Method for preparing and purifying GPR119 agonist compounds

Abstract

The present disclosure relates to improved processes for the preparation and purification of compounds of Formula (I) and pharmaceutically acceptable salts thereof, and intermediates thereof.

Description

[0001] This application claims the benefit of Indian Patent Application No. IN 202311054017, filed on August 11, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to improved methods for preparing and purifying GPR119 agonist compounds (e.g., compounds of formula (I) and pharmaceutically acceptable salts thereof) and intermediates thereof. The invention also relates to substantially pure GPR119 agonist compounds, such as substantially pure compounds of formula I or pharmaceutically acceptable salts thereof, and their uses. . Background Technology

[0003] Many medications exist for treating conditions such as diabetes, including GPR119 agonists. GPR119 agonists mediate a unique, nutrient-dependent dual increase in insulin and glucose-dependent insulinotropic peptide (GLP-1) levels. As standalone therapies or in combination with approved DPP-IV inhibitors, they may herald a new paradigm for type 2 diabetes treatment. Activation of GPR119 has been shown to stimulate intracellular cAMP and lead to glucose-dependent GLP-1 and insulin secretion.

[0004] U.S. Patent No. 10,208,030 describes GPR119 agonists, including 2-((S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)ethoxy)-6-(2-fluoro-4-(methanesulfonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole and methods for preparing the same.

[0005] However, improved methods are needed to prepare 2-((S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)ethoxy)-6-(2-fluoro-4-(methylsulfonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole and its pharmaceutically acceptable salts (and intermediates thereof). Summary of the Invention

[0006] In one aspect, the present invention relates to a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof. The method includes: (a) Reacting a compound of formula III-a or a salt thereof with a compound of formula IV-a or a salt thereof to obtain a compound of formula II-a or a salt thereof (e.g., a pharmaceutically acceptable salt thereof). ; Where X is a leaving group and n is 0, 1 or 2; (b) When n is 0 or 1, converting the compound of formula II-a into the compound of formula Ia or a pharmaceutically acceptable salt thereof. ; (c) Separating the desired isomer of the compound of Formula I or a pharmaceutically acceptable salt thereof; and (d) Optionally purify the desired isomer of the compound of formula I or a pharmaceutically acceptable salt thereof. Compounds of formulas II-a and IV-a may be racemic. Compounds of formula Ia may be racemic, for example, when the compound of formula II-a is racemic. In one embodiment, steps (a)-(d) are performed sequentially.

[0007] In another aspect, the present invention relates to a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof. The method includes: (a) Reacting a compound of formula III-1 or a salt thereof with a compound of formula IV or a salt thereof to obtain a compound of formula II or a salt thereof. , Where X is a leaving group; (b) Converting a compound of Formula II or a salt thereof into a compound of Formula I or a pharmaceutically acceptable salt thereof; and (c) Optionally purify the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0008] In one embodiment, the compound of formula III-1 or a salt thereof is prepared by a method comprising the following: (a) Reacting a compound of formula VIII with an acetyl halide to form a compound of formula VII. ; (b) Converting the compound of formula VII into the compound of formula V-1 in the presence of a solvent and a halogenating agent. Where X is a leaving group (e.g., a halogen-containing leaving group, such as Cl, Br and I); (c) Reacting the compound of formula V-1 with a compound of formula VI-1 or a salt thereof to obtain a compound of formula III-1 or a salt thereof. Where X is as defined above; and (d) Optionally, the compound of formula III-1 or its salt is purified using one or more suitable solvents.

[0009] In one embodiment, the acetyl halide is selected from acetyl fluoride, acetyl chloride, acetyl bromide, acetyl iodide, and any combination thereof. In one embodiment, the acetyl halide is acetyl chloride.

[0010] In one embodiment, the halogenating agent is selected from fluorine, chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide, and any combination thereof.

[0011] In one embodiment, the compound of formula IV or a salt thereof is prepared by a method comprising the following: (a) Reacting a compound of formula XI with a reducing agent to obtain a compound of formula X. ; (b) Reacting a compound of formula X with a compound of formula IX-a or a salt thereof in the presence of a solvent, wherein X is a leaving group (e.g., a halogen, such as Cl), to obtain a compound of formula IV. ;as well as (c) Optionally purify the compound of formula IV.

[0012] In one embodiment, the reducing agent is selected from Ni, Ramane Ni, Pd / C, Pd(OH)2, Na metal, Pt, PtO2, and any combination thereof.

[0013] In one embodiment, a method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprises: (a) Reacting the hydrobromide of a compound of formula III with a compound of formula IV or a salt thereof to give a compound of formula II-b or a salt thereof in racemic form. (b) To convert a compound of formula II-b or a salt thereof into a compound of formula Ia in racemic form or a pharmaceutically acceptable salt thereof. ; (c) Separating the desired isomer of the compound of Formula I or a pharmaceutically acceptable salt thereof; and (d) Optionally purify the desired isomer of the compound of formula I or a pharmaceutically acceptable salt thereof. In one embodiment, the compounds of formulas IV-a, II-b, and Ia are in racemic form.

[0014] In one implementation, step (c) includes (i) Adding a chiral acid to a compound of formula Ia or a pharmaceutically acceptable salt thereof in one or more solvents (e.g., wherein the compound of formula Ia or a salt thereof is in racemic form); (ii) Optionally, separate the chiral acid salt of the compound of formula I; (iii) Add alkali; (iv) Separating the desired isomer of the compound of Formula I or a pharmaceutically acceptable salt thereof; and (v) Optionally purify the desired isomer of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0015] In one embodiment, step (c) is carried out by chiral chromatography using a solvent or solvent mixture selected from dichloromethane, methanol, n-hexane, n-heptane, ethanol (EtOH), isopropanol (IPA), tetrahydrofuran (THF), acetonitrile (ACN), ethyl acetate (EtOAc), methyl tert-butyl ether (MTBE), n-butanol, and any combination thereof as the eluent.

[0016] In another aspect, the present invention relates to a method for purifying a compound of formula I or a pharmaceutically acceptable salt thereof. The method includes: (a) Provide a solution, dispersion or slurry of a compound of formula I or a pharmaceutically acceptable salt thereof in one or more solvents; (b) Heating the reactants from step (a); (c) Cool the reactants; (d) Optionally add one or more solvents and / or one or more antisolvents; and (e) Separate the purified compound of formula I or a pharmaceutically acceptable salt thereof.

