Preparation process of (S)-TERT-butyl 4,5-diamino-5-oxopentanoate

Abstract

To provide processes for the preparation of (S)-tert-butyl 4,5-diamino-5-oxopentanoate, or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopologue thereof and also provide solid forms of various intermediates and products obtained from the processes.SOLUTION: The target compound is synthesized by employing an amine compound as a protective agent, starting with the compound below.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] This application is a continuation of U.S. Provisional Application No. 62 / 548,268, filed August 21, 2017. Priority is claimed and is incorporated herein by reference in its entirety.

[0002] 1. Field As used herein, (S)-tert-butyl 4,5-diamino-5-oxopentanoate or its salts, solvates, hydrates, enantiomers, mixtures of enantiomers, or isomers thereof The present invention provides a process for preparing a substituted aryl group having an (S)-2-aminoglutarimide moiety. For example, (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1 2,6-dione, It can be used to generate compounds. [Background technology]

[0003] 2.Background Certain compounds containing glutarimide moieties have been reported to exhibit medicinal properties suitable for clinical development. One example is (S)-3-(4-((4-(morpholinomethyl)benzyl)o The compound is 1-oxoisoindolin-2-yl)piperidine-2,6-dione. The compound is described in U.S. Patent Publication No. 2011 / 0196150, which is The entirety of which is incorporated herein by reference.

[0004] Enantiomerically enriched or enantiomerically pure 3-(4-((4-(morpholinomethyl) Benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6 The synthesis process for -dione was previously described in U.S. Patent Publication No. 2014 / 0046058. This process is described in US Pat. As an important starting material for the construction of the (S)-2-aminoglutarimide moiety, (S) -tert-butyl 4,5-diamino-5-oxopentanoate hydrochloride is used.

[0005] Synthesis of (S)-tert-butyl 4,5-diamino-5-oxopentanoate hydrochloride has been reported previously. For example, a recent report showed that Cbz-(L)-Glu(tBu) (S)-tert-Butyl 4,5-diamino-5-oxopentanoate salt from -OH The synthesis of the acid salt is explained. J.Med.Chem.2016,59(19), 9107-9123(Support Information). [ka]

[0006] However, the reported method is not suitable for scale-up. It has been described to remove the solvent and dry the mixture, but this causes uncontrollable precipitation ( This can result in changes in purity.) Also, large volumes (up to 56 volumes, i.e. 1 The use of 56 mL per gram of ethanol has also been mentioned, which is ineffective on a large scale. Moreover, the process describes the control of the chiral center. There is no literature regarding the chiral purity of the product.

[0007] (S)-tert-Butyl 4,5-diamino-5-oxopentanoate hydrochloride is It is usually only available in gram quantities. Prices typically range from $300 to $800 per 100g of product. 0, making large-scale preparations of glutarimide-containing compounds prohibitively expensive. Delivery typically takes several weeks (e.g., about 12 weeks), and the chemical purity of commercial products is typically about Chiral purity is often reported as 95-98%. It has not been done.

[0008] Currently available, (S)-tert-butyl 4,5-diamino-5-oxopentane There remains a need to develop alternative synthetic processes for tanoate hydrochloride. Summary of the Invention

[0009] 3. Overview As used herein, a compound of formula (I): [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The compound of formula (I) is (S)-tert-butyl 4,5 The compound has the chemical name 5-diamino-5-oxopentanoate. The process involves preparing a salt of the compound. The present invention includes an optional step of manufacturing a

[0010] In one embodiment, the N-protected oxynitriles described herein include those containing ammonia or protected amines. A compound of formula (I), or a solvate thereof, comprising a ring-opening reaction of the sazolidin-5-one moiety, Provides a process for the preparation of hydrates, enantiomers, mixtures of enantiomers, or isotopically substituted forms do.

[0011] In one embodiment, the present invention relates to a method for the preparation of oxazolidine-2,5-diamine with ammonia. Compounds of formula (I) or solvates, hydrates, enantiomers thereof, including ring-opening reactions of the aryl moiety. , a mixture of enantiomers, or an isotopic substitution is provided.

[0012] In one embodiment, the present invention relates to the nucleophilic cleavage of N-protected pyridines with tert-butoxide nucleophiles. A compound of formula (I), or a solvate thereof, comprising a ring-opening reaction of the rolidin-2-one moiety. The present invention provides a process for the preparation of an isotopically modified solvate, enantiomer, mixture of enantiomers, or isotopically substituted solvate. do.

[0013] In one embodiment, the 2-((diphenylmethylene)amino)acetonyl tolyl, 2-((diphenylmethylene)amino)acetamide, or 2-((diphenyl Michael addition of dimethylamino)acetates to tert-butyl acrylate Compounds of formula (I) or solvates, hydrates, enantiomers, or enantiomers thereof, including reactions The present invention provides a process for preparing a mixture of isotopically substituted or isotopically substituted isomers of

[0014] In one embodiment, as described herein, 2-phenyloxazol-5(4H)-one a compound of formula (I) comprising a Michael addition reaction of 1,2-diphenyl ether with tert-butyl acrylate; The preparation of solvates, hydrates, enantiomers, mixtures of enantiomers, or isotopically substituted derivatives thereof The manufacturing process is provided.

[0015] Also referred to herein is a compound of formula (XIV): [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The present invention provides a process for the preparation of a recombinant aryl group, comprising reacting a compound of formula (I) with one of the starting materials, Use as.

[0016] Also referred to herein is a compound of formula (XV): [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The compound of formula (XV) can be prepared by the method of preparing the compound of formula (XIV). It can be used as an alternative starting material for

[0017] In one embodiment, the term "antibody" as used herein includes its solid forms (e.g., crystalline forms). An intermediate compound used in a process provided herein, or a compound prepared by that process. The present invention provides a product compound that can be used.

[0018] In one embodiment, the present disclosure provides a solid form comprising compound 7 of the following formula (e.g., Form A): ) to provide: [ka] .

[0019] In one embodiment, a solid form comprising racemic compound 7 of the formula: Form A) is provided: [ka] .

[0020] In one embodiment, the present disclosure provides a solid form comprising compound 8 of the following formula (e.g., Form A): ) to provide: [ka] .

[0021] In one embodiment, a solid form comprising racemic compound 8 of the formula: Form A) is provided: [ka] .

[0022] In one embodiment, the present disclosure provides a solid form comprising Compound 1 of the following formula (e.g., Form A): and form B): [ka] .

[0023] In one embodiment, a solid form comprising racemic compound 1 of the formula: Form A) is provided: [ka] .

[0024] In one embodiment, the solid form described herein includes compound 35 of the formula: A) Provide: [ka] .

[0025] In one embodiment, the solid form (e.g., form 37) comprising compound 37 of the following formula is provided herein: 1) Provide: [ka] .

[0026] In one embodiment, a solid form comprising racemic compound 37 of the formula , form 1) is provided: [ka] . [Brief description of the drawings]

[0027] [Figure 1] 1 shows a representative X-ray powder diffraction (XRPD) pattern of Form A of Compound 7.

[0028] [Diagram 2] 1 shows a representative differential scanning calorimetry (DSC) thermogram of Form A of Compound 7.

[0029] [Diagram 3] A representative XRPD pattern of Form A of racemic compound 7 is shown.

[0030] [Figure 4] 1 shows a representative DSC thermogram of Form A of racemic compound 7.

[0031] [Diagram 5] 1 shows a representative XRPD pattern of Form A of Compound 8.

[0032] [Figure 6] 1 shows a representative DSC thermogram of Form A of Compound 8.

[0033] [Figure 7] A representative XRPD pattern of Form A of racemic compound 8 is shown.

[0034] [Figure 8] 1 shows a representative DSC thermogram of Form A of racemic compound 8.

[0035] [Figure 9] 1 shows a representative XRPD pattern of Form A of Compound 1.

[0036] [Figure 10] 1 shows a representative DSC thermogram of Compound 1, Form A.

[0037] [Figure 11] 1 shows a representative XRPD pattern of Form B of Compound 1.

[0038] [Figure 12] 1 shows a representative DSC thermogram of Compound 1, Form B.

[0039] [Figure 13] A representative XRPD pattern of Form A of racemic compound 1 is shown.

[0040] [Figure 14] 1 shows a representative DSC thermogram of Form A of racemic compound 1.

[0041] [Figure 15] 1 shows a representative XRPD pattern of Form A of Compound 35.

[0042] [Figure 16] 1 shows a representative DSC thermogram of compound 35, Form A.

[0043] [Figure 17] 1 shows a representative XRPD pattern of Form 1 of Compound 37.

[0044] [Figure 18] 1 shows a representative DSC thermogram of Form 1 of Compound 37.

[0045] [Figure 19A] 1 shows a chiral HPLC chromatogram of a typical reaction to prepare compound 37 from compound 35.

[0046] [Figure 19B] 1 shows a chiral HPLC chromatogram of an atypical reaction to prepare compound 37 from compound 35.

[0047] [Figure 20] A representative XRPD pattern of Form 1 of racemic compound 37 is shown.

[0048] [Figure 21] A representative DSC thermogram of Form 1 of racemic compound 37 is shown.

[0049] [Figure 22]A representative crystalline molecular structure of Form A of Compound 35 is shown.

[0050] [Figure 23] A representative crystalline molecular structure of Form 1 of Compound 37 is shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0051] 5. Detailed Description 5.1 Definition As used herein, and unless otherwise specified, the term "pro" as provided herein "Process(s)" refers to any of the process(es) provided herein that are useful for preparing the compounds provided herein. Modifications to the methods provided herein (e.g., starting materials, reagents, protecting groups, Solvents, temperatures, reaction times, purification) are also encompassed by the present disclosure. The technical teachings of the embodiments may be incorporated into any of the techniques disclosed in any other embodiments provided herein. It can be combined with technical teachings.

[0052] When used in conjunction with the term "comprises" in the claims and / or specification, The use of the words "a" or "an" can mean "one," but can also mean "one or more," "at least one," or "one or more." "at least one" and "one or more."

[0053] As used herein, the terms "comprising" and "in The term "comprising" can be used interchangeably. and "including" means that the stated features or components are referred to. should be construed as specifying the presence of one or more features or configurations. It does not exclude the presence or addition of elements, or groups thereof. "Comprising" and "including" refer to the term " Therefore, the term "consisting of" is intended to include examples encompassed by "comprising" of the present invention. To provide a more specific embodiment of the present invention, the terms "comprising" and Can be used in place of "including."

[0054] The term "consisting of" means that the object comprises at least one of the stated features or components that it is made up of. It means that the compound has at least 90%, 95%, 97%, 98% or 99% of the desired molecular weight. In the embodiments, the term "consists of" includes all elements except those that are not essential to the technical effect to be achieved. Therefore, any other feature or component is excluded from the scope of any subsequent description.

[0055] As used herein, the term "or" means any one or any combination. Thus, "A, B or C" is an inclusive "or" means any of the following: "A; B; C; A and B; A and C; B and C; A, B and Exceptions to this definition are those where the combination of elements, functions, steps, or actions is in some way and this only occurs when the two are essentially mutually exclusive.

[0056] As used herein, unless otherwise specified, the terms "add," "react," " "Treat" or the like means to convert one reactant, reagent, solvent, catalyst, reactive group, etc., into another reactant, reagent, It means to contact with a reactant, a reagent, a solvent, a catalyst, a reactive group, etc. The reactants etc. can be added individually, simultaneously or separately and in any order. They can be added with or without heat and can be In some cases, the addition can be done under an inert atmosphere. It can refer to in situ formation or an intramolecular reaction when the two are within the same molecule.

[0057] As used herein, unless otherwise specified, the term "convert" refers to It refers to subjecting the compound at hand to suitable reaction conditions to form the desired compound. vinegar.

[0058] As used herein, and unless otherwise specified, the term "salt" includes any of the salts provided herein. These include, but are not limited to, salts of acidic or basic groups that may be present in the compounds provided. Compounds that are basic in nature can form a wide variety of salts with various inorganic and organic acids. The acids which can be used to prepare the salts of such basic compounds form salts containing anions. Acids that react with water include, for example, acetic acid, benzenesulfonic acid, benzoic acid, bicarbonic acid, bitartaric acid, bromide Calcium edetate, camsylate, carbonate, chloride, bromide, iodide, citrate Salt, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucuronide Arseptate, gluconate, glutamate, glycolyl arsenate, hexyl acetate Sorcinate, hydrabamine, hydroxynaphthoate, isethionate, lactate, lactate Tobionate, malate, maleate, mandelate, mesylate, methyl sulfate, Muscate, naphthyrate, nitrate, pantothenate, phosphate / diphosphate Phosphates, polygalacturonates, salicylates, stearates, succinates, sulfates, Tannate, tartrate, tetraoclate, triethiodide, and pamoate. Compounds containing amino groups also include, but are not limited to, various acids in addition to the acids listed above. Compounds that are acidic in nature can form salts with a variety of cations. Non-limiting examples of such salts include alkali metal salts. or alkaline earth metal salts, in some embodiments calcium, magnesium These include the sodium, lithium, zinc, potassium, and iron salts. Compounds which are also capable of forming base salts with compounds which contain an amino group.

[0059] As used herein, and unless otherwise specified, the term "solvate" refers to a non-covalent It means a compound that further contains a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0060] As used herein, and unless otherwise specified, the term "stereoisomer" includes All enantiomerically / stereomerically pure compounds and enantiomerically / stereomerically pure compounds provided in the specification Isomerically enriched compounds are included.

[0061] If the stereochemistry of a structure or portion thereof is not shown, e.g., by bold or dashed lines, then the The structure or part thereof contains all enantiomerically pure, enantiomerically enriched, diastereomeric Stereomerically pure, diastereomerically enriched compounds, and racemic compounds Mixtures should be understood to be included.

[0062] Unless otherwise noted, the terms "enantiomerically enriched" and "enantiomerically enriched" are used interchangeably herein. "Enantiomerically pure" and "enantiomerically pure" mean that the weight percentage of one enantiomer is equal to or greater than that of a reference enantiomer. greater than the amount of one enantiomer in a mixture of semi-compositions (e.g., by weight) (1:1 or greater) compositions, e.g., enantiomerically enriched in the (S)-enantiomer. The preparation is more than 50% by weight of the (S)-enantiomer relative to the (R)-enantiomer, e.g. For example, it means a preparation that is at least 75% by weight, or even at least 80% by weight of the compound. In some embodiments, the enrichment is well above 80% by weight and is "substantially optically "enantiomerically enriched," "substantially enantiomerically enriched," "substantially enantiomerically pure " or "substantially non-racemic" preparations, which may be obtained by mixing the other enantiomers. At least 85% by weight, for example at least 90% by weight, and for example at least In one embodiment, the composition comprises 95% by weight of one enantiomer. The product contains about 99% by weight of one enantiomer relative to the other. The composition is at least 99% by weight greater of one enantiomer relative to the other enantiomer. In some embodiments, the enantiomerically enriched composition comprises an enantiomerically enriched amount of therapeutic agent per unit mass. In terms of therapeutic utility, the composition has greater potency than the racemic mixture.

[0063] As used herein, and unless otherwise specified, the term "solid form" and related terms As used herein, the term "form" refers to a physical form that is not primarily in a liquid or gaseous state. The terms "solid" and "solid form" include semi-solids. Solid forms include crystalline, amorphous, partially crystalline, and solid forms. The amorphous phase may be crystalline, partially amorphous, or mixed.

[0064] The solid forms provided herein may have varying degrees of crystallinity or lattice order. The solid forms provided herein are not limited by any particular degree of crystallinity or lattice order. The crystallinity may be 0 to 100%. Suryanarayanan, R., X-Ray Power Diffractometry,Physical Characterization of Pharmaceutical Salts,HGBrittain,Ed. itor,Mercel Dekkter,Murray Hill,NJ,199 5, pp. 187-199, and are known to those skilled in the art. In some embodiments, the solid forms provided herein have a molecular weight of about 0, 5, 10, 15, 20 , 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, It is 90, 95 or 100% crystalline.

[0065] As used herein, and unless otherwise indicated, the term "result" "Crystals" and related terms, when used to describe a substance, ingredient, product, or form, A substance, component, product, or form is substantially crystalline as determined, for example, by X-ray diffraction. For example, Remington: The Science and Practice of Pharmacy, 21 st edition, Lippin cott,Williams and Wilkins,Baltimore,MD(2 005);The United States Pharmacopeia,23 rd See edition, 1843-1844 (1995).

[0066] As used herein, and unless otherwise specified, the term "crystalline form" "Crystal forms" and related terms refer to crystalline solid forms. Crystal forms include single component crystals. Crystal forms and multicomponent crystal forms are included, including polymorphs, solvates, hydrates, and other molecular complexes, as well as This includes salts, solvates of salts, hydrates of salts, cocrystals of salts, other molecular complexes of salts, and polymorphs thereof. In certain embodiments, the crystalline form of the substance includes, but is not limited to, amorphous forms and In certain embodiments, the crystalline form of the substance may be substantially free of other crystalline forms. is approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% by weight , 15%, 20%, 25%, 30%, 35%, 40%, 45% or less than 50% The compound may contain the above amorphous form(s) and / or other crystalline form(s). In embodiments, a crystalline form of a substance may be physically and / or chemically pure. In embodiments, a crystalline form of a substance is about 99%, 98%, 97%, or 100% physically and / or chemically stable. %, 96%, 95%, 94%, 93%, 92%, 91% or 90% pure .

[0067] Crystalline forms of substances can be obtained by a number of methods, including melt recrystallization. , melt cooling, solvent recrystallization, recrystallization in closed spaces, e.g., in nanopores or capillaries, e.g. Recrystallization on a surface or template, e.g., on a polymer, e.g., co-crystallization of a molecule, Recrystallization in the presence of additives, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, ascending These include, but are not limited to, flowering, grinding, and solvent drop grinding.

[0068] Unless otherwise indicated, the terms "polymorph," "polymorphic form," "polymorph(s)," "polymorphs," and "polymorphs" used herein are used interchangeably herein. "form(s)" and related terms refer to a set of molecules, molecules or ions that are essentially the same. Similar to different crystalline forms, different polymorphs are also called polymorphs, which are the distribution of a compound within a crystal lattice. As a result of various arrangements or conformations of molecules or ions, e.g., melting temperatures, heats of fusion, They may have different physical properties such as solubility, dissolution rate, and / or vibrational spectra. The differences in physical properties exhibited by the (important in bioavailability), and dissolution rate (important in bioavailability). Differences in stability can be due to changes in chemical reactivity (e.g., Dosage forms that consist of one polymorph tend to discolor more rapidly than those that consist of another polymorph. Differential oxidation) or mechanical changes (e.g., kinetically favored polymorphic transformations, as tablets This may be due to the breakdown of the polymorphic form during storage into a more thermodynamically stable polymorph, or both (e.g. (Some polymorphic tablets are more susceptible to degradation under high humidity conditions.) As a result of differences in solubility / disintegration In some extreme cases, some polymorphic transitions may result in a lack of efficacy or in other extreme cases. In addition, the physical properties of the crystals may be important in processing. (e.g., some polymorphs are more likely to form solvates or to be free of impurities) Filtering and cleaning can be difficult, and the particle shape and size distribution may vary between polymorphs).

[0069] As used herein, and unless otherwise specified, the term "non- "Amorphous," "crystalline," and related terms refer to the material, component, or product in question that is or becomes amorphous when exposed to X-ray radiation. It means that the crystals are not substantially crystalline as determined by diffraction. "Crystal form" refers to a disordered solid form, i.e., a solid form lacking long-range crystalline order. In embodiments, an amorphous form of a substance is substantially free of other amorphous and / or crystalline forms. In other embodiments, the amorphous form of the material is about 1%, 2%, 3%, 4% by weight. , 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50 % of one or more other amorphous and / or crystalline forms. In certain embodiments, an amorphous form of a substance may be physically and / or chemically pure. , an amorphous form of a substance is physically and / or chemically about 99%, 98%, 97%, 96%, It may be 95%, 94%, 93%, 92%, 91% or 90% pure. In this case, the amorphous form of the substance may be stabilized by the addition of additional components or ingredients (e.g., In certain embodiments, the composition may include an additive, polymer, or excipient that can act to enhance the stability of the composition. In terms of morphology, the amorphous form may be a solid solution.

[0070] Amorphous forms of substances can be obtained by a number of methods. Heating, melt cooling, rapid melt cooling, solvent evaporation, rapid solvent evaporation, desolvation, sublimation, grinding, ball These include, but are not limited to, milling, cryogenic grinding, spray drying, and freeze drying. .

[0071] Techniques for characterizing crystalline and amorphous forms include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and (DSC), X-ray powder diffraction (XRPD), single crystal X-ray diffraction, vibrational spectroscopy, e.g., red Infrared (IR) and Raman spectroscopy, solid-state and solution nuclear magnetic resonance (NMR) spectroscopy, optical microscopy method, high temperature optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size Analysis (PSA), surface area analysis, solubility measurement, disintegration measurement, elemental analysis, and Karl Fischer analysis. Characteristic unit cell parameters include, but are not limited to, unit cell analysis. Such diffraction methods include, but are not limited to, X-ray diffraction and neutron diffraction, including crystal diffraction and powder diffraction. The determination may be made using one or more techniques that are useful for the analysis of powder diffraction data. Used, for example, to analyze diffraction peaks associated with a single phase in a sample containing multiple solid phases Analysis of powder diffraction data includes profile refinement such as the Rietveld method. Another method useful for determining the structure of the compound is unit cell indexing, which allows those skilled in the art to easily determine the structure of the compound. can determine unit cell parameters from samples containing crystalline powders.

[0072] A solid form is one that has distinct physical characteristics that are unique to that particular solid form, such as the crystalline forms provided herein. These characterization data may include, for example, powder X-ray diffraction, differential scanning calorimetry, etc. These can be measured by a variety of techniques known to those skilled in the art, including spectroscopy, thermogravimetry, and nuclear magnetic resonance spectroscopy. The data provided by these techniques can be used to identify specific solid forms. One of skill in the art would be able to perform any of these characterization techniques and determine whether the resulting data is "Matches" the reference data provided herein that are identified as being characteristic of a particular solid form. It is possible to determine whether a solid form is one of the forms provided herein by determining whether the solid form is one of the forms provided herein. It can be determined whether the property data "matches" the property data of the reference solid form. It will be understood by one of skill in the art that the reference solid form corresponds to the same solid form. In analyzing whether a particular characterization data point is a "match," one skilled in the art will recognize that For example, experimental error and routine sample-to-sample analytical variability may result in reasonable variation. It is understood that the various formulations may vary in structure while still describing a given solid form.

[0073] As used herein, and unless otherwise specified, the terms "halo," "halogen," etc. etc. means -F, -Cl, -Br, or -I.

[0074] As used herein, and unless otherwise specified, the term "alkyl" means saturated, It means a monovalent, unbranched or branched hydrocarbon chain. Examples of alkyl groups include (C1-C6) Alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl Pyr, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-Methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl , 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-Methyl-2-pentyl, 4-Methyl-2-pentyl, 2,2-Dimethyl-1-butyl , 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, neopentyl, and hexyl. Longer alkyl groups include, but are not limited to, heptyl, octyl, nonyl, and decyl groups. Alkyl groups can be unsubstituted or substituted with one or more suitable substituents. The alkyl group may also contain isotopes of carbon and / or hydrogen (i.e., deuterium, or tritium) enriched in natural abundance alkyl groups. As used herein, and unless otherwise specified, the term "alkenyl" refers to any one of 1 to 10 alkyl, 1 to 10 alkoxy ... means an unbranched or branched monovalent hydrocarbon chain containing one or more carbon-carbon double bonds. As used herein, and unless otherwise specified, the term "alkynyl" refers to an alkynyl group having one or more carbon atoms. By "alkyl" is meant an unbranched or branched monovalent hydrocarbon chain containing a carbon-carbon triple bond.

[0075] As used herein, and unless otherwise specified, the term "alkoxy" refers to an oxygen atom or an alkoxy group. means an alkyl group that is attached through an atom to another group (i.e., -O-alkyl) An alkoxy group can be unsubstituted or substituted with one or more suitable substituents. Examples of alkoxy groups include (C1-C6)alkoxy groups, such as -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-2-methyl-1-propyl , -O-2-methyl-2-propyl, -O-2-methyl-1-butyl, -O-3-methyl -1-Butyl, -O-2-Methyl-3-Butyl, -O-2,2-Dimethyl-1-Propyl , -O-2-methyl-1-pentyl, 3-O-methyl-1-pentyl, -O-4-methyl -1-pentyl, -O-2-methyl-2-pentyl, -O-3-methyl-2-pentyl, -O-4-methyl-2-pentyl, -O-2,2-dimethyl-1-butyl, -O-3,3 -Dimethyl-1-butyl, -O-2-ethyl-1-butyl, -O-butyl, -O-isobutyl -butyl, -Ot-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl, and -O-hexyl. Examples include -O-heptyl, -O-octyl, -O-nonyl and -O-decyl groups. Alkoxy groups also include isotopes of carbon, oxygen and / or hydrogen (i.e., deuterium or tritium). Lithium) may be enriched in natural abundance isotopically substituted alkoxy groups.

[0076] As used herein, and unless otherwise stated, the term "cycloalkyl" or "Carbocyclyl" means a ring-shaped ring having 3 to 15, 3 to 9, 3 to 6, or 3 to 5 carbon atoms. Contains elementary atoms and has no alternating or resonating double bonds between carbon atoms It means an alkyl group. It may have 1 to 4 rings. Unsubstituted cycloalkyl Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and Cycloalkyl includes, but is not limited to, adamantyl. In some embodiments, cycloalkyl can be substituted with an aryl or or a cycloalkyl fused to a heteroaryl group.

[0077] As used herein, and unless otherwise stated, the term "heterocycloalkyl" Or "heterocyclyl" refers to an aryl group consisting of one or more, and in some embodiments one to three, carbon atoms. Cycloalkyl groups in which the carbon atom is replaced with a heteroatom, such as, but not limited to, N, S, and O. In some embodiments, the heterocycloalkyl group is an alkyl group having 3 to 15 carbon atoms. Contains 3 to 9, 3 to 6, or 3 to 5 carbon atoms and heteroatoms. In the present specification, heterocycloalkyl is a heterocycloalkyl fused to an aryl or heteroaryl group. It may be arylalkyl. 3-6 To heterocycloalkyl groups, use prefixes such as When mentioned, the carbon number (3-6 in this example) is meant to include the heteroatoms. For example, C 3-6 Heterocycloalkyl groups include, for example, tetrahydropyranyl (five carbon atoms). It is meant to contain one heteroatom (a carbon atom and one heteroatom replacing a carbon atom).

[0078] As used herein, and unless otherwise specified, the term "aryl" refers to any of 5 to 1 A carbocyclic aromatic ring containing 4 ring atoms. All of the ring atoms of a carbocyclic aryl group are carbon atoms. Aryl ring structures include one or more monocyclic, bicyclic, or tricyclic compounds. The above ring structures and benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl In particular, the aryl group may be monocyclic, bicyclic, or tricyclic. Representative aryl groups include phenyl, anthracenyl, fluorenyl, and indenyl. , azulenyl, phenanthrenyl and naphthyl.

[0079] As used herein, and unless otherwise specified, the term "heteroaryl" means In certain embodiments, it refers to about 5 to about 15 membered monocyclic or polycyclic aromatic ring systems, in which One or more, in some embodiments 1 to 3, atoms in the ring system are heteroatoms, i.e. , N, O or S. The group may optionally be fused to a benzene ring. Heteroaryl groups include furyl, imidazolyl, indolinyl, pyrrolidinyl, pyrimidinyl, tetrazolyl, thienyl, Pyridyl, pyrrolyl, N-methylpyrrolyl, quinolinyl and isoquinolinyl. But not limited to these.

[0080] As used herein, and unless otherwise specified, the term "alcohol" refers to an -O H groups. The alcohol group may also contain oxygen and / or hydrogen. isotope (i.e., deuterium or tritium) enriched natural abundance alcohol Isotopic substitutions of the group are also possible.

[0081] As used herein, and unless otherwise specified, the term "amino" or "amino "Group" refers to a group of the formula -NH2, -NH(alkyl), -NH(aryl), -N(alkyl)2 , -N(aryl)2 or -N(alkyl)(aryl) monovalent radicals. The group may contain isotopes of carbon, nitrogen and / or hydrogen (i.e., deuterium or tritium). It may be an isotopically substituted product of an amino group enriched in natural abundance.

[0082] Unless otherwise indicated, the compounds disclosed herein, including intermediates useful in the preparation of the compounds provided herein, are not intended to be limiting unless otherwise indicated. The compounds provided herein may contain reactive functional groups, including but not limited to, carboxy, hydroxy, and amino moieties), including protected derivatives thereof. (s) are blocked with one or more protecting groups (also known as blocking groups) Suitable protecting groups for the carboxy moiety include benzyl, t-butyl, and the like. Suitable protecting groups for amino and amido groups include acetonitrile, ... acetyl, trifluoroacetyl, t-butyloxycarbonyl, benzyloxycarbonyl Suitable protecting groups for hydroxy include benzyl and the like. Suitable protecting groups are well known to those skilled in the art. The selection and use of protecting groups, as well as the introduction and The reaction conditions for the removal and elimination of β-glucosamine were determined according to Greene's Protective Groups in Organic Synthesis,4th edition,John W. 1999, published by Iley & Sons, New York, 2007, is incorporated herein by reference in its entirety.

