sodium methoxide was prepared by mixing pre-cooled (approximately 0°C) methanol (5.0 volume) with a solution of 25% by weight sodium methoxide in methanol (0.03 equivalent) in a separate vessel. This solution was then charged into the XVI solution, and the resulting reaction mixture was stirred at approximately 0°C. The reaction was quenched at approximately 0°C with a 1.0 M phenylacetic acid THF solution (containing 0.045 equivalents of phenylacetic acid), and then warmed to approximately 20°C. After stirring for approximately 1 hour, the reaction mixture was passed through a fine filter, and the filtrate was concentrated under vacuum to approximately 2 volumes. The concentrate was then diluted with approximately 5 volumes of acetonitrile solution of 10% by weight water, and the resulting mixture was stirred at approximately 40°C for approximately 1 hour. The mixture was then concentrated under vacuum to approximately 2 volumes, and the resulting concentrate was diluted again with approximately 5 volumes of an acetonitrile solution of 10% by weight water. The resulting mixture was stirred at approximately 40°C for approximately 1 hour, then toluene (8.0 volumes) was added to the mixture, and the reactor contents were slowly cooled to approximately 10°C with stirring. The slurry was filtered, and the filter cake was washed with toluene (2 × 2.9 volumes) and then dried under vacuum at approximately 40°C to obtain XVII.

[0213] 1 H NMR (400MHz, DMSO-d6): δ 8.34 (s, 1H), 7.88 (s, 2H), 6.29-6.26 (m,1H), 5.62 (d, J = 4.0Hz, 1H), 5.35 (t, J = 8Hz, 1H), 4.62-4.60 (m, 1H), 3.71-3.67 (m, 1H), 3.62-3.54 (m, 1H), 3.52 (s, 1H), 2.76-2.72 (m, 1H), 2.50-2.43(m, 1H).

[0214] step 6.2- Phenylacetic acid (2R,3S,5R)-5-(6- amino -2- fluorine -9H- purine -9- base )-2- Acetylene -2- ((2- Phenylacetoxy ) methyl ) Tetrahydrofuran -3- esters ( I ) : Add XVII (1 equivalent, proportionality factor) to the reactor, followed by acetone (8.0 volume) and acetonitrile (2.0 volume). Stir the reactor contents and add... N1-Methylimidazole (4.2 equivalents). The resulting solution was cooled to approximately -10°C and then treated with a solution of phenylacetyl chloride (3.8 equivalents) in acetonitrile (6.0 volumes) at approximately -5°C to 0°C. After adding the phenylacetyl chloride solution, the reactor was heated to approximately 10°C and then stirred. Water (1.0 volume) was added to the reactor and then heated to approximately 40°C. Water (5.0 volume) was then added to the reactor, and the reactor contents were finely filtered into the reactor. The filtrate was cooled to approximately 30°C, and then seed crystals of I (0.008 equivalents) were added, and the mixture was stirred for approximately 1 hour. Subsequently, water (10.0 volume) was added to the reactor over approximately 1 hour. The reactor temperature was then cooled to approximately 10°C. The resulting slurry was stirred, then filtered, and washed with water (6.0 volume) and 2-propanol (4.0 volume). The solid was then vacuum dried at approximately 50°C to obtain I.

[0215] 1 H NMR (400MHz, chloroform-d) δ 7.75 (d, J = 1.4Hz, 1H), 7.41 – 7.19 (m,11H), 6.45 (s, 1H), 6.34 (t, J = 6.7Hz, 1H), 5.54 (dd, J = 6.8, 4.6Hz, 1H), 4.50 (d, J = 12.0Hz, 1H), 4.41 (d, J = 12.0Hz, 1H), 3.72 (s, 2H), 3.68 (s,2H), 2.67 – 2.53 (m, 2H), 2.44 (d, J = 0.8Hz, 1H).

[0216] Example 3. 2-Phenylacetic acid (2 R ,3 S 5 R )-5-(6-amino-2-fluoro-9H-purine-9-yl)-2-ethynyl-2- Preparation of alternatives to ((2-phenylacetoxy)methyl)tetrahydrofuran-3-yl ester (I) step 1.2- Phenylacetic acid (2R,3S)-2- Acetylene -5- Oxygenation -2-((2- Phenylacetoxy ) methyl ) Tetrahydrogen furans -3- esters ( XIX Preparation of ) : X (1.0 equivalent, scaling factor) was mixed with 1,2-dimethoxyethane (8.0 volume) and acetonitrile (1.0 volume) in a reactor, and the resulting solution was cooled to approximately -20°C. Then, 4-dimethylaminopyridine (0.05 equivalent) was added to the reactor, followed by 1-methylimidazole (2.8 equivalent). Subsequently, phenylacetyl chloride (2.5 equivalent) was added over a period of approximately 30 minutes, maintaining the reactor contents below 0°C. The reaction mixture was then aged at approximately 0°C for approximately 18 hours until the reaction was considered complete. Water (6.0 volume) and ethyl acetate (10 volume) were then added to the reactor, and the two-phase mixture was stirred at approximately 20°C for approximately 30 minutes, followed by sedimentation for phase separation. The bottom layer (aqueous phase) was discarded. The organic phase was concentrated under vacuum, and the crude product was purified by column chromatography.

[0217] 1 H NMR (400MHz, DMSO-d6): δ 7.39-7.30 (m, 10H), 5.51 (dd, J = 8Hz,4Hz, 1H), 4.41 (m, 2H), 4.01 (s, 1H), 3.79 (m, 4H), 3.10 (dd, J = 20Hz, 8Hz, 1H), 2.73 (dd, J = 20Hz, 4Hz, 1H).

