Process for preparation and purification of GPR119 agonist compounds

Abstract

This disclosure relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, as well as improved processes for the preparation and purification of intermediates thereof. JPEG2026528935000077.jpg25170

Description

[Technical Field]

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

[0002] The present invention relates to improved processes for the preparation and purification of GPR119 agonist compounds, such as the compound of formula (I) and its pharmaceutically acceptable salts, as well as intermediates thereof. The present invention also relates to substantially pure GPR119 agonist compounds, such as substantially pure compounds of formula I or its pharmaceutically acceptable salts, and their uses. [ka] [Background technology]

[0003] Many drugs are useful in treating conditions such as diabetes, and GPR119 agonists are among them. GPR119 agonists mediate a unique nutrient-dependent dual elevation of both insulin and glucagon-like peptide (glucose-dependent insulinotropic peptide) levels in vivo. Used as monotherapy or in combination with approved DPP-IV inhibitors, GPR119 agonists may herald a new treatment paradigm for type 2 diabetes. Activation of GPR119 has been shown to stimulate intracellular cAMP, leading to glucose-dependent GLP-1 and insulin secretion.

[0004] U.S. Patent No. 10,208,030 describes a GPR119 agonist comprising 2-((S)-1-(1-(5-ethylpyrimidine-2-yl)piperidine-4-yl)ethoxy)-6-(2-fluoro-4-(methylsulfonyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole, and a process for the preparation thereof.

[0005] However, there is a need for an improved process for the preparation of 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 their intermediates).

Summary of the Invention

[0006] In one aspect, the present invention is a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof, comprising

Chemical Formula

Chemical Formula

Chemical Formula

[0007] In another aspect, the present invention is a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt thereof, comprising [Chemical formula] The process comprises (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, [Chemical formula] wherein X is a leaving group, and obtaining; (b) converting a compound of formula II or a salt thereof into a compound of formula I or a pharmaceutically acceptable salt thereof; (c) optionally, purifying the compound of formula I or a pharmaceutically acceptable salt thereof. The process is related to this.

[0008] (a) reacting a compound of formula VIII with haloacetyl to form a compound of formula VII; [Chemical formula] (b) converting the compound of formula VII into a compound of formula V-1 in the presence of a solvent and a halogenating agent, [Chemical formula] wherein X is a leaving group (e.g., a halogen-containing leaving group, such as Cl, Br, and I), and converting; <00​​​​​​​​​​​​​​​In one embodiment, the halogenated acetyl is selected from acetyl fluoride, acetyl chloride, acetyl bromide, acetyl iodide, and any combination thereof, and in one embodiment, the halogenated acetyl 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, a compound of formula IV or a salt thereof is used. (a) Reacting the compound of formula XI with a reducing agent to obtain the compound of formula X, [ka] (b) Reacting a compound of formula X with a compound of formula IX-a or a salt thereof in the presence of a solvent to obtain a compound of formula IV, wherein X is a leaving group (e.g., halogen, e.g., Cl), [ka] (c) Optionally, purify the compound of formula IV, It is prepared by a process that includes [the following].

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

[0013] In one embodiment, a process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof is described as follows: (a) Reacting the hydrobromide salt of the compound of formula III with the compound of formula IV or a salt thereof to obtain a racemic form of the compound of formula II-b or a salt thereof, [ka] (b) Converting a compound of formula II-b or a salt thereof into a racemic form of a compound of formula Ia or a pharmaceutically acceptable salt thereof, [ka] (c) Separating desired isomers of the compound of formula I or its pharmaceutically acceptable salt, (d) Selectively purifying a desired isomer of the compound of formula I or a pharmaceutically acceptable salt thereof, This includes. In one embodiment, the compounds of formulas IV-a, II-b, and Ia are in racemic form.

[0014] In one embodiment, step (c) is (i) Adding a chiral acid to one or more solvents containing a compound of formula Ia or a pharmaceutically acceptable salt thereof (for example, if the compound of formula Ia or a salt thereof is in racemic form), (ii) Optionally, isolate the chiral salt of the compound of formula I, (iii) Adding a base, (iv) Separating desired isomers of the compound of formula I or its pharmaceutically acceptable salt, (v) Optionally, purify a desired isomer of the compound of formula I or a pharmaceutically acceptable salt thereof. Includes.

[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 (RINKAN), MTBE, n-butanol, and any combination thereof as the eluent.

[0016] In another embodiment, the present invention relates to a process for purifying a compound of formula I or a pharmaceutically acceptable salt thereof, [ka] The process is (a) To 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 reaction mass from step (a), (c) Cooling the reaction mass, (d) Optionally, one or more solvents and / or one or more poor solvents may be added. (e) Isolating the purified compound of formula I or a pharmaceutically acceptable salt thereof, This includes processes related to the process.

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

[0018] In another embodiment, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, [ka] A compound of formula I or a pharmaceutically acceptable salt thereof (i) Chemical purity of over 99%, (ii) Enantiomer excess of more than approximately 99%, or (iii) Both (i) and (ii), This relates to compounds or pharmaceutically acceptable salts thereof that possess [a certain characteristic].

