Method for manufacturing dihydro-3,5-dione derivatives

Abstract

The present invention aims to provide a method for preparing p-toluenesulfonate of 7-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-10-hydroxy-6-methyl-N-(4-methyl-2-(6-methylpyrimidin-4-yl)phenyl)-8-sideoxy-6,7-diazaspiro[4.5]dec-9-ene-9-methylamine, which is cheaper and easier to obtain than conventional methods and is industrially preferred. The present invention discovers a method for effectively obtaining the target substance by a step of obtaining a wet powder of p-toluenesulfonate of 7-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-10-hydroxy-6-methyl-N-(4-methyl-2-(6-methylpyrimidin-4-yl)phenyl)-8-sideoxy-6,7-diazaspiro[4.5]dec-9-ene-9-methylamine, and a further drying step.

Description

[Technical Field]

[0001] This invention relates to a method for manufacturing a dihydrotazo-3,5-dione derivative. [Previous Technology]

[0002] In patients with renal dysfunction such as chronic kidney disease (CKD) and end-stage renal disease (ESKD), phosphorus is known to accumulate in the body, causing hyperphosphatemia. Hyperphosphatemia-induced vascular calcification may contribute to cardiovascular dysfunction. Furthermore, it leads to excessive secretion of parathyroid hormone, causing bone lesions. Such hyperphosphatemia may be a factor worsening the prognosis and quality of life (QOL) of patients with end-stage renal failure and those on dialysis (Non-Patent Literature 1).

[0003] CKD is classified into stages 1 to 5 according to its progression (Non-Patent Literature 2, Non-Patent Literature 3). Serum phosphorus concentrations in patients with stage 3 and 4 CKD are associated with the morbidity and mortality of cardiovascular disease. Inhibiting serum phosphorus concentrations in these patients may reduce or prevent cardiovascular disease. Furthermore, earlier control of phosphate load in patients may reduce and / or prevent disease progression in early-stage CKD patients (Non-Patent Literature 4).

[0004] Current treatment for hyperphosphatemia involves the use of phosphate adsorbents aimed at inhibiting the absorption of phosphate in the digestive tract. Phosphate adsorbents include non-metallic polymeric adsorbents such as sevelamer hydrochloride, calcium salt preparations such as precipitated calcium carbonate, and metallic adsorbents such as lanthanum carbonate. However, there are reports of poor drug compliance due to the need to take several grams daily, and side effects caused by calcium accumulation in the body. Therefore, there is a strong desire to develop novel hyperphosphatemia treatments that can improve upon these problems with phosphate adsorbents (Non-Patent Literature 4).

[0005] Sodium-dependent phosphotransporters are known to belong to three families: NaPi-I, NaPi-II, and NaPi-III. These families are further classified into isotypes. In the case of the NaPi-II family, NaPi-IIa, NaPi-IIb, and NaPi-IIc are known. In particular, phosphotransporters such as NaPi-IIb, PiT-1, and PiT-2 are known to play a role in phosphate absorption in the digestive tract. By selectively inhibiting only these phosphotransporters associated with phosphate absorption, it is expected to produce a strong inhibitory effect on phosphate absorption in the digestive tract, thereby reducing the concentration of phosphorus in the blood (Non-Patent Literature 5, Non-Patent Literature 6, Non-Patent Literature 7, and Non-Patent Literature 8).

[0006] To date, as NaPi-IIb inhibitors, NTX1942 (Patent Document 1) and condensed thiophene derivatives (Patent Documents 2, 3, 4, and 5) have been reported. The dihydropyridine-3,5-dione derivative represented by 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-sideoxy-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-en-9-methoxyamine (hereinafter also referred to as Compound I) has been reported to exhibit inhibitory effects on NaPi-IIb, PiT-1, and PiT-2 (Patent Documents 6 and 7).

[0007] [Chemical 1]

[0008] In Patent Documents 6 and 7, compounds obtained by the Suzuki coupling reaction of phenylboronic acid ester derivatives and chloropyrimidine derivatives are used as intermediates to manufacture compounds represented by Formula 1. In the manufacture of compounds where the Suzuki coupling reaction includes a reaction step, manufacturing cost becomes a problem. For example, there are known examples where the use of palladium as a catalyst increases manufacturing cost, or where the use of bis(pinacolato)diboron as a borate ester raw material increases raw material cost (Non-Patent Document 9, Patent Document 8).