[0017] In one embodiment, one or more solvents are selected from methanol, ethanol, acetonitrile, dimethyl sulfoxide, cyclohexane, dichloromethane, and any combination thereof.

[0018] In another aspect, the present invention relates to compounds of formula I or pharmaceutically acceptable salts thereof. The compound of formula I or a pharmaceutically acceptable salt thereof has (i) Chemical purity exceeding approximately 99% (ii) More than 99% enantiomer excess, or (iii) At the same time (i) and (ii).

[0019] In another aspect, the present invention relates to compounds of formula I or pharmaceutically acceptable salts thereof. The compound of formula I or its pharmaceutically acceptable salts are substantially free of (e.g., contain less than about 0.2%, 0.1%, 0.05%, 0.02%, or 0.01% w / w) one or more compounds of formulas A, B, C, D, and E (e.g., substantially free of each of formulas A, B, C, D, and E).

[0020] .

[0021] In one embodiment, the compound of formula I or a salt thereof has (i) a di of less than about 60 µm. 90 (ii) d less than about 20µm 50 (iii) d less than about 10 µm 10 , or any combination of (iv), (i), (ii), and (iii).

[0022] In another aspect, the present invention relates to compounds of formula I or pharmaceutically acceptable salts thereof. The compound of formula I or a pharmaceutically acceptable salt thereof is characterized by having the following particle size distribution. (i) d 90 Less than approximately 60 µm (ii) d 50 Less than approximately 20 µm (iii) d 10 Less than approximately 10 µm, or (iv) Any combination of (i), (ii) and (iii). Detailed Implementation

[0023] As used herein, the term "substantially free" means that a compound of formula I having one or more compounds of formulas A, B, C, D, and E is present at less than about 0.3% of the HPLC area percentage, for example less than about 0.2% of the HPLC area percentage, or less than about 0.15%, 0.1%, 0.05%, 0.02%, or 0.01% of the HPLC area percentage. In one embodiment, a compound of formula I is free of one or more compounds of formulas A, B, C, D, and E, i.e., one or more compounds of formulas A, B, C, D, and E are not present in detectable amounts by HPLC area percentage.

[0024] As used herein, the term "basically pure" means that the chemical purity of a compound is at least about 85%, at least about 90%, at least about 95.0%, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.9%, as measured by HPLC.

[0025] Any salt of any compound (e.g., intermediate compound) mentioned herein may be a pharmaceutically acceptable salt.

[0026] Suitable pharmaceutically acceptable salts (or salts) for use in this invention may be, but are not limited to, salts of inorganic acids, such as salts of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; and salts of organic acids, such as succinic acid, formic acid, acetic acid, diphenylacetic acid, triphenylacetic acid, octanoic acid, dichloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, and parachlorogenic acid. Salts of benzoic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-2-naphthoic acid, hydroxy-2-naphthoic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethanesulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, and p-toluenesulfonic acid; salts of pharmaceutically acceptable bases, such as metal salts, including alkali metal or alkaline earth metal salts, such as sodium, potassium, magnesium, calcium, and zinc salts, and ammonium salts; and any combination of the foregoing.

[0027] As used herein, the term “suitable solvent” or “solvent” includes solvents that can be used to prepare compounds of formula I or pharmaceutically acceptable salts (and intermediates thereof), and may be selected from, but is not limited to, C1-C6 alcohols, C1-C8 hydrocarbons, halogenated hydrocarbons, ethers, C3-C8 ketones, esters, nitriles, sulfonamides, acetamides, pyrrolidines, formamides, water, and any mixtures thereof. Examples include, but are not limited to, methanol, ethanol, butanol, tert-butanol, isopropanol, n-propanol, isobutanol, pentanol, glycol, toluene, chlorobenzene, acetonitrile, dimethylacetamide (DMA), dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), hexamethylphosphoramide (HMPA), tetrahydrofuran (THF), methyltetrahydrofuran, dioxane, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl tert-butyl ketone, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, ethyl acetate, propyl acetate, propylene acetate, tert-butyl acetate, hexane, n-heptane, cyclohexane, petroleum ether, water, and any combination thereof.

[0028] As used herein, the term "suitable base" or "base" includes bases that can be used to prepare compounds of Formula I or their pharmaceutically acceptable salts (and intermediates thereof), bases for purification and crystallization, and may be selected from, but not limited to, alkali metal or alkaline earth metal hydrides, hydroxides, bicarbonates, carbonates, and any combination thereof. Examples include, but are not limited to, sodium hydride, sodium hydroxide, sodium bicarbonate, sodium carbonate, lithium hydroxide, potassium hydroxide, potassium bicarbonate, potassium carbonate, cesium hydroxide, cesium carbonate, magnesium carbonate, magnesium hydroxide, ammonia, ammonium hydroxide, alkylamines such as methylamine, ethylamine, dimethylamine, diethylamine, diisopropylamine, triethylamine, trimethylamine; and any combination thereof.

[0029] As used herein, the terms “reaction mixture” or “reactant” include, but are not limited to, clear solutions, partially dissolved solutions, suspensions, slurries, turbid solutions, mixtures, two-phase solutions, or any other phase known in the literature.

[0030] The invention will now be described in more detail. Although the invention is readily adaptable to various modifications and alternatives, specific embodiments thereof are described in detail below. However, it should be understood that the invention is not intended to be limited to the specific forms disclosed; rather, the invention is intended to cover all modifications, equivalents, and alternatives that fall within the scope of the invention.

[0031] The methods and steps provided may offer further details relevant to understanding the implementation of this disclosure, while avoiding obscuring this disclosure with details that are obvious to a person skilled in the art based on the description herein.

[0032] Salts of any intermediate described herein (e.g., compounds of formulas II, II-a, II-b, III, III-a, III-1, IV, IV-a, V-1, VI-1, VII, VIII, IX-a, X, and XI) may be pharmaceutically acceptable salts of that intermediate.

[0033] In a first aspect, the present invention relates to compounds of formula I. Or a pharmaceutically acceptable method using its own salts.