[0019] In another embodiment, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, [ka]

[0020] A compound of formula I or a pharmaceutically acceptable salt thereof is substantially free of one or more compounds of formulas A, B, C, D, and E (e.g., containing less than about 0.2%, 0.1%, 0.05%, 0.02%, or 0.01% w / w) (e.g., substantially free of each compound of formulas A, B, C, D, and E). [ka]

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

[0022] In another embodiment, the present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof, [ka] A compound of formula I or a pharmaceutically acceptable salt thereof (i) d less than approximately 60 μm 90 , (ii) d less than approximately 20 μm 50 , (iii) d less than approximately 10 μm 10 , or (iv) Any combination of (i), (ii), and (iii) This relates to a compound or a pharmaceutically acceptable salt thereof characterized by a particle size distribution having [a specific particle size distribution]. [Modes for carrying out the invention]

[0023] As used herein, the term “substantially absent” means that the compound of formula I contains one or more compounds of formulas A, B, C, D, and E present in less than about 0.3% of HPLC area percentage, for example, less than about 0.2% of HPLC area percentage, or less than about 0.15%, 0.1%, 0.05%, 0.02%, or 0.01% of HPLC area percentage. In one embodiment, the compound of formula I does not contain one or more compounds of formulas A, B, C, D, and E; that is, one or more compounds of formulas A, B, C, D, and E are absent in an amount detectable by HPLC area percentage.

[0024] As used herein, the term “substantially pure” means that the chemical purity of a compound, as measured by HPLC, 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%.

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

[0026] Suitable pharmaceutically acceptable salts (or salts) for use in the present invention include salts of inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; and salts of organic acids, e.g., succinic acid, formic acid, acetic acid, diphenylacetic acid, triphenylacetic acid, caprylic 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, p-chlorobenzoic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, and 1-hydroxynaphthalene-2-calcium carbonate. Salts of naphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethanesulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, etc.; salts of pharmaceutically acceptable bases, such as alkali metal salts or alkaline earth metal salts including sodium salts, potassium salts, magnesium salts, calcium salts and zinc salts, ammonium salts, etc.; and any combination of any of the above.

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

[0028] As used herein, the terms “suitable base” or “base” include bases that can be used for the preparation, purification, and crystallization of compounds of formula I or pharmaceutically acceptable salts thereof (and intermediates thereof), and may be selected from, but are 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 (e.g., methylamine, ethylamine, dimethylamine, diethylamine, diisopropylamine, triethylamine, trimethylamine); and any combination of any of the aforementioned.

[0029] As used herein, the terms “reaction mixture” or “reaction mass” 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 present invention will be described in further detail below. While various modifications and alternative forms of the present invention are possible, specific embodiments will be described in detail below. However, it should be understood that the present invention is not intended to be limited to any specific form disclosed, but rather, it encompasses all modifications, equivalents, and alternatives that fall within the scope of the present invention.

[0031] The steps of the method may provide more detailed information that is relevant to understanding embodiments of the present invention and will be readily apparent to those skilled in the art who benefit from the description herein, without obscuring the disclosure.

[0032] Salts of any of the intermediates 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) can be pharmaceutically acceptable salts of the intermediates.

[0033] In a first aspect, the invention relates to a process for the preparation of a compound of Formula I

Chemical formula

[0034] In a first embodiment, the process of the first aspect comprises (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,

Chemical formula

[0035] In the second embodiment, the process of the first embodiment is performed as follows: (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, [ka] (b) Converting a compound of formula II or a salt thereof to a compound of formula I or a pharmaceutically acceptable salt thereof (for example, by oxidizing the compound of formula II using a suitable oxidizing agent such as oxone), (c) Optionally, purify a compound of formula I or a pharmaceutically acceptable salt thereof (for example, by using one or more suitable solvents described herein), Includes.

[0036] In the third embodiment, the process of the first embodiment is performed. (a) Reacting the compound of formula VIII with acetyl halide to obtain the compound of formula VII, [ka] (b) Converting a compound of formula VII to a compound of formula V-1 or a salt thereof in the presence of a solvent and a halogenating agent, [ka] (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, [ka] (d) Optionally, purify the compound of formula III-1 or a salt thereof (for example, by using one or more suitable solvents described herein), (e) Converting a compound of formula III-1 or a salt thereof to a compound of formula I or a pharmaceutically acceptable salt thereof (for example, by coupling a compound of formula III-I (for example, where X is Br) with a compound of formula IV), During the ceremony, Each time X appears, a leaving group is independently released (e.g., halogens (e.g., fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I)), mesylates (-OMs), tosylates (-OTs), triflates (-OTf), dinitrogen (-N2)). + ), dialkyl ether (-OR2 + ), thioether (-SR2 + ), amine (-NR3 + ), ammonia (-NH3 + ), nitrate (-ONO2), phosphate (-OPO(OH)2), carboxylate (-OCOR), phenoxide (-OAr), hydroxide (-OH), alkoxide (-OR), water (-OH2) + ), and alcohol (-OHR + A leaving group selected from ), where each R group is independently H and C 1-3 Selected from alkyl groups, where Ar is an unsubstituted phenyl or halogen, C 1-3 The conversion is selected from alkyl groups and phenyl groups substituted with one or more substituents selected from any combination thereof. Includes.