[0083] Amino protecting groups known in the art include TW Green, Protective The conservation groups are described in detail in the Groups in Organic Synthesis. The amino protecting groups include -OH, -OR aa , -N(R cc )2, -C (=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C (=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2. -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C (=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 a alkyl (e.g., aralkyl groups), C 2-10 Alkenyl, C 2-10 Alkynyl, C3 -10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 Aryl, and 5-14 aryl groups, but are not limited to, wherein each alkyl, alkenyl, Aryl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and hetero Aryl is independently 0, 1, 2, 3, 4, or 5 R dd group; R aa Each instance of 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered Tetracyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl; alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heptyl. A heteroaryl is independently 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN , -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R c c )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc ) 2. -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O )(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1- 10Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alki Nill, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 Aryl, and and 5-14 membered heteroaryl, or two R bonded to the N atom cc base are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and Heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R dd Substituted with a group . R cc Each instance of 1-10 Alkyl, C 1-10 Perhaloarchi Lu, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3~1 4-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl; or two R attached to the N atom cc The group is also linked to a 3- to 14-membered heterocyclyl. or a 5- to 14-membered heteroaryl ring, bocyclyl, heterocyclyl, aryl, and heteroaryl are independently 0, 1, 2 , 3, 4, or 5 R dd The group is substituted. R dd Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, - SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3+ X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(=O )R ee 、-CO2H、-CO2R ee 、-OC(=O)R ee 、-OCO2R ee 、- C(=O)N(R ff )2、-OC(=O)N(R ff )2、-NR ff C(=O)R e e 、-NR ff CO2R ee 、-NR ff C(=O)N(R ff )2、-C(=NR ff )OR ee 、-OC(=NR ff )R ee 、-OC(=NR ff )OR ee 、-C(=N R ff )N(R ff )2、-OC(=NR ff )N(R ff )2、-NR ff C(=NR ff )N(R ff )2、-NR ff SO2R ee 、-SO2N(R ff )2、-SO2R ee 、-SO2OR ee 、-OSO2R ee 、-S(=O)R ee 、-Si(R ee )3 、-OSi(R ee )3、-C(=S)N(R ff )2、-C(=O)SR ee 、-C( =S)SR ee 、-SC(=S)SR ee 、-P(=O)2Ree , -P(=O)(R e e )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1-6 Alki Lu, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl each selected from alkyl, alkenyl, alkynyl, carbocyclyl, heteroaryl, aryl, aryl, and heteroaryl are independently 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd If the substituent is bonded to =O It is possible to form =S. R ee Each instance of 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2- 6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 Aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, each alkyl, Alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl. Each rule may independently contain 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each instance of 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heptane Rocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl; or two R attached to the N atom ff The group is bonded to a 3- to 14-membered heterocyclyl or a 5- Form a 14-membered heteroaryl ring, each alkyl, alkenyl, alkynyl, carbocyclyl aryl, heterocyclyl, aryl, and heteroaryl are independently 0, 1, 2, 3, 4 , or 5 R's gg substituted with a group; and R gg Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, - SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C1 -6 alkyl)2, -N(C 1-6 alkyl)3X, -NH(C 1-6 alkyl) 2X, -NH2(C 1-6 Alkyl)X, -NH3X, -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6 alkyl), -NH(OH), -SH, -SC 1- 6 alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 Alkyl), -CO 2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO 2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6alkyl), -NHCO2(C 1-6 a -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1- 6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl),-O C(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=N H)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 Alkyl), -C(=N H)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1- 6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, - NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 a Ru(Cl)2, -SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 a Rukill, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 a Ru(C) 1-6 alkyl)3, -OSi(C 1-6 Alkyl)3-C(=S) N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S )SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 Alkyl)2, -OP(=O)(OC 1-6 a Rukill) 2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C2 -6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 Aryl, 3-10 membered heterocyclic aryl, 5- to 10-membered heteroaryl; or two geminal R gg The substituent is bonded can combine to form =O or =S; In the formula, X - is the counter ion.

[0084] As used herein, a "counterion" is a positively charged ion that maintains electrical neutrality. A counterion is a negatively charged group associated with the quaternary amine. Exemplary counterions include halides. ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2 PO4 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethane Tanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid sulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1-sulfonic acid-2-sulfonic acid, etc.) and carboxylate ions (e.g., acetic acid, Ethanoic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, etc.) Counterions also include chiral counterions, some of which are chiral in racemic mixtures. It may be useful for chiral resolution. An exemplary chiral counterion is (S)-(+) mandelate. Acid, (D)-(+) tartaric acid, (+) 2,3-dibenzoyl-D-tartaric acid, N-acetyl- L-leucine, and N-acetyl-L-phenylalanine.

[0085] For example, an amino protecting group such as an amide group (e.g., -C(=O)R aa ) as Holm Amide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide cetoamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3 -Pyridylcarboxamides, N-benzoylphenylalanyl derivatives, benzamides, p -Phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide Amides, acetoacetamides, (N'-dithiobenzyloxycarbonylamino)acetamides amide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl -2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3- Methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives o-nitrobenzamide and o-(benzoyloxymethyl)benzamide. Examples include, but are not limited to:

[0086] Amino protecting groups such as carbamate groups (e.g., -C(=O)OR aa ) as methyl Carbamates, ethyl carbamates, 9-fluorenylmethyl carbamates (Fmoc) , 9-(2-sulfo)fluorenylmethylcarbamate, 9-(2,7-dibromo)fluor Oroenyl methyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo so-10,10,10,10-tetrahydrothioxanthryl)]methyl carbamate (D BD-Tmoc), 4-methoxyphenacylcarbamate (Phenoc), 2,2,2 -Trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate Teoc, 2-phenylethyl carbamate (hZ), 1-(1-adamantyl) -1-Methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate Carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BO C), 1,1-dimethyl-2,2,2-trichloroethylcarbamate (TCBOC), 1-Methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5 -Di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2 -(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-diphenyl Cyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (Boc) , 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl Carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8- Quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate Bamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Mo z), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chloro Benzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfini Benzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenyl methyl 2-Methylthioethyl carbamate, 2-methylsulfonylethyl carbamate carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-di thianil)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate ( Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonio Ethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p- Acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate , 5-Benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6- Chromonyl methyl carbamate (Tcroc), m-nitrophenyl carbamate, 3, 5-Dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxybenzyl Toxic-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate Bamate, t-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzene cyclobutyl carbamate, cyclohexyl carbamate, cyclopentane cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate Bamate, 2,2-dimethoxycarbonylvinylcarbamate, o-(N,N-dimethyl Carboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethyl 1,1-Dimethylpropynyl Carbamate, Di( 2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl Carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methyl Cyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1- Cyclopropyl methylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl) Ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate 1-Methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl) Ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate 2,4,6-tri-t-butylphenylcarbamate, 4-(trimethylammonium benzyl carbamate and 2,4,6-trimethylbenzyl carbamate. Examples include, but are not limited to:

[0087] Amino protecting groups such as sulfonamide groups (e.g., -S(=O)R aa ) as p- Toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl- 4-Methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide Sulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (P me), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte ), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzene Sulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide ( iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc ), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SE S), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl )Benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethyl These include, but are not limited to, arylsulfonamides, and phenacylsulfonamides. stomach.

[0088] Other amino protecting groups include phenothiazinyl-(10)-carbonyl derivatives, N'-p -Toluenesulfonylaminocarbonyl derivatives, N'-phenylaminothiocarbonyl derivatives Conductors, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5 -Diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide diphenylmaleimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-Tetramethyldisilylazacyclopentane adduct (STABASE ), 5-substituted 1,3-dimethyl-1,3,5 triazacyclohexan-2-one, 5-substituted 1,3-Dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3, 5-Dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylamino) Methylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine , N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine , Quaternary ammonium salt, N-benzylamine, N-di(4-methoxyphenyl)methyl Amines, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N -[(4-Methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenyl PhF, N-2,7-dichloro-9-fluorenylmethylene amine amine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxy N-Benzylideneamine, Np-Meth Benzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)methionine N-(N',N'-dimethylaminomethylene)amine, N,N' -Isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine amine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl ) Phenylmethyleneamine, N-Cyclohexylideneamine, N-(5,5-dimethyl- 3-Oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborine Acid derivatives, N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl ]Amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosamine , amine N-oxide, diphenylphosphine amide (Dpp), dimethylthiophosphine amide (Mpt), diphenylthiophosphine amide (Ppt), dialkylphosphor Amidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzene Sulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitro Benzenesulfenamide, Pentachlorobenzenesulfenamide, 2-nitro-4- Methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-diphenyl These include, but are not limited to, tropyridine sulfenamide (Npys).

[0089] As used herein, and unless otherwise stated, the term "hydroxyl protecting group" refers to a refers to a protecting group suitable for preventing undesired reactions at a hydroxyl group. Examples of aryl protecting groups are allyl, methyl, 2-methoxyethoxymethyl (MEM), and meth. methoxymethyl (MOM), methoxythiomethyl, t-butoxymethyl, tri-isopropyl Silyloxymethyl (TOM), ethyl, 1-ethoxyethyl, isopropyl, t-butyl benzyl, trityl (Tr), dimethoxytrityl (DMT), monomethoxytrityl Methoxybenzyl (MMT), p-methoxybenzyl (PMB), acetyl, chloroacetyl, trichloro trifluoroacetyl, pivaloyl (Piv), benzoyl, p-phenyl Benzoyl, trimethylsilyl (TMS), triisopropylsilyl (TIPS), t- butyldimethylsilyl (TBDMS), and tetrahydropyranyl. Further examples of hydroxyl protecting groups include, but are not limited to, Greene's Protective Groups. Active Groups in Organic Synthesis,4th ed. ition, John Wiley & Sons, New York, 2007 No. 6,393,636, which is incorporated herein by reference in its entirety.

[0090] As used herein, and unless otherwise indicated, the acronyms or symbols for groups or reagents are The symbols have the following definitions: HPLC = high performance liquid chromatography; THF = tetrahydrofuran Lofuran; CH3CN = acetonitrile; HOAc = acetic acid; DCM = dichloromethane.

[0091] As used herein, and unless otherwise specified, "substituted" or "substitution" When used to describe a chemical structure or moiety, it refers to a derivative of that structure or moiety. wherein one or more of the hydrogen atoms is selected from the group consisting of: alkyl, alkenyl, alkynyl, and cyclo. Alkyl, alkoxyalkyl; aroyl; halo; haloalkyl (e.g., trifluoro methyl);heterocycloalkyl;haloalkoxy (e.g., trifluoromethoxy); Hydroxy;Alkoxy;Cycloalkyloxy;Heterocyclooxy;Oxo;Alka noyl; aryl; heteroaryl (e.g., indolyl, imidazolyl, furyl, thienoyl, aryl, thiazolyl, pyrrolidyl, pyridyl, and pyrimidyl; arylalkyl; aryl Heteroaryl; Heteroarylalkyl; Heteroarylalkyl; Heteroarylalkyl; Heteroaryl Heterocyclo; Heterocycloalkyl-alkyl; Aryloxy, alkanoyloxy; Amino; Alkylamino; Arylamino; Arylalkylamino; Cycloalkyla Amino;Heterocycloamino;Mono- and di-substituted amino;Alkanoylamino;Aroylamino ;Aralkanoylamino;Aminoalkyl;Carbamyl (e.g., CONH2);Substituted carbamyl ruvamyls (e.g., CONH-alkyl, CONH-aryl, CONH-arylaryl) (alkyl or when there are two substituents on the nitrogen); carbonyl; alkoxycarbonyl; carboxy;cyano;ester;ether;guanidino;nitro;sulfonyl;alkyls sulfonyl; arylsulfonyl; arylalkylsulfonyl; sulfonamide (e.g. , SO2NH2);Substituted sulfonamide;Thiol;Alkylthio;Arylthio;Aryl aryl alkylthio;cycloalkylthio;heterocyclothio;alkylthiono;aryl and arylalkylthiono. In some embodiments, the substituents themselves are derivatives in which one or more substituted with a chemical moiety, including but not limited to, a chemical moiety described herein. Good too.

[0092] As used herein, and unless otherwise specified, the terms "about" and "approximately" mean The term "about" is used to indicate that a given value is approximately equal. When used in relation to temperature, the indicated temperature is increased by 30%, 25%, 20%, 15%, or 10%. or within 5% of the temperature deviation. Similarly, the term "about" refers to the reaction time. When used in connection with, for the period indicated, 30%, 25%, 20%, 15%, 10%, or indicates that deviations within 5% are included.

[0093] As used herein, and unless otherwise specified, the terms "about" and "approximately" mean For example, a particular temperature that describes the temperature of melting, dehydration, desolvation, or glass transition. or temperature range; mass change, e.g., mass change as a function of temperature or humidity; e.g. For example, solvent or water content in terms of mass or percentage; or, for example, IR or peak positions in Raman spectroscopy or XRPD analysis of a particular solid When used in conjunction with a numerical value or range of values ​​provided to characterize a feature, While a value or range of values ​​still describes a particular solid form, it is possible to determine the amount of the solid form that is reasonable for one of ordinary skill in the art. For example, in certain embodiments, the term "About" and "approximately," when used in this context, mean that a numerical value or range of values ​​does not exceed the stated value. or 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4% of the range of values , 3%, 2%, 1.5%, 1%, 0.5%, or 0.25%. For example, in some embodiments, the value of an XRPD peak position is While still describing the angle, it may vary by up to ±0.2° 2θ. When listing a number or range of values, a tilde (i.e., "~") precedes the number or range of values ​​to indicate "about" or " Indicates "approximately."

[0094] As used herein, and unless otherwise specified, the term "hydrogenated" refers to a compound having a hydrogen atom. This refers to the chemical process of adding to unsaturated bonds.

[0095] As used herein, and unless otherwise specified, "isotopic substitution" refers to an isotopically The term "isotopically enriched" refers to a compound that is enriched in the natural isotopes of that atom. "Isotopically enriched" refers to an atom that has an isotopic composition other than that of the Refers to a compound containing at least one atom that has an isotopic composition other than its natural isotopic composition. The term "isotopic composition" refers to the amount of each isotope present for a given atom; "Natural isotopic composition" refers to the naturally occurring isotopic composition or abundance for a given atom. Refers to...

[0096] The present disclosure is provided by way of the following detailed description and illustrative examples which are intended to illustrate non-limiting embodiments. A more complete understanding can be obtained by reference to the following examples.

[0097] Most of the embodiments and examples provided herein relate to the (S)-enantiomer of the compound. Inverting the stereochemistry of chiral reactants, reagents, solvents, catalysts, ligands, etc. The corresponding (R)-enantiomer of the compound can be prepared by the provided process. It should be understood that.

[0098] 5.2 Process As used herein, a compound of formula (I): [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof The compound of formula (I) is (S)-tert-butyl 4,5-diamine. It has the chemical name of amino-5-oxopentanoate. The process is to prepare a salt of the compound. The present invention includes any step of:

[0099] In certain embodiments, the processes provided herein comprise the steps of: This results in improved chiral purity of one or more intermediates and / or products.

[0100] Also referred to herein is a compound of formula (XIV): [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The present invention provides a process for the preparation of a recombinant aryl group, comprising reacting a compound of formula (I) with one of the starting materials, In one embodiment, the process comprises reacting a compound of formula (I) with a compound of formula (XV) (or its synthetic equivalent).

[0101] Also referred to herein is a compound of formula (XV): [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The compound of formula (XV) can be prepared by the method of preparing the compound of formula (XIV). In one embodiment, the process comprises the steps of: The formylation reaction of the compound VI) is also included.

[0102] 5.2.1 Process 1 for the preparation of compounds of formula (I) In one embodiment, the N-protected oxynitriles described herein include those containing ammonia or protected amines. A compound of formula (I), or a solvate thereof, comprising a ring-opening reaction of the sazolidin-5-one moiety, Provides a process for the preparation of hydrates, enantiomers, mixtures of enantiomers, or isotopically substituted forms The process includes the optional step of preparing a salt of the compound.

[0103] In one embodiment, the compound of formula (I) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The present invention provides a process for preparing a recombinant human ovarian ovarian medicament, the process comprising: (a) A compound of formula (II): [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof (In the formula, R 1 is a suitable amino protecting group), NH2-R 2 (In the formula, R 2 is hydrogen or a suitable amino protecting group) to give a compound of the formula ( Compound III: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Provide; (b) a compound of formula (III) or a solvate, hydrate, enantiomer, or antipodes thereof or a mixture thereof, to prepare a compound of formula (IV): [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Convert to; (c)-NH-R 1 The R 2 is a suitable amino protecting group, -NH-R 2 to obtain a compound of formula (I) or a solvate, hydrate, enantiomer, or mirror image thereof. providing a mixture of isomers or isotopic substitutions; and (d) optionally, a compound of formula (I) or a solvate, hydrate, enantiomer, or enantiomer thereof; This includes converting mixtures of enantiomers, or isotopic substitutions, into salts of the compounds.

[0104] In one embodiment, the compound of formula (I) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The present invention provides a process for preparing a recombinant human ovarian ovarian medicament, the process comprising: (c)-NH-R 1 The R 2 is a suitable amino protecting group, formula (IV) Compounds of: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof -NH-R 2The R 1 is a suitable amino protecting group, R 2 is hydrogen or a suitable amino protecting group), a compound of formula (I) or a solvate, hydrate thereof, providing an enantiomer, a mixture of enantiomers, or an isotopic substitution; and (d) optionally, a compound of formula (I) or a solvate, hydrate, enantiomer, or enantiomer thereof; This includes converting mixtures of enantiomers, or isotopic substitutions, into salts of the compounds.

[0105] In one embodiment, a compound of formula (IV) or a solvate, hydrate, enantiomer, or enantiomer thereof is A mixture of isomers or isotopic substitutions, (b) A compound of formula (III): [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof with a compound of formula (IV) or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof It is prepared by a process that includes converting it into an isotopic compound or an isotopic substitute.

[0106] In one embodiment, a compound of formula (III), or a solvate, hydrate, enantiomer thereof, A mixture of enantiomers or isotopic substitutions, (a) A compound of formula (II): [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof NH2-R 2 and contacting a compound of formula (III) or a solvate, hydrate, or mirror image thereof with To a process that includes providing an antipodal, enantiomeric, or isotopic substitute. Prepare according to the following:

[0107] In one embodiment, R 2 is hydrogen, i.e., NH2-R 2 is NH3. In one embodiment, the NH3 in step (a) is provided in the form of gaseous ammonia. The NH3 in step (a) is provided in the form of an ammonia solution. In one embodiment, the ammonia The solution is a solution of ammonia in water (e.g., NH4OH). The ammonia solution is a solution of ammonia in alcohol. In one embodiment, the alcohol is alcohol, ethanol, n-propanol, or isopropanol, or a mixture of these In one embodiment, the ammonia solution is a solution of ammonia in MeOH.

[0108] In one embodiment, the NH in step (a) is provided in the form of an ammonium salt. In the aqueous state, ammonium salts are (NH4)2CO3, NH4HCO3, NH4OAc, NH 4H2PO4, (NH4)2HPO4, or (NH4)3PO4. In one embodiment provides the NH3 of step (a) in the form of NH4HCO3.

[0109] In one embodiment, R 2 is a suitable amino protecting group. NH-R 1 Deprotection of the -NH-R group 2 Deprotection of the groups is carried out separately. In step (c), -NH-R 1 Deprotection of the -NH-R group 2 Deprotection of the aryl group is carried out simultaneously. .

[0110] In one embodiment, R 2 are allyl, t-butyl, methoxymethyl (MOM), methylthio Benzyloxymethyl (MTM), benzyloxymethyl (BOM), 2,2,2-trichloroethoxy Dimethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, cyanomethyl , pyrrolidinomethyl, methoxy, benzyloxy, methylthio, triphenylmethylthio , t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), 4 -Methoxyphenyl, 4-(methoxymethoxy)phenyl, 2-methoxy-1-naphthyl benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxy 2-Acetoxy-4-methoxybenzyl, 2-Nitrobenzyl, Bis(4- methoxyphenyl)methyl (DAM), bis(4-methoxyphenyl)phenylmethyl, Bis(4-methylsulfinylphenyl)methyl, triphenylmethyl (Tr), 9-phenyl Phenylfluorenyl (Pf), bis(trimethylsilyl)methyl, t-butoxycarbonyl benzyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl, ethoxycarbonyl carboxyl, p-toluenesulfonyl (Ts), butenyl, (E)-2-(methoxycarbonyl) vinyl, diethoxymethyl, 1-methoxy-2,2-dimethylpropyl, or 2 -(4-methylphenylsulfonyl)ethyl. In one embodiment, R 2 is benzyl (Bn), 4-methoxybenzyl (PMB), or 3,4-dimethoxybenzyl (DM PM). In one embodiment, R 2 is 1-phenylethyl. In one embodiment, R 2 is (S)-1-phenylethyl. In one embodiment, R 2 is (R)-1-phenyl It is ethyl.

[0111] In one embodiment, R 1 are allyl, t-butyl, methoxymethyl (MOM), methylthio Benzyloxymethyl (MTM), benzyloxymethyl (BOM), 2,2,2-trichloroethoxy Dimethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, cyanomethyl , pyrrolidinomethyl, methoxy, benzyloxy, methylthio, triphenylmethylthio , t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), 4 -Methoxyphenyl, 4-(methoxymethoxy)phenyl, 2-methoxy-1-naphthyl benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxy 2-Acetoxy-4-methoxybenzyl, 2-Nitrobenzyl, Bis(4- methoxyphenyl)methyl (DAM), bis(4-methoxyphenyl)phenylmethyl, Bis(4-methylsulfinylphenyl)methyl, triphenylmethyl (Tr), 9-phenyl Phenylfluorenyl (Pf), bis(trimethylsilyl)methyl, t-butoxycarbonyl benzyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl, ethoxycarbonyl carboxyl, p-toluenesulfonyl (Ts), butenyl, (E)-2-(methoxycarbonyl) vinyl, diethoxymethyl, 1-methoxy-2,2-dimethylpropyl, or 2 -(4-methylphenylsulfonyl)ethyl. In one embodiment, R 1 is benzyl (Bn), 4-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM) , benzyloxycarbonyl (Cbz), or p-methoxybenzyloxycarbonyl (Moz). In one embodiment, R 1 is benzyloxycarbonyl (Cbz) .

[0112] In one embodiment, step (c) is carried out under hydrogenation conditions. In one embodiment, the hydrogenation is carried out under Pd catalyst conditions. In one embodiment, the Pd catalyst is Pd / C. In one embodiment, the Pd catalyst is The oxidation was carried out on different materials including carbon, alumina, alkaline earth carbonates, clays, ceramics, and celite. The reaction is carried out in the presence of a palladium, platinum, rhodium, or ruthenium catalyst on a support such as palladium, platinum, rhodium, or ruthenium. In an embodiment, the hydrogenation is carried out in MeOH solvent. , isopropanol, 1-propanol, butanol, THF, 2-MeTHF, MTB E, isopropyl acetate, ethyl acetate, DMF, DMAc, or NMP solvent. In an embodiment, the hydrogenation is carried out under transfer hydrogenation conditions. include cyclohexene, cyclohexadiene, formic acid, or ammonium formate.

[0113] In one embodiment, step (b) comprises reacting a compound of formula (III) or a solvate or hydrate thereof. , enantiomer, mixture of enantiomers, or isotopically substituted with isobutylene or an equivalent to form a compound of formula (IV) or a solvate, hydrate, enantiomer, or isomeric form thereof In one embodiment, the isobutyric acid is provided as a mixture of isotopic forms or isotopic substitutions. The olefin equivalent is t-butyl 2,2,2-trichloroacetimidate. So, the isobutylene equivalent is Ot-Bu-DIC isourea [ka] In one embodiment, diisopropylcarbodiimide (DIC) is used in the presence of t-butanol and and a Cu(I) salt to form Ot-Bu-DIC isourea. In an embodiment, diisopropylcarbodiimide (DIC) is reacted with t-butanol in the presence of oxygen. and a Cu(I) salt to form Ot-Bu-DIC isourea. In one embodiment, oxygen is present in an amount up to about 22% of atmospheric oxygen. In one embodiment, oxygen is present in an amount of about 2% to about 10% of atmospheric oxygen. In one embodiment, oxygen is present in an amount of about 4% of atmospheric oxygen. In one embodiment, the Cu(I) salt is CuCl. In one embodiment, the Cu(I) salt is CuBr. In one embodiment, the Cu(I) salt is CuI. Other methods commonly known to those skilled in the art for the purpose of obtaining a hydroxyl group can also be used in step (b).

[0114] Step (d) optionally comprises reacting a compound of formula (I) or a solvate, hydrate, enantiomer thereof This includes converting a mixture of isomers, enantiomers, or isotopic substitutions of the compound into a salt. In one embodiment, the salt is an HCl, HBr, HOAc, or PhSO3H salt. In an embodiment, the salt is an HCl salt. The method of salt formation generally known to those skilled in the art can be carried out by the steps ( d) can be used.

[0115] In one embodiment, a compound of formula (II) or a solvate, hydrate, enantiomer, or enantiomer thereof is The mixture of enantiomers or isotopic substitutions may be prepared by the process of the present invention using a compound of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof With a source of formaldehyde. In one embodiment, the formaldehyde source is paraformaldehyde. The aldehyde source is 1,3,5-trioxane. In one embodiment, the reaction is carried out in the presence of an acid. In one embodiment, the acid is p-TsOH. In one embodiment, the acid is MsOH. In one embodiment, the acid is benzenesulfonic acid. In one embodiment, the acid is trifluoroacetic acid. In one embodiment, the acid is sulfuric acid. In one embodiment, the acid is trichloroacetic acid. In one embodiment, the acid is In one embodiment, the reaction is carried out in a PhMe solvent. The reaction is carried out in acetonitrile solvent.

[0116] In one embodiment, the compound of formula (I) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The present invention provides a process for preparing a recombinant human ovarian ovarian medicament, the process comprising: (a) Compound 4 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof of, [ka] and contacting the compound 5 with the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Provide; (b) Compound 5, or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof, or an isotopically substituted compound of the formula 6: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Convert to; (c) Compound 6, or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof, or isotopic deprotection to give the compound of formula (I) or a solvate, hydrate, or derivative thereof. providing an enantiomer, a mixture of enantiomers, or an isotopic substitution; and (d) optionally, a compound of formula (I) or a solvate, hydrate, enantiomer, or enantiomer thereof; Mixtures of enantiomers, or isotopic substitutions may be included by converting the compound to its HCl salt.

[0117] In one embodiment, the compound of formula (I) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The present invention provides a process for preparing a recombinant human ovarian ovarian medicament, the process comprising: (c) Compound 6 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Deprotection of the compound of formula (I) or a solvate, hydrate, enantiomer, or isomeric form thereof providing a mixture of isomers or isotopic substitutions; and (d) optionally, a compound of formula (I) or a solvate, hydrate, enantiomer, or enantiomer thereof; Mixtures of enantiomers, or isotopic substitutions may be included by converting the compound to its HCl salt.

[0118] In one embodiment, compound 6, or a solvate, hydrate, enantiomer, or Mixtures or isotopic substitutions, (b) Compound 5 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof with Compound 6, or a solvate, hydrate, enantiomer, mixture of enantiomers, or is prepared by a process which includes converting it to an isotopically substituted form.

[0119] In one embodiment, compound 5, or a solvate, hydrate, enantiomer, or Mixtures or isotopic substitutions, (a) Compound 4 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof of, [ka] contacting compound 5 or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof; Or, it is prepared by a process that includes providing an isotopic substitute.

[0120] In one embodiment, step (a) is carried out in MeOH solvent.

[0121] In one embodiment, step (b) comprises reacting compound 5, or a solvate, hydrate, or enantiomer thereof. , a mixture of enantiomers, or isotopically substituted 2,2,2-trichloroacetimide In one embodiment, the reaction includes reacting the tert-butyl ester with BF3 etherate. In one embodiment, the reaction is carried out in DCM solvent.

[0122] In one embodiment, step (b) comprises reacting compound 5, or a solvate, hydrate, or enantiomer thereof. , mixtures of enantiomers, or isotopically substituted species, reacted with Ot-Bu-DIC isourea In one embodiment, diisopropylcarbodiimide (DIC) is used to By reacting with ethanol and Cu(I) salt, Ot-Bu-DIC isourea was formed. In one embodiment, diisopropylcarbodiimide (DIC) is used in the presence of oxygen to form a t -Butanol and Cu(I) salt to give Ot-Bu-DIC isourea In one embodiment, oxygen is present in an amount up to about 22% of atmospheric oxygen. In one embodiment, oxygen is present in an amount of about 1% to about 10% of atmospheric oxygen. In one embodiment, oxygen is present in an amount of about 4% of atmospheric oxygen. In one embodiment, the Cu(I) salt is CuCl. In one embodiment, the Cu(I) salt is In one embodiment, the Cu(I) salt is CuI. In one embodiment, the 2- The reaction is carried out in MeTHF solvent. In one embodiment, THF, DCM, MTBE, 1,4- The reaction is carried out in dioxane or Et2O solvent.

[0123] In one embodiment, step (c) is carried out by hydrogenation in the presence of Pd / C. Hydrogenation is carried out on carbon, alumina, alkaline earth carbonates, clays, ceramics, and celite. In the presence of palladium, platinum, rhodium, or ruthenium catalysts on different supports including In one embodiment, the hydrogenation is carried out in MeOH solvent. Alcohol, isopropanol, 1-propanol, butanol, THF, 2-MeTHF , MTBE, isopropyl acetate, ethyl acetate, DMF, DMAc, or NMP solvents In one embodiment, the hydrogenation is carried out under transfer hydrogenation conditions. Conditions included cyclohexene, cyclohexadiene, formic acid, or ammonium formate. can be.

[0124] In one embodiment, the compound of formula (I) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The present invention provides a process for preparing a recombinant human ovarian ovarian medicament, the process comprising: (a) Compound 4 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof is contacted with NH to produce compound 7 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Provide; (b) Compound 7, or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof, or an isotopically substituted compound of the formula 8: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Convert to; (c) Compound 8, or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof, or isotopic deprotection to give the compound of formula (I) or a solvate, hydrate, or derivative thereof. providing an enantiomer, a mixture of enantiomers, or an isotopic substitution; and (d) optionally, a compound of formula (I) or a solvate, hydrate, enantiomer, or enantiomer thereof; Mixtures of enantiomers, or isotopic substitutions may be included by converting the compound to its HCl salt.

[0125] In one embodiment, the compound of formula (I) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The present invention provides a process for preparing a recombinant human ovarian ovarian medicament, the process comprising: (c) Compound 8 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Deprotection of the compound of formula (I) or a solvate, hydrate, enantiomer, or isomeric form thereof providing a mixture of isomers or isotopic substitutions; and (d) optionally, a compound of formula (I) or a solvate, hydrate, enantiomer, or enantiomer thereof; Mixtures of enantiomers, or isotopic substitutions may be included by converting the compound to its HCl salt.

[0126] In one embodiment, compound 8, or a solvate, hydrate, enantiomer, or Mixtures or isotopic substitutions, (b) Compound 7 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof with Compound 8, or a solvate, hydrate, enantiomer, mixture of enantiomers, or is prepared by a process which includes converting it to an isotopically substituted form.

[0127] In one embodiment, compound 7, or a solvate, hydrate, enantiomer, or Mixtures or isotopic substitutions, (a) Compound 4 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof is contacted with NH to produce compound 7 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof The compound is prepared by a process comprising providing:

[0128] In one embodiment, the NH in step (a) is provided in the form of NHOH. Step (a) is carried out in MeOH solvent.

[0129] In one embodiment, step (b) comprises reacting compound 7, or a solvate, hydrate, or enantiomer thereof. , a mixture of enantiomers, or isotopically substituted 2,2,2-trichloroacetimide In one embodiment, the reaction includes reacting the tert-butyl ester with BF3 etherate. In one embodiment, the reaction is carried out in DCM solvent.

[0130] In one embodiment, step (b) comprises reacting compound 7, or a solvate, hydrate, or enantiomer thereof. , mixtures of enantiomers, or isotopically substituted species, reacted with Ot-Bu-DIC isourea In one embodiment, diisopropylcarbodiimide (DIC) is used to By reacting with ethanol and Cu(I) salt, Ot-Bu-DIC isourea was formed. In one embodiment, diisopropylcarbodiimide (DIC) is used in the presence of oxygen to form a t -Butanol and Cu(I) salt to give Ot-Bu-DIC isourea In one embodiment, oxygen is present in an amount up to about 22% of atmospheric oxygen. In one embodiment, oxygen is present in an amount of about 1% to about 10% of atmospheric oxygen. In one embodiment, oxygen is present in an amount of about 4% of atmospheric oxygen. In one embodiment, the Cu(I) salt is CuCl. In one embodiment, the Cu(I) salt is In one embodiment, the Cu(I) salt is CuI. In one embodiment, the 2- The reaction is carried out in MeTHF solvent. In one embodiment, THF, DCM, MTBE, 1,4- The reaction is carried out in dioxane or Et2O solvent.