[0034] In the first implementation scheme, the method of the first aspect includes: (a) Reacting a compound of formula III-1 or a salt thereof with a compound of formula IV or a salt thereof to obtain a compound of formula II or a salt thereof. in X is a leaving group, selected from halogens (e.g., fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I)), methanesulfonates (-OMs), p-toluenesulfonates (-OTs), trifluoromethanesulfonates (-OTf), dinitrogen (-N2) + ), dialkyl ethers (-OR2) + ), sulfide (-SR2) + ), amine (-NR3) + ), ammonia (-NH3) + ), nitrate esters (-ONO2), phosphate esters (-OPO(OH)2), carboxylic acid esters (-OCOR), phenolates (-OAr), hydroxides (-OH), alkoxides (-OR), water (-OH2) + ), and alcohols (-OHR) + The leaving group of ), wherein each R group is independently selected from H and C. 1-3 Alkyl groups and Ar are selected from unsubstituted phenyl groups or are selected from one or more halogens, C 1-3 Alkyl groups and any combination thereof, substituted phenyl groups; (b) Converting a compound of formula II or a salt thereof into a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., by oxidizing a compound of formula II using a suitable oxidizing agent such as Oxone); and (c) Optionally purify the compound of formula I or its pharmaceutically acceptable salt (e.g., by using one or more suitable solvents as described herein).

[0035] In the second implementation scheme, the method of the first aspect includes: (a) Reacting a compound of formula III or a salt thereof with a compound of formula IV or a salt thereof to obtain a compound of formula II or a pharmaceutically acceptable salt thereof. ; (b) Converting a compound of formula II or a salt thereof into a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., by oxidizing a compound of formula II using a suitable oxidizing agent such as Oxone); and (c) Optionally purify the compound of formula I or its pharmaceutically acceptable salt (e.g., by using one or more suitable solvents as described herein).

[0036] In the third implementation scheme, the method of the first aspect includes: (a) Reacting the compound of formula VIII with an acetyl halide to obtain the compound of formula VII, ; (b) Converting a compound of formula VII into a compound of formula V-1 or a salt thereof in the presence of a solvent and a halogenating agent. ; (c) Reacting a compound of formula V-1 or a salt thereof with a compound of formula VI-1 or a salt thereof to obtain a compound of formula III-1 or a salt thereof. ; (d) Optionally purify the compound of formula III-1 or its salt (e.g., by using one or more suitable solvents as described herein); and (e) Converting a compound of formula III-1 or a salt thereof into a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., by coupling a compound of formula III-I (e.g., where X is Br) with a compound of formula IV), in Each occurrence of X is independently a leaving group (e.g., selected from halogens (e.g., fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I)), methanesulfonates (-OMs), p-toluenesulfonates (-OTs), trifluoromethanesulfonates (-OTf), dinitrogen (-N2) + ), dialkyl ethers (-OR2) + ), sulfide (-SR2) + ), amine (-NR3) + ), ammonia (-NH3) + ), nitrate esters (-ONO2), phosphate esters (-OPO(OH)2), carboxylic acid esters (-OCOR), phenolates (-OAr), hydroxides (-OH), alkoxides (-OR), water (-OH2) + ) and alcohols (-OHR) + The leaving group of ), wherein each R group is independently selected from H and C. 1-3 Alkyl groups and Ar are selected from unsubstituted phenyl groups or are selected from one or more halogens, C 1-3 Alkyl groups and any combination thereof, substituted phenyl groups.

[0037] In one embodiment, in step (a), the acetyl halide is selected from the group consisting of acetyl fluoride, acetyl chloride, acetyl bromide, acetyl iodide, or any combination thereof. In one embodiment, the acetyl halide is acetyl chloride.

[0038] In one embodiment, step (b) is carried out in the presence of a halogenating agent selected from the group consisting of: fluorine, chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide, and any combination thereof.

[0039] In the fourth implementation scheme, the method of the first aspect includes: (a) Reacting the compound of formula VIII with acetyl chloride to obtain the compound of formula VII, ; (b) Reacting the compound of formula VII with a brominating agent in the presence of a solvent to obtain the compound of formula V. ; (c) Reacting a compound of formula V with a compound of formula VI or a salt thereof to obtain a compound of formula III or a salt thereof. ; (d) Optionally purify the compound of formula III or its salt (e.g., by using one or more suitable solvents described herein); and (e) Converting a compound of formula III or a salt thereof into a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., by coupling a compound of formula III-I (e.g., where X is Br) with a compound of formula IV).

[0040] In the fifth implementation plan, the method of the first aspect includes: (a) Reacting a compound of formula XI or a salt thereof with a reducing agent to obtain a compound of formula X or a salt thereof. ; (b) Reacting a compound of formula X or a salt thereof with a compound of formula IX or a salt thereof in the presence of a solvent to obtain a compound of formula IV or a salt thereof. Formula IX ; (c) Optionally purify the compound of formula IV or its salt (e.g., by using one or more suitable solvents as described herein); and (e) Converting a compound of formula IV or a salt thereof into a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., by coupling a compound of formula III-I (e.g., where X is Br) to a compound of formula IV).

[0041] In one embodiment, in step (a), the reducing agent is a metal reducing agent (e.g., a transition metal catalyst). In one embodiment, the reducing agent is selected from Ni, Raney nickel, Pd / C, Pd(OH)2, metallic Na, Pt, PtO2, and any combination thereof.

[0042] In the sixth implementation plan, the method of the first aspect includes: (a) Reacting a compound of formula III or a salt thereof with a compound of formula IV-a or a salt thereof (e.g., a compound of formula IV-a in its racemic form) to obtain a compound of formula II-b or a salt thereof (e.g., a compound of formula II-b in its racemic form). ; (b) To convert a compound of formula II-b into a compound of formula Ia (e.g., by oxidizing a compound of formula II using a suitable oxidizing agent such as Oxone). ; (c) Desired isomers of compounds of formula I or their pharmaceutically acceptable salts (e.g., using chiral chromatography); and (d) Optionally purify the desired isomer of a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., by using one or more suitable solvents described herein).

[0043] In one embodiment, the compounds of formulas IV-a, II-b, and Ia are in racemic form.