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

[0039] In the fourth embodiment, the process of the first embodiment is performed. (a) Reacting the compound of formula VIII with acetyl chloride to obtain the compound of formula VII, [ka] (b) Reacting the compound of formula VII with a brominating agent in the presence of a solvent to obtain the compound of formula V, [ka] (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, [ka] (d) Optionally, purify the compound of formula III or a salt thereof (for example, by using one or more suitable solvents described herein), (e) Converting a compound of formula III or a salt thereof to a compound of formula I or a pharmaceutically acceptable salt thereof (for example, by coupling a compound of formula III-I (for example, where X is Br) with a compound of formula IV, Includes.

[0040] In the fifth embodiment, the process of the first embodiment is: (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, [ka] (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, [ka] (c) Optionally, purify the compound of formula IV or a salt thereof (for example, by using one or more suitable solvents described herein), (e) Converting a compound of formula IV or a salt thereof to a compound of formula I or a pharmaceutically acceptable salt thereof (for example, by coupling a compound of formula III-I (for example, where X is Br) with a compound of formula IV, Includes.

[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 Ni, Pd / C, Pd(OH)2, Na metal, Pt, PtO2, and any combination of the aforementioned.

[0042] In the sixth embodiment, the process of the first embodiment is: (a) Reacting a compound of formula III or a salt thereof with a compound of formula IV-a or a salt thereof (for example, where the compound of formula IV-a is in racemic form) to obtain a compound of formula II-b or a salt thereof (for example, where the compound of formula II-b is in racemic form), [ka] (b) Converting the compound of formula II-b to the compound of formula Ia (for example, by oxidizing the compound of formula II using a suitable oxidizing agent such as oxone), [ka] (c) Separating desired isomers of the compound of formula I or its pharmaceutically acceptable salt (for example, using chiral chromatography), (d) Optionally, purify a desired isomer of the compound of formula I or a pharmaceutically acceptable salt thereof (for example, by using one or more suitable solvents described herein), Includes.

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

[0044] In the seventh embodiment, the process of the first embodiment is performed. (a) Reacting a salt of the compound of formula III-a with the compound of formula IV-a or a salt thereof (for example, the compound of formula IV-a or a salt thereof in racemic form) to obtain the compound of formula II-a or a salt thereof (for example, the compound of formula II-a or a salt thereof in racemic form), [ka] During the ceremony, X is a leaving group (e.g., halogens (e.g., fluorine (-F), chlorine (-Cl), bromine (-Br), iodine (-I)), mesylate (-OMs), tosylate (-OTs), triflate (-OTf), dinitrogen (-N2) + ), dialkyl ether (-OR2 + ), thioether (-SR2 + ), amine (-NR3 + ), ammonia (-NH3 + ), nitrate (-ONO2), phosphate (-OPO(OH)2), carboxylate (-OCOR), phenoxide (-OAr), hydroxide (-OH), alkoxide (-OR), water (-OH2) + ), and alcohol (-OHR + A leaving group selected from ), where R, R2, and R3 are independently H and C 1-3 Selected from alkyl groups, where Ar is an unsubstituted phenyl or halogen, C 1-3 Selected from phenyl substituted with one or more substituents selected from alkyl groups and any combination thereof, n is selected from 0 to 2, and obtain it. (b) If n is 0 or 1, convert the compound of formula II-a or a salt thereof to the compound of formula I or a pharmaceutically acceptable salt thereof (for example, by oxidizing the compound of formula II using a suitable oxidizing agent such as oxone), (c) Separating desired isomers of the compound of formula I or its pharmaceutically acceptable salt (for example, using chiral chromatography), (d) Optionally, purify a desired isomer of the compound of formula I or a pharmaceutically acceptable salt thereof (for example, by using one or more suitable solvents described herein), Includes.

[0045] In a second embodiment, the present invention relates to a process for the chiral separation of a compound of formula I or a pharmaceutically acceptable salt thereof, (a) To provide a solution of a racemic compound of formula Ia or a pharmaceutically acceptable salt thereof in one or more solvents, (b) Separating desired isomers of the compound of formula I or its pharmaceutically acceptable salt using chiral chromatography, Regarding processes that include this.

[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-pentylacetic acid, 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, tetrachloromethane, chlorobenzene, dimethylacetamide (DMA), dimethylformamide (DMF), water, or any combination of the above.

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

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

[0049] In the first embodiment, the process of the third embodiment is (a) To 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 reaction mass from step (a) to an appropriate temperature, (c) Cooling the reaction mass, (d) Isolating a pure compound of formula I or a pharmaceutically acceptable salt thereof, Includes.