[0218] step 2.2- Phenylacetic acid (2R,3S)-2- Acetylene -5- hydroxyl -2-((2- Phenylacetoxy ) methyl ) Tetrahydrogen furans -3- esters ( XX Preparation of ) : XIX (1.0 equivalent, scaling factor) and 1,2-dimethoxyethane (DME, 8.0 volumes) were charged into the reactor. The resulting solution was cooled to approximately -55°C. A toluene solution of diisobutylaluminum hydride (DIBAL) (1.90 equivalents) was slowly charged into the reactor, maintaining the reactor contents below approximately -45°C. The resulting reaction mixture was quenched with acetic acid (5 equivalents), maintaining the reactor contents below approximately -20°C. The reaction mixture was washed with 1M aqueous H₂SO₄ (7.0 volumes) and 10% by weight NaCl (7.0 volumes), and then concentrated under vacuum to approximately 3 volumes. Toluene (7.0 volumes) was charged. The solution of crude XX in toluene was reused in the next step.

[0219] step 3.2- Phenylacetic acid (2R,3S)-5- Acetoxy -2- Acetylene -2-((2- Phenylacetoxy ) methyl ) Tetrahydrofuran -3- esters ( XXII-1 Preparation of ) : To a cooled toluene solution of XX (approximately 0°C), 4-dimethylaminopyridine (DMAP, 0.05 equivalents) and triethylamine (1.25 equivalents) were added, followed by the slow addition of acetic anhydride (1.25 equivalents), maintaining the reaction mixture below approximately 5°C. The reaction mixture was then quenched with water (0.4 volumes) and washed sequentially with 10% wt% aqueous citric acid solution (5.0 volumes), 5% wt% aqueous NaHCO3 solution (5.0 volumes), and water (5.0 volumes). The organic layer was concentrated under vacuum to approximately 2 volumes. Acetonitrile (7.0 volumes) was then added. The crude acetonitrile solution of XXII-1 was reused in the next step.

[0220] step 4.2- Phenylacetic acid (2R,3S,5R)-5-(6- amino -2- fluorine -9H- purine -9- base )-2- Acetylene -2- ((2- Phenylacetoxy ) methyl ) Tetrahydrofuran -3- esters ( I ) : 2-Fluoroadenine (XV, 1.1 equivalents), acetonitrile (10.0 volumes), and bis(trimethylsilyl)acetamide (BSA, 3.0 equivalents) were charged into the reactor. The reaction mixture was heated to about 72°C and maintained at that temperature for at least 1 hour. The reaction mixture was then cooled to about 20°C, and trimethylsilyl trifluoromethanesulfonate (TMSOTf, 1.1 equivalents) was charged. The reaction mixture was heated to about 72°C, and a solution of crude XXII-1 (1.0 equivalents, proportion factor) in acetonitrile was slowly added to the reaction mixture over about 30 minutes, maintaining the reactor contents above 70°C. Additional BSA (1.0 equivalents) was added, and the reaction mixture was concentrated under vacuum to about 3 volumes, diluted with acetone (6 volumes), and then diluted with water (7 volumes). The organic phase was separated and concentrated under vacuum to an oil. The crude product (a mixture of diastereomers and other byproducts) was purified by column chromatography to obtain I as a solid.

[0221] 1 H NMR (400MHz, chloroform-d) δ 7.75 (d, J = 1.4Hz, 1H), 7.41 – 7.19 (m,11H), 6.45 (s, 1H), 6.34 (t, J = 6.7Hz, 1H), 5.54 (dd, J = 6.8, 4.6Hz, 1H), 4.50 (d, J = 12.0Hz, 1H), 4.41 (d, J = 12.0Hz, 1H), 3.72 (s, 2H), 3.68 (s,2H), 2.67 – 2.53 (m, 2H), 2.44 (d, J = 0.8Hz, 1H).

[0222] All references, including publications, patents, and patent documents, are incorporated herein by reference as if they were separately incorporated by reference. This disclosure provides reference to various embodiments and techniques. However, it should be understood that many changes and modifications can be made while maintaining the spirit and scope of this disclosure.

Claims

1. A method for preparing compound of formula I: I Or by means of eutectic, solvate, salt or combination thereof; The method includes using a compound of formula XVII: XVII Or its eutectic, solvate, salt, or combination with compounds of formula XVIII: XVIII Where X is selected from halogens, -OCOCH2Ph ​​and OH, and Alkali reaction, To provide a compound of formula I or a eutectic, solvate, salt or combination thereof.

2. The method according to claim 1, wherein X is a halogen.

3. The method according to claim 1 or 2, wherein X is Cl.

4. The method according to claim 1, wherein X is OH, and the reaction is carried out in the presence of an activating agent.

5. The method according to claim 4, wherein the activating agent comprises a chlorinating agent, 1,1-carbonyldiimidazole, carbodiimide, peptide coupling agent, or a combination thereof.

6. The method according to claim 4 or 5, wherein the activating agent is selected from the group consisting of: oxalyl chloride, thionyl chloride, phosphoryl chloride, 1,1-carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, HATU, propylphosphonic anhydride and isobutyl chloroformate.

7. The method according to any one of claims 1 to 6, wherein the base comprises an aromatic amine, a tertiary alkylamine, a carbonate, or a combination thereof.