[0131] In one embodiment, step (c) is carried out by hydrogenation in the presence of Pd / C. Hydrogenation is carried out on carbon, alumina, alkaline earth carbonates, clays, ceramics, and celite. In the presence of palladium, platinum, rhodium, or ruthenium catalysts on different supports including In one embodiment, the hydrogenation is carried out in MeOH solvent. Alcohol, isopropanol, 1-propanol, butanol, THF, 2-MeTHF , MTBE, isopropyl acetate, ethyl acetate, DMF, DMAc, or NMP solvents In one embodiment, the hydrogenation is carried out under transfer hydrogenation conditions. Conditions included cyclohexene, cyclohexadiene, formic acid, or ammonium formate. can be.

[0132] In one embodiment, compound 4, or a solvate, hydrate, enantiomer, or The mixture or isotopically substituted compound 3 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof and a formaldehyde source. In one embodiment, the formaldehyde source is paraformaldehyde. 3,5-trioxane. In one embodiment, the reaction is carried out in the presence of an acid. In one embodiment, the acid is p-TsOH. In one embodiment, the acid is MsOH. In one embodiment, The acid is benzenesulfonic acid. In one embodiment, the acid is trifluoromethanesulfonic acid. In one embodiment, the acid is trifluoroacetic acid. In one embodiment, the acid is sulfuric acid. In one embodiment, the acid is trichloroacetic acid. In one embodiment, the acid is present in a catalytic amount. In one embodiment, the reaction is carried out in a PhMe solvent. In one embodiment, the reaction is carried out in an acetonitrile solvent. The reaction is carried out in a solvent.

[0133] In one embodiment, compound 3, or a solvate, hydrate, enantiomer, or The mixture or isotopically substituted compound 2 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof is prepared by a process comprising protecting with CbzCl. is carried out in the presence of a base. In one embodiment, the base is NaOH.

[0134] 5.2.2 Process 2 for preparing compounds of formula (I) In one embodiment, the present invention relates to a method for the preparation of oxazolidine-2,5-diamine with ammonia. Compounds of formula (I) or solvates, hydrates, enantiomers thereof, including ring-opening reactions of the aryl moiety. The present invention provides a process for the preparation of a mixture of enantiomers or isotopically substituted amines comprising the steps of: The optional step of preparing a salt of the compound is included.

[0135] In one embodiment, the compound of formula (I) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The present invention provides a process for preparing a recombinant human ovarian ovarian medicament, the process comprising: (a) A compound of formula (V): [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof (In the formula, R 3 is C 1-10 (alkyl) with NH3 to give a compound of formula (VI) : [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Provide; (b)R 3 If is not tert-butyl, R 3 The group is converted to tert-butyl to give the formula A compound of formula (I) or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof, if or isotopic substitutions, and (c) optionally, a compound of formula (I) or a solvate, hydrate, enantiomer, or enantiomer thereof; This includes converting mixtures of enantiomers, or isotopic substitutions, into salts of the compounds.

[0136] In one embodiment, the NH3 in step (a) is provided in the form of gaseous ammonia. In one embodiment, the NH3 in step (a) is provided in the form of an ammonia solution. The ammonia solution is a solution of ammonia in water (e.g., NH4OH). The ammonia solution is a solution of ammonia in alcohol. is methanol, ethanol, n-propanol, or isopropanol, or In one embodiment, the ammonia solution is a solution of ammonia in MeOH. It is.

[0137] In one embodiment, the NH in step (a) is provided in the form of an ammonium salt. In the aqueous state, ammonium salts are (NH4)2CO3, NH4HCO3, NH4OAc, NH 4H2PO4, (NH4)2HPO4, or (NH4)3PO4. In one embodiment provides the NH3 of step (a) in the form of NH4HCO3.

[0138] In one embodiment, R 3 is C 1-5 In one embodiment, R 3 tert- butyl. In one embodiment, R 3 is methyl, ethyl, n-propyl, or isopropyl. In one embodiment, R 3 is methyl.

[0139] In one embodiment, step (b) comprises reacting a compound of formula (VI) or a solvate, hydrate, or the like thereof, Enantiomers, mixtures of enantiomers, or isotopically substituted, optionally with tert-butanoates In one embodiment, step (b) comprises contacting the compound with t-BuOH in the presence of an oxide salt. ) tert-butoxide salt is LiO t Bu, NaO t Bu, or K.O. t Bu In one embodiment, the tert-butoxide salt of step (b) is KO t It's Bu.

[0140] In one embodiment, a compound of formula (V) or a solvate, hydrate, enantiomer, mirror image thereof The mixture of isomers or isotopic substitutions may be used to prepare a compound of formula (VII): [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof with a ring-forming agent.

[0141] In one embodiment, the ring-forming reagent is thionyl chloride, sulfuryl chloride, 4-dimethylamino Pyridine, phosgene, diphosgene, triphosgene, oxalyl chloride, carbodiimide, In one embodiment, the ring-forming reagent is a benzotriazole-1 -yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), N,N'-carbonyldiimidazole (CDI), 3-(diethoxyphos) (Diphenyloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), 1 -Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 2-(7 -Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronid Umium hexafluorophosphate (HATU), 2-(1H-benzotriazole-1- yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBT U), 1-hydroxybenzotriazole (HOBt), benzotriazol-1-yl -Oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP ), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluron Nitium tetrafluoroborate (TBTU), O-(3,4-dihydro-4-oxo-1 ,2,3-Benzotriazin-3-yl)-N,N,N,N-tetramethyluronium tetra tetrafluoroborate (TDBTU), 3-(diethyloxyphosphoryloxy)-1, 2,3-Benzotriazin-4(3H)-one (DEPBT), dicyclohexylcarbo Diimide (DCC), N,N'-diisopropylcarbodiimide (DIC), or 1- Hydroxy-7-azabenzotriazole (HOAt). In one embodiment, the ring formation In one embodiment, the ring-forming reagent is N,N'-carbonyldiimide. The compound is chloroquine (CDI).

[0142] Step (c) optionally comprises reacting a compound of formula (I) or a solvate, hydrate, enantiomer or mixture thereof with a compound of formula (I) or a solvate, hydrate, enantiomer or mixture thereof. This includes converting a mixture of isomers, enantiomers, or isotopic substitutions of the compound into a salt. In one embodiment, the salt is an HCl, HBr, HOAc, or PhSO3H salt. In an embodiment, the salt is an HCl salt. The method of salt formation generally known to those skilled in the art can be carried out by the steps ( c) can be used.

[0143] In one embodiment, the compound of formula (I) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The present invention provides a process for preparing a recombinant human ovarian ovarian medicament, the process comprising: (a) Compound 9 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof is contacted with NH to produce compound 10 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Provide; (b) Compound 10, or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof; or isotopic substitutions of the compound of formula (I) or a solvate, hydrate, enantiomer thereof. , a mixture of enantiomers, or an isotopically substituted form; and (c) optionally, a compound of formula (I) or a solvate, hydrate, enantiomer, or enantiomer thereof; Mixtures of enantiomers, or isotopic substitutions may be included by converting the compound to its HCl salt.

[0144] In one embodiment, the compound of formula (I) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The present invention provides a process for preparing a recombinant human ovarian ovarian medicament, the process comprising: (b) Compound 10 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof with a compound of formula (I) or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof or isotopic substitution; and (c) optionally, a compound of formula (I) or a solvate, hydrate, enantiomer, or enantiomer thereof; Mixtures of enantiomers, or isotopic substitutions may be included by converting the compound to its HCl salt.

[0145] In one embodiment, compound 10, or a solvate, hydrate, enantiomer, or or a mixture of isotopically substituted (a) Compound 9 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof with NH3 to produce compound 10, or a solvate, hydrate, enantiomer, or mirror image thereof. Prepared by a process that includes providing a mixture of isomers or isotopic substitutions. .

[0146] In one embodiment, the NH in step (a) is provided in the form of NHOH. Step (a) is carried out in MeOH solvent.

[0147] In one embodiment, step (b) comprises reacting a compound of formula (VI) or a solvate, hydrate, or the like thereof, Enantiomers, mixtures of enantiomers, or isotopically substituted KO t In the presence of Bu, t- This involves contacting with BuOH.

[0148] In one embodiment, compound 9, or a solvate, hydrate, enantiomer, or enantiomeric form thereof, The mixture or isotopic substitutions of the amino acid compound of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof With a ring-forming reagent. The ring-forming reagent is triphosgene. In one embodiment, the ring-forming reagent is an N,N'-carbonyl It is diimidazole (CDI).

[0149] In one embodiment, an amino acid compound, or a solvate, hydrate, enantiomer, or isoform thereof The mixture of isomers or isotopically substituted compounds of the formula 2: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof with an amino acid compound, or a solvate, hydrate, or mirror image thereof, under conditions suitable for ester formation. to a process involving conversion to an image, a mixture of enantiomers, or an isotopic substitution. In one embodiment, the conditions are reacting with MeOH in the presence of an acid. In one embodiment, the acid is HCl.

[0150] In one embodiment, the compound of formula (I) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The present invention provides a process for preparing a recombinant human ovarian ovarian medicament, the process comprising: (a) Compound 12 of the formula: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof with NH3 to produce a compound of formula (I), or a solvate, hydrate, enantiomer thereof. , a mixture of enantiomers, or isotopic substitutions; and (c) optionally, a compound of formula (I) or a solvate, hydrate, enantiomer, or enantiomer thereof; Mixtures of enantiomers, or isotopic substitutions may be included by converting the compound to its HCl salt.

[0151] In one embodiment, the NH3 in step (a) is provided in the form of NH4HCO3.

[0152] In one embodiment, compound 12, or a solvate, hydrate, enantiomer, or enantiomer thereof or a mixture of isotopically substituted compounds of the formula 11: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof With a ring-forming reagent. The ring-forming reagent is triphosgene. In one embodiment, the ring-forming reagent is an N,N'-carbonyl It is diimidazole (CDI).

[0153] In one embodiment, compound 11, or a solvate, hydrate, enantiomer, or enantiomer thereof or a mixture of isotopically substituted compounds of the formula 2: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof under conditions suitable for ester formation to afford compound 11, or a solvate, hydrate, or enantiomer thereof. by a process that includes converting it to a mixture of isomers, enantiomers, or isotopically substituted species. In one embodiment, the conditions are reacting with isobutylene in the presence of BF3Et2O. The aim is to make it possible.

[0154] 5.2.3 Process 3 for preparing compounds of formula (I) In one embodiment, the present invention relates to the nucleophilic cleavage of N-protected pyridines with tert-butoxide nucleophiles. A compound of formula (I), or a solvate thereof, comprising a ring-opening reaction of the rolidin-2-one moiety. The present invention provides a process for the preparation of an isotopically modified solvate, enantiomer, mixture of enantiomers, or isotopically substituted solvate. The process includes the optional step of preparing a salt of the compound.

[0155] In one embodiment, the compound of formula (I) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The present invention provides a process for preparing a recombinant human ovarian ovarian medicament, the process comprising: (a) A compound of formula (VIII): [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof (In the formula, R 4 is a suitable amino protecting group) with a t-butoxide nucleophile, Compound of formula (IX): [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Provide; (b) -NH-R 4Deprotecting the group to give a compound of formula (I) or a solvate or hydrate thereof , an enantiomer, a mixture of enantiomers, or an isotopic substitution; and (c) optionally, a compound of formula (I) or a solvate, hydrate, enantiomer, or enantiomer thereof; This includes converting mixtures of enantiomers, or isotopic substitutions, into salts of the compounds.

[0156] In one embodiment, the compound of formula (I) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. The present invention provides a process for preparing a recombinant human ovarian ovarian medicament, the process comprising: (b) a compound of formula (IX), 4 is a suitable amino protecting group): [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof -NH-R 4 to obtain a compound of formula (I) or a solvate, hydrate, mirror image thereof. providing a mixture of isomers, enantiomers, or isotopic substitutions; and (c) optionally, a compound of formula (I) or a solvate, hydrate, enantiomer, or enantiomer thereof; This includes converting mixtures of enantiomers, or isotopic substitutions, into salts of the compounds.

[0157] In one embodiment, a compound of formula (IX) or a solvate, hydrate, enantiomer, or enantiomer thereof is Mixtures of enantiomers, or isotopic substitutions, are prepared by a process which includes the following: (a) A compound of formula (VIII): [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof with a t-butoxide nucleophile to produce a compound of formula (IX), or a solvate thereof: Hydrates, enantiomers, mixtures of enantiomers, or isotopic substitutions are provided.

[0158] In one embodiment, R 4 are allyl, t-butyl, methoxymethyl (MOM), methylthio Benzyloxymethyl (MTM), benzyloxymethyl (BOM), 2,2,2-trichloroethoxy Dimethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, cyanomethyl , pyrrolidinomethyl, methoxy, benzyloxy, methylthio, triphenylmethylthio , t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), 4 -Methoxyphenyl, 4-(methoxymethoxy)phenyl, 2-methoxy-1-naphthyl benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxy 2-Acetoxy-4-methoxybenzyl, 2-Nitrobenzyl, Bis(4- methoxyphenyl)methyl (DAM), bis(4-methoxyphenyl)phenylmethyl, Bis(4-methylsulfinylphenyl)methyl, triphenylmethyl (Tr), 9-phenyl Phenylfluorenyl (Pf), bis(trimethylsilyl)methyl, t-butoxycarbonyl benzyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl, ethoxycarbonyl carboxyl, p-toluenesulfonyl (Ts), butenyl, (E)-2-(methoxycarbonyl) vinyl, diethoxymethyl, 1-methoxy-2,2-dimethylpropyl, or 2 -(4-methylphenylsulfonyl)ethyl. In one embodiment, R 4 is benzyl (Bn), 4-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM) , benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl (Mo z), or t-butoxycarbonyl (Boc). 4 Benji In one embodiment, R 4 is Boc.

[0159] R 4 In step (b), deprotection conditions generally known to those skilled in the art may be used depending on the In one embodiment, step (b) is carried out under hydrogenation conditions. is carried out in the presence of a Pd catalyst. In one embodiment, the Pd catalyst is Pd / C. Hydrogenation is carried out on carbon, alumina, alkaline earth carbonates, clays, ceramics, and celite. In the presence of palladium, platinum, rhodium, or ruthenium catalysts on different supports including In one embodiment, the hydrogenation is carried out in MeOH solvent. Alcohol, isopropanol, 1-propanol, butanol, THF, 2-MeTHF , MTBE, isopropyl acetate, ethyl acetate, DMF, DMAc, or NMP solvents In one embodiment, the hydrogenation is carried out under transfer hydrogenation conditions. Conditions included cyclohexene, cyclohexadiene, formic acid, or ammonium formate. can be.

[0160] In one embodiment, the tert-butoxide nucleophile in step (a) is LiO t Bu, Na O t Bu, or K.O. t In one embodiment, the tert-butoxy group in step (a) is Do nucleophiles, KOt It's Bu.

[0161] In one embodiment, a compound of formula (VIII) or a solvate, hydrate, enantiomer thereof , a mixture of enantiomers, or isotopically substituted compounds of the formula 14: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof to form a compound of formula (VIII) or a solvate, hydrate, enantiomer, or mirror image thereof It is prepared by a process that involves providing a mixture of isomers or isotopic substitutions.

[0162] Step (c) optionally comprises reacting a compound of formula (I) or a solvate, hydrate, enantiomer or mixture thereof with a compound of formula (I) or a solvate, hydrate, enantiomer or mixture thereof. This includes converting a mixture of isomers, enantiomers, or isotopic substitutions of the compound into a salt. In one embodiment, the salt is an HCl, HBr, HOAc, or PhSO3H salt. In an embodiment, the salt is an HCl salt. The method of salt formation generally known to those skilled in the art can be carried out by the steps ( c) can be used.

[0163] In one embodiment, compound 14, or a solvate, hydrate, enantiomer, or enantiomer thereof or a mixture of isotopically substituted compounds of the formula 13: [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof under conditions suitable for amide formation to afford compound 14, or a solvate, hydrate, or enantiomeric form thereof. by a process involving converting the In one embodiment, the conditions include isobutyl chloroformate or other chloroformate. The first step is to react the methyl group with the mate derivative, followed by ammonia.

[0164] 5.2.4 Process 4 for preparing compounds of formula (I) In one embodiment, the 2-((diphenylmethylene)amino)acetonyl tolyl, 2-((diphenylmethylene)amino)acetamide, or 2-((diphenyl Michael addition of dimethylamino)acetates to tert-butyl acrylate Compounds of formula (I) or solvates, hydrates, enantiomers, or enantiomers thereof, including reactions The present invention provides a process for the preparation of a mixture of isotopically substituted or isotopically substituted chiral compounds. The process also includes the optional step of preparing a salt of the compound.

[0165] In one embodiment, the compound of formula (I-rac) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, or isotopic substitution thereof providing a process, the process being (a) A compound of formula (XI): [ka] or a solvate, hydrate, or isotopically substituted derivative thereof (wherein R 5 -CONH2, -C N, or -CO2R 6 and R 6 is C 1-10 alkyl) in the presence of a base tert-butyl acrylate to produce a compound of formula (XII): [ka] or a solvate, hydrate, or isotopic substitution thereof; (b) a compound of formula (XII) or a solvate, hydrate, or isotopically substituted compound thereof , a compound of formula (XIII): [ka] or a solvate, hydrate, or isotopic derivative thereof in the presence of an acid; (c)R 5 If not -CONH2, R 5 The group is converted to -CONH2 to give the compound of formula (Ir or a solvate, hydrate, or isotopic substitution thereof, In this case, a compound of formula (XIII) or a solvate, hydrate, or isotopically substituted compound thereof is Optionally protecting and deprotecting the NH2 group in step (c); (d) optionally a compound of formula (I-rac) or a solvate, hydrate or isotopic substitutions are separated under chiral separation conditions to obtain a compound of formula (I): [ka] or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally a compound of formula (I) or a solvate, hydrate, or isotope thereof; This includes converting the substituent into a salt of the compound.

[0166] In one embodiment, the compound of formula (I-rac) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, or isotopic substitution thereof providing a process, the process being (b) A compound of formula (XII): [ka] or a solvate, hydrate, or isotopically substituted derivative thereof (wherein R 5 -CONH2, -C N, or -CO2R 6 and R 6 is C 1-10 alkyl) with a compound of formula (XIII) Compounds of: [ka] or a solvate, hydrate, or isotopic derivative thereof in the presence of an acid; (c)R 5 If not -CONH2, R 5 The group is converted to -CONH2 to give the compound of formula (Ir or a solvate, hydrate, or isotopic substitution thereof, In this case, a compound of formula (XIII) or a solvate, hydrate, or isotopically substituted compound thereof is Optionally protecting and deprotecting the NH2 group in step (c); (d) optionally a compound of formula (I-rac) or a solvate, hydrate or isotopic substitutions are separated under chiral separation conditions to obtain a compound of formula (I): [ka] or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally a compound of formula (I) or a solvate, hydrate, or isotope thereof; This includes converting the substituent into a salt of the compound.

[0167] In one embodiment, a compound of formula (XII) or a solvate, hydrate, or isomer thereof The isomeric substitute is prepared by a process which includes the following: (a) A compound of formula (XI): [ka] or a solvate, hydrate, or isotopic derivative thereof, in the presence of a base, and contacting the compound of formula (XII) with a dimethyl acrylate to form a compound of formula (XII) or a solvate, hydrate, or the like thereof. or isotopically substituted derivatives thereof.

[0168] In one embodiment, R 5 is -CONH. In one embodiment, R 5 is -CN. In one embodiment, R 5 -CO2R 6 and R 6 is C 1-10 In one embodiment, In terms of form, R 5 -CO2R 6 and R 6 is C 1-5 In one embodiment, , R 6 is methyl, ethyl, n-propyl, or isopropyl. , R 5 is -COMe. In one embodiment, R 5 is -CO2Et.

[0169] In one embodiment, R 5 is not -CONH2, step (c) comprises: (c1) adding an -NH2 group is protected with a protecting group, and (c2) R 5 (c3) converting the -NH group to -CONH; The method includes deprotecting the protecting group of

[0170] In one embodiment, R 5 In one embodiment, R 5 Based on - Convert to a COOH group, then convert the -COOH group to -CONH2.

[0171] In one embodiment, the protecting group for the -NH2 group in step (c1) is allyl, t-butyl, methoxy, Dimethyl (MOM), methylthiomethyl (MTM), benzyloxymethyl (BOM), 2,2,2-trichloroethoxymethyl, t-butyldimethylsiloxymethyl, pivaloy methoxy, benzyloxy, methyl Thio, triphenylmethylthio, t-butyldimethylsilyl (TBDMS), triisopropyl Tripropylsilyl (TIPS), 4-Methoxyphenyl, 4-(Methoxymethoxy)phenyl 2-Methoxy-1-naphthyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxy Dibenzyl, 3,4-dimethoxybenzyl, 2-acetoxy-4-methoxybenzyl, 2 -Nitrobenzyl, bis(4-methoxyphenyl)methyl (DAM), bis(4-methoxy Bis(4-methylsulfinylphenyl)methyl, triphenyl Phenylmethyl (Tr), 9-phenylfluorenyl (Pf), bis(trimethylsilyl) Methyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), Toxoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl (Ts), butenyl, (E)-2-(Methoxycarbonyl)vinyl, diethoxymethyl, 1-methoxy-2,2 -dimethylpropyl, or 2-(4-methylphenylsulfonyl)ethyl. In embodiments, the protecting groups are benzyl (Bn), 4-methoxybenzyl (PMB), 3,4- Dimethoxybenzyl (DMPM), benzyloxycarbonyl (Cbz), or p-methyl In one embodiment, the protecting group is benzyl In one embodiment, the protecting group is Cbz.

[0172] In one embodiment, the deprotection in step (c3) is carried out under hydrogenation conditions. Depending on the protecting group, Other deprotection conditions generally known to those skilled in the art can be used in step (c3).

[0173] In one embodiment, the base in step (a) is sodium C 1-14 Alkoxide, potassium C 1-14 Alkoxide, sodium hydride, potassium hydride, calcium hydride, carbonate Cesium, lithium hexamethyldisilazide (LiHMDS), lithium diisopropyl Amide (LDA), 2-tert-butyl-1,1,3,3-tetramethylguanidine ( Barton's base), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) , 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabi Cyclo(2.2.2)octane (DABCO), N,N-diisopropylethylamine ( DIPEA or Hunig's base), pyridine, 2,6-di-tert-butyl-pyridine lutidine, 2,6-lutidine, lithium tetramethylpiperidide (LiTMP or Harpur base), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (M TBD), 1,2,2,6,6-Pentamethylpiperidine (PMP), 2,2,6,6- Tetramethylpiperidine (TMP), tributylamine, 2,4,6-tri-tert- Butylpyridine, tris(trimethylsilyl)amine, n-butyllithium, sec-butyl tert-butyllithium, potassium bis(trimethylsilyl)amide, Sodium tert-butoxide, tert-butylimino-tris(dimethylamino) Phosphorane, or 2-tert-butylimino-2-diethylamino-1,3-dimethyl In one embodiment, the salt of step (a) is perhydro-1,3,2-diazaphosphorine. The groups are triethylamine, diisopropylethylamine, pyridine, 4-dimethylamino Pyridine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) In one embodiment, the base in step (a) is DBU. )The base is Cs2CO3.

[0174] In one embodiment, the acid in step (b) is formic acid, acetic acid, trifluoroacetic acid, benzoic acid, quenching acid, or the like. Sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid Acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, or phosphorus In one embodiment, the acid in step (b) is HCl, citric acid, or p-toluene. It is a sulfonic acid.

[0175] In one embodiment, step (d) comprises reacting a compound of formula (I-rac) or a solvate thereof, water The solvates, or isotopically substituted derivatives are contacted with a chiral acid to provide a diastereomeric mixture of salts. and separating the resulting diastereomeric mixture of salts by selective crystallization. In one embodiment, the chiral acid is tartaric acid, 2,3-dibenzoyltartaric acid, mandelic acid, Camphorsulfonic acid, N-Ac-N-leucine, or N-Ac-L-phenylalanine In one embodiment, the selective crystallization is carried out using MeOH, isopropanol, and n-propanol. The reaction is carried out in a solvent selected from the group consisting of propyl alcohol, propyl alcohol, and mixtures thereof. Other chiral separation methods can be used in step (d).

[0176] Step (e) optionally comprises reacting a compound of formula (I) or a solvate, hydrate, enantiomer thereof This includes converting a mixture of isomers, enantiomers, or isotopic substitutions of the compound into a salt. In one embodiment, the salt is an HCl, HBr, HOAc, or PhSO3H salt. In an embodiment, the salt is an HCl salt. The method of salt formation generally known to those skilled in the art can be carried out by the steps ( e) can be used.

[0177] In one embodiment, the compound of formula (I-rac) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, or isotopic substitution thereof providing a process, the process being (a) Compound 15 of the formula: [ka] or a solvate, hydrate, or isotopic derivative thereof, in the presence of a base, acrylate to form a compound of formula 17: [ka] or a solvate, hydrate, or isotopic substitution thereof; (b) Compound 17, or a solvate, hydrate, or isotopically substituted compound thereof, is prepared by reacting the compound with a compound of the formula: Compound 18: [ka] or a solvate, hydrate, or isotopic derivative thereof in the presence of an acid; (c1) Protecting the -NH group to obtain compound 19 of the following formula: [ka] or a solvate, hydrate, or isotopic substitution thereof; (c2) Converting the -CO2Me group to -CONH2 to give compound rac-8 of the formula: [ka] or a solvate, hydrate, or isotopic substitution thereof; (c3) Deprotecting the protecting group of the -NH2 group to obtain a compound of formula (I-rac) or a solution thereof. providing a solvate, hydrate, or isotopically substituted form; and (d) optionally a compound of formula (I-rac) or a solvate, hydrate or isotopic substitutions are separated under chiral separation conditions to obtain a compound of formula (I): [ka] or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally a compound of formula (I) or a solvate, hydrate, or isotope thereof; This involves converting the substituent to the HCl salt of the compound.

[0178] In one embodiment, the compound of formula (I-rac) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, or isotopic substitution thereof providing a process, the process being (c3) Compound rac-8 of the formula: [ka] or a solvate, hydrate, or isotope-substituted derivative thereof by deprotecting the -NH2 protecting group The present invention provides a compound of formula (I-rac) or a solvate, hydrate, or isotopically substituted compound thereof. Offering; (d) optionally a compound of formula (I-rac) or a solvate, hydrate or isotopic substitutions are separated under chiral separation conditions to obtain a compound of formula (I): [ka] or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally a compound of formula (I) or a solvate, hydrate, or isotope thereof; This involves converting the substituent to the HCl salt of the compound.

[0179] In one embodiment, the compound rac-8, or a solvate, hydrate, or isotopic derivative thereof. The conversion, (c2) Compound 19 of the formula: [ka] or its solvates, hydrates, or isotopically substituted -CO2Me groups to -CONH2 and converting to provide compound rac-8, or a solvate, hydrate, or isotopic substitution thereof. The compound is prepared by a process comprising providing

[0180] In one embodiment, compound 19, or a solvate, hydrate, or isotopic derivative thereof, is , (c1) Compound 18 of the formula: [ka] or a solvate, hydrate, or isotopically substituted form thereof, by protecting the -NH2 group to obtain compound 1 9, or a solvate, hydrate, or isotopic substitution thereof. Prepare by:

[0181] In one embodiment, compound 18, or a solvate, hydrate, or isotopic derivative thereof, is , (b) Compound 17 of the formula: [ka] or a solvate, hydrate, or isotopic substitution thereof, in the presence of an acid to form compound 18, can be prepared by a process that includes converting it to a solvate, hydrate, or isotopically substituted form. To manufacture.

[0182] In one embodiment, compound 17, or a solvate, hydrate, or isotopic derivative thereof, is , (a) Compound 15 of the formula: [ka] or a solvate, hydrate, or isotopic derivative thereof, in the presence of a base, and contacting the compound 17, or a solvate, hydrate, or isomer thereof, with a dimethyl acrylate to form a compound 17, or a solvate, hydrate, or isomer thereof. The compound is prepared by a process comprising providing a disubstituted isomer.

[0183] In one embodiment, the base in step (a) is DBU. In one embodiment, compound 17, or a solvate, hydrate, or the like thereof, is Or the isotopically substituted analogue is not isolated after step (a).

[0184] In one embodiment, the acid in step (b) is HCl. In one embodiment, step (b) is In one embodiment, the reaction is carried out in MeTHF solvent. Alternatively, the isotopic substitution is not isolated after step (b).

[0185] In one embodiment, step (c1) comprises reacting compound 18, or a solvate, hydrate, or comprises reacting the isotopic substitute with CbzCl. In one embodiment, step (c1) In one embodiment, step (c1) is carried out in the presence of KCO. In one embodiment, compound 19, or a solvate, hydrate, or isotopic substitution thereof, is The entity is not isolated after step (c1).

[0186] In one embodiment, step (c2) comprises reacting compound 19, or a solvate thereof, under basic conditions, The hydrate or isotopic derivative is hydrolyzed to give compound 20 of the formula: [ka] or a solvate, hydrate, or isotopically substituted thereof; and then reacting the compound by amide formation. The present invention provides the compound rac-8, or a solvate, hydrate, or isotopic substitution thereof. Includes.

[0187] In one embodiment, the basic conditions are in the presence of LiOH. The basic conditions are the presence of potassium trimethylsiloxide (TMSOK). In one embodiment, the hydrolysis is carried out in 2-MeTHF solvent.

[0188] In one embodiment, the amide formation is carried out using compound 20, or a solvate, hydrate, or The isotopic substitution involves reacting with isobutyl chloroformate followed by NH3.

[0189] In one embodiment, step (c3) is carried out by hydrogenation in the presence of a Pd catalyst.

[0190] In one embodiment, the compound of formula (I-rac) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, or isotopic substitution thereof providing a process, the process being (a) Compound 23 of the formula: [ka] or a solvate, hydrate, or isotopic derivative thereof, in the presence of a base, acrylate to produce a compound of formula 24: [ka] or a solvate, hydrate, or isotopic substitution thereof; (b) Compound 24, or a solvate, hydrate, or isotopic derivative thereof, is dissolved in water in the presence of an acid. The compound of formula (I-rac) or a solvate, hydrate, or isotopic derivative thereof is Convert; (d) optionally a compound of formula (I-rac) or a solvate, hydrate or isotopic substitutions are separated under chiral separation conditions to obtain a compound of formula (I): [ka] or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally a compound of formula (I) or a solvate, hydrate, or isotope thereof; This involves converting the substituent to the HCl salt of the compound.

[0191] In one embodiment, the compound of formula (I-rac) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, or isotopic substitution thereof providing a process, the process being (b) Compound 24 of the formula: [ka] or a solvate, hydrate, or isotopic substitution thereof in the presence of an acid, or a solvate, hydrate, or isotopically substituted compound thereof; (d) optionally a compound of formula (I-rac) or a solvate, hydrate or isotopic substitutions are separated under chiral separation conditions to obtain a compound of formula (I): [ka] or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally a compound of formula (I) or a solvate, hydrate, or isotope thereof; This involves converting the substituent to the HCl salt of the compound.