[0050] In the second embodiment, the process of the third embodiment is, (a) To provide a dispersion or slurry of a compound of formula I or a pharmaceutically acceptable salt thereof in a solvent (for example, by stirring), (b) Isolating the purified compound of formula I or a pharmaceutically acceptable salt thereof (for example, by filtration of a dispersion or slurry), Includes.

[0051] In the third embodiment, the process of the third aspect is (a) To provide a solution, dispersion, or slurry of a compound of formula I or a pharmaceutically acceptable salt thereof in a solvent, (b) Adding a poor solvent to the reaction mass in step (a), (c) Isolating the purified compound of formula I or a pharmaceutically acceptable salt thereof, Includes.

[0052] In the fourth embodiment, the process of the third embodiment is performed. (a) To 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 reaction mass from step (a) (for example, to an appropriate temperature), (c) Optionally, cooling the reaction mass, (d) Adding one or more solvents to the reaction mass, (e) Isolating the purified compound of formula I or a pharmaceutically acceptable salt thereof, Includes.

[0053] In a fourth embodiment, the present invention relates to a process for preparing pharmaceutically acceptable salts of compounds of formula I, (a) To provide a solution, dispersion, or slurry of a compound of formula I in one or more solvents, (b) Adding acid to the reaction mass from step (a), (c) Heating the reaction mass from step (b) (for example, to an appropriate temperature), (d) Cooling the reaction mass from step (c), (e) Isolating a pharmaceutically acceptable salt of the compound of formula I, This includes processes related to the process.

[0054] In a fifth aspect, the present invention relates to a process for preparing a substantially pure compound of formula I, (a) To provide a solution, dispersion, or slurry of a pharmaceutically acceptable salt of a compound of formula I in one or more solvents, (b) Adding a base to the reaction mass from step (a), (c) Heating the reaction mass from step (b) (for example, to an appropriate temperature), (d) Cooling the reaction mass, (e) to isolate a substantially pure compound of formula I, This includes processes related to the process.

[0055] In a sixth aspect, the present invention relates to a process for preparing a substantially pure compound of formula III or a salt thereof, (a) To 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 reaction mass from step (a) (for example, with hot ethanol to an appropriate temperature), (c) Cooling the reaction mass, (d) Isolating a substantially pure compound of formula III or a pharmaceutically acceptable salt thereof, This includes processes related to the process.

[0056] In a sixth embodiment, the present invention relates to a process for purifying a compound of formula III or a salt thereof.

[0057] In the first embodiment, the process of the sixth aspect is (a) To provide a dispersion or slurry of one or more compounds of formula III or salts thereof in one or more solvents (for example, by stirring), (b) Isolating the purified compound of formula III or a salt thereof (for example, by filtration of a dispersion or slurry), Includes.

[0058] In the second embodiment, the process of the sixth aspect is: (a) To provide a solution, dispersion, or slurry of a compound of formula III or a salt thereof in one or more solvents, (b) Adding a poor solvent to the reaction mass in step (a), (c) Isolating the purified compound of formula III or its salt, Includes.

[0059] In a seventh aspect, the present invention relates to a process for preparing a substantially pure compound of formula IV or a salt thereof, (a) To provide a solution, dispersion, or slurry of a compound of formula IV in one or more solvents, (b) Optionally, heat the reaction mass from step (a) (for example, to an appropriate temperature), (c) Cooling the reaction mass, (d) to isolate a substantially pure compound of formula IV or a salt thereof, This includes processes related to the process.

[0060] In an eighth aspect, the present invention relates to a process for purifying a compound of formula IV or a salt thereof.

[0061] In the first embodiment, the eighth aspect is (a) To provide a solution, dispersion, or slurry of the compound of formula IV or its salt in a solvent, (b) Isolating the compound of formula IV or a salt thereof that has been purified (for example, by filtration), Includes.

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

[0063] In any embodiment of the processes described herein (for example, the processes of the third, fourth, fifth, sixth, seventh, or eighth aspect 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 any embodiment of the processes described herein (for example, the processes of the third, fourth, fifth, sixth, seventh, or eighth aspect described herein), the solvent (or one or more solvents) is selected from methanol, acetonitrile, dichloromethane, cyclohexane, and any combination thereof.

[0065] In the second embodiment, the process of the eighth aspect is, (a) To provide a solution or dispersion of a compound of formula IV or a salt thereof in a solvent, (b) Adding a poor solvent to the reaction mass in step (a), (c) Isolating the purified compound of formula IV or a salt thereof, Includes.

[0066] In any additional embodiment of the processes described herein, the compound of formula III or a salt thereof has a chemical purity of at least about 90%, for example, at least about 95%, at least about 98%, or at least about 99%, as measured by HPLC.

[0067] In any additional embodiment of the processes described herein, the compound of formula IV or a salt thereof has a chemical purity of at least about 90%, for example, 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 processes described herein is substantially pure (i.e., substantially free of one or more of the compounds of formulas A, B, C, D, and E).

[0069] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof prepared by any of the processes described herein substantially contains no one or more of the compounds of formulas A, B, C, D, and E, with each of such compounds A, B, C, D, and / or E present at less than about 0.2% w / w.