8. The method according to any one of claims 1 to 7, wherein the base comprises an aromatic amine.

9. The method according to any one of claims 1 to 8, wherein the base is N-methylimidazole.

10. The method according to any one of claims 1 to 9, wherein the reaction is carried out in a first solvent comprising acetone and acetonitrile.

11. The method according to any one of claims 1 to 10, wherein the reaction is carried out in a temperature range of about -20°C to about 10°C.

12. The method according to any one of claims 1 to 11, wherein the reaction is carried out in the presence of a catalyst.

13. The method of claim 12, wherein the catalyst is selected from the group consisting of 4-dimethylaminopyridine, imidazole, triphenylphosphine oxide and 1-hydroxy-7-azabenzotriazole.

14. The method according to any one of claims 1 to 13, the method further comprising preparing the compound of formula XVII or its eutectic, solvate, salt or combination thereof by a method comprising: Compounds of formula XVI-A: XVI-A Or its eutectic, solvate, salt or combination thereof, Where P 1 Is it H or (R) 4 )3Si, where each R 4 C is independent 1-6 Alkyl groups, and Deacylation reagents and The second base reaction, To provide compounds of formula XVII or their eutectic, solvate, salt or combination thereof.

15. The method of claim 14, wherein P 1 It is trimethylsilyl.

16. The method according to claim 14 or 15, wherein the deacylation agent is C 1-4 alcohol.

17. The method according to any one of claims 14 to 16, wherein the deacylation agent is methanol.

18. The method according to any one of claims 14 to 17, wherein the second base comprises a hydroxide, an oxide, a methoxide, a tert-butoxide, a carbonate, or a combination thereof.

19. The method according to any one of claims 14 to 18, wherein the second base is sodium methoxide.

20. The method according to any one of claims 14 to 19, wherein the second base is used in an amount of about 0.02 equivalents to about 0.2 equivalents relative to the compound of formula XVI-A or its eutectic, solvate, salt or combination thereof.

21. The method according to any one of claims 14 to 20, wherein the reaction of the compound of formula XVI-A or its eutectic, solvate, salt or combination thereof is carried out in a second solvent comprising tetrahydrofuran and methanol.

22. The method according to any one of claims 14 to 21, wherein the reaction of the compound of formula XVI-A or its eutectic, solvate, salt or combination thereof is carried out in a temperature range of about -20°C to about 20°C.

23. The method according to any one of claims 14 to 22, the method further comprising preparing the compound of formula XVI-A or its cocrystal, solvate, salt or combination thereof by a method comprising: Compounds of formula XIV: XIV Or its eutectic, solvate, salt or combination thereof, Where R 1 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyloxy, benzyloxy, or optionally one to five independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl, Compounds of formula XV: XV Or its eutectic, solvate, salt or combination thereof, Silylating agents and Lewis acid reaction, To provide a compound of formula XVI-A or its eutectic, solvate, salt or combination thereof.

24. The method of claim 23, wherein the Lewis acid is selected from the group consisting of: trimethylsilyl trifluoromethane sulfonate, boron trifluoride diethyl ether, and tin tetrachloride.

25. The method according to claim 23 or 24, wherein the Lewis acid is a trimethylsilyltrifluoromethane sulfonate.

26. The method according to any one of claims 23 to 25, wherein the silylating agent is selected from the group consisting of bis(trimethylsilyl)acetamide and bis(trimethylsilyl)trifluoroacetamide.

27. The method according to any one of claims 23 to 26, wherein the silylating agent is bis(trimethylsilyl)acetamide.

28. The method according to any one of claims 23 to 27, wherein the reaction of the compound of formula XIV or its eutectic, solvate, salt or combination thereof is carried out in a third solvent comprising acetonitrile.

29. The method according to any one of claims 23 to 28, wherein the reaction of the compound of formula XIV or its eutectic, solvate, salt or combination thereof is carried out in a temperature range of about 60°C to about 100°C.

30. The method according to any one of claims 23 to 29, wherein R 1 It is a methyl group.

31. The method according to any one of claims 23 to 30, the method further comprising preparing the compound of formula XIV or its cocrystal, solvate, salt or combination thereof by a method comprising: Compound XII: XII Or its eutectic, solvate, salt or combination thereof, with Select free-form compound XIII-A: XIII-A Compounds in the group consisting of compounds of formula XIII-B: XIII-B, The third alkali and The second catalyst reaction, To provide the compound of formula XIV or its eutectic, solvate, salt or combination thereof.

32. The method of claim 31, wherein the method comprises reacting the compound of formula XII or its eutectic, solvate, salt or combination thereof with the compound of formula XIII-A.

33. The method according to claim 31 or 32, wherein the compound of formula XIII-A is selected from the group consisting of acetic anhydride, trifluoroacetic anhydride, propionic anhydride, benzoic anhydride, toluene anhydride and ditert-butyl dicarbonate.

34. The method according to any one of claims 31 to 33, wherein the compound of formula XIII-A is acetic anhydride.

35. The method of claim 31, wherein the method comprises reacting the compound of formula XII or its eutectic, solvate, salt or combination thereof with the compound of formula XIII-B.

36. The method according to claim 31 or 35, wherein the compound of formula XIII-B is selected from the group consisting of acetyl chloride, propionyl chloride, benzoyl chloride, tolueneyl chloride, methyl chloroformate, ethyl chloroformate and benzyl chloroformate.

37. The method according to any one of claims 31 to 36, wherein the third base comprises an aromatic amine, a tertiary alkyl amine, a carbonate, or a combination thereof.