[0044] In the seventh implementation scheme, the method of the first aspect includes: (a) Reacting a salt of a compound of formula III-a with a compound of formula IV-a or a salt thereof (e.g., a compound of formula IV-a or a salt thereof in a racemic form) to obtain a compound of formula II-a or a salt thereof (e.g., a compound of formula II-a or a salt thereof in a racemic form). , in X is a leaving group (e.g., selected from halogens (e.g., fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I)), methanesulfonates (-OMs), p-toluenesulfonates (-OTs), trifluoromethanesulfonates (-OTf), dinitrogen (-N2) + ), dialkyl ethers (-OR2) + ), sulfide (-SR2) + ), amine (-NR3) + ), ammonia (-NH3) + ), nitrate esters (-ONO2), phosphate esters (-OPO(OH)2), carboxylic acid esters (-OCOR), phenolates (-OAr), hydroxides (-OH), alkoxides (-OR), water (-OH2) + ) and alcohols (-OHR) + The leaving groups of ), wherein R, R2, and R3 are each independently selected from H and C. 1-3 Alkyl group, and Ar is selected from unsubstituted phenyl groups or is selected from one or more halogens, C 1-3Alkyl groups and any combination thereof, and substituted phenyl groups; and n is selected from 0 to 2; (b) When n is 0 or 1, convert a compound of formula II-a or a salt thereof into a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., by oxidizing a compound of formula II by using a suitable oxidizing agent such as Oxone); (c) Desired isomers of compounds of formula I or their pharmaceutically acceptable salts (e.g., using chiral chromatography); and (d) Optionally purify the desired isomer of a compound of formula I or a pharmaceutically acceptable salt thereof (e.g., by using one or more suitable solvents described herein).

[0045] In a second aspect, the present invention relates to a method for chiral separation of a compound of formula I or a pharmaceutically acceptable salt thereof, the method comprising: (a) Providing a solution of a racemic compound of formula Ia or a pharmaceutically acceptable salt thereof in one or more solvents; and (b) Using chiral chromatography to separate the desired isomers of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0046] In one embodiment, in step (a), one or more solvents are selected from methanol, ethanol, 1-propanol, 2-propanol, n-butanol, isobutanol, nitromethane, chloroform, acetonitrile, acetone, MIBK, MEK, toluene, heptane, ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, propionitrile, diethyl ether, dimethyl ether, diisopropyl ether, diphenyl ether, MTBE, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, dimethoxyethane, o-xylene, m-xylene, p-xylene, n-pentane, cyclopentane, n-hexane, cyclohexane, benzene, dichloromethane, dichloroethane, carbon tetrachloride, chlorobenzene, dimethylacetamide (DMA), dimethylformamide (DMF), water, or any combination thereof.

[0047] In one embodiment, in step (b), chiral chromatography is performed in a solvent selected from dichloromethane, methanol, n-hexane, n-heptane, EtOH, IPA, THF, ACN, EtOAc, MTBE, n-butanol, or any combination thereof as the eluent.

[0048] In a third aspect, the present invention relates to a method for purifying a compound of formula I or a pharmaceutically acceptable salt thereof.

[0049] In the first implementation scheme, the method of the third aspect includes: (a) Provide a solution, dispersion or slurry of a compound of formula I or a pharmaceutically acceptable salt thereof in one or more solvents; (b) Optionally, the reactants from step (a) are heated to a suitable temperature; (c) Cooling the reactants; and (d) Pure compounds of formula I or pharmaceutically acceptable salts thereof.

[0050] In the second implementation scheme, the method of the third aspect includes: (a) Providing a dispersion or slurry (e.g., by stirring) of a compound of formula I or a pharmaceutically acceptable salt thereof in a solvent; and (b) Isolate and purify the compound of formula I or its pharmaceutically acceptable salt (e.g., by filtration of a dispersion or slurry).

[0051] In the third implementation scheme, the third aspect of the method includes: (a) Provide a solution, dispersion or slurry of a compound of formula I or a pharmaceutically acceptable salt thereof in a solvent; (b) Adding an anti-solvent to the reactants of step (a); and (c) Isolate and purify a compound of formula I or a pharmaceutically acceptable salt thereof.

[0052] In the fourth implementation plan, the method of the third aspect includes: (a) Provide a solution, dispersion or slurry of a compound of formula I or a pharmaceutically acceptable salt thereof in one or more solvents; (b) Optionally heat the reactants from step (a) (e.g., to a suitable temperature); (c) Optionally, the reactants are cooled; (d) Adding one or more solvents to the reactants; and (e) Separate the purified compound of formula I or a pharmaceutically acceptable salt thereof.

[0053] In a fourth aspect, the present invention relates to a method for preparing pharmaceutically acceptable salts of compounds of formula I, said method comprising: (a) Providing a solution, dispersion or slurry of a compound of Formula I in one or more solvents; (b) Add acid to the reactants from step (a); (c) Heat the reactants from step (b) (e.g., to a suitable temperature); (d) Cooling the reactants from step (c); and (e) Pharmaceutically acceptable salts of compounds of formula I.

[0054] In a fifth aspect, the present invention relates to a method for preparing substantially pure compounds of formula I, said method comprising: (a) Providing a solution, dispersion or slurry of a pharmaceutically acceptable salt of compound I in one or more solvents; (b) Add alkali to the reactants from step (a); (c) Heat the reactants from step (b) (e.g., to a suitable temperature); (d) Cooling the reactants; and (e) Isolate compounds of formula I that are essentially pure.

[0055] In a sixth aspect, the present invention relates to a method for preparing substantially pure compounds of formula III or salts thereof, said method comprising: (a) Provide a solution, dispersion or slurry of a compound of formula III or a pharmaceutically acceptable salt thereof in one or more solvents; (b) Optionally heat the reactants from step (a) (e.g., to a suitable temperature, such as using hot ethanol); (c) Cooling the reactants; and (d) A basic pure compound of the isolated form III or a pharmaceutically acceptable salt thereof.

[0056] In a sixth aspect, the present invention relates to a method for purifying compounds of formula III or salts thereof.

[0057] In the first implementation scheme, the method of the sixth aspect includes: (a) Providing a dispersion or slurry of a compound of formula III or a salt thereof in one or more solvents (e.g., by stirring); and (b) Separation and purification of compounds of formula III or their salts (e.g., by filtration of dispersions or slurries).

[0058] In the second implementation scheme, the sixth aspect of the method includes: (a) Providing a solution, dispersion, or slurry of a compound of formula III or a salt thereof in one or more solvents; and (b) Adding an anti-solvent to the reactants of step (a); and (c) Isolate and purify the compound of formula III or its salt.