[0192] In one embodiment, compound 24, or a solvate, hydrate, or isotopic derivative thereof, is , (a) Compound 23 of the formula: [ka] or a solvate, hydrate, or isotopic derivative thereof, in the presence of a base, and contacting the compound with a methacrylate to form compound 24, or a solvate, hydrate, or isotope thereof. The compound is prepared by a process comprising providing a disubstituted isomer.

[0193] In one embodiment, the base in step (a) is DBU. The group is Cs2CO3. In one embodiment, step (a) is carried out in MeCN solvent.

[0194] In one embodiment, the acid in step (b) is HCl. In one embodiment, step (b) is The reaction is carried out in MeTHF solvent.

[0195] In one embodiment, compound 23, or a solvate, hydrate, enantiomer, or enantiomer thereof or a mixture of isotopically substituted compounds of the formula 21: [ka] or a solvate, hydrate, or isotopic substitution thereof with a compound of formula 22: [ka] or a solvate, hydrate, or isotopic variant thereof. In one embodiment, the reaction is carried out in the presence of a base. is NEt3. In one embodiment, the reaction is carried out in 1,2-dichloroethane (DCE) solvent. conduct.

[0196] In one embodiment, the compound of formula (I-rac) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, or isotopic substitution thereof providing a process, the process being (a) Compound 25 of the formula: [ka] or a solvate, hydrate, or isotopic derivative thereof, in the presence of a base, acrylate to form a compound of formula 26: [ka] or a solvate, hydrate, or isotopic substitution thereof; (b) Reacting compound 26, or a solvate, hydrate, or isotopically substituted compound thereof, with a compound of the formula Compound 27: [ka] or a solvate, hydrate, or isotopic derivative thereof in the presence of an acid; (c1) Protecting the -NH2 group to obtain compound 28 of the following formula: [ka] or a solvate, hydrate, or isotopic substitution thereof; (c2) Converting the -CN group to -CONH to give compound 29 of the formula: [ka] or a solvate, hydrate, or isotopic substitution thereof; (c3) Deprotecting the protecting group of the -NH2 group to obtain a compound of formula (I-rac) or a compound thereof Provide solvates, hydrates, or isotopically substituted forms; (d) optionally a compound of formula (I-rac) or a solvate, hydrate or isotopic substitutions are separated under chiral separation conditions to obtain a compound of formula (I): [ka] or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally a compound of formula (I) or a solvate, hydrate, or isotope thereof; This involves converting the substituent to the HCl salt of the compound.

[0197] In one embodiment, the compound of formula (I-rac) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, or isotopic substitution thereof providing a process, the process being (c3) Compound 29 of the formula: [ka] or a solvate, hydrate, or isotope-substituted derivative thereof by deprotecting the -NH2 protecting group The present invention provides a compound of formula (I-rac) or a solvate, hydrate, or isotopically substituted compound thereof. Offering; (d) optionally a compound of formula (I-rac) or a solvate, hydrate or isotopic substitutions are separated under chiral separation conditions to obtain a compound of formula (I): [ka] or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally a compound of formula (I) or a solvate, hydrate, or isotope thereof; This involves converting the substituent to the HCl salt of the compound.

[0198] In one embodiment, compound 29, or a solvate, hydrate, or isotopic derivative thereof, is , (c2) Compound 28 of the formula: [ka] Convert the -CN group of, or its solvate, hydrate, or isotopic substitution to -CONH2 To provide compound 29, or a solvate, hydrate, or isotopic substitution thereof. The compound is prepared by a process comprising:

[0199] In one embodiment, compound 28, or a solvate, hydrate, or isotopic derivative thereof, is , (c1) Compound 27 of the formula: [ka] or a solvate, hydrate, or isotopically substituted form thereof, by protecting the -NH2 group to obtain compound 2 8, or a solvate, hydrate, or isotopic substitution thereof. Prepare by:

[0200] In one embodiment, compound 27, or a solvate, hydrate, or isotopic derivative thereof, is , (b) Compound 26 of the formula: [ka] or a solvate, hydrate, or isotopic substitution thereof, in the presence of an acid to compound 27, can be prepared by a process that includes converting it to a solvate, hydrate, or isotopically substituted form. To manufacture.

[0201] In one embodiment, compound 26, or a solvate, hydrate, or isotopic derivative thereof, is , (a) Compound 25 of the formula: [ka] or a solvate, hydrate, or isotopic derivative thereof, in the presence of a base, and contacting the compound with a methacrylate to form compound 26, or a solvate, hydrate, or isotope thereof. The compound is prepared by a process comprising providing a disubstituted isomer.

[0202] In one embodiment, the base in step (a) is DBU. Carry out in eCN solvent.

[0203] In one embodiment, the acid in step (b) is HCl. In one embodiment, step (b) is In one embodiment, the reaction is carried out in MeTHF solvent. Alternatively, the isotopic substitution is not isolated after step (b).

[0204] In one embodiment, step (c1) comprises reacting compound 27, or a solvate, hydrate, or involves reacting the isotopically substituted compound with benzaldehyde followed by a reducing agent. In one embodiment, the reducing agent is sodium triacetoxyborohydride (STAB).

[0205] In one embodiment, step (c2) comprises reacting a formaldehyde catalyst and a hydroxide base in the presence of the .... Compound 28, or a solvate, hydrate, or isotopic substitution thereof, is hydrolyzed to obtain the compound The present invention includes providing compound 29, or a solvate, hydrate, or isotopic substitution thereof. Other methods of nitrile hydrolysis commonly known to those skilled in the art may be used in step (c2). can.

[0206] In one embodiment, step (c3) is carried out by hydrogenation in the presence of a Pd catalyst.

[0207] 5.2.5 Process 5 for preparing compounds of formula (I) In one embodiment, as described herein, 2-phenyloxazol-5(4H)-one a compound of formula (I) comprising a Michael addition reaction of 1,2-diphenyl ether with tert-butyl acrylate; The preparation of solvates, hydrates, enantiomers, mixtures of enantiomers, or isotopically substituted derivatives thereof The process includes an optional step of chiral separation. The present invention also includes the optional step of preparing a salt of the compound.

[0208] In one embodiment, the compound of formula (I-rac) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, or isotopic substitution thereof providing a process, the process being (a) Compound 31 of the formula: [ka] or a solvate, hydrate, or isotopic derivative thereof, in the presence of a base, acrylate to produce a compound of formula 32: [ka] or a solvate, hydrate, or isotopic substitution thereof; (b) Compound 32, or a solvate, hydrate, or isotopically substituted compound thereof, is reacted with NH contacting to form a compound of formula 33: [ka] or a solvate, hydrate, or isotopic substitution thereof; (c) deprotecting the -NHBz group to give a compound of formula (I-rac) or a solvate thereof: Provide hydrates or isotopically substituted derivatives; (d) optionally a compound of formula (I-rac) or a solvate, hydrate or isotopic substitutions are separated under chiral separation conditions to obtain a compound of formula (I): [ka] or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally a compound of formula (I) or a solvate, hydrate, or isotope thereof; This includes converting the substituent into a salt of the compound.

[0209] In one embodiment, the compound of formula (I-rac) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, or isotopic substitution thereof providing a process, the process being (c) Compound 33 of the formula: [ka] or a solvate, hydrate, or isotope-substituted form thereof, by deprotecting the -NHBz group to obtain a compound of the formula ( I-rac), or a solvate, hydrate, or isotopic substitution thereof; (d) optionally a compound of formula (I-rac) or a solvate, hydrate or isotopic substitutions are separated under chiral separation conditions to obtain a compound of formula (I): [ka] or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally a compound of formula (I) or a solvate, hydrate, or isotope thereof; This includes converting the substituent into a salt of the compound.

[0210] In one embodiment, compound 33, or a solvate, hydrate, or isotopic derivative thereof, is , (a) Compound 32 of the formula: [ka] or a solvate, hydrate, or isotopic substitution thereof is contacted with NH3 to obtain compound 3 3, or a solvate, hydrate, or isotopic substitution thereof. Prepare by:

[0211] In one embodiment, compound 32, or a solvate, hydrate, or isotopic derivative thereof, is , (a) Compound 31 of the formula: [ka] or a solvate, hydrate, or isotopic derivative thereof, in the presence of a base, and contacting the compound with a methacrylate to form compound 32, or a solvate, hydrate, or isotope thereof. providing a disubstituted isomer of the compound;

[0212] In one embodiment, the base in step (a) is sodium C 1-14 Alkoxide, potassium C 1-14 Alkoxide, sodium hydride, potassium hydride, calcium hydride, carbonate Cesium, lithium hexamethyldisilazide (LiHMDS), lithium diisopropyl Amide (LDA), 2-tert-butyl-1,1,3,3-tetramethylguanidine ( Barton's base), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) , 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabi Cyclo(2.2.2)octane (DABCO), N,N-diisopropylethylamine ( DIPEA or Hunig's base), pyridine, 2,6-di-tert-butyl-pyridine lutidine, 2,6-lutidine, lithium tetramethylpiperidide (LiTMP or Harpur base), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (M TBD), 1,2,2,6,6-Pentamethylpiperidine (PMP), 2,2,6,6- Tetramethylpiperidine (TMP), tributylamine, 2,4,6-tri-tert- Butylpyridine, tris(trimethylsilyl)amine, n-butyllithium, sec-butyl tert-butyllithium, potassium bis(trimethylsilyl)amide, Sodium tert-butoxide, tert-butylimino-tris(dimethylamino) Phosphorane, or 2-tert-butylimino-2-diethylamino-1,3-dimethyl In one embodiment, the salt of step (a) is perhydro-1,3,2-diazaphosphorine. The groups are triethylamine, diisopropylethylamine, pyridine, 4-dimethylamino Pyridine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) In one embodiment, the base in step (a) is DBU. )The base is Cs2CO3.

[0213] In one embodiment, the NH3 in step (b) is provided in the form of gaseous ammonia. In one embodiment, the NH3 in step (b) is provided in the form of an ammonia solution. The ammonia solution is a solution of ammonia in water (e.g., NH4OH). The ammonia solution is a solution of ammonia in alcohol. is methanol, ethanol, n-propanol, or isopropanol, or In one embodiment, the ammonia solution is a solution of ammonia in MeOH. It is.

[0214] In one embodiment, the NH in step (b) is provided in the form of an ammonium salt. In the aqueous state, ammonium salts are (NH4)2CO3, NH4HCO3, NH4OAc, NH 4H2PO4, (NH4)2HPO4, or (NH4)3PO4. In one embodiment provides the NH3 of step (b) in the form of NH4HCO3.

[0215] In one embodiment, the deprotection in step (c) is carried out in the presence of a base. Other methods of benzoyl deprotection of can be used in step (c).

[0216] In one embodiment, step (d) comprises reacting a compound of formula (I-rac) or a solvate thereof, water The solvates, or isotopically substituted derivatives are contacted with a chiral acid to provide a diastereomeric mixture of salts. and separating the resulting diastereomeric mixture of salts by selective crystallization. In one embodiment, the chiral acid is tartaric acid, 2,3-dibenzoyltartaric acid, mandelic acid, Camphorsulfonic acid, N-Ac-N-leucine, or N-Ac-L-phenylalanine In one embodiment, the selective crystallization is carried out using MeOH, isopropanol, and n-propanol. The reaction is carried out in a solvent selected from the group consisting of propyl alcohol, propanol, and mixtures thereof.

[0217] Step (e) optionally comprises reacting a compound of formula (I) or a solvate, hydrate, enantiomer thereof This includes converting a mixture of isomers, enantiomers, or isotopic substitutions of the compound into a salt. In one embodiment, the salt is an HCl, HBr, HOAc, or PhSO3H salt. In an embodiment, the salt is an HCl salt. The method of salt formation generally known to those skilled in the art can be carried out by the steps ( e) can be used.

[0218] In one embodiment, compound 31, or a solvate, hydrate, or isotopic derivative thereof, is , Compound 30 of the formula: [ka] or a solvate, hydrate, or isotopically substituted derivative thereof with a ring-forming agent. In one embodiment, the ring-forming reagent is DCC.

[0219] 5.2.6 Preparation of compounds of formula (XIV) The preparation of the compound of formula (XIV) (i.e., compound 37) was previously described in U.S. Pat. No. 014 / 0046058, which is incorporated herein by reference in its entirety. Its preparation is summarized in the following scheme: [ka]

[0220] This process has been implemented to produce multi-kilogram batches of 37 but has several drawbacks. The process involves multiple steps (six bond-making and -breaking reactions). However, there are no crystalline, separable intermediates. Compounds 37-3, 37-4, and 37-5 are It is not a crystalline solid. This precludes the use of crystallization for purification. Generally, it is the preferred method for purification on a kilogram or larger scale. As a result, the final step (3 The isolation of 7) entails a large purification burden and requires two types of crystallization. The first is physical crystallization. The process produces radicals that can rapidly generate heat. The reaction (37-3~37-4) uses a cyclohexanediamine, but this heat is generated by the formation of by-products (ring The process involves the use of bulky silyl protecting groups (3 7-3, 37-4, and 37-5). This is a high-order reaction that does not add any atoms to the final compound. An alternative synthesis process for compounds of formula (XIV), such as compound 37, has been developed. There is still a need to provide

[0221] In one embodiment, the compound of formula (I) and a 2-formyl benzoate are described herein. (or a synthetic equivalent), or its salts, solvates, hydrates, enantiomers, mixtures of enantiomers, or isotopically substituted derivatives thereof The process comprises crystallizing the product from a solvent or mixture of solvents. In certain embodiments, the process provided herein comprises any of the steps of The synthesis is significantly shorter (only two steps from the compound of formula (XVI)) and gives a higher yield than that of Glass.

[0222] In one embodiment, the compound of formula (XIV) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. conversion (in the formula, R 7 is hydrogen or a suitable hydroxyl protecting group) The process provides (a) A compound of formula (XV): [ka] or a compound of formula (XV) having an aldehyde equivalent group and / or a carboxylic acid equivalent group Analogs, or solvates, hydrates, enantiomers, mixtures of enantiomers, or isomers thereof substituent (in the formula, R 8 is hydrogen, alkyl, or aryl) to a compound of formula (I) thing: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. to obtain a compound of formula (XIV) or a salt, solvate, hydrate, enantiomeric providing a mixture of isomers, enantiomers, or isotopically substituted isomers; and (b) optionally a compound of formula (XIV) or a salt, solvate, hydrate, enantiomer thereof The isomer, mixture of enantiomers, or isotopically substituted isomers are crystallized from a solvent or mixture of solvents. This includes transforming it into a

[0223] In one embodiment, R 7 is hydrogen. In one embodiment, R 7 is a hydroxyl protecting group In one embodiment, R 7 are allyl, methyl, and 2-methoxyethoxymethyl (MEM) , methoxymethyl (MOM), methoxythiomethyl, t-butoxymethyl, tri-isopropyl propylsilyloxymethyl (TOM), ethyl, 1-ethoxyethyl, isopropyl, t -Butyl, benzyl, trityl (Tr), dimethoxytrityl (DMT), monomethoxy Trityl (MMT), p-methoxybenzyl (PMB), acetyl, chloroacetyl, trityl Trichloroacetyl, trifluoroacetyl, pivaloyl (Piv), benzoyl, p-fluoroacetyl Phenylbenzoyl, trimethylsilyl (TMS), triisopropylsilyl (TIPS) , t-butyldimethylsilyl (TBDMS), and tetrahydropyranyl is the hydroxyl protecting group of choice.

[0224] In one embodiment, R 8 is alkyl. In one embodiment, R 8 is C 1-5 With alkyl In one embodiment, R 8 is methyl, ethyl, n-propyl, isopropyl, or In one embodiment, R 8 is methyl. In one embodiment, R 8 is hydrogen. In one embodiment, R 8 is aryl. In one embodiment, R 8 is C6 -10 It is aryl.

[0225] In one embodiment, the aldehyde equivalent group is an acetal, hemiacetal, or thioacetal. , dithioacetal, aminal, or hemiaminal. aldehyde equivalent groups with adjacent carboxyl equivalent groups (thereby forming a fused ring structure) (This results in the creation of

[0226] In one embodiment, the carboxylic acid equivalent group is a carboxylic acid, a carboxylic acid ester, a carboxylic acid It is an amide, a carboxylic acid halide, a lactone, a lactam, or a thiolactone.

[0227] In one embodiment, a compound of formula (XV) having an aldehyde equivalent group and / or a carboxyl equivalent group is provided. An analog of the compound of formula: [ka] and During the ceremony: R a Each instance of is independently hydrogen, alkyl, aryl, acyl, or carbamoyl. can be; X is Cl, Br, OR b , S.R. c , SO3R c , or N.R. a R a and; R b is hydrogen, alkyl, aryl, acyl, or silyl; and R c is hydrogen, alkyl, or aryl.

[0228] In one embodiment, a compound of formula (XV) having an aldehyde equivalent group and / or a carboxyl equivalent group is provided. The analogue of the compound is 4-hydroxy-3-alkoxyisobenzofuran-1(3H) -On.

[0229] In one embodiment, step (a) is carried out using a hydrochloride, a sulfonate, a phosphate, an achiral carboxylate, The present invention is carried out using a salt of the compound of formula (I) selected from the group consisting of acid salts, chiral carboxylates, and mineral acid salts. In one embodiment, step (a) is carried out with the hydrochloride salt of a compound of formula (I).

[0230] In one embodiment, step (a) is carried out in the presence of a reducing agent and, optionally, a base. Without wishing to be bound by theory, it is believed that the salt of the compound of formula (I) can be destroyed using a base. and the base can be omitted depending on the identity or lack thereof of the salt.

[0231] In one embodiment, the reducing reagent is NaBH(OAc)3, NaBH4, NaBH3CN, In one embodiment, the transition metal catalyst is a combination of silane or H2 and a transition metal catalyst. The catalyst is a Pd, Pt, Rh, or Ir catalyst. In one embodiment, the transition metal catalyst is In one embodiment, the reducing agent is NaBH(OAc)3.

[0232] In one embodiment, the base is iPr2NEt, Et3N, n-Bu3N, DBU, or Tetramethylguanidine. In one embodiment, the base is iPr2Net.

[0233] In one embodiment, step (a) is carried out with a mixture of DMAc, MeOH, EtOH, trifluoroethanol, alcohol, i-PrOH, 1-propanol, t-butanol, MeCN, DMF, NMP, A solvent selected from THF, 2-MeTHF, DCM, and DCE, or a mixture thereof. In one embodiment, step (a) is carried out in a DMAc solvent.

[0234] In one embodiment, the reaction temperature in step (a) is about 5° C. or less. XV) and the compound of formula (I) after contacting, before adding the reducing agent, step (a) The reaction temperature is about 5° C. or less. In one embodiment, the reaction temperature is about 0° C. to about 5° C.

[0235] In one embodiment, the crystallization in step (b) is carried out in a mixed solvent of DMAc and water. In this embodiment, the crystallization in step (b) is carried out in a mixed solvent of THF and heptane.

[0236] 5.2.7 Preparation of compounds of formula (XV) In one embodiment, the method described herein comprises a formylation reaction of a compound of formula (XVI): A compound of formula (XV) or a salt, solvate, hydrate, enantiomer, or mixture of enantiomers thereof The present invention provides a process for the preparation of a compound, or an isotopically substituted compound, comprising the steps of: The process includes the optional step of crystallizing the product from the mixture.

[0237] In one embodiment, the compound of formula (XV) is provided herein: [ka] or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof. conversion (in the formula, R 7 is hydrogen or a suitable hydroxyl protecting group, and R 8 is hydrogen, alkyl The present invention provides a process for preparing a compound, the compound being an alkyl, aryl, or aryl, the process comprising: (a) A compound of formula (XVI): [ka] or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof with a formylation reagent to produce a compound of formula (XV), or a salt, solvate, hydrate thereof. providing an isomer, enantiomer, mixture of enantiomers, or isotopic substitution; and (b) optionally a compound of formula (XV) or a salt, solvate, hydrate, enantiomer thereof Crystallization of an isomer, a mixture of enantiomers, or an isotopically substituted isomer from a solvent or mixture of solvents. This includes making the person do so.

[0238] In one embodiment, R 7 is hydrogen. In one embodiment, R 7 is a hydroxyl protecting group In one embodiment, R 7 are allyl, methyl, and 2-methoxyethoxymethyl (MEM) , methoxymethyl (MOM), methoxythiomethyl, t-butoxymethyl, tri-isopropyl propylsilyloxymethyl (TOM), ethyl, 1-ethoxyethyl, isopropyl, t -Butyl, benzyl, trityl (Tr), dimethoxytrityl (DMT), monomethoxy Trityl (MMT), p-methoxybenzyl (PMB), acetyl, chloroacetyl, trityl Trichloroacetyl, trifluoroacetyl, pivaloyl (Piv), benzoyl, p-fluoroacetyl Phenylbenzoyl, trimethylsilyl (TMS), triisopropylsilyl (TIPS) , t-butyldimethylsilyl (TBDMS), and tetrahydropyranyl is the hydroxyl protecting group of choice.

[0239] In one embodiment, R 8 is alkyl. In one embodiment, R 8 is C 1-5 With alkyl In one embodiment, R 8 is methyl, ethyl, n-propyl, isopropyl, or In one embodiment, R 8 is methyl. In one embodiment, R 8 is hydrogen. In one embodiment, R 8 is aryl. In one embodiment, R 8 is C6 -10It is aryl.

[0240] In one embodiment, the formylating reagent in step (a) is hexamethylenetetramine (HMT A) Combination of POCl3 and DMF (e.g., Vilsmeier-Haack reaction), chloride Oxalyl and DMF (e.g., Vilsmeier-Haack reaction), CHCl3 and KOH (e.g., the Reimer-Tsiemann reaction), HCN, HCl, and Al Combinations of Cl3 (e.g., Gattermann reaction), as well as combinations of CO and HCl (e.g., the Gattermann-Koch reaction). In one embodiment, the formyl The cationization reagent is hexamethylenetetramine (HMTA). HMTA has the following structure: [ka] .

[0241] In one embodiment, the crystallization in step (b) is carried out using MeOH, EtOH, iPrOH, n-Pro Butanol, t-butanol, n-butanol, MeCN, DMSO, DMAc, DMF, In one embodiment, the reaction is carried out in a solvent selected from NMP, THF, water, or a mixture thereof. In one embodiment, the crystallization in step (b) is carried out in a mixed solvent of MeOH and water. b) Crystallization is carried out in a mixed solvent of iPrOH and water.

[0242] In one embodiment, step (b) further comprises adjusting the pH with a base. In an embodiment, the pH is adjusted to about 2.5 to about 4. In one embodiment, the base is a carbonate, a lysine salt, or a phosphate salt. In one embodiment, the base is a phosphate, bicarbonate, hydroxide, acetate, or benzoate. In one embodiment, the base is a carbonate base. In one embodiment, the base is KCO. In this case, the bases are potassium acetate, sodium carbonate, lithium carbonate, hydroxides, bicarbonates, etc. It is a tertiary amine, DBU, or guanidine.

[0243] In one embodiment, the product from step (b) is reacted with a mixture of a water-miscible solvent and an acidic solvent. In one embodiment, the water-miscible solvent is methanol, ethanol, propane, or the like. propyl alcohol, acetonitrile, DMF, DMAc, NMP, DMSO, or THF. In one embodiment, the water-miscible solvent is i-PrOH. In one embodiment, the acidic solvent is , AcOH, a sulfonic acid, a carboxylic acid, a mineral acid, or an amino acid. The acidic solvent is AcOH. In one embodiment, the product from step (b) is reacted with i-PrOH and AcOH.

[0244] In one embodiment, the orthometalation of an O-protected compound of formula (XVI) followed by reaction with a formylating agent (e.g., DMF) to give a compound of formula (XV), or its salts, solvates, hydrates, enantiomers, mixtures of enantiomers, or isotopically substituted derivatives thereof Also provided is a process for the preparation of: One embodiment of the process is shown in the following scheme: [ka]

[0245] In one embodiment, the compound described herein is 2-chloro-6-hydroxybenzaldehyde ( For example, the compound of formula (XV) can be prepared by carboxymetallation with Pd / CO / MeOH. or its salts, solvates, hydrates, enantiomers, mixtures of enantiomers, or isotopically substituted A process for the preparation of the body is also provided. One embodiment of the process is shown in the following scheme: [ka]

[0246] 5.2.8 Preparation of Ot-Bu-DIC isourea In one embodiment, a process for the preparation of Ot-Bu-DIC isourea of ​​the following structure is provided: : [ka] The process involves the use of diisopropylcarbodiimide (DIC) with t-butanol and Cu(I). The method includes reacting the compound with a salt in the presence of oxygen.

[0247] In one embodiment, oxygen is present in an amount up to about 22% of atmospheric oxygen. In one embodiment, oxygen is present in an amount of about 2% to about 10% of atmospheric oxygen. 6%. In one embodiment, oxygen is present in an amount of about 4% of atmospheric oxygen.

[0248] In one embodiment, the Cu(I) salt is CuCl. In one embodiment, the Cu(I) salt is C uBr. In one embodiment, the Cu(I) salt is CuI.

[0249] t-Butyl esterification using Ot-Bu-DIC isourea as provided herein The compound (e.g., the compound of formula (IV)) and other t-butyl ester compounds are reacted with the corresponding acids. In chemistry, the performance of organic reactions under oxygen is of particular importance. It is generally known that large-scale explosions are dangerous. However, the amount of oxygen provided herein (e.g., about 4% oxygen in nitrogen) is safe and The advantages offered by the presence of oxygen are particularly evident at large scale. In some cases, it's not a trivial matter.

[0250] 5.3 Solid form In one embodiment, the process provided herein includes a method for the preparation of a compound according to the invention, including its solid form (e.g., crystalline form). The intermediate compounds used in the process or the product compounds prepared by the process are In one embodiment, the solid form (e.g., Form A) is provided herein. In one embodiment, the compound 7 is provided herein having a solid form (e.g., In one embodiment, the solid form of the compound described herein is a racemic compound 7 having Form A). In one embodiment, the compound 8 described herein has a cyclic morphology (e.g., Form A). In one embodiment, racemic compound 8 is provided having a solid form (e.g., Form A). Provided herein is Compound 1 having solid forms (e.g., Form A and Form B). In one embodiment, the racemic form having a solid form (e.g., Form A) is provided herein. Compound 1 is provided herein. In one embodiment, the solid form (e.g., Form A) is In one embodiment, the compound 35 described herein is in solid form (e.g., Compound 37 is provided herein having Form 1). In one embodiment, the solid form (eg, Form 1).

[0251] 5.3.1 Form A of Compound 7 In one embodiment, provided herein is compound 7 having a solid form of the following formula: [ka] In that case, the solid form is Form A (of Compound 7).

[0252] A representative XRPD pattern of Form A is shown in Figure 1. In one embodiment, , at or approximately at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or all Compound 7 is provided having a solid form characterized by XRPD peaks of: 6.7, 9.0, 10.7, 13.0, 16.6, 17.1, 18.7, 19.6, 20.1, 21.5, 21.8, 23.7, 24.3, 24.9, 25.5, 26.3, 28.7, 29.0, 30.4, 31.5, 31.8, and 34.8 degrees 2θ. In one embodiment, the solid form is In one embodiment, the solid form is characterized by five peaks. In an embodiment, the solid form is characterized by seven peaks. In one embodiment, the solid form is characterized by: In one embodiment, the solid form is characterized by 13 peaks. In one embodiment, the solid form is characterized by all of the peaks.

[0253] In one embodiment, the nucleophilic acid salts described herein are at approximately 9.0, 10.7, and 23.7 degrees 2θ. Compound 7 is provided having a solid form with an XRPD pattern having peaks. In the form, the XRPD pattern has peaks at approximately 13.0, 17.1, and 18.7 degrees 2θ. In one embodiment, the XRPD pattern further comprises a 21.8 and 25.5 In one embodiment, the XRPD pattern further has a peak at approximately 9.0, 10.7, 13.0, 17.1, 18.7, 20.1, 21.5, 21.8, 23.7, It has peaks at 25.5, 28.7 and 30.4 degrees 2θ.

[0254] In one embodiment, the XRPD patterns described herein match the XRPD patterns shown in FIG. Compound 7 is provided having a solid form with pattern D.

[0255] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0256] A representative DSC thermogram of Form A is shown in FIG. to obtain a solid form having a DSC thermogram that includes a thermal event with an onset temperature of about 180° C. In one embodiment, the thermal event also has a peak temperature of about 180° C. In one embodiment, the DSC thermogram shown in FIG. Compound 7 is provided having a solid form having a DSC thermogram that

[0257] 5.3.2 Form A of racemic compound 7 In one embodiment, there is provided herein racemic compound 7 having a solid form of the following formula: : [ka] In that case the solid form is Form A (of racemic compound 7).

[0258] A representative XRPD pattern of Form A is shown in Figure 3. In one embodiment, , at or approximately at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or all XRPD peaks The present invention provides racemic compound 7 having the solid forms characterized as: 6.6, 8.5, 10.1, 1 1.5, 14.9, 17.6, 20.0, 20.8, 23.1, 23.7, 24.7, 2 4.9, 25.8, 27.5, 27.6, 28.1, 30.7, 33.7, and 35.9 °2θ. In one embodiment, the solid form is characterized by three peaks. In one embodiment, the solid form is characterized by five peaks. In one embodiment, the solid form is characterized by seven peaks. In one embodiment, the solid form is characterized by 10 peaks. In one embodiment, the solid form is characterized by 13 peaks. It is characterized by its

[0259] In one embodiment, the nucleophilic acid salts described herein are at approximately 8.5, 14.9, and 20.8 degrees 2θ. Provided is racemic compound 7 having a solid form with an XRPD pattern having peaks. In one embodiment, the XRPD pattern has approximately 10.1, 20.0, and 23.1 degrees 2θ In one embodiment, the XRPD pattern further has peaks at approximately 24.7 and 3 In one embodiment, the XRPD pattern further comprises a peak at approximately 6 .6, 8.5, 10.1, 14.9, 20.0, 20.8, 23.1, 24.7, 27. It has peaks at 5, 27.6, 28.1, 30.7, and 33.7 degrees 2θ.

[0260] In one embodiment, the XRPD pattern as used herein matches the XRPD pattern shown in FIG. The present invention provides racemic compound 7 having a solid form with pattern D.

[0261] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0262] A representative DSC thermogram of Form A is shown in Figure 4. In one embodiment, to obtain a solid form having a DSC thermogram containing a thermal event with an onset temperature of about 156° C. In one embodiment, the thermal event also has a peak at about 158° C. In one embodiment, the DSC thermogram shown in FIG. Racemic compound 7 is provided having a solid form with a matching DSC thermogram.

[0263] 5.3.3 Form A of Compound 8 In one embodiment, provided herein is compound 8 having a solid form of the following formula: [ka] In that case, the solid form is Form A (of Compound 8).