38. The method according to any one of claims 31 to 37, wherein the third base is triethylamine.

39. The method according to any one of claims 31 to 38, wherein the second catalyst is selected from the group consisting of 4-dimethylaminopyridine, imidazole, triphenylphosphine oxide and 1-hydroxy-7-azabenzotriazole.

40. The method according to any one of claims 31 to 39, wherein the second catalyst is 4-dimethylaminopyridine.

41. The method according to any one of claims 31 to 40, wherein the reaction of the compound of formula XII or its eutectic, solvate, salt or combination thereof is carried out in a fourth solvent comprising toluene.

42. The method according to any one of claims 31 to 41, wherein the reaction of the compound of formula XII or its eutectic, solvate, salt or combination thereof is carried out in a temperature range of about -50°C to about 50°C.

43. The method according to any one of claims 31 to 42, the method further comprising preparing the compound of formula XII or its eutectic, solvate, salt or combination thereof by a method comprising: Reduce compound XI with a reducing agent: XI Or its eutectic, solvate, salt or combination thereof, To provide the compound of formula XII or its eutectic, solvate, salt or combination thereof.

44. The method of claim 43, wherein the reducing agent is selected from the group consisting of: diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, lithium aluminum hydride, lithium borohydride, and lithium tritert-butoxyaluminum hydride.

45. The method according to claim 43 or 44, wherein the reducing agent is diisobutylaluminum hydride.

46. ​​The method according to any one of claims 43 to 45, wherein the reduction is performed in a fifth solvent comprising 1,2-dimethoxyethane.

47. The method according to any one of claims 43 to 46, wherein the reduction is carried out in a temperature range of about -80°C to about -30°C.

48. The method according to any one of claims 43 to 47, the method further comprising preparing the compound of formula XI or its eutectic, solvate, salt or combination thereof by a method comprising: Compound X: X Or its eutectic, solvate, salt or combination thereof, with Fourth base, The third catalyst, and Esterification is performed using acylation reagents. To provide a compound of formula XI or a eutectic, solvate, salt or combination thereof.

49. The method according to claim 48, wherein the fourth base is an organic base or an inorganic base.

50. The method of claim 49, wherein the organic base is selected from the group consisting of: N-methylimidazole, triethylamine, Wrenning base, pyridine, imidazole, DABCO, and DBU.

51. The method according to claim 49, wherein the inorganic base is selected from the group consisting of: Na2CO3, Cs2CO3, K2CO3, NaOH and KOH.

52. The method according to any one of claims 48 to 51, wherein the fourth base is N-methylimidazole.

53. The method according to any one of claims 48 to 52, wherein the third catalyst comprises an aromatic base.

54. The method according to any one of claims 48 to 53, wherein the third catalyst is selected from the group consisting of 4-dimethylaminopyridine, pyridine, imidazole and 4-pyrrolidinylpyridine.

55. The method according to any one of claims 48 to 54, wherein the third catalyst is 4-dimethylaminopyridine.

56. The method according to any one of claims 48 to 55, wherein the acylation agent is selected from the group consisting of toluene chloride and toluene.

57. The method according to any one of claims 48 to 56, wherein the acylation agent is tolueneyl chloride.

58. The method according to any one of claims 48 to 57, wherein the acylation agent is toluene, and the esterification is performed in the presence of a carboxylic acid activator.

59. The method according to claim 58, wherein the carboxylic acid activator is selected from the group consisting of 1,1'-carbonyldiimidazole, thionyl chloride and oxalyl chloride.

60. The method according to any one of claims 48 to 59, wherein the esterification is performed in a sixth solvent comprising 1,2-dimethoxyethane and acetonitrile.

61. The method according to any one of claims 48 to 60, wherein the esterification is carried out in a temperature range of about -20°C to about 40°C.

62. A method for preparing compound of formula I: I Or by means of eutectic, solvate, salt or combination thereof; The method includes using a compound of formula XXII: XXII Or its eutectic, solvate, salt or combination thereof, Where R 6 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyloxy, benzyloxy, or optionally one to five independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl, Compounds of formula XV: XV, Silylating agents and Lewis acid reaction, To provide a compound of formula I or a eutectic, solvate, salt or combination thereof.

63. The method of claim 62, wherein the Lewis acid is selected from the group consisting of: trimethylsilyl trifluoromethane sulfonate, boron trifluoride diethyl ether, and tin tetrachloride.

64. The method according to claim 62 or 63, wherein the Lewis acid is a trimethylsilyltrifluoromethane sulfonate.

65. The method according to any one of claims 62 to 64, wherein the silylating agent is selected from the group consisting of bis(trimethylsilyl)acetamide and bis(trimethylsilyl)trifluoroacetamide.

66. The method according to any one of claims 62 to 65, wherein the silylating agent is bis(trimethylsilyl)acetamide.

67. The method according to any one of claims 62 to 66, wherein the reaction is carried out in a first solvent comprising acetonitrile.

68. The method according to any one of claims 62 to 67, wherein the reaction is carried out in a temperature range of about 60°C to about 100°C.

69. The method according to any one of claims 62 to 68, wherein R 6 It is a methyl group.

70. The method according to any one of claims 62 to 69, the method further comprising preparing the compound of formula XXII or its cocrystal, solvate, salt or combination thereof by a method comprising: Compounds with formula XX: XX Or its eutectic, solvate, salt or combination thereof, with Select free XXI-A compounds: XXI-A Compounds in the group consisting of compounds of formula XXI-B: XXI-B, alkali and Catalytic reaction, To provide the compound of formula XXII or its eutectic, solvate, salt or combination thereof.