[0059] In a seventh aspect, the present invention relates to a method for preparing substantially pure compounds of formula IV or salts thereof, said method comprising: (a) Providing a solution, dispersion or slurry of a compound of formula IV in one or more solvents; (b) Optionally, the reactants from step (a) are heated (e.g., to a suitable temperature); (c) Cooling the reactants; and (d) Separate essentially pure compounds of formula IV or their salts.

[0060] In an eighth aspect, the present invention relates to a method for purifying compounds of formula IV or salts thereof.

[0061] In the first implementation scheme, the eighth aspect includes: (a) Providing a solution, dispersion, or slurry of a compound of formula IV or a salt thereof in a solvent; and (b) Separate and purify compounds of formula IV or their salts (e.g., by filtration).

[0062] In one embodiment, the compound of formula IV is dissolved in solution while impurities remain undissolved and are removed by filtration. In another embodiment, the compound of formula IV remains undissolved in solution while impurities dissolve, and the compound of formula IV is separated by filtration.

[0063] In one embodiment of any of the methods described herein (such as the methods of the third, fourth, fifth, sixth, seventh, or eighth aspects described herein), the solvent (or one or more solvents) is selected from methanol, ethanol, acetonitrile, dimethyl sulfoxide, cyclohexane, dichloromethane, and any combination thereof.

[0064] In one embodiment of any of the methods described herein (such as the methods of the third, fourth, fifth, sixth, seventh, or eighth aspects described herein), the solvent (or one or more solvents) is selected from methanol, acetonitrile, dichloromethane, cyclohexane, and any combination thereof.

[0065] In the second implementation scheme, the method of the eighth aspect includes: (a) Provide a solution or dispersion of compound IV or a salt thereof in a solvent; and (b) Adding an anti-solvent to the reactants of step (a); and (c) Isolate and purify compounds of formula IV or their salts.

[0066] In any further embodiments of any of the methods described herein, the compound of Formula III or a salt thereof has a chemical purity of at least about 90% (e.g., at least about 95%, at least about 98%, or at least about 99%), as measured by HPLC.

[0067] In further embodiments of any of the methods described herein, the compound of formula IV or a salt thereof has a chemical purity of at least about 90% (e.g., at least about 95%, at least about 98%, or at least about 99%), as measured by HPLC.

[0068] In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof prepared by any of the methods described herein is substantially pure (i.e. substantially free of one or more compounds of formulas A, B, C, D and E).

[0069] In another embodiment, the compound of formula I or its pharmaceutically acceptable salt prepared by any of the methods described herein is substantially free of one or more compounds of formulas A, B, C, D and E, wherein each compound of formula A, B, C, D and / or E is present in an amount of less than about 0.2% w / w.

[0070] In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof prepared by any of the methods described herein is substantially free of one or more compounds of formulas A, B, C, D and E.

[0071] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof (or any intermediate thereof) prepared by any of the methods described herein is separated from the reaction mixture using techniques such as, but not limited to, extraction, evaporation, distillation, centrifugation, filtration or scraping, or by shaking the container, removing the solvent (including using a rotary distillation apparatus such as a Buchi rotary evaporator), spray drying, stirred film drying, freeze drying (lyophilization), or any other technique applicable to the equipment used.

[0072] In one embodiment of any of the methods described herein, the cooling step involves cooling from any higher temperature to approximately 0°C, depending on the requirements of the reaction steps.

[0073] In one embodiment of any of the methods described herein, the cooling step involves cooling from room temperature to approximately 0°C, depending on the requirements of the reaction steps.

[0074] In one embodiment of any of the methods described herein, the cooling step involves cooling from room temperature to approximately 10°C.

[0075] In certain embodiments of any of the methods described herein, a pharmaceutically acceptable salt of a compound of Formula I (or any intermediate thereof) is selected from hydrochloride, hydrobromide, sulfate, phosphate, acetate, succinate, tartrate, fumarate, formate, oxalate, (S)-(+)-2-methoxy-2-(1-naphthyl)propionate, chiral phthalate, chiral dichlorophthalate, (-)-malate, (-)-mandelate, and (+)-camphor-10-sulfonate.

[0076] In further embodiments of any of the methods described herein, a pharmaceutically acceptable salt of the compound of Formula I (or any intermediate thereof) is selected from hydrochloride, hydrobromide, tartrate, fumarate, formate, oxalate, (S)-(+)-2-methoxy-2-(1-naphthyl)propionate, chiral phthalate, chiral dichlorophthalate, (-)-malate, (-)-mandelate, and (+)-camphor-10-sulfonate.

[0077] In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof prepared by any method described herein is in an amorphous form or any crystalline form or any weight percentage of any of the foregoing forms. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof prepared by any method described herein is amorphous. In one embodiment, the compound of Formula I or a pharmaceutically acceptable salt thereof prepared by any method described herein is crystalline.

[0078] In one embodiment of any of the methods described herein, the preparation of a compound of Formula I or a pharmaceutically acceptable salt thereof is carried out in situ without the need to isolate intermediates.

[0079] In any further embodiments of any of the methods described herein, the compound of Formula I or a pharmaceutically acceptable salt thereof has a chemical purity of at least about 90% (e.g., at least about 95%, at least about 98%, at least about 99%, or at least about 99.9%), as measured by HPLC.

[0080] In any further embodiments of any of the methods described herein, the compound of Formula I or a pharmaceutically acceptable salt thereof has an enantiomer purity of at least about 90% (e.g., at least about 95%, at least about 98%, at least about 99%, or at least about 99.9%), as measured by HPLC.

[0081] In any further embodiments of any of the methods described herein, the compound of Formula I or a pharmaceutically acceptable salt thereof has an enantiomeric excess of at least about 90% (e.g., at least about 95%, at least about 98%, at least about 99%, or at least about 99.9%), as measured by HPLC.

[0082] In any further embodiments of the methods described herein, the compound of Formula I or a pharmaceutically acceptable salt thereof has an isomer purity of at least about 97% (e.g., at least about 99%, at least about 99.5%, or at least about 99.9%).

[0083] In further embodiments of any of the methods described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is characterized by a particle size distribution, wherein d 90 It ranges from approximately 0.1 µm to approximately 200 µm.