[0264] A representative XRPD pattern of Form A is shown in Figure 5. In one embodiment, , at or approximately at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or all XRPD peaks Compound 8 is provided having the solid forms characterized as: 6.0, 9.1, 11.3, 12.0 , 13.9, 15.3, 16.6, 18.1, 19.4, 21.3, 22.3, 22.8 , 24.2, 25.2, 28.0, 28.2, 30.7, 33.5, and 34.2° 2θ In one embodiment, the solid form is characterized by three peaks. In one embodiment, the solid form is characterized by 7 peaks. In one embodiment, the solid form is characterized by 10 peaks. The form is characterized by 13 peaks. In one embodiment, the solid form has all of the peaks. It is characterized by:

[0265] In one embodiment, the nucleophilic acid salts described herein are at approximately 6.0, 18.1, and 19.4 degrees 2θ. Compound 8 is provided having a solid form with an XRPD pattern having peaks. In the form, the XRPD pattern has peaks at approximately 11.3, 13.9, and 16.6 degrees 2θ. In one embodiment, the XRPD pattern further comprises a 24.2 and 25.2 In one embodiment, the XRPD pattern further has a peak at approximately 6.0, 9.1, 11.3, 13.9, 16.6, 18.1, 19.4, 22.3, 24.2, 2 It has peaks at 5.2 and 28.2 degrees 2θ.

[0266] In one embodiment, the XRPD pattern as used herein matches the XRPD pattern shown in FIG. Compound 8 is provided having a solid form with pattern D.

[0267] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0268] A representative DSC thermogram of Form A is shown in Figure 6. In one embodiment, to obtain a solid form having a DSC thermogram containing a thermal event with an onset temperature of about 139° C. In one embodiment, the thermal event also has a peak temperature of about 140° C. In one embodiment, the DSC thermogram shown in FIG. Compound 8 is provided having a solid form having a DSC thermogram that

[0269] 5.3.4 Form A of racemic compound 8 In one embodiment, there is provided herein a racemic compound 8 having a solid form of the following formula: : [ka] In that case the solid form is Form A (of racemic compound 8).

[0270] A representative XRPD pattern of Form A is shown in Figure 7. In one embodiment, , at or approximately at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 2 We present racemic compound 8, which has a solid form characterized by four or all of the XRPD peaks. Provided: 6.4, 8.6, 9.0, 9.6, 10.5, 15.1, 16.0, 16.7, 17.1, 18.1, 18.5, 18.9, 19.3, 19.6, 20.1, 20.3, 20.5, 21.3, 21.4, 22.2, 22.4, 22.6, 22.9, 23.5, and 24.8° 2θ. In one embodiment, the solid form is characterized by three peaks. In one embodiment, the solid form is characterized by five peaks. In one embodiment, the solid form is characterized by seven peaks. In one embodiment, the solid form is characterized by 10 peaks. In an embodiment, the solid form is characterized by 13 peaks. , all peaks are characterized.

[0271] In one embodiment, the peaks at approximately 6.4, 8.6, and 16.7 degrees 2θ are used herein. The present invention provides a racemic compound 8 having a solid form with an XRPD pattern having a peak. In an embodiment, the XRPD pattern has peaks at approximately 10.5, 17.1, and 20.5 degrees 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 15.1 and 19 0.6°2θ. In one embodiment, the XRPD pattern has a peak at approximately 6. 4, 8.6, 10.5, 15.1, 16.0, 16.7, 17.1, 18.1, 19.6 , 20.1, 20.3, 20.5, 21.3, and 23.5 degrees 2θ.

[0272] In one embodiment, the XRPD pattern as used herein matches the XRPD pattern shown in FIG. The present invention provides racemic compound 8 having a solid form with pattern D.

[0273] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0274] A representative DSC thermogram of Form A is shown in Figure 8. In one embodiment, to obtain a solid form having a DSC thermogram that includes a thermal event with an onset temperature of about 122° C. In one embodiment, the thermal event also provides racemic compound 8 having a peak at about 124° C. In one embodiment, the DSC thermogram shown in FIG. Racemic compound 8 is provided having a solid form with a matching DSC thermogram.

[0275] 5.3.5 Compound 1 Form A In one embodiment, provided herein is compound 1 having a solid form of the following formula: [ka] In that case, the solid form is Form A (of Compound 1).

[0276] A representative XRPD pattern of Form A is shown in Figure 9. In one embodiment, , or 1, 2, 3, 4, 5, 6, 7, 8, 9, or provides compound 1 having a solid form characterized by all XRPD peaks: 4.8, 14.4, 15.6, 19.2, 24.1, 24.9, 29.0, 34.0, 34.9, and 39.0° 2θ. In one embodiment, the solid form is characterized by three peaks. In one embodiment, the solid form is characterized by five peaks. In one embodiment, the solid form is characterized by seven peaks. In one embodiment, the solid form is characterized by 10 peaks. In an embodiment, the solid form is characterized by all of the peaks.

[0277] In one embodiment, the nucleophilic acid salts described herein are at approximately 4.8, 19.2, and 24.1 degrees 2θ. Compound 1 is provided having a solid form having an XRPD pattern with peaks. In this form, the XRPD pattern further exhibits peaks at approximately 14.4 and 29.0 degrees 2θ. In one embodiment, the XRPD pattern is approximately 4.8, 14.4, 15.6, 19 It has peaks at 0.2, 24.1, 24.9, 29.0, and 34.0 degrees 2θ.

[0278] In one embodiment, the XRPD pattern as used herein matches the XRPD pattern shown in FIG. Compound 1 is provided having a solid form with a D pattern.

[0279] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0280] A representative DSC thermogram of Form A is shown in Figure 10. In one embodiment, the The first thermal event had an onset temperature of about 197° C., the second thermal event had an onset temperature of about 206° C. and a solid form having a DSC thermogram that includes a third thermal event with an onset temperature of about 218° C. In one embodiment, the first thermal event also includes a compound having a temperature of about 197° C. The first thermal event also had a peak temperature of about 207° C., and the third thermal event The event also has a peak temperature of about 224° C. 10. A solid form having a DSC thermogram matching that shown in The present invention provides compound 1.

[0281] 5.3.6 Form B of Compound 1 In one embodiment, provided herein is compound 1 having a solid form of the following formula: [ka] In that case, the solid form is Form B (of Compound 1).

[0282] A representative XRPD pattern of Form B is shown in Figure 11. In one embodiment, and located at or approximately at: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 pieces or compound 1 having a solid form characterized by all XRPD peaks:7 .7, 12.1, 15.4, 16.0, 18.1, 18.8, 19.2, 19.4, 22 .1, 24.4, 24.9, 27.1, 28.1, 28.6, 29.4, 31.1, 31 .4, 32.4, 32.6, 32.8, 34.5, 36.1, 36.2, and 36.9° 2θ. In one embodiment, the solid form is characterized by three peaks. The form is characterized by five peaks. In one embodiment, the solid form is characterized by seven peaks. In one embodiment, the solid form is characterized by 10 peaks. The solid form is characterized by 13 peaks. In one embodiment, the solid form is characterized by all peaks. It is characterized by

[0283] In one embodiment, the chromatic aberrations herein are approximately 12.1, 18.8, and 19.4 degrees 2θ. Compound 1 is provided having a solid form having an XRPD pattern with a peak at In an embodiment, the XRPD pattern has peaks at approximately 19.2, 24.9, and 31.1 degrees 2θ. In one embodiment, the XRPD pattern further comprises a peak at approximately 18.1 and 28. 6° 2θ. In one embodiment, the XRPD pattern has a peak at approximately 12. 1, 18.1, 18.8, 19.2, 19.4, 22.1, 24.4, 24.9, 27. It has peaks at 1, 28.6, and 31.1 degrees 2θ.

[0284] In one embodiment, the present invention relates to a compound having an XRPD pattern matching the XRPD pattern shown in FIG. Compound 1 is provided having a solid form with a PD pattern.

[0285] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0286] A representative DSC thermogram of Form B is shown in Figure 12. In one embodiment, the A first thermal event with an onset temperature of about 139° C., a second thermal event with an onset temperature of about 193° C. , a third thermal event with an onset temperature of about 205° C., and a fourth thermal event with an onset temperature of about 224° C. In one embodiment, Compound 1 is provided having a solid form having a DSC thermogram comprising: The first thermal event also had a peak temperature of about 146° C., and the second thermal event also had a peak temperature of about The first thermal event had a peak temperature of about 197° C., and the third thermal event also had a peak temperature of about 208° C. The fourth thermal event also has a peak temperature of about 224° C. A solid having a DSC thermogram matching the DSC thermogram shown in FIG. Compound 1 is provided having the form:

[0287] 5.3.7 Form A of Racemic Compound 1 In one embodiment, there is provided herein a racemic compound 1 having a solid form of the formula: : [ka] In that case, the solid form is Form A (of racemic compound 1).

[0288] A representative XRPD pattern of Form A is shown in Figure 13. In one embodiment, and located at or approximately at: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, and provides racemic compound 1 having a solid form characterized by all XRPD peaks:7 .9, 9.2, 12.2, 13.7, 16.2, 16.4, 17.0, 18.7, 19. 7, 20.2, 20.4, 21.0, 21.3, 22.7, 23.7, 25.9, 26. 3, 28.1, 29.7, 31.1, 32.2, 33.0, and 34.2 degrees 2θ. In one embodiment, the solid form is characterized by three peaks. In one embodiment, the solid form is characterized by five peaks. In one embodiment, the solid form is characterized by seven peaks. In an embodiment, the solid form is characterized by 10 peaks. In one embodiment, the solid form is characterized by: In one embodiment, the solid form is characterized by all 13 peaks. do.

[0289] In one embodiment, the chromatic aberrations herein are approximately 18.7, 21.3, and 25.9 degrees 2θ. to provide racemic compound 1 having a solid form with an XRPD pattern having a peak at In one embodiment, the XRPD pattern has approximately 7.9, 20.2, and 22.7 degrees 2θ In one embodiment, the XRPD pattern further has peaks at approximately 9.2 and 19 0.7°2θ. In one embodiment, the XRPD pattern has a peak at approximately 7. 9, 9.2, 13.7, 18.7, 19.7, 20.2, 20.4, 21.0, 21.3 , 22.7, 25.9, and 34.2° 2θ.

[0290] In one embodiment, the present invention relates to a compound having an XRPD pattern matching the XRPD pattern shown in FIG. Provided is racemic compound 1 having a solid form with a PD pattern.

[0291] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0292] A representative DSC thermogram of Form A is shown in Figure 14. In one embodiment, the A first thermal event with an onset temperature of about 186° C. and a second thermal event with an onset temperature of about 207° C. The present invention provides a racemic compound 1 having a solid form with a DSC thermogram containing the events. In an embodiment, the first thermal event also has a peak temperature of about 189° C. and the second thermal event Also has a peak temperature of about 212° C. In one embodiment, The solid form of the compound has a DSC thermogram that matches the DSC thermogram shown in Semi-compound 1 is provided.

[0293] 5.3.8 Form A of Compound 35 In one embodiment, provided herein is compound 35 having a solid form of the following formula: [ka] In that case, the solid form is Form A (of Compound 35).

[0294] A representative XRPD pattern of Form A is shown in Figure 15. In one embodiment, and located at or approximately at: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, or all XRPD peaks Compound 35 having the following structures: 9.1, 12.0, 15.6, 18.1, 19.8, 24.1, 24.6, 25.0, 25.3, 26.2, 27.1, 28.5, 29.9, 31.8, 36.6, and 37.8 °2θ. In one embodiment, the solid form has three peaks In one embodiment, the solid form is characterized by five peaks. In one embodiment, the solid form is characterized by seven peaks. In one embodiment, the solid form is characterized by ten peaks. In one embodiment, the solid form is characterized by 13 peaks. In terms of morphology, the solid form is characterized by all peaks.

[0295] In one embodiment, the concentrations of about 12.0, 15.6, and 24.1 degrees 2θ are used herein. Compound 35 is provided having a solid form with an XRPD pattern having a peak at 1. In an embodiment, the XRPD pattern has peaks at approximately 9.1, 18.1, and 19.8 degrees 2θ. In one embodiment, the XRPD pattern further comprises a 25.0 and 27.1 In one embodiment, the XRPD pattern further has a peak at approximately 9.1, 12.0, 15.6, 18.1, 19.8, 24.1, 24.6, 25.0, 25.3, It has peaks at 26.2, 27.1, 28.5, and 29.9 degrees 2θ.

[0296] In one embodiment, the present invention relates to a compound having an XRPD pattern matching the XRPD pattern shown in FIG. Compound 35 is provided, which has a solid form with a PD pattern.

[0297] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0298] A representative DSC thermogram of Form A is shown in Figure 16. In one embodiment, the A first thermal event with an onset temperature of about 58° C. and a second thermal event with an onset temperature of about 119° C. Compound 35 is provided having a solid form with a DSC thermogram that includes a morphology. In this embodiment, the first thermal event also has a peak temperature of about 60° C. and the second thermal event also has In one embodiment, the D Compound 35 has a solid form with a DSC thermogram that matches the SC thermogram to provide.

[0299] In one embodiment, Form A has the general structure: a=19.5 Å, b=3.8 Å, c=11.3 Å. , α=90°, β=90°, and γ=90°. In one embodiment, Form A is roughly: a=19.46 Å, b=3.78 Å, c=11.26 Å, α=90° , β=90°, and γ=90°. In one embodiment, Form A has unit cell dimensions of approximately :a=19.458Å, b=3.781Å, c=11.261Å, α=90°, β= 90°, and γ=90°. In one embodiment, Form A is Pna2 1. In one embodiment, Form A has a unit cell of about 828.43 Å 3 / lattice In one embodiment, Form A has a Z value of 4. In one embodiment, Form A is about 1.444g / cm 3 has a density of

[0300] 5.3.9 Form 1 of Compound 37 In one embodiment, provided herein is compound 37 having a solid form of the following formula: [ka] In that case, the solid form is Form 1 (of Compound 37).

[0301] A representative XRPD pattern of Form 1 is shown in Figure 17. In one embodiment, and located at or approximately at: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 pieces or compound 37 having a solid form characterized by all XRPD peaks: 5.4, ​​10.3, 10.7, 11.9, 13.5, 14.4, 16.0, 16.1, 1 8.0, 18.4, 18.7, 19.2, 19.6, 20.1, 20.7, 21.0, 2 2.2, 22.3, 23.0, 23.3, 24.7, 25.8, 26.2, and 27.0 °2θ. In one embodiment, the solid form is characterized by three peaks. In one embodiment, the solid form is characterized by five peaks. In one embodiment, the solid form is characterized by seven peaks. In one embodiment, the solid form is characterized by 10 peaks. In one embodiment, the solid form is characterized by 13 peaks. It is characterized by its

[0302] In one embodiment, the nucleophilic acid salts described herein are at approximately 5.4, 16.0, and 18.0 degrees 2θ. Compound 37 is provided having a solid form with an XRPD pattern having peaks. In an embodiment, the XRPD pattern has peaks at approximately 10.7, 20.1, and 27.0 degrees 2θ. In one embodiment, the XRPD pattern further comprises peaks at approximately 14.4 and 23. In one embodiment, the XRPD pattern further has a peak at approximately 5.4 , 10.3, 10.7, 11.9, 13.5, 14.4, 16.0, 18.0, 18.4 , 18.7, 19.2, 19.6, 20.1, 21.0, 22.2, 23.0, 24.7 , 25.8, and 27.0° 2θ.

[0303] In one embodiment, the present invention relates to a compound having an XRPD pattern matching the XRPD pattern shown in FIG. Compound 37 is provided, which has a solid form with a PD pattern.

[0304] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0305] A representative DSC thermogram of Form 1 is shown in Figure 18. In one embodiment, A first thermal event with an onset temperature of about 189° C. and a second thermal event with an onset temperature of about 206° C. Compound 37 is provided having a solid form with a DSC thermogram including the events. In one embodiment, the first thermal event also has a peak temperature of about 191° C. and the second thermal event also has a peak temperature of about 191° C. and has a peak temperature of about 208° C. In one embodiment, the Compounds with solid forms that have DSC thermograms that match those of Offers 37.

[0306] In one embodiment, Form A has the general structure: a=10.1 Å, b=10.9 Å, c=32.7 Å. In one embodiment, the unit cell dimensions are: .ANG., .alpha.=90.degree., .beta.=90.degree., and .gamma.=90.degree. , Form 1 is roughly: a = 10.07 Å, b = 10.89 Å, c = 32.70 Å, α = 9 0°, β=90°, and γ=90°. In one embodiment, Form 1 is , roughly: a = 10.066 Å, b = 10.887 Å, c = 32.698 Å, α = 90° , β=90°, and γ=90°. In one embodiment, Form 1 is 212121. In one embodiment, Form 1 has a unit cell of about 3583.0 Å 3 In one embodiment, Form 1 has a Z value of 8. Form 1 is about 1.240 g / cm 3 has a density of

[0307] 5.3.10 Form 1 of Racemic Compound 37 In one embodiment, the present disclosure relates to a racemic compound 37 having a solid form of the following formula: [ka] Provide In that case the solid form is Form 1 (of racemic compound 37).

[0308] A representative XRPD pattern of Form 1 is shown in Figure 20. In one embodiment, and located at or approximately at: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, Racemic compounds with solid forms characterized by 24, 25, or all XRPD peaks Provides object 37: 7.2, 7.5, 11.4, 12.5, 12.9, 14.3, 14. 8, 15.0, 16.1, 16.8, 18.5, 19.7, 20.5, 21.1, 22. 6, 23.7, 24.2, 25.2, 25.4, 25.9, 26.5, 28.1, 30. 3, 30.6, 37.5, and 39.5° 2θ. In one embodiment, the solid form has three peaks In one embodiment, the solid form is characterized by five peaks. In one embodiment, the solid form is characterized by seven peaks. In one embodiment, the solid form is characterized by ten peaks. In one embodiment, the solid form is characterized by 13 peaks. In an embodiment, the solid form is characterized by all of the peaks.

[0309] In one embodiment, the nucleophilic acid salts described herein are at approximately 7.5, 11.4, and 25.9 degrees 2θ. To provide racemic compound 37 having a solid form with an XRPD pattern having peaks In one embodiment, the XRPD pattern has approximately 16.8, 19.7, and 25.4 degrees 2θ In one embodiment, the XRPD pattern further has peaks at approximately 12.9 and 2 In one embodiment, the XRPD pattern further has a peak at approximately 7 .5, 11.4, 12.5, 12.9, 15.0, 16.8, 19.7, 22.6, 25 It has peaks at 25.4 and 25.9°2θ.

[0310] In one embodiment, the present invention relates to a compound having an XRPD pattern matching the XRPD pattern shown in FIG. The racemic compound 37 is provided in a solid form having a PD pattern.

[0311] In one embodiment, the XRPD pattern is obtained using Cu Kα radiation.

[0312] A representative DSC thermogram of Form 1 is shown in Figure 21. In one embodiment, and a solid form having a DSC thermogram including a first thermal event with an onset temperature of about 163° C. In one embodiment, the first thermal event also provides racemic compound 37 having a 1:1 phase. In one embodiment, the DSC thermogram has a peak temperature of about 207° C. In one embodiment, the method further comprises the step of: A solid form having a DSC thermogram matching that shown in FIG. The compound 37 is obtained as racemic compound 37.

[0313] All combinations of the above embodiments are encompassed by the present invention. EXAMPLES

[0314] 6. Working Example As used herein, the symbols used in these processes, schemes, and examples are and conventions are consistent with those in the current scientific literature, regardless of whether a particular abbreviation is specifically defined. For example, the Journal of the American Chemical Society ciety or Journal of Biological Chemistry Specifically, in the examples and throughout the specification, The following abbreviations may be used, but are not limited to: g (grams); mg (milligrams); grams; mL (milliliters); μL (microliters); M (moles); mM (milliliters) mole; μM (micromolar); eq. (equivalent); mmol (millimolar); Hz (Hertz) ); MHz (megahertz); hr or hrs (hours); min (minutes); and MS (mass) Unless otherwise stated, the water content of the compounds provided herein is based on the Karl Filler method. Measured by the KF method.

[0315] For all of the following examples, unless otherwise stated, standard work-up procedures known to those skilled in the art were used. and purification methods are available. Unless otherwise stated, all temperatures are in degrees Celsius. Unless otherwise noted, all reactions were carried out at room temperature. The synthesis is intended to illustrate the applicable chemistry through the use of specific examples and is not intended to be limiting. This does not indicate the scope of the disclosure.

[0316] Example 1 [ka] Step 1: Synthesis of Compound 3 L-glutamic acid (2, 10 g, 68.0 mmol) was added to 60 ml of water. To the suspension, benzyl chloroformate (CbzCl, 9.16 ml, 63.9 mmol) was slowly added. 2N NaOH (60 mL) was added at the same time to maintain the pH at 10-12. The addition rate was adjusted to maintain the batch temperature at 0-5°C. After the addition of CbzCl, mixing was continued. The mixture was stirred at 5°C for 1 hour, then at 20-25°C for an additional 16 hours. The product was washed with EtOAc. The aqueous layer containing the product was adjusted to pH 2-4 by adding concentrated hydrochloric acid. The mixture was acidified to pH 3 and then extracted with EtOAc. The organic layer was dried over Na2SO4 and The solid was dried overnight in an oven at 35-40°C to give 16 g of ethyl acetate. Compound 3 (84%) was obtained. LC-MS: calculated m / e (M+1), 282.1; Actual value: 282.2. 1 H NMR (DMSO-d6,): δ (ppm) = 1.68 -1.83 (m, 1H), 1.91-2.03 (m, 1H), 2.27-2.35 (m, 2H), 3.99-4.22 (m, 1H), 5.03 (s, 2H), 7 .29-7.40 (m, 5H), 7.59 (d, J = 8.13 Hz, 1H), 12.40 (wide line s, 2H).

[0317] Step 2: Synthesis of Compound 4 Compound 3 (10 g, 35.6 mmol) in toluene (150 ml) was diluted with paraformaldehyde. aldehyde (2.67 g, 89 mmol) and toluenesulfonic acid (0.62 g, 3.56 The mixture was stirred for approximately 3 hours in a Dean-Stark apparatus with water. The mixture was concentrated under reduced pressure and the resulting oil was further purified. It was used in the next step without any problems.

[0318] Step 3: Synthesis of Compound 5 Compound 4 (3 g, 10.23 mmol) was diluted with methanol (30 ml, 10 volumes). Then, (S)α-methylbenzylamine (3.7 g, 30.7 mmol) was added at room temperature. The mixture was stirred at 20-25° C. for 5 hours. The mixture was concentrated under reduced pressure to remove methanol. The resulting oil was dissolved in water and the pH was adjusted to pH 10 with 0.3 M K2CO3. The mixture was washed with EtOAc, and then the aqueous layer containing the product was diluted with 35% HCl to pH = 2-3. The resulting suspension was filtered and the solid was dried in an oven under vacuum to give Compound 5 was obtained in 73% yield (from compound 3 in two steps). LC-MS m / e calculated 385.2 (M+1);observed value 385.4. 1 H NMR (DMSO-d6,): δ (ppm) 1.34 (d, J= 6.97 Hz, 3H), 1.64-1.90 (m , 2H), 2.17 (t, J=8.24 Hz, 2H), 3.98-4.10 (m , 1H), 4.84-4.93 (m, 1H), 5.05 (s, 2H), 7.17 -7.26 (m, 1H), 7.28-7.40 (m, 10H), 8.36 (d, J= 8.14 Hz, 1H), 12.11 (broad line s, 1H).

[0319] Step 4: Synthesis of Compound 6 [ka] Compound 5 (0.1 g, 0.26 mmol) and tert-butyl A suspension of 2,2,2-trichloroacetimide (0.38 g, 1.71 mmol) was added to 0 The mixture was cooled to °C. BF3 etherate (0.02 ml, 0.015 mmol) was added to the mixture. The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with 10% aqueous K2CO3 solution. The organic layer containing the product was washed with 10% aqueous K2CO3 and then with water. Concentration under reduced pressure gave compound 6. LC-MS m / e calculated 441.2 (M+1); Actual value: 441.4. 1 H NMR (DMSO-d6,): δ (ppm) 1.33 ( s, 3H), 1.37 (s, 9H), 1.64-1.85 (m, 2H), 2.1 4 (t, J = 8.10Hz, 2H), 4.00-4.08 (m, 1H), 4. 84-4.94 (m, 1H), 5.07 (s, 2H), 7.19-7.24 (m , 1H), 7.26-7.36 (m, 10H), 8.37 (d, J = 9.0H z, 1H).

[0320] Step 5: Synthesis of Compound 1 A hydrogen source such as H2 and a catalyst such as Pd / C (palladium on carbon) are used, and and then treated with HCl to convert compound 6 to compound 1.

[0321] Example 2 [ka] Example 2 differs from Example 1 in the selection of the amine nucleophile for cleavage of the lactone. In Example 1, a protected amine is used, whereas in Example 2, ammonia is used directly. There are.

[0322] Step 3: Synthesis of Compound 7 Compound 4 (1.1 g, 3.75 mmol) was dissolved in methanol (20 ml) and hydroxylated Ammonium (20-30 wt%, 10 ml, 20 eq.) was added at 20-25°C. The mixture was stirred for 5 days at 20 to 25° C. The mixture was concentrated under reduced pressure to remove methanol. The resulting oil was dissolved in water. The mixture was washed with EtOAc, and the aqueous layer was then washed with 35% H The mixture was acidified with Cl to pH = 2-3. The acidified mixture was diluted with EtOAc (20 mL × 3). The organic layer was dried over MgSO4 and concentrated on a rotary evaporator. The solid was dried in an oven under vacuum to give compound 7. LC-MS m / e calculated value 2 81.1 (M+1);observed value 281.2. 1 H NMR (DMSO-d6,): δ ( ppm) 1.65-1.78 (m, 1H), 1.82-1.95 (m, 1H), 2.24 (t, J = 7.9 Hz, 2H), 3.90-3.98 (m, 1H), 5.06 (s, 2H), 7.07 (s, 1H), 7.30-7.37 (m, 7H ), 12.10 (wide line s, 1H).

[0323] Example 2A [ka] Step 1: Synthesis of Compound 7 Compound 3, 1,3,5-trioxane, methanesulfonic acid (MsOH) and acetonite The batch was then heated in water with ammonium hydroxide (CH3CN). (NH4OH, aq.) and stirred to form the ammonium salt of compound 7, The ammonium salt of compound 7 was returned to the reactor and then diluted with acetonitrile. The mixture was added with ethanol, water, phosphoric acid (H3PO4), and a seed crystal of compound 7. The resulting suspension of compound 7 was The slurry was filtered, washed with acetonitrile / water and dried to give final compound 7.

[0324] Step 2: Synthesis of Compound 8 Compound 7 and 2-methyltetrahydrofuran (2-MeTHF), followed by Ot-Bu -DIC isourea (diisopropylcarbodiimide) with t-butanol and CuCl and acid The reaction mixture was heated to form compound 8. After the reaction was complete, the product-free solids were removed by filtration and the batch was diluted with bicarbonate. Sodium solution (NaHCO3) and water, and then distilled with fresh 2-MeTHF and water. The molecular weight content was reduced by adding n-heptane and, optionally, seed crystals of compound 8. The crude compound 8 was filtered, washed with n-heptane and 2-MeTHF, and It was dried under pressure.

[0325] The crude compound 8 is returned to the reactor and methanol (MeOH) is added until the batch is dissolved. Water and seed crystals of compound 8 were added to induce crystallization, after which more water was added. The resulting pure compound 8 was filtered, washed with water / methanol, and dried under reduced pressure to give compound 8. obtained.

[0326] Step 3: Synthesis of Compound 1 Compound 8, Pd / C, and methanol were placed in a reactor. The atmosphere was replaced with hydrogen (H2). The reaction was then warmed to give the free base of compound 1. After the reaction was complete, the batch was filtered and the Pd / C was removed. Optionally, the batch was treated with a palladium scavenger in solid phase or in a phosphine-based solution. Processed in a jar.

[0327] The batch was solvent exchanged into isopropanol (iPrOH) and some of the HCl in iPrOH was removed. Seed the mixture with compound 1 to induce crystallization, followed by additional HCl in iPrOH. The salt was completely formed by adding isopropyl acetate (iPrOAc) to desaturate the mixture. The batch was filtered, washed with iPrOH / iPrOAc, and dried under reduced pressure to give compound 1. Ta.

[0328] Example 2B Step 1: Synthesis of Compound 7 [ka] Compound 3 (250 g, 1.00 × wt), 1,3,5-trioxane (96.0 g, 0 384×wt) and MeCN (2L, 8 volumes) were placed in reactor 1. A small amount of MeCN can be used. Alternative formaldehyde sources to xanthane can be used. Methanesulfonic acid (7.5m 1, 0.030 times the amount) was added to reactor 1. Alternatively, 0.01 to 0.1 times the amount was added. Benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethane Alternative acids such as sulfonic, trifluoroacetic, sulfuric, or trichloroacetic acid may be used. The reaction mixture was stirred and heated to 70°C for 12 hours. It can be used for 6 to 36 hours.

[0329] MeCN (2 L, 8 volumes) and 23-30% aqueous NH4OH (365 mL, 1.4 6 times the amount of MeCN was placed in the reactor 2. 4 to 20 times the amount of MeCN can be used. A different ammonia source can be used, such as ammonium nitrate.

[0330] While maintaining a temperature of about 20° C., the lactone solution in reactor 1 is added to the ammonia solution in reactor 2. over a 4 hour period. Addition times of 0.5 to 24 hours can be used. A temperature of 0° C. can be used. The batch in Reactor 2 is then heated to about 30° C. for 13 hours. Temperatures from 10 to 50°C can be used. Times from 2 to 48 hours can be used. The slurry obtained in reactor 2 was cooled to about 20°C. A temperature of 4 to 30°C can be used. The slurry in reactor 2 is filtered and washed with MeCN (0.85 L, 3.4 volumes). A washing amount of 0 to 10 times MeCN can be used. The obtained ammonium salt can be The mixture was dried under vacuum at 35°C. Temperatures between 10 and 50°C may also be used. A nitrogen sweep was used during drying. may also be used.

[0331] The ammonium salt was dissolved in MeCN (563 mL, 2.25 vol.) and HO (680 mL, 2.72 times the amount of MeCN) was added to reactor 3. 1 to 5 times the amount of MeCN can be used. 1 to 5 volumes of water can be used. While maintaining the temperature at 25°C, add 1M H3P O4 (250 mL, 1.00 vol) was added over at least 0.5 h. Phosphoric acid at a concentration of up to 14.8M can be used. Phosphoric acid is incubated for 0.1 to 12 hours. Temperatures between 10 and 40°C can be used. For example, other mineral acids (HCl, H2SO4) or organic acids (citric acid, tartaric acid) can be used. It is possible.

[0332] Seed crystals of the final product (0.63 g, 0.0025 × wt) were added. A thin slurry was aged at 20°C for 1 hour. The chip can be aged for 0.5 to 12 hours. The temperature can be 0 to 30°C. 1M H3PO4 (550mL, 2.20 volumes) was added at 20°C for 10 hours. Phosphoric acid concentrations of 0.1 to 14.8 M can be used. Phosphoric acid is added for 2 h. The time period can be up to 24 hours. Temperatures of 10 to 40°C can be used. Phosphoric acid Acids other than those mentioned above, such as other mineral acids (HCl, H2SO4) or organic acids (citric acid, tartaric acid, etc.) The slurry in reactor 3 was aged for 1 hour. The batch was The slurry was filtered and the cake was diluted with MeCN: Wash with HO (1:2.5 volume ratio, 1 L, 4.00 volumes). Different solvent ratios and solvent volumes The cake was dried in vacuum at 35°C to obtain compound 7 (yield 168-175%). g, molar yield 67-70%). Temperatures of 10-50°C may be used. A group may also be used.