[0009] Non-Patent Document 10 describes a salt of the compound represented by Formula 1 and a method for manufacturing its crystallization. Furthermore, in polymorphic crystals, it is desirable to select the most thermodynamically stable crystalline form of the solid low-molecular-weight compound active pharmaceutical ingredient near room temperature. It is known that selecting the most stable form as the crystal for developing candidate products and establishing a stable manufacturing method are important factors directly related to development costs (Non-Patent Document 11). [Prior Art Documents] [Patent Documents]

[0010] [Patent Document 1] International Publication No. 2012 / 006475 [Patent Document 2] International Publication No. 2011 / 136269 [Patent Document 3] International Publication No. 2013 / 062065 [Patent Document 4] International Publication No. 2014 / 003153 [Patent Document 5] International Publication No. 2018 / 034883 [Patent Document 6] International Publication No. 2014 / 142273 [Patent Document 7] International Publication No. 2016 / 039458 [Patent Document 8] International Publication No. 2019 / 142854 [Non-Patent Documents]

[0011] [Non-Patent Literature 1] Hruska, KA et al., Kidney Int., 2008, 74(2), 148-157. [Non-Patent Literature 2] “Chapter 1: Definition and classification of CKD” Kidney Int. Suppl., 2013, 3(1), 19-62. [Non-Patent Literature 3] Levey, AS et al., Kidney Int., 2005, 67(6), 2089-2100. [Non-Patent Literature 4] Ritter, CS et al., Clin. J.Am.Soc.Nephrol.2016, 11(6), 1088-1100. [Non-Patent Literature 5] Miyamoto, K et al., J. Pharm. Sci., 2011, 100(9), 3719-3730. [Non-Patent Literature 6] Sabbagh, Y et al., J. Am. Soc. Nephrol., 2009, 20(11), 2348-2358. [Non-Patent Literature 7] Forster IC et al., Mol Aspects Med., 2013, 34(2-3), 386-395. [Non-Patent Literature 8] Lederer E et al., Eur. J. Physiol., 2019, 471(1), 137-148. [Non-Patent Literature 9] Vijayalakshmi C et al., Lett. Org. Chem., 2020, 17(1), 68-72. [Non-Patent Literature 10] Invention Promotion Association Publication No. 2017-501666 [Non-Patent Literature 11] Chemburkar SR et al., Org. Proc. Res. Dev. 2000, 4(5), 413-417. [Summary of the Invention]

[0012] [The problem the invention aims to solve]

[0013] Dihydropyridine-3,5-dione derivatives are considered for use as treatments for chronic diseases such as hyperphosphatemia, i.e., treatments requiring long-term drug administration. In order to ensure a stable supply of pharmaceutical products and reduce manufacturing costs, the inventors of this case carefully examined the manufacturing method of the active pharmaceutical ingredient from the perspectives of raw material costs and reaction conditions.

[0014] Specifically, a method for manufacturing p-toluenesulfonate of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-sideoxy-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-en-9-carboxylamine, represented by Formula 1, was discussed. The key intermediate for manufacturing the compound represented by Formula 1, 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (compound II), is described below:

[0015] [Chemical 2]

[0016] The expensive raw material 2-(4,4,5,5-tetramethyl-1,3,2-diborane-2-yl)-4-(trifluoromethyl)aniline used in Compound II significantly impacts manufacturing costs, contributing to increased production costs of the active pharmaceutical ingredient. Furthermore, in the process of manufacturing a specific crystalline form of the p-toluenesulfonate of the compound represented by Formula 1, which can be used as an active ingredient, problems such as slow crystallization, oil out in the reaction solution, and decreased yield of the target compound have been observed, along with the problem of contamination with other crystalline forms. [Solutions]

[0017] In order to solve the above-mentioned problems, the inventors conducted in-depth research. They discovered a method for obtaining p-toluenesulfonate of the compound represented by Formula 1 without the increase of impurities mixed into the active pharmaceutical ingredient, compared with conventional methods, using raw materials that are expensive alternatives to phenylboronic acid derivatives. Furthermore, compared with the conventional method, which obtains p-toluenesulfonate of the compound represented by Formula 1 by mixing the compound represented by Formula 1 and p-toluenesulfonic acid, it was discovered that after obtaining a specific solvent compound of p-toluenesulfonate of the compound represented by Formula 1, the target crystal can be obtained in good yield by solvent removal, and the target crystal can be obtained without the mixing of other crystal forms, thus completing the present invention.

[0018] That is, this specification contains the disclosure of the following inventions.

[0019] [1-1] A method for manufacturing a crystalline powder of p-toluenesulfonate of a compound represented by Formula 1, [Chemical 3]

[0020] The aforementioned method comprises: converting the compound represented by Formula 1 into the aforementioned p-toluenesulfonate in a solvent, recovering the precipitated solid, and obtaining a wet powder of the aforementioned p-toluenesulfonate; subjecting the aforementioned wet powder to drying conditions to obtain a type I crystalline dry powder of the aforementioned p-toluenesulfonate.