[0084] In further embodiments of any of the methods described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is characterized by a particle size distribution, wherein d 90 It ranges from approximately 2 µm to approximately 150 µm.

[0085] In further embodiments of any of the methods described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is characterized by a particle size distribution, wherein d 90 Less than approximately 100 µm.

[0086] In further embodiments of any of the methods described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is characterized by a particle size distribution, wherein d 90 Less than approximately 60 µm, d 50 Less than approximately 20 µm and d 10 Less than approximately 10 µm.

[0087] Scheme 1 illustrates an exemplary method for preparing compounds of formula I or pharmaceutically acceptable salts thereof.

[0088] Option 1 Scheme 2 illustrates an exemplary method for preparing compounds of formula III or pharmaceutically acceptable salts thereof.

[0089] Option 2 Scheme 3 illustrates an exemplary method for preparing compounds of formula IV or pharmaceutically acceptable salts thereof.

[0090] Option 3 Scheme 4 demonstrates another exemplary method for preparing compounds of formula I or pharmaceutically acceptable salts thereof.

[0091] Option 4 Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following embodiments, which are provided for illustrative purposes only and should not be construed as limiting the scope of this application in any way. As will be apparent to those skilled in the art, variations of the procedures are intended to be within the scope of this application.

[0092] Example Particle size analysis was performed using a Malvern Mastersizer 3000 particle size analyzer (Malvern Instrument Ltd).

[0093] Sample preparation Accurately weigh 100 mg of sample into a 100 mL beaker. Add 3 drops of Tween-80 and 1 mL of water, and use a glass rod to help form a paste. Then add 10 mL of water and sonicate externally for 10 seconds with continuous shaking.

[0094] Instrument parameters

[0095] program After cleaning, initialize the system and measure the background value. Add sample to bring the turbidity to between 10% and 20%, and wait for the turbidity to stabilize. Begin analysis according to the given instrument parameters or run the standard operating procedure. Analyze the sample in duplicate and report the results for both preparations at D... 10 D 50 and D 90 The average result at the location (instrument average).

[0096] Example 1: Preparation of compounds of formula X A solution of (1S)-1-(4-pyridinyl)ethanol (200 g, 1.626 mol, 99% ee) in methanol (3 L) was loaded with Pd / C (40 g) under a nitrogen atmosphere. The mixture was evacuated and purged several times with hydrogen, then stirred at 60 °C for 24 h under a hydrogen atmosphere. After completion, the reaction mixture was filtered through a diatomaceous earth bed and washed with methanol (3.0 L). All organic solvents were evaporated under reduced pressure to give (1R)-1-(4-piperidinyl)ethanol (200.0 g, 95.0%) as a grayish-white solid.

[0097] Chemical purity: 95% as determined by titration. Titration procedure: Accurately weigh approximately 200 mg of the test sample and transfer it to a clean, dry 100.0 mL titration container. Add 50.0 mL of glacial acetic acid.

[0098] Titrate with 0.1 M perchloric acid using potentiometric titration and record the reading (V).

[0099] Similarly, a blank titration was performed by omitting the test sample, and the reading was recorded (B).

[0100] Instrument parameters

[0101] Specific rotation (1% dichloromethane solution): -16.835 o Example 2: Preparation of compounds of formula VII Dichloromethane (100 mL) was added to a round-bottom flask. AlCl3 (11.26 g, 84.50 mmol) was added in one addition at 0 °C, and the resulting solution was stirred for 45 min. Acetyl chloride (5.77 mL, 80.98 mmol) was added dropwise, and the mixture was stirred for 1 h at the same temperature. A solution of formula VIII (10.0 g, 70.42 mmol) in dichloromethane (10 mL) was then slowly added at 0 °C. The mixture was then stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the reactants were poured into ice water (200 mL) and then extracted with dichloromethane (200 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was washed with cyclohexane (20 mL) to give the title compound (10.0 g, 77%) as a light brown solid with a melting point of 61 °C–62 °C.

[0102] Chemical purity: 99.86% as determined by HPLC. Chromatographic conditions

[0103] Example 3: Preparation of compounds of formula V A solution of bromine (5.61 mL, 108.6 mmol) in dioxane (200 mL) was slowly added to a stirred solution of formula VII (20.0 g, 108.6 mmol) in dioxane (200 mL) at room temperature (RT). The mixture was then stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was complete, the reactants were poured into ice water (200 mL). The precipitated solid was filtered and dried under vacuum to give the title compound (13.3 g, 78%) as a brown solid (melting point 55-59 °C).

[0104] Chemical purity: 93.56% (based on HPLC) Chromatographic conditions

[0105] Example 4: Preparation of Compound VI Bromine (23.70 g, 148.32 mmol) was added dropwise to a stirred solution of 1,3,4-thiadiazole-2-amine (5 g, 49.44 mmol) in methanol (250 mL) at room temperature, and the resulting mixture was stirred for 3 h. The reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure. After adding water to the reactants, a solid precipitated, which was separated by filtration. The solid was washed with water and dried under vacuum to give the title compound of formula VI (6.5 g, 72.95%) as a yellow solid.

[0106] Example 5: Preparation of Compound IV At room temperature, compound IX (shown below) (210.0 g, 1.472 mol) was added to a solution of compound X (200.0 g, 1.550 mol) in 1,4-dioxane (1.0 L) and water (1.0 L). NaHCO3 (390.6 g, 4.651 mol) was then added to the reaction mixture and refluxed at 100 °C for 16 h. After the reaction was complete, the reactants were cooled to 20 °C, water (2.0 L) was added, and the product was extracted with EtOAc (2.0 L × 3). The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure to give compound IV (500.0 g, crude) as a pale yellow viscous solid.

[0107] Formula IX Example 6: Purification of compounds of formula IV The pale yellow viscous solid (500 g) obtained in Example 5 was purified by stirring with cyclohexane (1.0 L) at 10 °C. The solid was filtered and dried to give a compound of formula IV (320.0 g, 88.0%) as a grayish-white solid.

[0108] Chemical purity: 99.6% (based on HPLC) Chromatographic conditions Use a 50 x 4.6 mm Ghost Buster column (e.g., a Welch Materials, Inc. product) and a 6.5 cm long HPLC tubing. Install the Ghost Buster after the in-line filter and before the injector in the aqueous HPLC system.