[0333] The above crystallization process can improve the chiral purity of compound 7. Let us start with compound 3, which has a chiral purity of 98.14% (enantiomer D / R ratio of 1.86%). The reaction yielded 99.80% chiral purity (0.2% of the R enantiomer of compound 7). Compound 7 is obtained.

[0334] Analytical data for compound 7: HPLC purity: 99.09%. HPLC chiral purity: 100. 0%. 1 H NMR (DMSO-d6, 300 MHz):δ = 7.36 - 7.30 (m, 7 H), 7.03 (s, 1 H), 5.02 (s, 2H), 3.93 ( ddd, J = 8.7, 5.1 Hz, 1 H), 2.23 (t, J = 7.8 H z, 2 H), 1.94 - 1.83 (m, 1 H), 1.78-1.65 (m, 1 H). 13 C NMR (DMSO-d6, 75 MHz):δ = 173.9, 17 3.4, 155.9, 137.0, 128.3, 127.7, 127.6, 65. 4, 53.9, 30.3, 27.2. MS analysis: Calculated: [M+1]=281.28 ;Found: [M+1]=281.2. CHN Analysis: Calculated: C: 55.71%; H: 5. 75%;N:10.00%;Actual values: C:55.46%, H:5.75%, N:10. 00%.

[0335] One crystalline form of Compound 7 has been identified and is designated Form A of Compound 7. This form is designated XR Characterization was performed by PD and DSC, and representative results are shown in Figure 1 (XRPD) and Figure 2 (DSC). ) as shown in

[0336] This synthetic route can be used to start with racemic starting materials or to racemize stereocenters. Racemic compound 7 can be prepared by the following procedure. A form was identified and designated Form A of racemic compound 7. This form was identified by XRPD and DSC. They were characterized accordingly, and representative results are shown in Figure 3 (XRPD) and Figure 4 (DSC).

[0337] Step 2: Synthesis of Compound 8 [ka] Isourea Reagent Preparation: CuCl (2.02 g, 0.02×wt) was charged to Reactor 1. CuCl of 0.01 to 0.10 × wt can be added. CuBr or CuI, etc. Any alternative Cu(I) salt can be used. Into reactor 1 was charged 126.8 mL (1.27 vol.) of N,N'-diimide. An initial charge of isopropylcarbodiimide can be used (0 to 3.17 times the amount). An atmosphere of 4% O2 was established in the chamber 1. An atmosphere of up to 22% O2 can be used. The reaction mixture was stirred at 25°C for 1 hour while maintaining an atmosphere of 10-4% O2 in the vessel. Temperature of 0°C can be used. Maximum 22% O2 atmosphere can be used inside the container. Agitation times of 0 to 12 hours can be used. While keeping the temperature ≤30°C, add N,N '-Diisopropylcarbodiimide (190.2 mL, 1.9 volumes) was added to reactor 1. Alternatively, a second charge of N,N'-diisopropylcarbodiimide could be used. (0 to 3.17 times the amount). Temperatures of 10 to 40°C can be used. Temperatures of ≦30°C While maintaining the temperature at 0° C., tert-butanol (182 g, 1.82×wt) was charged to reactor 1. Using alternative tert-butanol inputs (1.51–3.02 × wt), Temperatures between 10 and 40°C can be used. Re-establish a 4% O2 atmosphere and allow the reaction to proceed. The container 1 was sealed. A maximum of 22% O2 can be used in the container. The reactor 1 was stirred at 25°C for 12 hours while maintaining the internal atmosphere at 22% O2. The internal atmosphere can be used. Temperatures of 10 to 40°C can be used. 4 to 72 hours A reaction time in between can be used.

[0338] Esterification: Compound 7 (100 g, 1×wt) and 2-MeTHF (1 L, 10 vol.) was charged into reactor 2. 6 to 20 times the amount of 2-MeTHF can be used. THF, Use alternative solvents including DCM, MTBE, 1,4-dioxane, Et2O, etc. While maintaining the temperature at ≦40°C, isourea (386 mL, 3.86 volumes) was added over 2 hours. Alternatively, 0.96 to 7.72 times the amount of isourea was added to reactor 2. The isourea may be added over a period of 1 to 12 hours. The contents of reactor 2 were stirred and heated at 35°C for 5 hours. 50℃ can be used. 2 to 48 hours can be used. Water (0.01 to 1 times Celite (30 g, 0.3×wt) was charged to reactor 2. 0-1×wt Celite can be used. The batch is filtered into reactor 3 and The mixture was washed twice with -MeTHF (400 mL, 4 volumes per wash). 0 to 3 washes can be used. The batch is then washed with sodium bicarbonate. The plate was washed twice with 300 mL of solution (3 volumes per wash). 0 to 3 washes can be used. The batch was washed with water (300 mL). 0 to 6 wash volumes can be used per wash. 0 to 2 washes can be used. 2-MeTHF was distilled off under reduced pressure up to 10 times the amount. Temperatures between 150 and 500 Torr can be used. A double endpoint amount of 2-MeTHF can be used. A four-fold increase in the amount of 2-MeTHF can be used. F was added and distillation continued at 10 times the volume. Temperatures between 25 and 55°C can be used. Pressures of 150 to 500 torr can be used. 6 to 14 times the total amount of 2-MeTHF 0 to 12 times the amount of 2-MeTHF can be added. Distillation is carried out under reduced pressure. The mixture was stirred at room temperature for 5 times the volume. Temperatures of 25 to 55°C can be used. A pressure of 0.1 torr can be used. 4 to 8 times the amount of 2-MeTHF at the end point can be used. The batch is cooled to 25° C. and diluted with n-heptane (50 mL, 0.5 vol). A temperature of 10 to 30°C can be used. 0 to 2 times the amount of n-heptane is added. The slurry was aged for 0.5 hours. Allow to age for 2 hours. Seed the batch with product crystals (0.25 g, 0.00 25×wt) was added. 0 to 50 wt% of seed crystals can be used. The slurry was stirred for 2 The slurry can be aged for 0 to 24 hours. Heptane (1.5 L, 15 vol) was charged to reactor 3 over 8 hours. n-Heptane The time period can be from 2 hours to 24 hours. Temperatures of 10 to 40°C can be used. The slurry was aged for 3 hours. Batches were allowed to age for 0 to 24 hours. The slurry is filtered in reactor 3 and 2-MeTHF / n-heptane (volume ratio 1: 3, 400 mL, 4 volumes) for slurry washing, and 2-MeTHF / n-heptane (volume The mixture was washed with 1:3 ratio, 400 mL, 4 volumes. Different solvent ratios and volumes may be used. The crude product of compound 8 was dried in vacuum at 35°C. Temperatures between 10 and 50°C can be used. A nitrogen sweep can be used during drying.

[0339] Recrystallization of the crude product: Compound 8 crude product (85 g, 1×wt) and MeOH (595 m 100 mL, 7 times the amount) was charged into reactor 4. MeOH in an amount of 6 to 10 times the amount can be used. Water (85 mL, 1 volume) was added to reactor 4 over 1 hour. eTHF can be used. Seed crystals of product (0.212 g, 0.0025×wt) The slurry was charged into the reactor 4. 0 to 50 wt % of seed crystals can be used. The slurry was aged for 1 hour in the vessel 4. The slurry was aged for 0.5 to 12 hours. Water (510 mL, 6 volumes) was added to reactor 4 over a period of 6 hours. The time period can be from 10 to 24 hours. The temperature can be from 10 to 30°C. The rally was aged for 3 hours. Batches could be aged from 0 to 24 hours. The slurry in reactor 4 is filtered and diluted with MeOH / H2O (1:1 by volume, 340 mL, 4x The product was washed with 35 ml of ethyl acetate (100 ml). Different washing solvent ratios and amounts of washing solvent can be used. The mixture was dried in vacuum at 10° C. to give compound 8 (yield: 66-78 g, molar yield: 55-65%). Temperatures between 0 and 50° C. can be used. A nitrogen sweep can be used during drying.

[0340] This process produced compound 7 with chiral purity of 97.2% (the enantiomer of compound 7 is 2.8%) ) and crystallized to obtain compound 8 with chiral purity of 99.9% (the enantiomers of compound 8 0.1%) can be generated.

[0341] Analytical data for compound 8: HPLC purity: 99.46%. HPLC chiral purity: 99.9 7%. 1 H NMR (DMSO-d6, 300 MHz):δ = 7.36 - 7.30 (m, 7H), 7.05 (s, 1H), 5.07 - 5.02 (m, 2H), 3.93 (ddd, J = 8.7, 5.1 Hz, 1 H), 2.22 (t, J = 7.8 Hz, 2 H), 1.94 - 1.82 (m, 1 H), 1.76-1. 64 (m, 1H), 1.38 (s, 9H). 13 C NMR (DMSO-d6, 75 MHz):δ = 173.8, 172.1, 156.4, 137.5, 128 .8, 128.2, 128.1, 80.1, 65.9, 54.2, 31.9, 2 8.2, 27.7. MS analysis: Calculated: [M+1] = 337.17; Found: [M+1 ] = 337.1. CHN analysis: Calculated: C: 60.70%; H: 7.19%; N: 8. 33%;Actual values: C: 60.86%, H: 7.06%, N: 8.30%.

[0342] One crystalline form of Compound 8 has been identified and is designated Form A of Compound 8. This form is designated XR Characterization was performed by PD and DSC, with representative results shown in Figure 5 (XRPD) and Figure 6 (DSC). ) as shown in

[0343] This synthetic route can be used to start with racemic starting materials or to racemize stereocenters. Racemic compound 8 can be prepared by the following procedure. A form was identified and designated Form A of racemic compound 8. This form was identified by XRPD and DSC. They were characterized accordingly, and representative results are shown in Figure 7 (XRPD) and Figure 8 (DSC).

[0344] Step 3: Synthesis of Compound 1 [ka] Compound 8 (10.0g, 1×wt), 10%Pd / C (0.250g, 0.025×w t) and MeOH (100 mL, 10-fold amount) were charged into reactor 1. In addition to MeOH, another alcohol solvent is ethanol. , isopropanol, 1-propanol, and butanol. Solvents include T HF, 2-MeTHF, MTBE, isopropyl acetate, ethyl acetate, DMF, DMAc, Or NMP may also be included. 5% to 10% Pd / C can be used. The catalyst can be carbon, alumina, alkaline earth carbon, etc. Palladium, platinum, rhodium, and cadmium on a variety of supports including palladium salts, clays, ceramics, and celite. The amount of the catalyst added is in the range of 1% by weight to 100% by weight. It is possible.

[0345] The batch was purged 3 times with N2, followed by 3 times with H2. N2 and using H2 The batch can be purged 1 to 10 times. The batch was pressurized to 15 psi H2. The batch can be pressurized with H2 to 15 psi to 60 psi. Utilizing transfer hydrogenation conditions involving cyclohexadiene, formic acid, and ammonium formate. The batch was heated to 20-30°C (target 25°C). The batch temperature range was 15°C. ~60°C. Keep the batch at 20-30°C (target 25°C) for no more than 4 hours. Reaction times of 1 hour to 36 hours can be used. Completion of the reaction can be monitored by in-process monitoring. The results were determined according to the International Petroleum Commission (IPC).

[0346] The batch was then washed with Celite (4.0 g, 0.4×wt, pre-wetted with MeOH) The mixture was filtered through an in-line filter of 1uM or less and placed in reactor R-2. Various amounts of Celite can be used, up to 100% Celite by weight. (20 mL) of MeOH and pass through a 1 μM in-line filter onto Celite The mixture was filtered through a pad into reactor R-2. An additional wash volume of 0 to 10 times the volume of the mixture could be used. The Celite pad is filtered through a 1uM in-line filter with 2x the volume (20mL). The mixture was washed with MeOH and placed in reactor R-2. An additional wash volume of 0 to 10 times the volume may be used. The batch was heated to 35-45°C (target 40°C). Alternative temperatures from 22-65°C were used. Distill the batch under reduced pressure to 5 times its volume while maintaining the temperature at 30-45°C. The batch can be distilled to dryness or anywhere from 1 to 8 volumes. Temperatures between 20 and 83°C can be used. The temperature is maintained at 30 to 45°C and the batch volume is The batch was diluted with 12 volumes (120 mL) of IPA under reduced pressure, maintaining the volume at 5 volumes (50 mL). The batch was distilled to dryness and then subjected to constant volume distillation at 100°C. Constant volume distillation is not necessary. The batch was distilled to dryness and then subjected to constant volume distillation at 100°C. A can be refilled with water. Temperatures of 20 to 83°C can be used. Temperatures of 35 to While maintaining the temperature at 45°C, three volumes (30 mL) of isopropyl acetate were added. The amount of propyl can be varied between 1 and 5 times the amount of MeCN, toluene, Other solvents such as MTBE, ethyl acetate, heptane, and acetone are used as antisolvents 0.025 times the amount (0.250 mL) of trioctylphosphine was added. The amount of added water can be varied between 0.01 and 1.0 times. Activated carbon, silica-supported resin Use of alternative Pd scavengers including grease, and polymer-supported resins and fibers. Alternative alkyl phosphines can be used, including triethylphosphine. Examples of the phosphine include sphingosine, tributylphosphine, and trihexylphosphine. can be carried out without the use of a palladium scavenger.

[0347] HCl in IPA (0.065 volumes (0.650 mL) or 0.1 equivalents) was added dropwise. Various concentrations of HCl in IPA can be used, from 1M to 6M. Different mineral or organic acids, such as phosphoric acid, sulfuric acid, hydrobromic acid, or acetic acid, were used to produce different The salt can be prepared by seeding the batch with 0.01×wt (100 mg) of compound 1. The seed crystals can be added in an amount of 0 to 50% by weight. The slurry is heated to 35 to 45° C. The slurry was aged at 40°C (target temperature) for 1 hour or less. The slurry was aged for 0 to 24 hours. While maintaining the temperature at 35-45°C, add HCl (0. 52 volumes (5.2 mL) or 0.8 equivalents) were added dropwise over a period of 3 hours in IPA. HCl can be used in various concentrations from 1M to 6M. The addition time can range from 5 minutes to 24 hours. The batch is held at 35-45°C (target temperature is 40°C) for 30 minutes. The holding time can be varied from 0 minutes to 24 hours. The batch was kept for less than 2 hours. Cool to 20-25°C. A temperature gradient of 0.5 to 12 hours can be used. HCl in IPA (0.065 volumes (0.650 mL) or 0.1 equivalents) for 30 min. HCl in IPA can be used in various concentrations from 1M to 6M. The HCl addition time may vary from 5 minutes to 24 hours. The slurry is heated to 20-25°C. Batches were aged for 0 to 24 hours. The slurry was filtered through filter F-2. The cake was diluted with 1:1 The mixture was washed twice with 100 ml of IPA / iPrOAc. Different solvent volumes and ratios may be used. The product was dried in vacuum at 20-40°C to obtain compound 1. The temperature was 10-50°C. A nitrogen sweep can be used during drying.

[0348] This process afforded compound 8, which contained 2.27% R-enantiomer, in a yield of 99.9%. The chiral purity of the compound can be improved to compound 1.

[0349] Analytical data for compound 1: HPLC purity: 99.12%. HPLC chiral purity: 99.9 8%. 1 H NMR (DMSO-d6, 300 MHz): δ = 8.38 (broad line s , 1 H), 8.07 (s, 1 H), 7.55 (s, 1H), 3.77 (t, J = 6.3 Hz, 1 H), 2.32-2.29 (m, 2 H), 1.99 - 1 .91 (m, 2 H), 1.39 (s, 9 H). 13 C NMR (DMSO-d6 , 75 MHz):δ = 171.5, 170.4, 80.5, 51.8, 30.8 , 29.7, 28.2, 26.6. MS analysis: Calculated for [M+1] (free base) = 203.17; Found: [M+1] (free base) = 203.1.

[0350] Two crystalline forms of Compound 1 have been identified, designated Compound 1, Form A and Form B. Form A Form A was obtained from the isopropanol / isopropyl acetate system. C, and representative results are shown in Figure 9 (XRPD) and Figure 10 (DSC). Form B was obtained from the methanol / isopropyl acetate system. Form B was analyzed by XRPD and DS. C, and representative results are shown in Figure 11 (XRPD) and Figure 12 (DSC). .

[0351] This synthetic route can be used to start with racemic starting materials or to racemize stereocenters. Racemic Compound 1 can be prepared by: A form was identified and designated Form A of racemic compound 1. This form was identified by XRPD and DSC. They were characterized accordingly and representative results are shown in Figure 13 (XRPD) and Figure 14 (DSC).

[0352] Example 3 [ka] Reaction of L-glutamic acid 2 with methanol in the presence of HCl, followed by phosgenation reaction This then gives compound 9. This is followed by the addition of ammonia (a solution in a solvent such as water or methanol) Addition of tert-butyl ether of the methyl ester forms the amide 10. The conversion to esters was carried out with the aid of the catalyst potassium tert-butyl oxide in tert-butanol. Finally, the target molecule 1 is obtained by formation of the HCl salt of the aminoamide. do.

[0353] Example 4 [ka] Isobutylene and L-glutamate in THF in the presence of catalysts BF3Et2O and H3PO4 Reaction of the amine acid 2 gives the 5-tert-butyl ester compound 11. Or, N,N'-carbonyldiimidazole (CDI) is used to prepare N-carboxylic acid anhydrides. This results in the formation of 12. This is followed by the addition of ammonia (as a solution in a solvent such as water or methanol). to give the free base amide 1. Finally, addition of HCl to the free base aminoamide gives the free base amide 2. Salt formation gives the target molecule 1.

[0354] Example 5 [ka] Step 1: Synthesis of compound 14 Pyroglutamic acid 13 with triethylamine (or other amine base) followed by isobutyric acid By reaction with chloroformates (or other such chloroformate derivatives), A mixed carbonate intermediate is obtained, followed by the subsequent conversion of this species to ammonia (water or methanol). Addition of 1,2-dichlorophenyl (as a solution in a solvent such as ethanol) forms the primary amide 14. 4 can be prepared by alternative carboxylic acid activation procedures commonly known in the art and subsequent ammonia It can also be prepared by reaction with a niobium source.

[0355] Step 2: Synthesis of Compound 1 Selective lactam N-protection of 14 (with Boc, Cbz or other such protecting groups) This makes the oxopyrrolidine accessible to ring opening by a suitable nucleophile such as tBuOK. After removal of the protecting group, 1-free base is obtained. Formation of the HCl salt of the aminoamide of the free base Thus, target molecule 1 is obtained.

[0356] Example 6 [ka] Step 1: Synthesis of compound 17 Methyl 2-((diphenylmethylene)amino)acetate in MeCN (200 mL) To a solution of 15 (24.6 g), DBU (1.45 mL) was added followed by tert-butyl acrylate (1.45 mL). Rate 16 (17.0 mL) was added. The resulting yellow solution was stirred at room temperature (25° C.). After 24 hours, the reaction was found to have stopped, so additional tert-butyl acrylate was added. A portion of 16 (4.26 mL) was added. When the reaction was judged to be complete (approximately 100 mL by LCAP), (3% SM remains), and the solution is concentrated under reduced pressure to about three times the volume (about 70 mL) and then transferred to the next step. LCMS of compound 17: LC-MS m / e calculated 382.2 (M+1); Value 382.2.

[0357] Step 2: Synthesis of compound 18 To a stirred solution of compound 17 in MeCN was added 2-MeTHF (110 mL) and 1N HCl ( 80 mL) was added. After 5 h at room temperature (25° C.), the phases were separated. The organic phase was removed and the aqueous phase (Desired free base 18: (LC-MS m / e calculated 218.1 (M+1); found 2 18.0) was carried to the next step as an aqueous solution.

[0358] Step 3: Synthesis of compound 19 Adjust the aqueous phase to pH 4 to pH 9 using K2CO3 (86 mL of a 10% aqueous solution is required). (necessary), 2-MeTHF (105 mL) was added to the solution. Benzyl chloroformate (11 mL) was added over 5.5 hours and the reaction mixture was heated to 25°C. The mixture was reacted at 4° C. for 2 days. The phases were separated (aqueous layer: about 175 mL, organic layer: about 125 mL), and the aqueous layer was removed. The organic layer containing the product (19: LC-MS m / e calculated 352.2 (M+1) Found 352.2) was carried onto the next step as a solution in 2-MeTHF.

[0359] Step 4: Synthesis of compound 20 The crude solution of 19 from the previous step was diluted with 2-MeTHF to a total volume of 150 mL and treated with LiOH( After 3 hours, 9.35 mL of water was added to the aqueous layer. The hydrolysis of the methyl ester was monitored by HPLC and the reaction was The reaction appeared to cease periodically, so additional 0.1 equivalent portions of LiOH were added as needed. Upon completion of the reaction, a total of 17.4 mL of 10% aqueous LiOH (1.8 equiv.) was added. The solution was adjusted from pH=12 to pH=3 using HCl (72 mL of 1N solution was The organic phase was washed with half-saturated brine solution (2×20 mL) and diluted with 500 The 2- The solvent was exchanged from MeTHF to toluene. The solution was concentrated to about 5 times the volume (70 mL). Seeded with 20. A thin seed bed was allowed to form for 2 hours. Heptane (84 mL) was added over 2 hours via syringe pump and stirred for an additional 16 hours. was filtered, washed with 1:2 toluene:heptane (60 mL), and vacuum dried under N 20 (13.35 g, 41% over 4 steps) was obtained as a white solid. LC-MS m / e Calculated 338.2 (M+1); Measured 338.1. 1 H NMR (300 MHz, DM SO-d6) δ 1.38 (s, 9H), 1.70-180 (m, 1H), 1.8 9-2.00 (m, 1H), 2.20-2.40 (m, 2H), 3.97-4.0 2 (m, 1H), 5.03 (s, 2H), 7.31-7.37 (m, 5H), 7.56-7.59 (d, 1H), 12.6 (s, 1H).

[0360] Alternatively, the formation of 20 can be confirmed by the reaction of potassium trimethylsilyloxy (TMSOK) in 2-MeTHF. This was achieved by reaction of 19 with 1.0 equiv.

[0361] Step 5: Synthesis of compound rac-8 To a solution of 20 (1.00 g) in 2-MeTHF (10 mL) at 0 °C under N2, tri Ethylamine (0.413 mL) was added. Then isobutyl chloroformate (0.384 mL) was added. L) was added dropwise via syringe over 10 min. After 10 min, ammonia (2 L in MeOH) was added dropwise. M solution (2.22 mL) was added in one portion and the solution was allowed to react at 0° C. for 3 hours. A portion of isobutyl acetate (96 μL) was added to give >95% conversion. Water (5 mL) was added. The reaction was quenched by adding 10 mL of 2-MeTHF, the phases were separated, and the aqueous layer was extracted with 2-MeTHF (2×4 mL). The combined organic phase was washed with half-saturated brine solution (2×4 mL). The water was removed azeotropically using a rotary evaporator, and the solution was reduced to approximately 10 times its volume (9.8 mL). Heptane (9.8 mL) was added over 1 h via syringe pump and then eluted for 1 h. After aging, an additional 5 mL of heptane was added over 1 h using a syringe pump. The resulting solid was filtered and washed with 7.5 mL of 3:2 heptane:2-MeTHF. rac-8 (0.630 g, 63% yield) was obtained as a white solid. LC-MS m / e calculated 337.2 (M+1); 1 H NMR (300 MHz, DMSO-d6) δ 1.40 (s, 9H), 1. 62-1.81 (m, 1H), 1.82-1.94 (m, 1H), 2.16-2. 30 (m, 2H), 3.47 (s, 2H), 3.85-4.00 (m, 1H), 5.02 (d, 2H), 7.05 (s, 1H), 7.23-7.42 (m, 5 H).

[0362] Step 6: Synthesis of compound rac-1 free base Rac-1-free base is prepared from rac-8 in the presence of hydrogen and a palladium catalyst.

[0363] Step 7: Synthesis of Compound 1 - Chiral Salt Selection from a diastereomeric mixture of salts from the reaction of the rac-1-free base with a chiral acid The chiral acid for the formation of diastereomeric salts is In a series of organic solvents such as MeOH, IPA, and n-propanol, tartaric acid, 2,3- Dibenzoyltartaric acid, Mandelic acid, Camphorsulfonic acid, N-Ac-N-Leucine, N -Ac-L-phenylalanine and the like.

[0364] Step 8: Synthesis of Compound 1 Compound 1 can be prepared by generating the free base from the 1-chiral salt using an appropriate inorganic or organic base. , followed by the addition of HCl.

[0365] Example 7 [ka] Step 1: Synthesis of compound 23 Weigh out 2-aminoacetamide hydrochloride 21 (0.553 g) and add a stir bar, pressure release valve, and The sample was placed in a 20 mL scintillation vial equipped with a cap and a N2 needle, and DCE (3 mL) was added. In a separate vial, triethylamine (0.767 mL) and Benzoic acid (0.5 mL) were added. Zofenone imine 22 (0.839 mL) was dissolved in DCE (3 mL). The combined reaction mixture was transferred dropwise via syringe to the 21 solution over a period of 10 minutes. The mixture was heated to 80° C. for 16 hours. It was cooled to room temperature and the precipitated solid was filtered. The crude solid was slurried in heptane / MTBE and stirred at room temperature overnight. The material was filtered and dried under vacuum with N2. Recovered 0.8184 g of compound 23 LC-MS m / e calculated 239.1 (M+1);found 239.1.

[0366] Step 2: Synthesis of compound 24 Presence of organic amine bases such as DBU or inorganic bases such as Cs2CO3 and other carbonates Compound 23 is added to tert-butyl acrylate 16 by Michael addition as shown below: Compound 24 is prepared.

[0367] Step 3: Synthesis of compound rac-1-free base Inorganic acids (e.g., aqueous HCl) in various solvents such as 2-MeTHF or MTBE The hydrolysis of imine 24 in the presence of organic acids (such as citric acid or p-toluenesulfonic acid) The rac-1-free base is prepared by decomposition.

[0368] Step 4: Synthesis of Compound 1 - Chiral Salt Selection from a diastereomeric mixture of salts from the reaction of the rac-1-free base with a chiral acid The chiral acid for the formation of diastereomeric salts is In a series of organic solvents such as MeOH, IPA, and n-propanol, tartaric acid, 2,3- Dibenzoyltartaric acid, Mandelic acid, Camphorsulfonic acid, N-Ac-N-Leucine, N -Ac-L-phenylalanine and the like.

[0369] Step 5: Synthesis of Compound 1 Generation of the free base from the 1-chiral salt using an appropriate inorganic or organic base, followed by HC After addition of l, compound 1 is formed.

[0370] Example 8 [ka] Step 1: Synthesis of compound 26 2-((diphenylmethylene)amino)acetonitrile 25 in MeCN (60 mL) To a solution of (6.4 g), DBU (0.433 mL) was added followed by tert-butyl acrylate (0.433 mL). The resulting yellow / orange solution was stirred at room temperature (25 °C) for 1 h. After 16 hours, the reaction mixture was concentrated on a rotary evaporator and subjected to ISCO separation. The desired product 26 was isolated using silica gel chromatography on a 500 rpm HPLC column. Compound 26 LC-MS m / e calculated 349.2 (M+1); found 349.2. 1 H NMR (300 MHz, DMSO-d6) δ 1.39 (s, 9H), 2. 18-2.22 (m, 2H), 2.42-2.49 (m, 2H), 4.32 (t , 1H), 7.20-7.24 (m, 2H), 7.33-7.38 (m, 2H) , 7.43-7.52 (m, 4H), 7.63-7.66 (m, 2H).

[0371] Step 2: Synthesis of compound 27 Inorganic acids (e.g., aqueous HCl) in various solvents such as 2-MeTHF or MTBE The imine hydrolysis of 26 in the presence of organic acids (such as citric acid or p-toluenesulfonic acid) By decomposition, compound 27 is prepared.

[0372] Step 3: Synthesis of compound 28 Compound 27 was carried forward without isolation and was dissolved in sodium triacetoxyborohydride (STAB ) or other similar reducing reagents. To obtain compound 28.

[0373] Step 4: Synthesis of compound 29 Hydrolysis of nitrile 28 in the presence of formaldehyde catalyst and hydroxide base afforded aryl 26. Alternative nitrile hydrolysis conditions may be used to obtain amide 29. stomach.

[0374] Step 5: Synthesis of compound rac-1-free base Hydrogenation of compound 29 in the presence of palladium catalyst to prepare Rac-1-free base do.

[0375] Step 6: Synthesis of Compound 1 - Chiral Salt Selection from a diastereomeric mixture of salts from the reaction of the rac-1-free base with a chiral acid The chiral acid for the formation of diastereomeric salts is In a series of organic solvents such as MeOH, IPA, and n-propanol, tartaric acid, 2,3- Dibenzoyltartaric acid, Mandelic acid, Camphorsulfonic acid, N-Ac-N-Leucine, N -Ac-L-phenylalanine and the like.

[0376] Step 7: Synthesis of Compound 1 Generation of the free base from the 1-chiral salt using an appropriate inorganic or organic base, followed by HC After addition of l, compound 1 is formed.

[0377] Example 9 [ka] Step 1: Synthesis of Compound 31 To a suspension of hippuric acid 30 (1.08 g) in DCM (25 mL), DCC (1.23 g) After 3 h, the mixture was filtered through a short plug of Celite and the filtrate was centrifuged on a rotary evaporator. Concentrate on an evaporator to give an off-white solid. The crude product was purified by diluting with heptane / EtOAc. (3:2) and stirred overnight. The solids (DCU by-product) were filtered off and the filtrate was concentrated. Condensation gave the desired product 31 (0.631 g) as a yellow solid. LC-MS m / z e Calculated 162.1 (M+1); Observed 162.0.

[0378] Step 2: Synthesis of compound 32 Organic amine bases such as DBU or inorganic bases such as Cs2CO3 or other carbonates Michael addition of azlactone 31 to tert-butyl acrylate 16 in the presence of Compound 32 is prepared by the following procedure.

[0379] Step 3: Synthesis of compound 33 Addition of ammonia (as a solution in MeOH or water) affords the azlactone of compound 32. Compound 33 is prepared by ring cleavage.

[0380] Step 4: Synthesis of compound rac-1 free base Rac-1-free base was prepared by removing the benzoyl protecting group of compound 33. do.

[0381] Step 5: Synthesis of Compound 1 - Chiral Salt Selection from a diastereomeric mixture of salts from the reaction of the rac-1-free base with a chiral acid The chiral acid for the formation of diastereomeric salts is In a series of organic solvents such as MeOH, IPA, and n-propanol, tartaric acid, 2,3- Dibenzoyltartaric acid, Mandelic acid, Camphorsulfonic acid, N-Ac-N-Leucine, N -Ac-L-phenylalanine and the like.

[0382] Step 6: Synthesis of Compound 1 Generation of the free base from the 1-chiral salt using an appropriate inorganic or organic base, followed by HC After addition of l, compound 1 is formed.