71. The method of claim 70, wherein the method comprises reacting the compound of formula XX or its eutectic, solvate, salt or combination thereof with the compound of formula XXI-A.

72. The method according to claim 70 or 71, wherein the compound of formula XXI-A is selected from the group consisting of: acetic anhydride, trifluoroacetic anhydride, propionic anhydride, benzoic anhydride, toluene anhydride and di-tert-butyl dicarbonate.

73. The method according to any one of claims 70 to 72, wherein the compound of formula XXI-A is acetic anhydride.

74. The method of claim 70, wherein the method comprises reacting the compound of formula XX or its eutectic, solvate, salt or combination thereof with the compound of formula XXI-B.

75. The method according to claim 70 or 74, wherein the compound of formula XXI-B is selected from the group consisting of acetyl chloride, propionyl chloride, benzoyl chloride, tolueneyl chloride, methyl chloroformate, ethyl chloroformate, and benzyl chloroformate.

76. The method according to any one of claims 70 to 75, wherein the base comprises an aromatic amine, a tertiary alkylamine, a carbonate, or a combination thereof.

77. The method according to any one of claims 70 to 76, wherein the base is triethylamine.

78. The method according to any one of claims 70 to 77, wherein the catalyst is selected from the group consisting of 4-dimethylaminopyridine, imidazole, triphenylphosphine oxide and 1-hydroxy-7-azabenzotriazole.

79. The method according to any one of claims 70 to 78, wherein the catalyst is 4-dimethylaminopyridine.

80. The method according to any one of claims 70 to 79, wherein the reaction of the compound of formula XX or its eutectic, solvate, salt or combination thereof is carried out in a second solvent comprising toluene.

81. The method according to any one of claims 70 to 80, wherein the reaction of the compound of formula XX or its eutectic, solvate, salt or combination thereof is carried out in a temperature range of about -50°C to about 50°C.

82. The method according to any one of claims 70 to 81, the method further comprising preparing the compound of formula XX or its cocrystal, solvate, salt or combination thereof by a method comprising: Reduce compound XIX with a reducing agent: XIX Or its eutectic, solvate, salt or combination thereof, To provide a compound of formula XX or its eutectic, solvate, salt or combination thereof.

83. The method according to claim 82, wherein the reducing agent is selected from the group consisting of: diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, lithium aluminum hydride, lithium borohydride and lithium tritert-butoxyaluminum hydride.

84. The method according to claim 82 or 83, wherein the reducing agent is diisobutylaluminum hydride.

85. The method according to any one of claims 82 to 84, wherein the reduction is performed in a third solvent comprising 1,2-dimethoxyethane.

86. The method according to any one of claims 82 to 85, wherein the reduction is carried out in a temperature range of about -80°C to about -30°C.

87. The method according to any one of claims 82 to 86, the method further comprising preparing the compound of formula XIX or its cocrystal, solvate, salt or combination thereof by a method comprising: Compound X: X Or its eutectic, solvate, salt or combination thereof Second alkali, and The second catalyst is used for esterification. To provide a compound of formula XIX or its eutectic, solvate, salt or combination thereof.

88. The method according to claim 87, wherein the second base is an organic base or an inorganic base.

89. The method according to claim 88, wherein the organic base is selected from the group consisting of: N-methylimidazole, triethylamine, Wrenning base, pyridine, imidazole, DABCO, and DBU.

90. The method according to claim 88, wherein the inorganic base is selected from the group consisting of: Na2CO3, Cs2CO3, K2CO3, NaOH and KOH.

91. The method according to any one of claims 87 to 89, wherein the second base is N-methylimidazole.

92. The method according to any one of claims 87 to 91, wherein the second catalyst comprises an aromatic base.

93. The method according to any one of claims 87 to 92, wherein the second catalyst is selected from the group consisting of 4-dimethylaminopyridine, pyridine, imidazole and 4-pyrrolylpyridine.

94. The method according to any one of claims 87 to 93, wherein the second catalyst is 4-dimethylaminopyridine.

95. The method according to any one of claims 87 to 94, wherein the esterification is performed in a fourth solvent comprising 1,2-dimethoxyethane and acetonitrile.

96. The method according to any one of claims 87 to 95, wherein the esterification is carried out in a temperature range of about -20°C to about 25°C.

97. The method according to any one of claims 48 to 61 and 87 to 96, the method further comprising preparing the compound of formula X or its cocrystal, solvate, salt or combination thereof by a method comprising: Compounds of formula IX: IX Or its eutectic, solvate, salt or combination thereof, with Acid reaction, To provide a compound of formula X or a eutectic, solvate, salt or combination thereof.

98. The method of claim 97, wherein the acid is a strong protic acid or a strong Lewis acid.

99. The method according to claim 97 or 98, wherein the acid is HCl.

100. The method according to any one of claims 97 to 99, wherein the reaction of the compound of formula IX or its eutectic, solvate, salt or combination thereof is carried out in a seventh solvent comprising 1,2-dimethoxyethane.

101. The method according to any one of claims 97 to 100, wherein the reaction of the compound of formula IX or its eutectic, solvate, salt or combination thereof is carried out in a temperature range of about 30°C to about 60°C.