[0109] Isomer purity (enantiomer excess): 99.32% (ee 98.64%) Specific rotation (1% dichloromethane solution): +5.9 o Example 7: Preparation of Compound III Compound VI (13.66 g, 76.33 mmol) was added to a stirred solution of compound V (20.0 g, 76.33 mmol) in ethanol (200 mL), and the resulting reaction mixture was refluxed at 90 °C for 24 h. After the reaction was complete, the reaction mixture was cooled to 50 °C, filtered, and dried to obtain the crude compound of formula III.

[0110] Example 8: Purification of compounds of formula III The crude compound of formula III obtained in Example 7 was washed with hot ethanol and then dried under vacuum to give a brown solid of formula III (20.0 g, 77%).

[0111] Chemical purity: 98.69% (based on HPLC) Chromatographic conditions Use a 50 x 4.6 mm Ghost Buster column (e.g., a Welch Materials, Inc. product) and a 6.5 cm long HPLC tubing. Install the Ghost Buster after the in-line filter and before the injector in the aqueous HPLC system.

[0112] Example 9: Preparation of compounds of formula II Compound III (1.75 kg, 4.116 mol) was added to a stirred solution of compound IV (1 kg, 4.249 mol) in dimethylformamide at 25–30 °C, and the reactants were then cooled to 10 °C. Sodium hydride (0.43 kg, 10.75 mol) was then added in portions over 45 minutes while maintaining the internal temperature below 35 °C. The reactants were stirred at 35–40 °C for 3 hours. After the reaction was complete, the reactants were poured into ice water (15 L). The resulting solid precipitate was separated by filtration, washed with water (10 L), and dried under vacuum overnight. The obtained solid material was stirred with MeOH (7.5 L) for 1 h and filtered. This process was repeated (2 x 5 L MeOH) to give compound II (1.3 kg, 70%) as a grayish-white solid.

[0113] Chemical purity: 99.6% (based on HPLC)

[0114] Isomer purity (enantiomer excess): 99.82% (ee 99.64%) Specific rotation (1% dichloromethane solution): -26.2 o Example 10: Preparation of compounds of formula I A solution of Oxone (potassium persulfate complex salt) (1.25 kg, 4.090 mol) in water (7.5 L) was slowly added to a stirred solution of compound II (0.75 kg, 1.5151 mol) in acetone (7.5 L) at 0 °C, maintaining the temperature below 25 °C. The resulting mixture was stirred at 25 °C for 3 h. After the reaction was complete, cold water (15 L) was added to the reactants, followed by ethyl acetate (7.5 L), and the mixture was stirred for 30 min. The organic layer was separated, and the aqueous layer was extracted again with ethyl acetate (2 x 7.5 L) and separated. The combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure to give compound I (1.0 kg, crude product) as a pale yellow solid.

[0115] Example 11: Purification of compounds of formula I Methanol (5.25 L) was added to the crude product of Formula I (1.0 Kg) obtained in Example 10, and the resulting reaction mixture was stirred for 1 h. The solid precipitate was filtered and washed with methanol (0.6 L). The resulting wet cake was stirred again with methanol (2.25 L), then filtered and dried to give a grayish-white solid of Formula I (0.7 Kg). The dried solid was then placed in acetonitrile (4.2 L). The resulting slurry was stirred at 27°C–33°C for 3 h, then filtered and washed with acetonitrile (1 L). The resulting solid material was dried and stirred again with methanol (3.5 L) at 25°C–30°C for 1 h. The formed solid was filtered, washed with methanol (0.56 L, 0.8 V), and dried in a vacuum tray dryer (VTD) at 55°C–60°C to give a grayish-white solid of Formula I (0.52 Kg, 67%).

[0116] Chemical purity: 99.86% (HPLC) Chromatographic conditions Use a 50 x 4.6 mm Ghost Buster column (e.g., a Welch Materials, Inc. product) and a 6.5 cm long HPLC tubing. Install the Ghost Buster after the in-line filter and before the injector in the aqueous HPLC system.

[0117] Isomer purity (enantiomer excess): 99.98% (ee 99.96%) Specific rotation (1% dichloromethane solution): -25.8 o Example 12: Preparation of racemic II-b compounds Compound III (0.875 kg, 2.0575 mol) was added to a solution of racemic compound IV (0.500 kg, 2.124 mol) in dimethylformamide while maintaining the temperature at 25°C–30°C. The mixture was then cooled to 10°C. Sodium hydride (0.215 kg, 5.375 mol) was then added in portions over 45 minutes while keeping the internal temperature below 35°C. The reaction mixture was stirred at 35°C–40°C for 3 hours. After the reaction was complete, the reaction mixture was poured into ice water (7.5 L), and the resulting solid precipitate was filtered, washed with water (5 L), and dried under vacuum overnight. The resulting solid material was stirred with methanol (3.75 L) for 1 hour and filtered. This process was repeated (2 x 5 L MeOH) to give a racemic compound II-b (0.65 kg, 70%) as a grayish-white solid.

[0118] Chemical purity: 99.37% (based on HPLC)

[0119] Example 13: Preparation of racemic I compounds At 0 °C, a solution of Oxone (0.625 kg, 2.045 mol) in water (3.75 L) was slowly added to a stirred solution of racemic II-b (0.375 kg, 0.7575 mol) in acetone (3.75 L) while maintaining the temperature below 25 °C. The resulting mixture was stirred at 25 °C for 3 h. After the reaction was complete, cold water (7.5 L) was added to the reactants, followed by ethyl acetate (3.75 L). The resulting mixture was stirred for 30 min. The organic layer was separated, and the aqueous layer was extracted again with ethyl acetate (2 × 3.75 L) and separated. The combined organic layers were dried over Na₂SO₄ and then concentrated under reduced pressure to give racemic Ia (0.5 kg, crude product) as a pale yellow solid. Methanol (2.5 L) was added to the crude product of racemic Ia (0.5 kg) and stirred for 1 h. The resulting solid precipitate was filtered and washed with methanol (0.3 L). The obtained wet cake was stirred again with methanol (1.1 L), filtered and dried to obtain a racemic compound of formula Ia as a grayish-white solid (0.35 kg).