[0383] Example 10 [ka] [Table 1] In a 5 L jacketed vessel, methyl 3-hydroxybenzoate (34) and trimethyl benzoate were added. Fluoroacetic acid (TFA) was added. The jacket was cooled to keep the internal temperature below 30°C. While holding the sample, slowly inject hexamethylenetetramine (HMTA) over a period of 10 to 15 minutes. The resulting solution was heated to an internal temperature of 65-70°C for 1 hour. The resulting solution was aged at this temperature for 10-12 hours, then heated at 20-25°C for 1 hour. The final reaction mixture was cooled to an internal temperature of 15° C. under reduced pressure (15-80 mm Hg partial pressure). The mixture was concentrated to a total volume of 1230-1240 mL (approximately 8 volumes per 34 mL). The temperature was maintained below 40°C.

[0384] Separately, add methanol (MeOH) (150 mL) and water (300 mL) to a 5 L flask. The concentrated reaction solution and 33 were added together with seed crystals of compound 35 (360 mg). A wt% K2CO3 aqueous solution (744 g of K2CO3 was dissolved in 1.54 L of water) was prepared. The mixture is then pumped, optionally using a peristaltic pump, while maintaining the internal temperature at 30°C or less. The two were added simultaneously at a rate such that each was added over a period of 1 hour. The pH was maintained at pH=2.5-4.0 throughout. The resulting slurry (pH=3. 3) was aged for at least 2 hours.

[0385] The slurry was filtered and the cake was manually compressed to a volume of approximately 400 mL. The mixture was replaced with MeOH:H2O (400 mL). The wet cake was stirred at 20-25 °C for 3 h. The solids were collected and the initially isolated material was dried using a vacuum / N2 sweep. Add 1:1 IPA:0.58 N AcOH (600 mL) with overhead stirring. The mixture was then transferred to a 2 L flask. After aging for 3.5 hours with stirring, H2O (30 0 mL) was added over 2 h. The resulting slurry was aged for 3-4 h. The slurry was filtered and the cake was replaced with 1:3 IPA:H2O (300 mL). The cake was dried by vacuum / N2 sweep at 20-25°C for 3 hours. The solid (96.4 g) was 95.3 wt% of the desired aldehyde and 4.7 wt% of the aldehyde. The percentage of unwanted aldehydes (aldehydes para to esters) was analyzed. The final purity of the combined aldehyde was 99.9% by weight.

[0386] 35 characterization data: 1 H NMR (300 MHz, CDCl3) δ ppm:1 2.20 (s, 1H), 10.62 (s, 1H), 7.55 (t, 1H), 7 .46 (d, lH), 7.18 (d, 1H), 3.95 (s, 3H); 13 C NMR (75 MHz, CDCl3) δ ppm:197.3, 166.0, 162 .9, 135.6, 133.3, 122.3, 122.0, 118.1, 52.6 ;LRMS [MH] - Calculated for C9H8O4: 179.03, Found: 178 .93.

[0387] 36 feature determination data: 1 H NMR (300 MHz, CDCl3) δ ppm:1 0.95 (s, 1H), 9.97 (s, 1H), 7.68-7.64 (m, 3H ), 3.95 (s, 3H); 13 C NMR (75 MHz, CDCl3) δpp m:196.6, 165.8, 161.3, 137.4, 133.7, 123.0 , 120.5, 119.2, 52.8.

[0388] One crystalline form of Compound 35 has been identified and is designated Form A of Compound 35. This form is Characterization was performed by XRPD and DSC, with representative results shown in Figure 15 (XRPD) and Figure 16 (DSC).

[0389] Example 10A: [ka] Methyl 3-hydroxybenzoate (250 g, 1.0 equiv., 1.0×wt) and TFA ( 5000L, 20 times the amount) was charged into reactor 1. Methyl was replaced with H, ethyl, propyl, and butyl. Any type of hydroxybenzoate may be used if it can be replaced by The amount of solvent can be varied from 5 to 100 times. It may also be used as a solvent. i While maintaining <50°C, HMTA (253 g, 1.1 eq. Amount of HMTA (1.01×wt) was gradually added to reactor 1. 1.0 to 1.5 equivalents of HMTA were added. The temperature can be varied from 50 to 72°C. 0 to 5% by weight water Various moisture contents are acceptable. Heat the batch to 65±5°C and maintain temperature for 10-12 hours. The temperature can be varied from 55 to 72°C. The reaction time can be varied from 10 to 72 hours. The crude reaction mixture can be mixed with T i The temperature was cooled to 20-25°C. The temperature can be varied in the range of 0 to 50° C. The mixture is concentrated under reduced pressure to a total volume of about 7 times. The reaction was concentrated to 5 to 10 times the volume. can be done.

[0390] A solution of K2CO3 (1200 g, 5.3 equivalents, 4.8 × wt) in H2O (10 volumes) was reacted. It was prepared in reactor 2. K2CO3 was prepared by mixing potassium acetate, sodium carbonate, lithium carbonate, and water. It can be replaced by inorganic bases such as oxides and bicarbonates. Tertiary amines, DBU, Organic bases including anidine and the like can be used. The amount of solvent can be varied. .

[0391] Into reactor 3, IPA (1 volume), HO (2 volumes), and seed crystals (0.001×wt% ) was added. IPA is a mixture of methanol, ethanol, n-propanol, MeCN, DM SO, DMAc, DMF, NMP, THF can be substituted. Seed loading is 0~ The amount of IPA solvent can be varied from 0 to 10 times. The amount of water or poor solvent added can be varied from 0 to 10 times the amount.

[0392] The solutions in reactor 1 and reactor 2 were added simultaneously to reactor 3, and the pH was maintained at 2 to 4. The pH can be varied from 2 to 6. A conventional biphasic workup using a water-immiscible base and a water-immiscible organic solvent is possible. The slurry was filtered. The cake was displacement washed with 1:3 IPA:H2O (4 volumes). The amount of substitution can be varied. Other ratios of IPA:H2O can be used. The solid was dried. The solid can be dried at 0 to 40 °C.

[0393] The isolated solids were reslurried in reactor 4 and reactor 4 was charged with 1:1 i-PrOH:0. 55N AcOH (4 times the amount) was added in advance. Methanol, ethanol, propanol, etc. Other aqueous solutions, including acetonitrile, DMF, DMAc, NMP, DMSO, and THF, are also available. Miscible solvents can be used. AcOH is a sulfonic acid, carboxylic acid, mineral acid, amino acid, Acid can be substituted. Other concentrations of AcOH from 0 to 100% can be used. Various ratios of IPA / AcOH can be used. Slowly add H2O (2x volume) The amount of H2O was varied from 0 to 100 times the amount of The slurry in reactor 4 is filtered and the cake is mixed with an IP A:H2O (3 volumes) was used for replacement washing. The replacement volume can be changed. PA:H2O can be used. Dry the solids with a vacuum / N2 sweep and Compound 35 was obtained. The solid matter can be dried at 0 to 40°C.

[0394] 35 characterization data: 1 H NMR (300 MHz, CDCl3) δ ppm:1 2.20 (s, 1H), 10.62 (s, 1H), 7.55 (t, 1H), 7 .46 (d, 1H), 7.18 (d, 1H), 3.95 (s, 3H); 13 C NMR (75 MHz, CDCl3) δ ppm:197.3, 166.0, 162 .9, 135.6, 133.3, 122.3, 122.0, 118.1, 52.6 ;LRMS [MH] - Calculated for C9H8O4: 179.03, Found: 178 .93. The XRPD and DSC are consistent with Figure 15 (XRPD) and Figure 16 (DSC). do.

[0395] Example 11 [ka] [Table 2] The HCl salt of compound 1 and dimethylacetamide (DMAc) were added to the vessel, and the resulting suspension was The slurry was stirred slowly. Diisopropylethylamine (iPr2NEt) was added. The resulting homogeneous solution was aged at 20 to 25° C. for 1 hour.

[0396] The homogeneous solution was then cooled to 0-5°C and AcOH was added. After re-cooling, the internal temperature was increased to 5 The aldehyde 35 was added as a solid while maintaining the temperature below 50° C. The resulting homogeneous solution was After the addition of the aldehyde, the mixture was aged for 1.5 to 2 hours. The internal temperature was kept below 5°C. Then, sodium triacetoxyborohydride (STAB) was divided into 4 equal parts as a solid ( The resulting slurry was aged at 0-5°C for 8-10 hours. I had him do it.

[0397] Heat the jacket to 20-25°C for 30-60 minutes, keeping the internal temperature at 20-25°C. The slurry was aged for 1 h at RT. H2O (300 mL) was added over 30–60 min. (Note: gas evolution was observed upon quenching of excess STAB) and the resulting homogeneous solution The solution was seeded with compound 37 (0.1 wt%) and the resulting seed bed was aged for 2 hours. Ta.

[0398] Additional HO (900 mL) was added over 1.5-2 h, and the resulting slurry was Aged for at least 1 hour. The slurry was filtered and the cake was diluted with 1:8 DMAc: The mixture was then replaced with H2O (250 mL) and then with H2O (250 mL). The isolates were dried at 0-25°C for 12 h by vacuum / N2 sweep. .6g), analyzed to be 98.8% by weight (88.5% IY, 99% ee).

[0399] 1 H NMR(300 MHz, DMSO-d6) δ ppm:10.03 (s, l H), 7.56 (s, lH), 7.31 (dd, J1= J2= 7.7 Hz, lH), 7.18 (s, lH), 7.15 (d, J = 7.5 Hz, lH), 6.98 (d, J = 7.7 Hz, 1H), 4.71 (dd, J1= 10.4 Hz, J2= 4.4 Hz, lH), 4.49 (d, J = 17.6 Hz, lH) ), 4.31 (d, J = 17.6 Hz, lH), 2.21-2.09 (m, 3 H), 1.32 (s, 9H); 13 C NMR (75 MHz, DMSO-d6) δ ppm:172.0, 171.4, 168.2, 133.7, 129.3, 128 .3, 79.8, 53.5, 44.9, 31.8, 27.7, 25.0;LRMS [M+H] + C 17 H 22 Calculated for N2O5 335.16, Measured 335. 15.

[0400] One crystalline form of Compound 37 has been identified and is designated Form 1 of Compound 37. This form is Characterization was performed by XRPD and DSC, with representative results shown in Figure 17 (XRPD) and Figure 18 (DSC).

[0401] The above procedure afforded product 37 with a high enantiomeric ratio (>99.75:0.25). Deviations, especially with respect to temperature control, can result in ratios of <98:2. An example of a chiral HPLC chromatogram of a typical reaction using this sequence is shown in Figure 19A (compound Substance 37, eluted at 9.19 minutes, area 3109516, area percentage 99.94, height 1611 94; R-enantiomer, eluted at 6.27 minutes, area 1791, area percentage 0.06, height 1 06). After the addition of 35 and before the addition of STAB, the reaction temperature was raised to T i =15~ An example of a chiral HPLC chromatogram of an atypical reaction maintained at 20° C. is shown in FIG. Compound 37 eluted at 9.47 minutes, area 4366151, height 259118; R-enantiomer Eluted at 6.32 minutes, area 80091, height 4543).

[0402] Example 11A [ka] Compound 1 (60.0 g, 1.15 equivalents, 1.52×wt) was charged to reactor 1. Compound 1 can be added in an amount of 0 to 20 equivalents. Compound 1 can also be used as a free base. Compound 1, including (chiral) carboxylates, sulfonates, phosphates, and mineral acid salts, Substitute salts are available.

[0403] DMAc (120 mL, 3.0-fold volume) was added to reactor 1. Various solvent amounts can be used. DMF, NMP, acetonitrile, THF, 2-Me Alternative solvents such as THF, DCM, and DCE may also be used. Methanol, ethanol, Trifluoroethanol, isopropanol, 1-propanol, and tert-butanoic acid Polar protic solvents such as alcohol can be used. i While maintaining <35°C iPr2NEt (45.7 mL, 1.2 equiv., 1.16 vol.) was charged to reactor 1. Various amounts of iPr2NEt can be used ranging from 1 equivalent to 20 equivalents. Alternative bases such as -Bu3N, DBU, and tetramethylguanidine may be used. Inorganic bases including hydroxides, tribasic phosphates, etc. may be used. If the free base of T is used, no base is required. i Stir at 30±5℃ for 4 to 6 hours The batch temperature can range from 0°C to 40°C. The batch can be mixed for 5 minutes to 72 hours. The crude reaction mixture can be stirred for a period of time. i The reaction temperature was cooled to 0±5°C. The temperature can be varied from 0 to 40 °C. AcOH (18.8 mL, 1.5 equiv., 0.48 times the amount) was charged to reactor 1. Various amounts of AcOH ranging from 0 to 20 equivalents were used. It is possible to use other carboxylic acids (alkyl, aryl, TFA), sulfonic acids, monosalts. Other acids may be used, including basic phosphoric acid. i PrO)4, Ti(OEt)4, A l( i PrO3, boronic acids, orthoformates, and other catalysts such as activated molecular sieves. Reagents can also be used. i While maintaining ≦10°C, solid compound 35 (39.4 g, 1.0 eq, 1.0×wt) was charged to reactor 1. The batch temperature range was T i <= 1 The temperature can be between 0°C and 40°C. i Aging at 0±5℃ for 2~3 hours Various aging times from 1 hour to 24 hours may be used. The temperature is 0 to 40 STAB (69.5 g, 1.5 equivalents, 1.65 x wt) Divide into 5 equal parts and add T i The temperature was kept below 5℃ and the mixture was added at intervals of 30 min or less. BH3CN, silane, and other reducing agents such as H2 were reacted with transition metal catalysts (Pd, Pt, Rh, STAB should be added in 1-10 portions at 0-12 hour intervals. Various temperatures between 0 and 40°C may be used. i = 8 to 10 at 0±5℃ The aging time may vary between 5 and 72 hours. Other temperatures up to 40°C can be used. The solution is heated at T for 1-2 hours. i =20 The samples were heated to ±5°C and held at this temperature for 2-3 hours. The temperature gradient was varied between 0 and 5 hours. The temperature can be changed in the range of 20 to 40°C. The range can be 0 to 72 hours. H2O (6.0 volumes) is added to reactor 1 for 0.5 to 10 minutes. The water was added over a period of 1 hour. The amount of water added can be varied from 3 to 6 times the amount. Addition time The range can be 0 to 12 hours. Seed crystals are added and aged for 1 to 2 hours. The seed crystal addition can be varied from 0 to 50% by weight. The incubation time can be varied between 0 and 12 hours. Addition time was 4-6 hours. Alternative solvent amounts can be used. The aging time can vary from 30 minutes to 12 hours. The slurry is aged for up to 2 hours. The batch can be aged for 0 to 24 hours. The slurry is filtered and The cake was displacement washed with 5 volumes of 1:8 DMAc:H2O (vol:vol). The cake was washed with H2O (5 times the volume). The product was dried under vacuum / N2 sweep to give compound 37. Temperatures between 10 and 50° C. can be used. The nitrogen sweep can be omitted.

[0404] Analytical data for compound 37: HPLC purity: 100%. HPLC chiral purity: 99.98 %. 1 H NMR (DMSO-d6, 300 MHz):δ = 10.01 (s, 1H ), 7.55 (s, 1H), 7.30 (t, J= 8Hz, 1H), 7.16- 7.14 (m, 2H), 6.99 (d, J=8Hz, 1H), 4.73-4.6 1 (m, 1H), 4.40 (AB quartet, J=17Hz, 2H), 2.18-2 .10 (m, 3H), 2.03-1.90 (m, 1H), 1.42 (s, 9H) . 13 C NMR (DMSO-d6, 75 MHz): δ ppm:172.0, 17 1.4, 168.2, 133.7, 129.3, 128.3, 79.8, 53.5 , 44.9, 31.8, 27.7, 25.0. LRMS [M+H] + C 17 H2 Calculated for 2N2O5 335.16, Found 335.15. XRPD and DSC is consistent with Figure 17 (XRPD) and Figure 18 (DSC).

[0405] In a separate experiment, compound 1, dimethylacetamide (DMAc), and N,N-diisopropyl Propylethylamine (iPrNEt) was charged to the reactor and stirred. The batch was cooled and Acetic acid (AcOH) was added, followed by compound 35. The dihydride (NaB(OAc)3H) was added.

[0406] After the reaction was complete, the batch was warmed and water was added, followed by seed crystals of compound 37, and then additional water. The resulting solid was filtered and washed with water / DMAc and then with water. Drying under vacuum gave compound 37.

[0407] Use synthetic routes that start with racemic starting materials or racemize stereocenters Racemic compound 37 can be prepared by the above procedure. A form was identified and designated Form 1 of racemic compound 1. This form was identified by XRPD and DSC. They were characterized accordingly and representative results are shown in Figure 20 (XRPD) and Figure 21 (DSC).

[0408] Example 12. Single crystal experiment of compound 35 Single crystals of compound 35 suitable for single crystal XRD analysis were grown from sample compound 35. Compound 35 was dissolved in a mixture of methyl tert-butyl ether / heptane (2.5 mL, 5 / 1) to obtain a saturated solution and store it in a hood at room temperature. After 14 days, planar crystals were formed. It was recognized.

[0409] A crystalline sample of compound 35 was analyzed by single crystal X-ray diffraction (XRD). The structure was confirmed. The empirical formula is C9H8O4. (Molecular weight = 180.2).

[0410] Formula units using the Bruker SHELXTL Software Package The structure was solved and refined for C9H8O4 using space group Pna 21, Z=4. F with 124 variables 2 The final anisotropic full matrix least-squares refinement of The fit converged to R1 = 3.24% for the first time and wR2 = 8.41% for all data. The final maximum peak in the difference electron density synthesis was 0.177e - / Å 3 And the best The large hall is -0.203e - / Å 3 , RMS deviation is 0.047e - / Å 3 It was. Based on the model, the calculated density is 1.444 g / cm 3 and F(000), 376 e - It was.

[0411] The crystal data are shown in Table 1. Details of data collection and structure refinement are shown in Table 2. Compound 35 The molecular structure of Form A is shown in FIG. Table 1. Crystal data for Form A of compound 35 [Table 3] Table 2. Data collection and structure refinement of compound 35 form A. [Table 4]

[0412] Example 13. Single crystal experiment of compound 37 Single crystals of compound 37 suitable for single crystal XRD analysis were grown from sample compound 37. Compound 37 was dissolved in a mixture of ethyl acetate / methanol (1.2 mL, 4 / 1). A saturated solution was obtained and stored in a Dewar flask at room temperature. After 11 days, planar crystals were observed. Ta.

[0413] A crystalline sample of compound 37 was analyzed by single crystal X-ray diffraction (XRD). The structure was confirmed. The empirical formula is C 17 H 22 N2O5. (Molecular weight = 334.36).

[0414] Formula units using the Bruker SHELXTL Software Package C 17 H 22 The structure of N2O5 was solved using the space group P 21 21 21, Z=8. The F model, which contains 463 variables, was refined. 2 The final anisotropic full matrix least squares refinement of ,R1=3.20% for observed data, and wR2=8.66% for all data. The goodness of fit was 1.020. The maximum peak of the final difference electron density synthesis was 0.205e - / Å 3 And the maximum hole is -0.226e - / Å 3 , RMS deviation is 0.038e - / Å 3 in Based on the final model, the calculated density was 1.240 g / cm 3 and F(00 0), 1424e - It was.

[0415] Crystallographic data are shown in Table 3. Details of data collection and structure refinement are shown in Table 4. Compound 37 The molecular structure of Form 1 is shown in FIG. Table 3. Crystal data for Form 1 of compound 37 [Table 5] Table 4. Data collection and structure refinement of Form 1 of compound 37 [Table 6]

[0416] The above embodiments are intended to be merely illustrative, and those of ordinary skill in the art will appreciate that The ability to recognize, using no more than routine experimentation, numerous equivalents to objects, materials, and procedures; or All such equivalents are within the scope of the claimed subject matter. and are encompassed by the appended claims.

[0417] All patents, patent applications, and publications mentioned herein are hereby incorporated by reference in their entirety. Citation or identification of any reference in this application does not imply that such reference is expressly incorporated by reference. No admission is made that the claimed subject matter is available as prior art. The present application provides the following aspects of the invention. (Aspect 1) Compounds of formula (I): (chemical 1) TIFF0007665000000177.tif31170 or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof A process for preparing a recombinant (a) A compound of formula (II): (Case 2) TIFF0007665000000178.tif31170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof (In the formula, R 1 is a suitable amino protecting group), NH2-R 2 Contact with (In the formula, R 2 is hydrogen or a suitable amino protecting group), Compound: (C3) TIFF0007665000000179.tif31170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Provide; (b) A compound of the formula (III) or a solvate, hydrate, enantiomer, or isoform thereof A mixture of isomers or isotopic substitutions may be used to prepare a compound of formula (IV): (C4) TIFF0007665000000180.tif31170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Convert to; (c) -NH-R 1 The R 2 is a suitable amino protecting group, NH-R 2 to obtain a compound of formula (I) or a solvate, hydrate, enantiomeric providing a mixture of isomers, enantiomers, or isotopically substituted isomers; and (d) optionally a compound of formula (I) or a solvate, hydrate, or enantiomer thereof; , a mixture of enantiomers, or isotopic substitutions, into a salt of said compound. , the preparation process. (Aspect 2) Compounds of formula (I): (C5) TIFF0007665000000181.tif32170 or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof A process for preparing a recombinant (c) A compound of formula (IV): (6) TIFF0007665000000182.tif31170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof The -NH-R 1 The R 2 is a suitable amino protecting group, said -NH- R 2 The R 1 is a suitable amino protecting group, R 2 is hydrogen or the appropriate a compound of formula (I) or a solvate, hydrate, or enantiomer thereof , a mixture of enantiomers, or isotopic substitutions; and (d) optionally a compound of formula (I) or a solvate, hydrate, or enantiomer thereof; , a mixture of enantiomers, or isotopic substitutions, into a salt of said compound. , the preparation process. (Aspect 3) The compound of formula (IV) or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof Compounds or isotopic substitutions, (b) A compound of formula (III): (C7) TIFF0007665000000183.tif32170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof with a compound of formula (IV) or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof The method according to claim 2, wherein the compound is prepared by a process comprising converting the compound to an isotopically substituted compound or an isotopically substituted compound. The process of installation. (Aspect 4) The compound of formula (III) or a solvate, hydrate, enantiomer, or derivative thereof Mixtures or isotopic substitutions, (a) A compound of formula (II): (C8) TIFF0007665000000184.tif31170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof NH2-R 2 and contacting a compound of formula (III) or a solvate, hydrate, or mirror image thereof with To a process that includes providing an antipodal, enantiomeric, or isotopic substitute. The process according to embodiment 3, wherein the compound is prepared by (Aspect 5) The compound of formula (II) or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof (x) a compound of the formula: (9) TIFF0007665000000185.tif31170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof and a formaldehyde source. 4. (Aspect 6) The formaldehyde source is paraformaldehyde or 1,3,5-trioxane. The process of embodiment 5. (Aspect 7) The process according to embodiment 5 or 6, wherein step (x) is carried out in the presence of an acid. (Aspect 8) The acid is p-TsOH, MsOH, benzenesulfonic acid, trifluoromethanesulfonate 8. The process of claim 7, wherein the acetic acid is phosphoric acid, trifluoroacetic acid, sulfuric acid, or trichloroacetic acid. . (Aspect 9) R 2 The process of any one of embodiments 1 to 8, wherein is hydrogen. (Aspect 10) The NH-R 2 (i.e., NH3) in water or MeOH 10. The process according to embodiment 9, wherein the ammonia is provided in the form of ammonia solution or in the form of gaseous ammonia. vinegar. (Aspect 11) R 2 The process according to any one of the preceding aspects, wherein is a suitable amino protecting group. (Aspect 12) The -NH-R in step (c) 1 Deprotection of the -NH-R 2 Deprotection of 12. The process according to embodiment 11, wherein (Aspect 13) The -NH-R in step (c) 1 Deprotection of the -NH-R 2 Simultaneously deprotection of 12. The process according to embodiment 11, wherein (Aspect 14) R 2 is benzyl, 4-methoxybenzyl, or 3,4-dimethoxybenzyl 14. The process according to any one of embodiments 11 to 13. (Aspect 15) R 2 is (S)-1-phenylethyl. Process. (Aspect 16) R 1However, benzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, benzyl o 16. The method of claim 1, wherein the aryloxycarbonyl is p-methoxybenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, or p-methoxybenzyloxycarbonyl. 2. The process according to any one of claims 1 to 11. (Aspect 17) R 1 The process of embodiment 16, wherein is benzyloxycarbonyl. (Aspect 18) Step (b) is carried out in the presence of t-butyl 2,2,2-trichloroacetimidate; The process according to any one of embodiments 1 to 17. (Aspect 19) Any of aspects 1 to 17, wherein step (b) is carried out in the presence of Ot-Bu-DIC isourea. 3. The process according to claim 1. (Aspect 20) The Ot-Bu-DIC isourea was treated with diisopropylcarbodiimide (DIC) 1. The compound according to claim 1, wherein the compound is formed by reacting t-butanol and a Cu(I) salt in the presence of 9. The process according to claim 9. (Aspect 21) Oxygen is reduced to about 22% of atmospheric oxygen, about 1% to about 10%, about 2% to about 6%, or about 21. The process of embodiment 20, wherein said compound is present in an amount of 4%. (Aspect 22) The process according to any one of the preceding aspects, wherein step (c) is carried out under hydrogenation conditions. (Aspect 23) 23. Any of aspects 1 to 22, wherein the compound is converted to a hydrochloride salt of the compound in step (d). 2. The process according to any one of claims 1 to 11. (Aspect 24) Compounds of formula (I): (C10) TIFF0007665000000186.tif31170 or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof A process for preparing a recombinant (a) A compound of formula (V): (Chem.11) TIFF0007665000000187.tif26170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof (In the formula, R 3 is C 1-10 (alkyl) with NH3 to give a compound of formula (VI) : (C12) TIFF0007665000000188.tif22170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Provide; (b)R 3 is not tert-butyl, 3 Converting the group to tert-butyl , a compound of formula (I) or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof, or an isotopic substitution is provided, and (c) optionally a compound of formula (I) or a solvate, hydrate, or enantiomer thereof; , a mixture of enantiomers, or isotopic substitutions, into a salt of said compound. , the preparation process. (Aspect 25) The NH3 in step (a) is provided in the form of a solution of ammonia in water or MeOH. 25. The process according to claim 24. (Aspect 26) The process according to embodiment 24, wherein the NH in step (a) is provided in the form of an ammonium salt. Seth. (Aspect 27) 27. The process according to claim 26, wherein the NH in step (a) is provided in the form of NHHCO. Seth. (Aspect 28) R 3 The process of any one of aspects 24-27, wherein is tert-butyl. (Aspect 29) R3 The process according to any one of aspects 24 to 27, wherein is methyl. (Aspect 30) Step (b) comprises preparing a compound of formula (VI) or a solvate, hydrate or enantiomer thereof, Mixtures of enantiomers or isotopically substituted, optionally in the presence of tert-butoxide salts 30. The process of embodiment 29, comprising contacting with t-BuOH in the presence of (Aspect 31) A compound of formula (V) or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof or an isotopic substitution thereof to a compound of formula (VII): (C13) TIFF0007665000000189.tif21170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof and a ring-forming agent. 2. The process according to any one of claims 1 to 11. (Aspect 32) The ring-forming reagent is triphosgene or N,N'-carbonyldiimidazole (CDI 32. The process of embodiment 31, wherein (Aspect 33) The compound according to any one of embodiments 24 to 32, wherein the compound is converted to a hydrochloride salt of the compound in step (c). 2. The process according to any one of claims 1 to 11. (Aspect 34) Compounds of formula (I): (C14) TIFF0007665000000190.tif31170 or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof A process for preparing a recombinant (a) A compound of formula (VIII): (C15) TIFF0007665000000191.tif21170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof (In the formula, R 4 is a suitable amino protecting group) is contacted with a tert-butoxide nucleophile. Thus, a compound of formula (IX): (C16) TIFF0007665000000192.tif31170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof Provide; (b) -NH-R 4 to obtain a compound of formula (I), or a solvate thereof, providing an isomer, an enantiomer, a mixture of enantiomers, or an isotopic substitution; and (c) optionally a compound of formula (I) or a solvate, hydrate, or enantiomer thereof; , a mixture of enantiomers, or isotopic substitutions, into a salt of said compound. , the preparation process. (Aspect 35) Compounds of formula (I): (C17) TIFF0007665000000193.tif31170 or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof A process for preparing a recombinant (b) A compound of formula (IX): (C18) TIFF0007665000000194.tif31170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof (In the formula, R 4 is a suitable amino protecting group), 4 By deprotecting the group, a compound of formula (I ) or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof, or providing an isotopic substitute; and (c) optionally a compound of formula (I) or a solvate, hydrate, or enantiomer thereof; , a mixture of enantiomers, or isotopic substitutions, into a salt of said compound. , the preparation process. (Aspect 36) The compound of formula (IX) or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof Compounds or isotopic substitutions, (a) A compound of formula (VIII): (C19) TIFF0007665000000195.tif21170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof with a t-butoxide nucleophile to produce a compound of formula (IX), or a solvate thereof: This includes providing a hydrate, enantiomer, mixture of enantiomers, or isotopic substitution. The process of embodiment 35, wherein the compound is prepared by a process. (Aspect 37) R 4 However, benzyl (Bn), 4-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (PMB) benzyl (DMPM), benzyloxycarbonyl (Cbz), p-methoxybenzyloxy 34-, wherein the aryl group is t-butoxycarbonyl (Moz), or t-butoxycarbonyl (Boc). 36. The process according to any one of claims 36 to 38. (Aspect 38) R 4 is Boc or Cbz. (Aspect 39) The tert-butoxide nucleophile of step (a) is LiO t Bu, NaO t Bu, Ma KO t The process according to any one of embodiments 34 to 38, wherein Bu is (Aspect 40) The compound of formula (VIII), or a solvate, hydrate, enantiomer, or mixture of enantiomers thereof The compound or isotopic substitution is then carried out to obtain compound 14 of the formula: (20) TIFF0007665000000196.tif25170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof by protecting said compound of formula (VIII) or a solvate, hydrate, or enantiomer thereof, Prepared by a process that includes providing a mixture of enantiomers or isotopic substitutions. The process according to any one of aspects 34 to 39, (Aspect 41) The compound according to any one of embodiments 34 to 40, wherein in step (c), the compound is converted to a hydrochloride salt of the compound. 2. The process according to any one of claims 1 to 11. (Aspect 42) Compounds of formula (I-rac): (21) TIFF0007665000000197.tif31170 or a salt, solvate, hydrate, enantiomer, or isotopic derivative thereof There was, (a) A compound of formula (XI): (22) TIFF0007665000000198.tif17170 or a solvate, hydrate, or isotopically substituted derivative thereof (wherein, R 5 -CONH2, -C N, or -CO2R 6 and R 6 is C 1-10 alkyl) in the presence of a base tert-butyl acrylate to produce a compound of formula (XII): (23) TIFF0007665000000199.tif26170 or a solvate, hydrate, or isotopic substitution thereof; (b) a compound of formula (XII) or a solvate, hydrate, or isotopically substituted compound thereof The body is treated with a compound of formula (XIII): (24) TIFF0007665000000200.tif24170 or a solvate, hydrate, or isotopic substitution thereof in the presence of an acid; (c)R 5 is not -CONH2, 5 The group is converted to -CONH2 to give a compound of formula (I or a solvate, hydrate, or isotopic substitution thereof, In the case of the compound of formula (XIII), or a solvate, hydrate, or isotopic equivalent thereof, Optionally protecting and deprotecting said -NH2 group of the derivative in step (c); (d) optionally, a compound of formula (I-rac) or a solvate, hydrate, or the like thereof; or isotopic substitutions are separated under chiral separation conditions to obtain a compound of formula (I): (25) TIFF0007665000000201.tif31170 or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally, a compound of formula (I) or a solvate, hydrate, or equivalent thereof; The preparation process further comprises converting a stereoisomer into a salt of the compound. (Aspect 43) Compounds of formula (I-rac): (26) TIFF0007665000000202.tif31170 or a salt, solvate, hydrate, enantiomer, or isotopic derivative thereof There was, (b) A compound of formula (XII): (27) TIFF0007665000000203.tif25170 or a solvate, hydrate, or isotopically substituted derivative thereof (wherein, R 5 -CONH2, -C N, or -CO2R 6 and R 6 is C 1-10 alkyl) with a compound of formula (XIII) Compounds of: (28) TIFF0007665000000204.tif26170 or a solvate, hydrate, or isotopic substitution thereof in the presence of an acid; (c)R 5 is not -CONH2, 5 The group is converted to -CONH2 to give a compound of formula (I or a solvate, hydrate, or isotopic substitution thereof, In the case of the compound of formula (XIII), or a solvate, hydrate, or isotopic equivalent thereof, Optionally protecting and deprotecting said -NH2 group of the derivative in step (c); (d) optionally, a compound of formula (I-rac) or a solvate, hydrate, or the like thereof; or isotopic substitutions are separated under chiral separation conditions to obtain a compound of formula (I): (C29) TIFF0007665000000205.tif31170 or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally, a compound of formula (I) or a solvate, hydrate, or equivalent thereof; The preparation process further comprises converting a stereoisomer into a salt of the compound. (Aspect 44) The compound of formula (XII) or a solvate, hydrate, or isotopically substituted compound thereof, (a) A compound of formula (XI): (30) TIFF0007665000000206.tif16170 or a solvate, hydrate, or isotopic derivative thereof is reacted with tert-butyl ether in the presence of a base. and contacting the compound of formula (XII) with a dimethyl acrylate to form a compound of formula (XII) or a solvate, hydrate, or the like thereof. or isotopic substitution of the compound according to embodiment 43. process. (Aspect 45) R 5The process of any one of embodiments 42-44, wherein is -CONH2. (Aspect 46) R 5 The process of any one of embodiments 42-44, wherein is -CN. (Aspect 47) R 5 The process of any one of embodiments 42-44, wherein is -CO2Me. (Aspect 48) The step (c) comprises (c1) protecting the -NH group with a protecting group, and (c2) 5 Group -C and (c3) deprotecting the protecting group of the -NH2 group. 48. The process according to embodiment 46 or 47. (Aspect 49) R 5 The process according to embodiment 48, wherein the group is directly converted to -CONH2. (Aspect 50) R 5 The -COOH group is then converted to -CONH2. The process of embodiment 48, (Aspect 51) The protecting group of the -NH2 group in step (c1) is benzyl (Bn), 4-methoxybenzene PMB, 3,4-dimethoxybenzyl (DMPM), benzyloxycarbonyl (Cbz), or p-methoxybenzyloxycarbonyl (Moz). The process described in any one of claims 1 to 50. (Aspect 52) The protecting group of the -NH2 group in step (c1) is benzyl or Cbz. 1. The process described in (Aspect 53) 53. The method according to any one of aspects 48 to 52, wherein the deprotection in step (c3) is carried out under hydrogenation conditions. The process of installation. (Aspect 54) The base in step (a) is triethylamine, diisopropylethylamine, pyridine , 4-dimethylaminopyridine, or 1,8-diazabicyclo[5.4.0]undeca 54. The process of any one of embodiments 42 to 53, wherein the aryl group is 3-7-ene (DBU). (Aspect 55) 55. The process according to embodiment 54, wherein the base in step (a) is DBU. (Aspect 56) 54. The method according to any one of aspects 42 to 53, wherein the base in step (a) is CsCO. process. (Aspect 57) The acid in step (b) is formic acid, acetic acid, trifluoroacetic acid, benzoic acid, citric acid, sulfo sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid sulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid. 57. The process according to any one of claims 42 to 56. (Aspect 58) The acid in step (b) is HCl, citric acid, or p-toluenesulfonic acid. The process described in 57. (Aspect 59) Step (d) is the step of preparing a compound of formula (I-rac) or a solvate, hydrate or isotopically substituted compounds are contacted with a chiral acid to provide a diastereomeric mixture of salts, and separating the diastereomeric mixture of said salts by selective crystallization. 42-58. The process according to any one of claims 42 to 58. (Aspect 60) The chiral acid is tartaric acid, 2,3-dibenzoyltartaric acid, mandelic acid, camphor acid, N-Ac-N-leucine, or N-Ac-L-phenylalanine. 59. The process according to claim 59. (Aspect 61) The selective crystallization is carried out using MeOH, isopropanol, and n-propanol, or 61. The process according to embodiment 59 or 60, wherein the process is carried out in a solvent selected from the group consisting of: (Aspect 62) The compound according to any one of aspects 42 to 61, wherein the compound is converted to a hydrochloride salt of the compound in step (e). 2. The process according to any one of claims 1 to 11. (Aspect 63) Compounds of formula (I-rac): (31) TIFF0007665000000207.tif31170 or a salt, solvate, hydrate, enantiomer, or isotopic derivative thereof There was, (a) Compound 31 of the formula: (C32) TIFF0007665000000208.tif31170 or a solvate, hydrate, or isotopic derivative thereof is reacted with tert-butyl ether in the presence of a base. acrylate to produce a compound of formula 32: (33) TIFF0007665000000209.tif30170 or a solvate, hydrate, or isotopic substitution thereof; (b) Compound 32, or a solvate, hydrate, or isotopically substituted compound thereof, is reacted with NH contacting to form a compound of formula 33: (34) TIFF0007665000000210.tif31170 or a solvate, hydrate, or isotopic substitution thereof; (c) deprotecting the -NHBz group to give a compound of formula (I-rac), or a solvate thereof. providing a compound, hydrate, or isotopically substituted compound; (d) optionally, a compound of formula (I-rac) or a solvate, hydrate, or the like thereof; or isotopic substitutions are separated under chiral separation conditions to obtain a compound of formula (I): (35) TIFF0007665000000211.tif31170 or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally, a compound of formula (I) or a solvate, hydrate, or equivalent thereof; The preparation process further comprises converting a stereoisomer into a salt of the compound. (Aspect 64) The base in step (a) is triethylamine, diisopropylethylamine, pyridine , 4-dimethylaminopyridine, or 1,8-diazabicyclo[5.4.0]undeca 64. The process of embodiment 63, wherein the compound is 3-7-ene (DBU). (Aspect 65) 65. The process according to embodiment 64, wherein the base in step (a) is DBU. (Aspect 66) 64. The process of embodiment 63, wherein the base in step (a) is Cs2CO3. (Aspect 67) The NH3 in step (b) is provided in the form of a solution of ammonia in water or MeOH. 67. The process according to any one of embodiments 63 to 66, (Aspect 68) Step (d) is the step of preparing a compound of formula (I-rac) or a solvate, hydrate or isotopically substituted compounds are contacted with a chiral acid to provide a diastereomeric mixture of salts, and separating the diastereomeric mixture of said salts by selective crystallization. 68. The process according to any one of claims 63 to 67. (Aspect 69) The chiral acid is tartaric acid, 2,3-dibenzoyltartaric acid, mandelic acid, camphor acid, N-Ac-N-leucine, or N-Ac-L-phenylalanine. 68. The process according to claim 68. (Aspect 70) The selective crystallization is carried out using MeOH, isopropanol, and n-propanol, or 70. The process according to embodiment 68 or 69, wherein the process is carried out in a solvent selected from the group consisting of: (Aspect 71) The compound according to any one of claims 63 to 70, wherein the compound is converted to a hydrochloride salt of the compound in step (e). 2. The process according to any one of claims 1 to 11. (Aspect 72) Compound of formula (XIV): (36) TIFF0007665000000212.tif30170 or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof conversion (in the formula, R 7 is hydrogen or a suitable hydroxyl protecting group) hand, (a) A compound of formula (XV): (37) TIFF0007665000000213.tif24170 or a compound of formula (XV) having an aldehyde equivalent group and / or a carboxylic acid equivalent group Analogs, or solvates, hydrates, enantiomers, mixtures of enantiomers, or isomers thereof substituent (in the formula, R 8 is hydrogen, alkyl, or aryl) to a compound of formula (I) thing: (38) TIFF0007665000000214.tif31170 or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof to obtain a compound of formula (XIV) or a salt, solvate, hydrate, enantiomeric providing a mixture of isomers, enantiomers, or isotopically substituted isomers; and (b) optionally a compound of formula (XIV) or a salt, solvate, hydrate, enantiomer thereof The isomer, mixture of enantiomers, or isotopically substituted isomers are crystallized from a solvent or mixture of solvents. The preparation process comprising: (Aspect 73) R7