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

[0071] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof (or any of its intermediates) prepared by any of the processes described herein is isolated from the reaction mixture by techniques, but not limited to, extraction, evaporation, distillation, centrifugation, filtration, scraping, vessel shaking, solvent removal including the use of a rotary distillation apparatus such as a Buchi rotary evaporator, spray drying, stirred thin-film drying, freeze-drying, or any other technique specific to the equipment used.

[0072] In any embodiment of the processes described herein, the cooling step includes cooling from any higher temperature to about 0°C, as required by the reaction step.

[0073] In any embodiment of the processes described herein, the cooling step includes cooling from room temperature to about 0°C, as required by the reaction step.

[0074] In any embodiment of the processes described herein, the cooling step includes cooling from room temperature to about 10°C.

[0075] In any particular embodiment of the processes described herein, the pharmaceutically acceptable salt (or any intermediate thereof) of the compound of formula I 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 any additional embodiment of the processes described herein, the pharmaceutically acceptable salt (or any intermediate thereof) of the compound of formula I 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 process described herein, is in amorphous form, any crystalline form, or any combination of the aforementioned in any weight percent content. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof, prepared by any process described herein, is amorphous. In one embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof, prepared by any process described herein, is crystalline.

[0078] In any embodiment of the processes described herein, the preparation of the compound of formula I or a pharmaceutically acceptable salt thereof is carried out in situ without isolating the intermediate.

[0079] In any additional embodiment of the processes described herein, the compound of formula I or a pharmaceutically acceptable salt thereof has a chemical purity of at least about 90%, for example, 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 additional embodiment of the processes described herein, the compound of formula I or a pharmaceutically acceptable salt thereof has an enantiomer purity of at least about 90%, for example, 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 additional embodiment of the processes described herein, the compound of formula I or a pharmaceutically acceptable salt thereof has an enantiomer excess of at least about 90%, for example, 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 additional embodiment of the processes described herein, the compound of formula I or a pharmaceutically acceptable salt thereof has an isomer purity of at least about 97%, for example, at least about 99%, at least about 99.5%, or at least about 99.9%.

[0083] In any additional embodiment of the process described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is used in a d-column with a diameter of about 0.1 μm to about 200 μm. 90 It is characterized by the particle size distribution.

[0084] In any additional embodiment of the process described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is d 90 It is characterized by the particle size distribution.

[0085] In any additional embodiment of the process described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is less than about 100 μm. 90 It is characterized by the particle size distribution.

[0086] In any additional embodiment of the process described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is less than about 60 μm in size. 90 d less than approximately 20 μm 50 and d less than approximately 10 μm 10 It is characterized by the particle size distribution.

[0087] Scheme 1 illustrates an exemplary process for the preparation of the compound of formula I or a pharmaceutically acceptable salt thereof. Scheme 1 [ka]

[0088] Scheme 2 shows an exemplary process for the preparation of the compound of Formula III or a pharmaceutically acceptable salt thereof. Scheme 2 [ka]

[0089] Scheme 3 shows an exemplary process for the preparation of the compound of formula IV or a pharmaceutically acceptable salt thereof. Scheme 3 [ka]

[0090] Scheme 4 shows another exemplary process for the preparation of the compound of formula I or a pharmaceutically acceptable salt thereof. Scheme 4 [ka]

[0091] Specific aspects and embodiments of the present invention will be described in more detail with reference to the following examples. These 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 described procedures are intended to fall within the scope of this application. [Examples]

[0092] Particle size analysis was performed using a Malvern particle size analyzer (Mastersizer 3000, 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 prepare a paste using a glass rod. Next, add 10 mL of water and sonicate from the outside for 10 seconds while continuing to shake. [Table 1]

[0094] procedure After cleaning, initialize the system and measure the background. Add the sample until a shielding rate of 10% to 20% is reached, and wait until a stable shielding rate is achieved. Start the analysis according to the specified instrument parameters or perform the standard operating procedure. Analyze the sample in two sequences, and D 10 , D 50 , and D 90 Report the average result (instrumental mean) of the two preparations.

[0095] Example 1: Preparation of compound X [ka] Under a nitrogen atmosphere, Pd / C (40 g) was added to a solution of (1S)-1-(4-pyridinyl)ethanol (200 g, 1.626 mol, 99% ee) in methanol (3 L). The mixture was purged several times with exhaust and hydrogen, and then stirred at 60°C under a hydrogen atmosphere for 24 hours. After completion, the reaction mixture was filtered through a Celite bed and washed with methanol (3 L). All organic solvents were removed under reduced pressure to obtain (1R)-1-(4-piperidinyl)ethanol (200.0 g, 95.0%) as an off-white solid. Chemical purity: 95% by titration

[0096] Titration procedure: Accurately weigh approximately 200 mg of the test sample and transfer it to a clean, dry 100.0 mL dry titration vessel. Add 50.0 mL of glacial acetic acid.