[0120] Chemical purity: 98.5% (based on HPLC) Chromatographic conditions Use a 50 x 4.6 mm Ghost Buster column (e.g., a Welch Materials, Inc. product) and a 6.5 cm long HPLC tubing. Install the Ghost Buster after the in-line filter and before the injector in the aqueous HPLC system.

[0121] Example 14: Chiral purification of racemic I compounds The enantiomers of racemic compound Ia (0.35 kg) were separated by chiral preparative HPLC. For this separation, an ID-CHIRALPAK IG column (250 mm × 4.6, 5 µm) was used for better peak shape and separation performance. The mobile phase was a 50:50 mixture of methanol and dichloromethane, and the wavelength was 305 nm. The flow rate was 1.5 mL / min, and the column temperature was maintained at 25 °C. The eluent was concentrated under reduced pressure to give compound I (0.15 kg, 43%).

[0122] Chemical purity: 99.9% (based on HPLC) Isomer purity (enantiomer excess): 99.96% (ee 99.92%) Specific rotation (1% dichloromethane solution): -25.8 o All references and patent publications cited in this article are hereby incorporated by way of citation.

Claims

1. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof. The method includes: (a) Reacting a compound of formula III-a or a salt thereof with a compound of formula IV-a or a salt thereof to obtain a compound of formula II-a or a salt thereof. ； Where X is a leaving group and n is 0, 1 or 2; (b) When n is 0 or 1, converting the compound of formula II-a into the compound of formula Ia or a pharmaceutically acceptable salt thereof. ； (c) Separating the desired isomer of the compound of Formula I or a pharmaceutically acceptable salt thereof; and (d) Optionally purify the desired isomer of the compound of Formula I or a pharmaceutically acceptable salt thereof.

2. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof. The method includes: (a) Reacting a compound of formula III-1 or a salt thereof with a compound of formula IV or a salt thereof to obtain a compound of formula II or a salt thereof. ， ， Where X is a leaving group; (b) Converting a compound of Formula II or a salt thereof into a compound of Formula I or a pharmaceutically acceptable salt thereof; as well as (c) Optionally purify the compound of Formula I or a pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein the compound of formula III-1 or a salt thereof is prepared by a method comprising: (a) Reacting a compound of formula VIII with an acetyl halide to form a compound of formula VII. ； (b) Converting the compound of formula VII into the compound of formula V-1 in the presence of a solvent and a halogenating agent. Where X is a leaving group; (c) Reacting the compound of formula V-1 with a compound of formula VI-1 or a salt thereof to obtain a compound of formula III-1 or a salt thereof. Where X is as defined above; and (d) Optionally, the compound of Formula III-1 or its pharmaceutically acceptable salt may be purified using one or more suitable solvents.

4. The method of claim 3, wherein the acetyl halide is selected from acetyl fluoride, acetyl chloride, acetyl bromide, acetyl iodine, and any combination thereof, preferably acetyl chloride.

5. The method of claim 3, wherein the halogenating agent is selected from fluorine, chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide, and any combination thereof.

6. The method of claim 2, wherein the compound of formula IV or a salt thereof is prepared by a method comprising: (a) Reacting a compound of formula XI with a reducing agent to obtain a compound of formula X. ； (b) Reacting the compound of formula X with the compound of formula IX-a in the presence of a solvent to obtain the compound of formula IV. ;as well as (c) Optionally purify the compound of formula IV.

7. The method of claim 6, wherein the reducing agent is selected from Ni, Raney nickel, Pd / C, Pd(OH)2, Na metal, Pt, PtO2 and any combination thereof.

8. The method of claim 1, wherein the method comprises: (a) Reacting the hydrobromide of a compound of formula III with a compound of formula IV-a or a salt thereof to give a compound of formula II-b or a salt thereof. 、 ； (b) To convert a compound of formula II-b or a salt thereof into a racemic compound of formula Ia or a pharmaceutically acceptable salt thereof. ； (c) Separating the desired isomer of the compound of Formula I or a pharmaceutically acceptable salt thereof; and (d) Optionally purify the desired isomer of the compound of Formula I or a pharmaceutically acceptable salt thereof.

9. The method of claim 1, wherein step (c) comprises (a) Adding a chiral acid to a compound of formula Ia or a pharmaceutically acceptable salt thereof in one or more solvents; (b) Optionally, separate the chiral acid salts of the compounds of Formula I; (c) Add alkali; (c) Separating the desired isomer of the compound of Formula I or a pharmaceutically acceptable salt thereof; and (e) Optionally purify the desired isomer of the compound of Formula I or a pharmaceutically acceptable salt thereof.

10. The method of claim 8, wherein step (c) is carried out by chiral chromatography using a solvent or solvent mixture selected from dichloromethane, methanol, n-hexane, n-heptane, EtOH, IPA, THF, ACN, EtOAc, MTBE, n-butanol, and any combination thereof as the eluent.

11. A method for purifying a compound of formula I or a pharmaceutically acceptable salt thereof. The method includes: (a) Provide a solution, dispersion or slurry of a compound of formula I or a pharmaceutically acceptable salt thereof in one or more solvents; (b) Heating the reactants from step (a); (c) Cool the reactants; (d) Optionally add one or more solvents; and (e) Separate the purified compound of formula I or a pharmaceutically acceptable salt thereof.

12. The method of claim 13, wherein the one or more solvents are selected from methanol, ethanol, acetonitrile, dimethyl sulfoxide, cyclohexane, dichloromethane, and any combination thereof.

13. A compound of formula I or a pharmaceutically acceptable salt thereof. The compound of Formula I or a pharmaceutically acceptable salt thereof has (i) Chemical purity exceeding approximately 99% (ii) More than 99% enantiomer excess, or (iii) At the same time (i) and (ii).

14. A compound of formula I or a pharmaceutically acceptable salt thereof. The compounds of formula I or their pharmaceutically acceptable salts thereof are substantially free of one or more compounds of formulas A, B, C, D and E. 。 15. A compound of formula I or a pharmaceutically acceptable salt thereof. The compound of Formula I or a pharmaceutically acceptable salt thereof is characterized by the following particle size distribution, wherein (i) d 90 Less than approximately 60 µm (ii) d 50 Less than approximately 20 µm (iii) d 10 Less than approximately 10 µm, or (iv) Any combination of any of (i), (ii) and (iii).

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