102. The method according to any one of claims 97 to 101, the method further comprising preparing the compound of formula IX or its cocrystal, solvate, salt or combination thereof by a method comprising: Compound VIII-A: VIII-A Where P 2 Yes (R) 5 )3Si, where each R 5 C is independent 1-6 alkyl; Or its eutectic, solvate, salt or combination thereof The fluoride source undergoes desilylation. To provide a compound of formula IX or a eutectic, solvate, salt or combination thereof.

103. The method of claim 102, wherein P 2 It is triisopropylsilyl.

104. The method according to claim 102 or 103, wherein the fluoride source is selected from the group consisting of alkali metal fluorides, alkaline earth metal fluorides, hydrofluoric acid, pyridine-trihydrofluoride, tetrabutylammonium fluoride, and their hydrates.

105. The method according to any one of claims 102 to 104, wherein the fluoride source is tetrabutylammonium fluoride trihydrate.

106. The method according to any one of claims 102 to 105, wherein the desilylation is performed in an eighth solvent comprising tetrahydrofuran.

107. The method according to any one of claims 102 to 106, wherein the desilylation is performed in a temperature range of about -10°C to about 35°C.

108. The method according to any one of claims 102 to 107, the method further comprising preparing the compound of formula VIII-A or its cocrystal, solvate, salt or combination thereof by a method comprising: Compounds of formula VII-A: VII-A Or its eutectic, solvate, salt or combination thereof, with hydrogen source, and The fourth catalyst reaction, To provide the compound of formula VIII-A or its eutectic, solvate, salt or combination thereof.

109. The method according to claim 108, wherein the hydrogen source is selected from the group consisting of formic acid, formate, aqueous sodium formate solution, secondary alcohol or hansyl ester.

110. The method according to claim 108 or 109, wherein the hydrogen source is a trimethylamine formate complex.

111. The method according to any one of claims 108 to 110, wherein the fourth catalyst is a transition metal catalyst.

112. The method according to any one of claims 108 to 111, wherein the fourth catalyst comprises ruthenium, iron, osmium, cobalt, rhodium, iridium, nickel, palladium, gold, or combinations thereof.

113. The method according to any one of claims 108 to 112, wherein the fourth catalyst is a ruthenium catalyst.

114. The method according to any one of claims 108 to 113, wherein the fourth catalyst is N-[(1S,2S)-1,2-diphenyl-2-(2-(4-methylbenzyloxy)ethylamino)-ethyl]-4-methylbenzenesulfonamide (chloro)ruthenium(II).

115. The method according to any one of claims 108 to 114, wherein the reaction of the compound of formula VII-A or its eutectic, solvate, salt or combination thereof is carried out in a ninth solvent comprising tetrahydrofuran.

116. The method according to any one of claims 108 to 115, wherein the reaction of the compound of formula VII-A or its eutectic, solvate, salt or combination thereof is carried out in a temperature range of about 30°C to about 60°C.

117. The method according to any one of claims 108 to 116, the method further comprising preparing the compound of formula VII-A or its eutectic, solvate, salt or combination thereof by a method comprising: Compounds of formula VI-A: VI-A Or its eutectic, solvate, salt or combination thereof, Where R 2 and R 3 Independently selected from C3-C7 cycloalkyl, C 1-6 Alkyl and benzyl, and Second acid, Second activating agent, monomalonate, and Fifth base reaction, To provide the compound of formula VII-A or its eutectic, solvate, salt or combination thereof.

118. The method of claim 117, wherein R 2 and R 3 It is cyclohexyl.

119. The method according to claim 117 or 118, wherein the second acid is a protic acid.

120. The method according to any one of claims 117 to 119, wherein the second acid is citric acid.

121. The method according to any one of claims 117 to 120, wherein the second activator is a carbonyl transfer reagent.

122. The method according to any one of claims 117 to 121, wherein the second activator is 1,1'-carbonyldiimidazole.

123. The method according to any one of claims 117 to 122, wherein the malonic acid monoester is tert-butyl malonic acid monoester.

124. The method according to any one of claims 117 to 123, wherein the fifth base is a Grignard reagent.

125. The method according to any one of claims 117 to 124, wherein the fifth base is isopropyl magnesium chloride.

126. The method according to any one of claims 117 to 125, wherein the reaction of the compound of formula VI-A or its eutectic, solvate, salt or combination thereof is carried out in a tenth solvent comprising methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or combinations thereof.

127. The method according to any one of claims 117 to 126, wherein the reaction of the compound of formula VI-A or its eutectic, solvate, salt or combination thereof is carried out in a temperature range of about 0°C to about 30°C.

128. The method according to any one of claims 117 to 127, the method further comprising preparing the compound of formula VI-A or its cocrystal, solvate, salt or combination thereof by a method comprising: Compound VA: VA Or its eutectic, solvate, salt or combination thereof, with Oxidizing reagents Fifth catalyst The sixth base, and Oxidation of salt-forming reagents To provide a compound of formula VI-A or its eutectic, solvate, salt or combination thereof.

129. The method of claim 128, wherein the oxidizing agent is selected from the group consisting of: high-valent iodine reagents, activated DMSO, copper reagents, and sulfur reagents.

130. The method according to claim 128 or 129, wherein the oxidizing agent is (diacetoxyiodine)benzene (DAIB).

131. The method according to any one of claims 128 to 130, wherein the fifth catalyst is selected from the group consisting of nitrogen oxides, organic peroxides, and azo radical initiators.

132. The method according to any one of claims 128 to 131, wherein the fifth catalyst is (2,2,6,6-tetramethylpiperidin-1-yl)oxy radical (TEMPO).