[0097] Perform a potentiometric titration with 0.1M perchloric acid and record the reading (V).

[0098] Similarly, perform a blank titration without the test sample and record the reading (B). [Table 2] Specific rotation (1% solution in dichloromethane): -16.835 o

[0099] Example 2: Preparation of the compound of formula VII [ka] Dichloromethane (100 mL) was placed in a round-bottom flask. AlCl3 (11.26 g, 84.50 mmol) was added all at once at 0°C, and the resulting solution was stirred for 45 minutes. Acetyl chloride (5.77 mL, 80.98 mmol) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. To this, the solution of formula VIII (10.0 g, 70.42 mmol) in dichloromethane (10 mL) was slowly added at 0°C. Next, the mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mass was poured into well-chilled water (200 mL) and 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 obtain the title compound (10.0 g, 77%) as a light brown solid. Melting point: 61-62°C. Chemical purity: 99.86% by HPLC [Table 3]

[0100] Example 3: Preparation of compound V [ka] To a stirred solution of formula VII (20.0 g, 108.6 mmol) in dioxane (200 mL), a solution of bromine (5.61 mL, 108.6 mmol) in dioxane (200 mL) was slowly added at room temperature (RT). The mixture was then stirred at RT for 3 hours. The progress of the reaction was monitored by TLC. After completion, the reaction mass was poured into well-chilled water (200 mL). The precipitated solid was filtered and dried under vacuum to obtain the title compound (13.3 g, 78%) as a brown solid (melting point 55-59°C). Chemical purity: 93.56% by HPLC [Table 4]

[0101] Example 4: Preparation of the compound of formula VI [ka] 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 hours. The completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure. After adding water to the reaction mass, a solid precipitated and was isolated by filtration. The solid was washed with water and dried under vacuum to obtain the title compound of formula VI (6.5 g, 72.95%) as a yellow solid.

[0102] Example 5: Preparation of the compound of formula IV [ka] To a solution of compound X (200.0 g, 1.550 mol) in 1,4-dioxane (1.0 L) and water (1.0 L), compound IX (210.0 g, 1.472 mol) (shown below) was added at room temperature. Next, NaHCO3 (390.6 g, 4.651 mol) was added to the reaction mixture and refluxed at 100°C for 16 hours. After completion, the reaction mass was cooled to 20°C, water (2.0 L) was added, and the product was extracted with SiO2 (2.0 L × 3). The combined organic layer was dried over Na2SO4 and then concentrated under reduced pressure to obtain compound IV (500.0 g crude product) as a pale yellow, sticky solid. [ka]

[0103] Example 6: Purification of the compound 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 obtain the compound of formula IV (320.0 g, 88.0%) as an off-white solid. Chemical purity: 99.6% by HPLC

[0104] chromatography conditions Use a 50 x 4.6 mm Ghost Buster column (e.g., Welch Materials, Inc.) and a 6.5 cm long HPLC tube. Place the Ghost Buster after inline filtering and before injection into the water HPLC system. [Table 5] Isomer purity (enantiomer excess): 99.32% (ee 98.64%) Specific rotation (1% solution in dichloromethane): +5.9°

[0105] Example 7: Preparation of compound III [ka] 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 mass was refluxed at 90°C for 24 hours. After completion, the reaction mass was cooled to 50°C, filtered, and dried to obtain the crude compound III.

[0106] Example 8: Purification of compound III The crude compound of formula III obtained in Example 7 was washed with hot ethanol and then dried under vacuum to obtain the compound of formula III (20.0 g, 77%) as a brown solid. Chemical purity: 98.69% by HPLC

[0107] chromatography conditions Use a 50 x 4.6 mm Ghost Buster column (e.g., Welch Materials, Inc.) and a 6.5 cm long HPLC tube. Place the Ghost Buster after inline filtering and before injection into the water HPLC system. [Table 6]

[0108] Example 9: Preparation of compound II [ka] To a stirred solution of compound IV (1 kg, 4.249 mol) in dimethylformamide, compound III (1.75 kg, 4.116 mol) was added at 25-30°C, and the reaction mass was cooled to 10°C. Next, sodium hydride (0.43 kg, 10.75 mol) was gradually added over 45 minutes while maintaining the internal temperature below 35°C. The reaction mass was stirred at 35-40°C for 3 hours. After completion, the reaction mass was poured into well-chilled water (15 L). The resulting solid precipitate was isolated by filtration, washed with water (10 L), and dried overnight under vacuum. The resulting solid was stirred with MeOH (7.5 L) for 1 hour and filtered. This process was repeated (2 × 5 L MeOH) to obtain compound II (1.3 kg, 70%) as an off-white solid. Chemical purity: 99.6% by HPLC [Table 7] Isomer purity (enantiomer excess): 99.82% (ee 99.64%) Specific rotation (1% solution in dichloromethane): -26.2°

[0109] Example 10: Preparation of compound I [ka] To a stirred solution of compound II (0.75 kg, 1.5151 mol) in acetone (7.5 L), a solution of oxone (potassium peroxymonosulfate) (1.25 kg, 4.090 mol) in water (7.5 L) was slowly added at 0°C, maintaining the temperature below 25°C. The resulting mixture was stirred at 25°C for 3 hours. After completion, cold water (15 L) was added to the reaction mass, followed by ethyl acetate (7.5 L), and the resulting mixture was stirred for 30 minutes. The organic layer was separated, and the aqueous layer was again extracted and separated with ethyl acetate (2 × 7.5 L). The combined organic layers were dried over Na₂SO₄ and then concentrated under reduced pressure to obtain compound I (1.0 kg, crude product) as a pale yellow solid.