[0082] 73. The process of embodiment 72, wherein is hydrogen. (Aspect 74) R 7 However, allyl, methyl, 2-methoxyethoxymethyl (MEM), methoxymethyl ( MOM), methoxythiomethyl, t-butoxymethyl, tri-isopropylsilyloxy Methyl (TOM), ethyl, 1-ethoxyethyl, isopropyl, t-butyl, benzyl , Trityl (Tr), Dimethoxytrityl (DMT), Monomethoxytrityl (MMT) , p-Methoxybenzyl (PMB), acetyl, chloroacetyl, trichloroacetyl, Trifluoroacetyl, pivaloyl (Piv), benzoyl, p-phenylbenzoyl, Trimethylsilyl (TMS), triisopropylsilyl (TIPS), t-butyldimethyl hydroxypropyl silyl (TBDMS), and tetrahydropyranyl 73. The process according to embodiment 72, wherein the protecting group is a silyl protecting group. (Aspect 75) R 8 The process of any one of embodiments 72-74, wherein is alkyl. (Aspect 76) R 8 is methyl. (Aspect 77) The compound of formula (XV) having an aldehyde equivalent group and / or a carboxyl equivalent group The analogue may be a compound of the formula: (39) TIFF0007665000000215.tif29170, During the ceremony: R a Each instance of is independently hydrogen, alkyl, aryl, acyl, or carbamoyl. can be; X is Cl, Br, OR b , S.R. c , SO3R c , or N.R.a R a and; R b is hydrogen, alkyl, aryl, acyl, or silyl; and R c is hydrogen, alkyl, or aryl. process. (Aspect 78) Step (a) is carried out using hydrochlorides, sulfonates, phosphates, achiral carboxylates, and chiral The method according to any one of the embodiments 72 to 77, which is carried out using a salt of a compound of formula (I) selected from carboxylates. 2. The process according to any one of claims 1 to 11. (Aspect 79) The process according to embodiment 78, wherein step (a) is carried out using the hydrochloride salt of the compound of formula (I). vinegar. (Aspect 80) 80. Any of aspects 72 to 79, wherein step (a) is carried out in the presence of a reducing agent and optionally a base. 3. The process according to claim 1 . (Aspect 81) The reducing agent may be NaBH(OAc)3, NaBH4, NaBH3CN, silane, or is a combination of H2 and a transition metal catalyst. (Aspect 82) 82. The process of embodiment 81, wherein the reducing reagent is NaBH(OAc). (Aspect 83) The base is iPr2NEt, Et3N, n-Bu3N, DBU, or tetramethyl 83. The process according to any one of aspects 80 to 82, wherein the compound is guanidine. (Aspect 84) The process according to embodiment 83, wherein the base is iPr2Net. (Aspect 85) Step (a) is carried out using DMAc, MeOH, EtOH, trifluoroethanol, i-PrO H, 1-propanol, t-butanol, MeCN, DMF, NMP, THF, 2-Me In a solvent selected from THF, DCM, and DCE, or a mixture thereof. 72-84. The process according to any one of claims 72 to 84. (Aspect 86) The process of embodiment 85, wherein step (a) is carried out in a DMAc solvent. (Aspect 87) 87. The method according to any one of aspects 72 to 86, wherein the reaction temperature in step (a) is about 5° C. or less. process. (Aspect 88) The process of embodiment 87, wherein the reaction temperature in step (a) is from about 0 °C to about 5 °C. (Aspect 89) Any of aspects 72 to 88, wherein the crystallization in step (b) is carried out in a mixed solvent of DMAc and water. The process according to any one of claims 1 to 5. (Aspect 90) The crystallization of step (b) is carried out in a mixed solvent of THF and heptane. 2. The process according to any one of claims 1 to 11. (Aspect 91) Compound of formula (XV): (40) TIFF0007665000000216.tif25170 or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic derivative thereof conversion (in the formula, R 7 is hydrogen or a suitable hydroxyl protecting group, and R 8 is hydrogen, alkyl 2. A process for the preparation of a compound of formula (I) comprising the steps of: (a) A compound of formula (XVI): (C41) TIFF0007665000000217.tif25170 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof with a formylation reagent to produce a compound of formula (XV), or a salt, solvate, hydrate thereof. providing an isomer, enantiomer, mixture of enantiomers, or isotopic substitution; and (b) optionally a compound of formula (XV) or a salt, solvate, hydrate, mirror image thereof; The isomer, mixture of enantiomers, or isotopic substitutions are isolated from a solvent or mixture of solvents. The process for preparing said product further comprising crystallizing said product. (Aspect 92) R 7 92. The process of embodiment 91, wherein is hydrogen. (Aspect 93) R 7 However, allyl, methyl, 2-methoxyethoxymethyl (MEM), methoxymethyl ( MOM), methoxythiomethyl, t-butoxymethyl, tri-isopropylsilyloxy Methyl (TOM), ethyl, 1-ethoxyethyl, isopropyl, t-butyl, benzyl , Trityl (Tr), Dimethoxytrityl (DMT), Monomethoxytrityl (MMT) , p-Methoxybenzyl (PMB), acetyl, chloroacetyl, trichloroacetyl, Trifluoroacetyl, pivaloyl (Piv), benzoyl, p-phenylbenzoyl, Trimethylsilyl (TMS), triisopropylsilyl (TIPS), t-butyldimethyl hydroxypropyl silyl (TBDMS), and tetrahydropyranyl 92. The process according to embodiment 91, wherein the protecting group is a silyl protecting group. (Aspect 94) R 8 The process of any one of embodiments 91-93, wherein is alkyl. (Aspect 95) R 8 is methyl. (Aspect 96) The formylation reagent in step (a) is hexamethylenetetramine (HMTA), POC l3 and DMF, oxalyl chloride and DMF, CHCl3 and KOH combination of HCN, HCl, and AlCl3, and combination of CO and HCl. The process according to any one of embodiments 91 to 95, which is a combination. (Aspect 97) The formylating agent in step (a) is hexamethylenetetramine (HMTA). The process described in US Pat. No. 96. (Aspect 98) The crystallization in step (b) is carried out using MeOH, EtOH, iPrOH, n-propanol, t -Butanol, n-butanol, MeCN, DMSO, DMAc, DMF, NMP, TH Any of embodiments 91 to 97, wherein the method is carried out in a solvent selected from F, water, or a mixture thereof. 3. The process according to claim 1. (Aspect 99) 99. The process according to claim 98, wherein the crystallization in step (b) is carried out in a mixed solvent of MeOH and water. Seth. (Aspect 100) The process according to embodiment 98, wherein the crystallization in step (b) is carried out in a mixed solvent of iPrOH and water. Process. (Aspect 101) A solid form comprising compound 7 of the formula: (C42) TIFF0007665000000218.tif30170 The solid form, wherein the solid form is Form A of Compound 7. (Aspect 102) It has an XRPD pattern with peaks at approximately 9.0, 10.7, and 23.7 degrees 2θ. 102. The solid form of embodiment 101, (Aspect 103) The XRPD pattern shows peaks at approximately 13.0, 17.1, and 18.7 degrees 2θ. The solid form according to embodiment 102, further comprising: (Aspect 104) A solid form comprising racemic compound 7 of the formula: (C43) TIFF0007665000000219.tif31170 The solid form, wherein the solid form is Form A of racemic compound 7. (Aspect 105) It has an XRPD pattern with peaks at approximately 8.5, 14.9, and 20.8 degrees 2θ. 105. The solid form of embodiment 104, (Aspect 106) The XRPD pattern shows peaks at approximately 10.1, 20.0, and 23.1 degrees 2θ. The solid form of embodiment 105, further comprising: (Aspect 107) A solid form comprising compound 8 of the formula: (C44) TIFF0007665000000220.tif32170 The solid form, wherein the solid form is Form A of Compound 8. (Aspect 108) It has an XRPD pattern with peaks at approximately 6.0, 18.1, and 19.4 degrees 2θ. 108. The solid form of embodiment 107, (Aspect 109) The XRPD pattern shows peaks at approximately 11.3, 13.9, and 16.6 degrees 2θ. The solid form of embodiment 108, further comprising: (Aspect 110) A solid form comprising racemic compound 8 of the formula: (C45) TIFF0007665000000221.tif32170 The solid form, wherein the solid form is Form A of racemic compound 8. (Aspect 111) having an XRPD pattern with peaks at approximately 6.4, 8.6, and 16.7 degrees 2θ 111. The solid form of embodiment 110, (Aspect 112) The XRPD pattern shows peaks at approximately 10.5, 17.1, and 20.5 degrees 2θ. The solid form of embodiment 111, further comprising: (Aspect 113) A solid form comprising compound 1 of the formula: (C46) TIFF0007665000000222.tif36170 The solid form, wherein the solid form is Form A of Compound 1. (Aspect 114) It has an XRPD pattern with peaks at approximately 4.8, 19.2, and 24.1 degrees 2θ. 114. The solid form of embodiment 113, (Aspect 115) The XRPD pattern further has peaks at approximately 14.4 and 29.0 degrees 2θ. 115. The solid form of embodiment 114, (Aspect 116) A solid form comprising compound 1 of the formula: (C47) TIFF0007665000000223.tif35170 The solid form, wherein the solid form is Form B of Compound 1. (Aspect 117) The XRPD pattern had peaks at approximately 12.1, 18.8, and 19.4 degrees 2θ. 117. The solid form of embodiment 116, comprising: (Aspect 118) The XRPD pattern shows peaks at approximately 19.2, 24.9, and 31.1 degrees 2θ. The solid form of embodiment 117, further comprising: (Aspect 119) A solid form comprising racemic compound 1 of the formula: (C48) TIFF0007665000000224.tif35170 The solid form, wherein the solid form is Form A of racemic compound 1. (Aspect 120) The XRPD pattern had peaks at approximately 18.7, 21.3, and 25.9 degrees 2θ. 120. The solid form of embodiment 119, comprising: (Aspect 121) The XRPD pattern shows peaks at approximately 7.9, 20.2, and 22.7 degrees 2θ. The solid form according to embodiment 120, further comprising: (Aspect 122) A solid form comprising compound 35 of the formula: (C49) TIFF0007665000000225.tif30170 The solid form, wherein the solid form is Form A of Compound 35. (Aspect 123) The XRPD pattern had peaks at approximately 12.0, 15.6, and 24.1 degrees 2θ. 123. The solid form of embodiment 122, comprising: (Aspect 124) The XRPD pattern shows peaks at approximately 9.1, 18.1, and 19.8 degrees 2θ. The solid form of embodiment 123, further comprising: (Aspect 125) A solid form comprising compound 37 of the formula: (50) TIFF0007665000000226.tif32170 The solid form, wherein the solid form is Form 1 of Compound 37. (Aspect 126) It has an XRPD pattern with peaks at approximately 5.4, 16.0, and 18.0 degrees 2θ. 126. The solid form of embodiment 125, (Aspect 127) The XRPD pattern shows peaks at approximately 10.7, 20.1, and 27.0 degrees 2θ. The solid form of embodiment 126, further comprising: (Aspect 128) A solid form comprising racemic compound 37 of the formula: (51) TIFF0007665000000227.tif32170 The solid form, wherein the solid form is Form 1 of racemic compound 37. (Aspect 129) It has an XRPD pattern with peaks at approximately 7.5, 11.4, and 25.9° 2θ. 129. The solid form of embodiment 128, (Aspect 130) The XRPD pattern shows peaks at approximately 16.8, 19.7, and 25.4 degrees 2θ. The solid form of embodiment 129, further comprising: (Aspect 131) 1. A process for the preparation of Ot-Bu-DIC isourea of ​​the following structure: (52) TIFF0007665000000228.tif27170Diisopropylcarbodiimide (DIC) was mixed with t-butanol and Cu(I) salts under oxygen. The process for preparing said compound comprising reacting in the presence of (Aspect 132) The oxygen is increased to about 22% of atmospheric oxygen, about 1% to about 10%, about 2% to about 6%, or is present in an amount of about 4%.

Claims

1. Compounds of formula (I): 【Chemistry 1】 or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic substitution thereof, comprising the steps of: (a) A compound of formula (V): 【Chemistry 2】 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof (wherein R ３ is C １－１０ alkyl) by NH ３ and contacting the compound of formula (VI): 【Chemistry 3】 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic substitution thereof; (b) R ３ is not tert-butyl, ３ converting the group to tert-butyl to provide a compound of formula (I), or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic substitution thereof; and (c) optionally converting said compound of formula (I) or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic substitution thereof into a salt of said compound; The preparation process comprising:

2. Compounds of formula (I): 【Chemistry 4】 or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic substitution thereof, comprising the steps of: (a) A compound of formula (VIII): 【Chemistry 5】 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof (wherein R ４ are allyl, t-butyl, methoxymethyl (MOM), methylthiomethyl (MTM), benzyloxymethyl (BOM), 2,2,2-trichloroethoxymethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, cyanomethyl, pyrrolidinomethyl, methoxy, benzyloxy, methylthio, triphenylmethylthio, t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), 4-methoxyphenyl, 4-(methyoxymethoxy)phenyl, 2-methoxy-1-naphthyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2-acetoxy-4-methoxybenzyl, 2-nitrobenzyl, bis(4-methoxyphenyl), (E)-2-(methoxycarbonyl)vinyl, diethoxymethyl, 1-methoxy-2,2-dimethylpropyl, and 2-(4-methylphenylsulfonyl)ethyl) is contacted with a t-butoxide nucleophile to produce a compound of formula (IX): 【Chemistry 6】 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic substitution thereof; (b) -NH-R ４ deprotecting the group to provide a compound of formula (I), or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic substitution thereof; and (c) optionally converting said compound of formula (I) or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic substitution thereof into a salt of said compound; The preparation process comprising:

3. Compounds of formula (I): 【Chemistry 7】 or a salt, solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic substitution thereof, comprising the steps of: (b) A compound of formula (IX): 【Chemistry 8】 or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopically substituted derivative thereof (wherein R ４ are allyl, t-butyl, methoxymethyl (MOM), methylthiomethyl (MTM), benzyloxymethyl (BOM), 2,2,2-trichloroethoxymethyl, t-butyldimethylsiloxymethyl, pivaloyloxymethyl, cyanomethyl, pyrrolidinomethyl, methoxy, benzyloxy, methylthio, triphenylmethylthio, t-butyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), 4-methoxyphenyl, 4-(methyoxymethoxy)phenyl, 2-methoxy-1-naphthyl, benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2-acetoxy-4-methoxybenzyl, 2-nitrobenzyl, and n is an integer from 1 to 5, and n is an integer from 1 to 5. The -NH-R of -NH-R is a suitable amino protecting group selected from the group consisting of diphenyl, bis(4-methoxyphenyl)methyl (DAM), bis(4-methoxyphenyl)phenylmethyl, bis(4-methylsulfinylphenyl)methyl, triphenylmethyl (Tr), 9-phenylfluorenyl (Pf), bis(trimethylsilyl)methyl, t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl (Ts), butenyl, (E)-2-(methoxycarbonyl)vinyl, diethoxymethyl, 1-methoxy-2,2-dimethylpropyl, and 2-(4-methylphenylsulfonyl)ethyl. ４ deprotecting the group to provide a compound of formula (I), or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic substitution thereof; and (c) optionally converting the compound of formula (I), or a solvate, hydrate, enantiomer, mixture of enantiomers, or isotopic substitution thereof, into a salt of said compound.

4. Compound of formula (I-rac): 【Chemistry 9】 or a salt, solvate, hydrate, enantiomer, or isotopic substitution thereof, comprising the steps of: (a) A compound of formula (XI): 【Chemistry 10】 or a solvate, hydrate, or isotopically substituted derivative thereof (wherein R ５ Ha-CONH ２ , -CN, or -CO ２ R ６ and R ６ is C １－１０ (XII) is contacted with tert-butyl acrylate in the presence of a base to produce a compound of formula (XII): 【Chemistry 11】 or a solvate, hydrate, or isotopic substitution thereof; (b) reacting the compound of formula (XII) or a solvate, hydrate, or isotopic derivative thereof with a compound of formula (XIII): 【Chemistry 12】 or a solvate, hydrate, or isotopic derivative thereof in the presence of an acid; (c) R ５ Ga-CONH ２ Otherwise, the R ５ The group is -CONH ２ to provide a compound of formula (I-rac) or a solvate, hydrate, or isotopic substitution thereof, optionally comprising converting said -NH of said compound of formula (XIII) or a solvate, hydrate, or isotopic substitution thereof into ２ providing said group is protected and deprotected in step (c); (d) optionally separating the compound of formula (I-rac), or a solvate, hydrate, or isotopic substitution thereof, under chiral separation conditions to obtain a compound of formula (I): 【Chemistry 13】 or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally converting the compound of formula (I) or a solvate, hydrate, or isotopic substitution thereof into a salt of said compound; The preparation process comprising:

5. Compound of formula (I-rac): 【Chemistry 14】 or a salt, solvate, hydrate, enantiomer, or isotopic substitution thereof, comprising the steps of: (b) A compound of formula (XII): 【Chemistry 15】 or a solvate, hydrate, or isotopically substituted derivative thereof (wherein R ５ Ha-CONH ２ , -CN, or -CO ２ R ６ and R ６ is C １－１０ alkyl) to a compound of formula (XIII): 【Chemistry 16】 or a solvate, hydrate, or isotopic derivative thereof in the presence of an acid; (c) R ５ Ga-CONH ２ Otherwise, the R ５ The group is -CONH ２ to provide a compound of formula (I-rac) or a solvate, hydrate, or isotopic substitution thereof, optionally comprising converting said -NH of said compound of formula (XIII) or a solvate, hydrate, or isotopic substitution thereof into ２ providing said group is protected and deprotected in step (c); (d) optionally separating the compound of formula (I-rac), or a solvate, hydrate, or isotopic substitution thereof, under chiral separation conditions to obtain a compound of formula (I): 【Chemistry 17】 or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally converting the compound of formula (I) or a solvate, hydrate, or isotopic substitution thereof into a salt of said compound; The preparation process comprising:

6. The compound of formula (XII) or a solvate, hydrate, or isotopically substituted compound thereof, (a) A compound of formula (XI): 【Chemistry 18】 6. The process of claim 5, wherein the compound of formula (XII), or a solvate, hydrate, or isotopic substitution thereof, is prepared by a process comprising contacting the compound of formula (XII), or a solvate, hydrate, or isotopic substitution thereof, with tert-butyl acrylate in the presence of a base to provide the compound of formula (XII), or a solvate, hydrate, or isotopic substitution thereof.

7. R ５ Ga-CONH ２ The process according to any one of claims 4 to 6, wherein

8. R ５ The process of any one of claims 4 to 6, wherein is -CN.

9. R ５ Ga-CO ２ The process according to any one of claims 4 to 6, wherein Me is

10. Step (c) includes (c1) the -NH ２ (c2) protecting the R ５ The group is -CONH ２ and (c3) converting said -NH ２ 10. The process of claim 8 or 9, further comprising deprotecting said protecting group of the group.

11. The R ５ The group is directly -CONH ２ The process of claim 10, wherein

12. The R ５ group to a -COOH group, and then converting the -COOH group to a -CONH ２ The process of claim 10, wherein

13. The -NH ２ 13. The process of any one of claims 10 to 12, wherein the protecting group of a group is benzyl (Bn), 4-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), benzyloxycarbonyl (Cbz), or p-methoxybenzyloxycarbonyl (Moz).

14. The -NH ２ 14. The process of claim 13, wherein the protecting group of the group is benzyl or Cbz.

15. The process according to any one of claims 10 to 14, wherein the deprotection in step (c3) is carried out under hydrogenation conditions.

16. 16. The process of any one of claims 4 to 15, wherein the base in step (a) is triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

17. 17. The process of claim 16, wherein the base in step (a) is DBU.

18. The base in step (a) is Cs ２ CO ３ The process according to any one of claims 4 to 15, wherein

19. 19. The process of any one of claims 4 to 18, wherein the acid in step (b) is formic acid, acetic acid, trifluoroacetic acid, benzoic acid, citric acid, sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid.

20. 20. The process of claim 19, wherein the acid in step (b) is HCl, citric acid, or p-toluenesulfonic acid.

21. 21. The process according to any one of claims 4 to 20, wherein step (d) comprises contacting the compound of formula (I-rac), or a solvate, hydrate, or isotopically substituted thereof, with a chiral acid to provide a diastereomeric mixture of salts, and separating the resulting diastereomeric mixture of salts by selective crystallization.

22. 22. The process of claim 21, wherein the chiral acid is tartaric acid, 2,3-dibenzoyltartaric acid, mandelic acid, camphorsulfonic acid, N-Ac-N-leucine, or N-Ac-L-phenylalanine.

23. 23. The process of claim 21 or 22, wherein the selective crystallization is carried out in a solvent selected from MeOH, isopropanol, and n-propanol, or a mixture thereof.

24. The process according to any one of claims 4 to 23, wherein the compound is converted to a hydrochloride salt of the compound in step (e).

25. Compound of formula (I-rac): 【Chemistry 19】 or a salt, solvate, hydrate, enantiomer, or isotopic substitution thereof, comprising the steps of: (a) Compound 31 of the formula: 【Chemistry 20】 or a solvate, hydrate, or isotopic variant thereof is contacted with tert-butyl acrylate in the presence of a base to give compound 32 of the formula: 【Chemistry 21】 or a solvate, hydrate, or isotopic substitution thereof; (b) Compound 32, or a solvate, hydrate, or isotopically substituted compound thereof, is reacted with NH ３ to produce a compound of formula 33: 【Chemical 22】 or a solvate, hydrate, or isotopic substitution thereof; (c) deprotecting the -NHBz group to provide a compound of formula (I-rac), or a solvate, hydrate, or isotopic substitution thereof; (d) optionally separating the compound of formula (I-rac), or a solvate, hydrate, or isotopic substitution thereof, under chiral separation conditions to obtain a compound of formula (I): 【Chemistry 23】 or a solvate, hydrate, or isotopic substitution thereof; and (e) optionally converting the compound of formula (I) or a solvate, hydrate, or isotopic substitution thereof into a salt of said compound; The preparation process comprising:

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