133. The method according to any one of claims 128 to 132, wherein the sixth base comprises a phosphate or a carbonate.

134. The method according to any one of claims 128 to 133, wherein the sixth base is disodium hydrogen phosphate.

135. The method according to any one of claims 128 to 134, wherein the salt-forming reagent has the formula R 2 R 3 Secondary amines of NH.

136. The method according to any one of claims 128 to 135, wherein the salt-forming agent is dicyclohexylamine.

137. The method according to any one of claims 128 to 136, wherein the oxidation is performed in an eleventh solvent comprising acetonitrile and water.

138. The method according to any one of claims 128 to 137, wherein the oxidation is carried out in a temperature range of about 0°C to about 50°C.

139. The method according to any one of claims 128 to 139, the method further comprising preparing the VA compound or its cocrystal, solvate, salt or combination thereof by a method comprising: Compounds of formula IV-A: IV-A Or its eutectic, solvate, salt or combination thereof, with acid catalysts 1,2-Diol protecting reagent, and The seventh base reaction, To provide the VA compound or its eutectic, solvate, salt or combination thereof.

140. The method of claim 139, wherein the acid catalyst is a weak acid with a pKa in the range of about 4 to about 6.

141. The method according to claim 139 or 140, wherein the acid catalyst is pyridinium p-toluenesulfonate (PPTS).

142. The method according to any one of claims 139 to 141, wherein the 1,2-diol protecting agent is selected from the group consisting of 2,2-dimethoxypropane, acetone and isopropyl acetate.

143. The method according to any one of claims 139 to 142, wherein the 1,2-diol protecting agent is 2,2-dimethoxypropane.

144. The method according to any one of claims 139 to 143, wherein the seventh base comprises an alkoxide or a hydroxide.

145. The method according to any one of claims 139 to 144, wherein the seventh alkali comprises sodium methoxide.

146. The method according to any one of claims 139 to 145, wherein the reaction of the compound of formula IV-A or its eutectic, solvate, salt or combination thereof is carried out in a twelfth solvent comprising methyl tert-butyl ether and acetonitrile.

147. The method according to any one of claims 139 to 146, wherein the reaction of the compound of formula IV-A or its eutectic, solvate, salt or combination thereof is carried out in a temperature range of about 20°C to about 80°C.

148. The method according to any one of claims 139 to 147, the method further comprising preparing the compound of formula IV-A or its cocrystal, solvate, salt or combination thereof by a method comprising: Compounds of formula III-A: III-A Or its eutectic, solvate, salt or combination thereof, with Eighth base, and Enzyme reaction, To provide the compound of formula IV-A or its eutectic, solvate, salt or combination thereof.

149. The method of claim 148, wherein the eighth base comprises an alkali metal hydroxide and an alkali metal buffer.

150. The method according to claim 148 or 149, wherein the eighth base comprises potassium hydroxide and KH2PO4 aqueous buffer solution.

151. The method according to any one of claims 148 to 150, wherein the reaction of the compound of formula III-A or its eutectic, solvate, salt or combination thereof is carried out at a pH in the range of about 5 to about 7.

152. The method according to any one of claims 148 to 151, wherein the reaction of the compound of formula III-A or its eutectic, solvate, salt or combination thereof is carried out at a pH in the range of about 5 to about 5.

8.

153. The method according to any one of claims 148 to 152, wherein the enzyme comprises Candida antarcticis lipase A (CALA).

154. The method according to any one of claims 148 to 153, wherein the reaction of the compound of formula III-A or its eutectic, solvate, salt or combination thereof is carried out in a thirteenth solvent comprising methanol.

155. The method according to any one of claims 148 to 154, wherein the reaction of the compound of formula III-A or its eutectic, solvate, salt or combination thereof is carried out in a temperature range of about 5°C to about 65°C.

156. The method according to any one of claims 148 to 155, the method further comprising preparing the compound of formula III-A or its cocrystal, solvate, salt or combination thereof by a method comprising: Compound of formula II: II Or its eutectic, solvate, salt or combination thereof, with Formula P 2 - Acetylene compounds, and The ninth base reaction, To provide the compound of formula III-A or its eutectic, solvate, salt or combination thereof.

157. The method according to claim 156, wherein formula P 2 -The acetylene compound is (triisopropylsilyl)acetylene.

158. The method according to claim 156 or 157, wherein the ninth base comprises alkyllithium, aryllithium, Grignard reagent, diisopropylaminolithium, hexamethyldisilazanelithium, hexamethyldisilazanesodium, hexamethyldisilazanepotassium, aminolithium, aminosodium, metal hydride, alkoxide, or combinations thereof.

159. The method according to any one of claims 156 to 158, wherein the ninth base comprises n-butyllithium.

160. The method according to any one of claims 156 to 159, wherein the reaction of the compound of formula II or its eutectic, solvate, salt or combination thereof is carried out in a fourteenth solvent comprising tetrahydrofuran.

161. The method according to any one of claims 156 to 160, wherein the reaction of the compound of formula II or its eutectic, solvate, salt or combination thereof is carried out in a temperature range of about -100°C to about -40°C.