[0110] Example 11: Purification of compound 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 mass was stirred for 1 hour. The solid precipitate was filtered and washed with methanol (0.6 L). The resulting wet cake was stirred again with methanol (2.25 L), filtered, and dried to obtain the compound of formula I (0.7 kg) as an off-white solid. Next, the dried solid was incorporated into acetonitrile (4.2 L). The resulting slurry was stirred at 27-33°C for 3 hours, filtered, and washed with acetonitrile (1 L). The resulting solid was dried and stirred again with methanol (3.5 L) at 25-30°C for 1 hour. The formed solid was filtered, washed with methanol (0.56 L, 0.8 V), and dried in a vacuum tray dryer (VTD) at 55-60°C to obtain the compound of formula I (0.52 kg, 67%) as an off-white solid. Chemical purity: 99.86% (HPLC)

[0111] chromatography conditions Use a 50 x 4.6 mm Ghost Buster column (e.g., Welch Materials, Inc.) and a 6.5 cm long HPLC tube. Place the Ghost Buster after inline filtering and before injection into the water HPLC system. [Table 8] Isomer purity (enantiomer excess): 99.98% (ee 99.96%) Specific rotation (1% solution in dichloromethane): -25.8°

[0112] Example 12: Preparation of a racemic compound II-b [ka] To a stirred solution of the racemic compound of formula IV (0.500 kg, 2.124 mol) in dimethylformamide, the compound of formula III (0.875 kg, 2.0575 mol) was added at 25-30°C, and the mixture was cooled to 10°C. Next, sodium hydride (0.215 kg, 5.375 mol) was gradually added over 45 minutes while maintaining the internal temperature below 35°C. The reaction mass was stirred at 35-40°C for 3 hours. After completion, the reaction mass was poured into well-chilled water (7.5 L), the resulting solid precipitate was filtered, washed with water (5 L), and dried overnight under vacuum. The resulting solid was stirred with methanol (3.75 L) for 1 hour and filtered. This process was repeated to obtain the (2 × 5 L MeOH) racemic compound of formula II-b (0.65 kg, 70%) as an off-white solid. Chemical purity: 99.37% by HPLC [Table 9]

[0113] Example 13: Preparation of a compound of racemic formula I [ka] To a stirred solution of the racemic compound II-b (0.375 kg, 0.7575 mol) in acetone (3.75 L), a solution of oxone (0.625 kg, 2.045 mol) in water (3.75 L) was slowly added at 0°C, maintaining the temperature below 25°C. The resulting mixture was stirred at 25°C for 3 hours. After completion, cold water (7.5 L) was added to the reaction mass, followed by the addition of ethyl acetate (3.75 L). The resulting mixture was stirred for 30 minutes. The organic layer was separated, and the aqueous layer was again extracted and separated with ethyl acetate (2 × 3.75 L). The combined organic layers were dried over Na₂SO₄ and then concentrated under reduced pressure to obtain the racemic compound Ia (0.5 kg, crude product) as a pale yellow solid. Methanol (2.5 L) was added to the crude product of racemic compound Ia (0.5 kg), and the mixture was stirred for 1 hour. The resulting solid precipitate was filtered and washed with methanol (0.3 L). The resulting wet cake was stirred again with methanol (1.1 L), filtered, and dried to obtain the racemic compound Ia (0.35 kg) as an off-white solid. Chemical purity: 98.5% by HPLC

[0114] chromatography conditions Use a 50 x 4.6 mm Ghost Buster column (e.g., Welch Materials, Inc.) and a 6.5 cm long HPLC tube. Place the Ghost Buster after inline filtering and before injection into the water HPLC system. [Table 10]

[0115] Example 14: Chiral purification of racemic compound I The enantiomer of the racemic compound Ia (0.35 kg) was separated by chiral preparative HPLC. For this separation, a column ID-CHIRALPAK IG, 250 mm × 4.6 mm, 5 μm, mobile phase: a 50:50 mixture of methanol and dichloromethane, with a wavelength of 305 nm, was used based on better peak shape and separation. The flow rate used was 1.5 ml / min, and the column temperature was maintained at 25°C. The eluent was concentrated under reduced pressure to obtain the compound of formula I (0.15 kg, 43%). Chemical purity: 99.9% by HPLC Isomer purity (enantiomer excess): 99.96% (ee 99.92%) Specific rotation (1% solution in dichloromethane): -25.8°

[0116] All references and patent publications cited herein are incorporated herein by reference.