162. A method for preparing compound of formula I: I A method comprising: or a eutectic, solvate, salt, or combination thereof, said method comprising: (a) Compound X: X Or its eutectic, solvate, salt or combination thereof Fourth base, The third catalyst, and Esterification is performed using acylation reagents. To provide compounds of formula XI: XI Or its eutectic, solvate, salt or combination thereof; (b) Reducing the compound of formula XI or its eutectic, solvate, salt or combination thereof with a reducing agent. To provide compound of formula XII: XII Or its eutectic, solvate, salt or combination thereof; (c) Mixing the compound of formula XII or its eutectic, solvate, salt or combination with... Select free-form compound XIII-A: XIII-A Compounds in the group consisting of compounds of formula XIII-B: XIII-B Where R 1 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyloxy, benzyloxy, or optionally one to five independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl, The third alkali and The second catalyst reaction, Provided as a compound of formula XIV: XIV Or its eutectic, solvate, salt or combination thereof; (d) Mixing the compound of formula XIV or its eutectic, solvate, salt or combination with the compound of formula XV: XV Or its eutectic, solvate, salt or combination thereof, Silylating agents and Lewis acid reaction, To provide a compound of formula XVI-A: XVI-A Or its eutectic, solvate, salt or combination thereof, Where P 1 Is it H or (R) 4 )3Si, where each R 4 C is independent 1-6 alkyl; (e) To react the compound of formula XVI or its eutectic, solvate, salt or combination with: Deacylation reagents and The second base reaction, To provide compounds of formula XVII: XVII or its eutectic, solvate, salt or combination thereof; and (f) To react the compound of formula XVII or its eutectic, solvate, salt or combination with: Compound XVIII: XVIII Where X is selected from halogens, acid anhydrides, and OH, and Alkali reaction, To provide a compound of formula I or a eutectic, solvate, salt or combination thereof.

163. A method for preparing compound of formula I: I A method comprising: or a eutectic, solvate, salt, or combination thereof, said method comprising: (a) Compound X: X Or its eutectic, solvate, salt or combination thereof Second alkali, and The second catalyst is used for esterification. Provided as a compound of formula XIX: XIX Or its eutectic, solvate, salt or combination thereof; (b) Reducing the compound of formula XIX or its eutectic, solvate, salt or combination thereof with a reducing agent. Provide compound of formula XX: XX Or its eutectic, solvate, salt or combination thereof; (c) Mixing the compound of formula XX or its eutectic, solvate, salt or combination with... Select free XXI-A compounds: XXI-A Compounds in the group consisting of compounds of formula XXI-B: XXI-B Where R 6 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyloxy, benzyloxy, or optionally one to five independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl, alkali and Catalytic reaction, To provide compound of formula XXII: XXII or its eutectic, solvate, salt or combination thereof; and (d) To make the compound of formula XXII or its eutectic, solvate, salt or combination thereof, Compounds of formula XV: XV, Silylating agents and Lewis acid reaction, To provide a compound of formula I or a eutectic, solvate, salt or combination thereof.

164. The method according to claim 162 or 163, wherein the compound of formula X or its eutectic, solvate, salt or combination thereof is prepared by a method comprising: (a) Make compound II: II Or its eutectic, solvate, salt or combination thereof, with Formula P 2 - Acetylene compounds, where P 2 Yes (R) 4 )3Si, where each R 4 C is independent 1-6 Alkyl groups, and The ninth base reaction, To provide compounds of formula III-A: III-A Or its eutectic, solvate, salt or combination thereof; (b) To react the compound of formula III-A or its eutectic, solvate, salt or combination with... Eighth base, and Enzyme reaction, To provide compounds of formula IV-A: IV-A Or its eutectic, solvate, salt or combination thereof; (c) Mixing the compound of formula IV-A or its eutectic, solvate, salt or combination with... acid catalysts 1,2-Diol protecting reagent, and The seventh base reaction, Provided VA compound: VA Or its eutectic, solvate, salt or combination thereof; (d) Using the VA compound or its eutectic, solvate, salt or combination thereof with... Oxidizing reagents Fifth catalyst The sixth base, and Oxidation of salt-forming reagents To provide a compound of formula VI-A: VI-A Or its eutectic, solvate, salt or combination thereof, Where R 2 and R 3 Independently selected from C3-C7 cycloalkyl, C 1-6 Alkyl and benzyl; (e) Mixing the compound of formula VI-A or its eutectic, solvate, salt or combination with... Second acid, Second activating agent, monomalonate, and Fifth base reaction, To provide compounds of formula VII-A: VII-A Or its eutectic, solvate, salt or combination thereof; (f) To react the compound of formula VII-A or its eutectic, solvate, salt or combination with: hydrogen source, and The fourth catalyst reaction, To provide compounds of formula VIII-A: VIII-A Or its eutectic, solvate, salt or combination thereof; (g) The compound of formula VIII-A or its eutectic, solvate, salt or combination thereof is disposed of using... The fluoride source undergoes desilylation. To provide compounds of formula IX: IX or its eutectic, solvate, salt or combination thereof; and (h) Mixing the compound of formula IX or its eutectic, solvate, salt or combination with... Acid reaction, To provide a compound of formula X or a eutectic, solvate, salt or combination thereof.

165. A compound of formula XIX: XIX Or its eutectic, solvate, salt or combination thereof.

166. A compound with formula XX: XX Or its eutectic, solvate, salt or combination thereof.

167. A compound of formula XXII: XXII Or its eutectic, solvate, salt or combination thereof, Where R 6 Selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkyloxy, benzyloxy, or optionally one to five independently selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl groups, halogens, C 1-4 The C substituent of alkoxy or benzyloxy 6-10 Aryl.

168. The compound according to claim 167, wherein R 6 It is a methyl group.

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