Claims

1. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 The aforementioned process, (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, 【Chemistry 2】 In the formula, X is a leaving group, and n is 0, 1, or 2, and the above-mentioned obtaining (b) If n is 0 or 1, convert the compound of formula II-a to the compound of formula I-a or a pharmaceutically acceptable salt thereof, 【Transformation 3】 (c) Separating desired isomers of the compound of formula I or its pharmaceutically acceptable salt, (d) Optionally, purify the desired isomer of the compound of formula I or a pharmaceutically acceptable salt thereof, The process including the process described above.

2. A process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof, 【Chemistry 4】 The aforementioned process, (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, 【Transformation 5】 In the formula, X is a leaving group, and the above-mentioned obtaining (b) Converting the compound of formula II or a salt thereof into the compound of formula I or a pharmaceutically acceptable salt thereof, (c) Optionally, purify the compound of formula I or a pharmaceutically acceptable salt thereof. The process including the process described above.

3. The compound of formula III-1 or a salt thereof, (a) Reacting the compound of formula VIII with acetyl halogen to form the compound of formula VII, 【Transformation 6】 (b) Converting the compound of formula VII to the compound of formula V-1 in the presence of a solvent and a halogenating agent, 【Transformation 7】 In the formula, X is a leaving group, and the above transformation, (c) Reacting the compound of formula V-1 with the compound of formula VI-1 or a salt thereof to obtain the compound of formula III-1 or a salt thereof, 【Transformation 8】 In the formula, X is as defined above, and the above-mentioned result is obtained, (d) Optionally, purify the compound of formula III-1 or a pharmaceutically acceptable salt thereof using one or more suitable solvents, The process according to claim 2, which is prepared by a process including the following:

4. The process according to claim 3, wherein the halogenated acetyl is selected from acetyl fluoride, acetyl chloride, acetyl bromide, acetyl iodide, and any combination thereof, preferably acetyl chloride.

5. The process according to 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 compound of formula IV or a salt thereof, (a) Reacting the compound of formula XI with a reducing agent to obtain the compound of formula X, 【Chemistry 9】 (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, 【Chemistry 10】 (c) Optionally, purify the compound of formula IV, The process according to claim 2, which is prepared by a process including the following:

7. The reducing agent is Ni, Raney Ni, Pd / C, Pd(OH) ２ , Na metal, Pt, PtO ２ The process according to claim 6, selected from any combination thereof.

8. The aforementioned process, (a) Reacting the hydrobromide salt of the compound of formula III with the compound of formula IV-a or a salt thereof to obtain the compound of formula II-b or a salt thereof, 【Chemistry 11】 (b) Converting the compound of formula II-b or a salt thereof into the compound of racemic formula I-a or a pharmaceutically acceptable salt thereof, 【Chemistry 12】 (c) Separating the desired isomer of the compound of formula I or a pharmaceutically acceptable salt thereof, (d) Optionally, purify the desired isomer of the compound of formula I or a pharmaceutically acceptable salt thereof, The process including the process described above.

9. Step (c) is (a) Adding a chiral acid to one or more solvents the compound of formula I-a or a pharmaceutically acceptable salt thereof, (b) Optionally, isolate the chiral salt of the compound of formula I, (c) Adding a base, (c) Separating the desired isomer of the compound of formula I or a pharmaceutically acceptable salt thereof, (e) Optionally, purify the desired isomer of the compound of formula I or a pharmaceutically acceptable salt thereof, The process according to claim 1, including the process described in claim 1.

10. The process according to 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 of the aforementioned as the eluent.

11. A process for the purification of a compound of formula I or a pharmaceutically acceptable salt thereof, 【Chemistry 13】 The aforementioned process (a) To provide a solution, dispersion, or slurry of the compound of formula I or a pharmaceutically acceptable salt thereof in one or more solvents, (b) Heating the reaction mass from step (a), (c) Cooling the reaction mass, (d) Adding one or more solvents as an option, (e) Isolating the purified compound of formula I or a pharmaceutically acceptable salt thereof, The process including the process described above.

12. The process according to 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, 【Chemistry 14】 The compound of formula I or a pharmaceutically acceptable salt thereof (i) Chemical purity of over 99%, (ii) Enantiomer excess rate of over 99%, or (iii)(i) and (ii), The compound or a pharmaceutically acceptable salt thereof having the above.

14. A compound of formula I or a pharmaceutically acceptable salt thereof, 【Chemistry 15】 The compound of formula I or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof that substantially does not contain one or more compounds from formulas A, B, C, D, and E. 【Chemistry 16】

15. A compound of formula I or a pharmaceutically acceptable salt thereof, 【Chemistry 17】 The compound of formula I or a pharmaceutically acceptable salt thereof (i) d less than approximately 60 μm ９０ , (ii) d less than approximately 20 μm ５０ , (iii) d less than approximately 10 μm １０ , or Any combination of (iv), (i), (ii), and (iii), The compound or a pharmaceutically acceptable salt thereof, characterized by the particle size distribution.

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