[0021] [1-2] [1-1] The method described herein includes: A1) preparing a compound represented by Formula 1 and an ethanol solution of p-toluenesulfonic acid, A2) adding a poor solvent to the solution and precipitating a solid, A3) recovering the solid and obtaining a wet powder of the aforementioned p-toluenesulfonate, and A4) subjecting the wet powder to drying conditions to obtain a type I crystalline dry powder of the aforementioned p-toluenesulfonate.

[0022] [1-3] [1-2] The method described herein, wherein the undesirable solvent used in A2 is used in a range of 0.8 parts by weight or more and 3.5 parts by weight or less relative to 1 part by weight of ethanol used in A1. [1-4] [1-1] The method described herein includes: B1) dissolving the compound represented by Formula 1 in a mixed solvent containing ethanol and the undesirable solvent to obtain a solution; B2) adding an ethanol solution of p-toluenesulfonic acid to the solution to precipitate a solid; B3) recovering the solid and obtaining a wet powder of the aforementioned p-toluenesulfonate; and B4) subjecting the wet powder to drying conditions to obtain a type I crystalline dry powder of the aforementioned p-toluenesulfonate.

[0023] [1-5] [1-4] The method described herein uses 0.8 parts by weight or more of the aforementioned undesirable solvent relative to 1 part by weight of ethanol used in B1. [1-6] [1-4] The method described herein uses the aforementioned undesirable solvent in the range of 0.8 parts by weight or more and 3.5 parts by weight or less relative to 1 part by weight of ethanol used in B1.

[0024] [1-7] The method described in any one of [1-1] to [1-6] includes further adding the undesirable solvent to the mixture containing the solids before recovery. [1-8] The method described in any one of [1-2] to [1-7], wherein the aforementioned undesirable solvent is a solvent containing hexane or heptane; a solvent containing hexane and heptane; or a mixed solvent containing hexane and heptane.

[0025] [1-9] [1-1]~[1-8] The method described herein, wherein the dried powder of the aforementioned type I crystal of p-toluenesulfonate has a powder X-ray diffraction pattern, wherein the powder X-ray diffraction pattern includes at least one peak selected from 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9° and 22.6° (±0.5°) as the diffraction angle 2θ in the powder X-ray diffraction.

[0026] [1-10] [1-1]~[1-9] The method described herein, wherein the dried powder of the aforementioned type I crystal of p-toluenesulfonate has a powder X-ray diffraction pattern, wherein the powder X-ray diffraction pattern includes at least one peak selected from 4.9°, 9.4°, 15.8°, 18.9° and 22.6° (±0.5°) as the diffraction angle 2θ in the powder X-ray diffraction.

[0027] [1-11] [1-1]~[1-10] The method described herein, wherein the dried powder of the aforementioned type I crystal of p-toluenesulfonate has a powder X-ray diffraction pattern, wherein the powder X-ray diffraction pattern comprises a peak of 15.8° (±0.5°) as a diffraction angle 2θ in the powder X-ray diffraction.

[0028] [1-12] [1-1] to [1-11] The method described herein, wherein the dried powder of the aforementioned type I crystal of p-toluenesulfonate has a powder X-ray diffraction pattern, wherein the powder X-ray diffraction pattern comprises at least one peak selected from 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9° and 22.6° (±0.2°) as the diffraction angle 2θ in the powder X-ray diffraction.

[0029] [1-13] The method described in any one of [1-1] to [1-12], wherein the aforementioned wet powder is a wet crystal. [1-14] The method described in [1-13], wherein the wet crystal contains ethanol.

[0030] [1-15] The method described in any one of [1-2] to [1-14], wherein the aforementioned unsuitable solvent comprises heptane, hexane, or pentane. [1-16] The method described in any one of [1-1] to [1-15], wherein the dried powder of the aforementioned type I crystals of p-toluenesulfonate has a powder X-ray diffraction pattern, wherein the powder X-ray diffraction pattern contains peaks at 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.5°) as diffraction angles 2θ.

[0031] [1-17] [1-1]~[1-16] The method wherein the dried powder of the aforementioned type I crystal of p-toluenesulfonate has a powder X-ray diffraction pattern, wherein the powder X-ray diffraction pattern contains peaks at 4.9°, 9.4°, 15.8°, 18.9° and 22.6° (±0.5°) as diffraction angles 2θ in the powder X-ray diffraction.

[0032] [1-18] [1-1]~[1-17] The method described herein, wherein the dried powder of the aforementioned type I crystal of p-toluenesulfonate has a powder X-ray diffraction pattern, wherein the powder X-ray diffraction pattern contains a peak at 15.8° (±0.5°) as a diffraction angle 2θ in the powder X-ray diffraction.

[0033] [1-19] [1-1]~[1-18] The method described herein, wherein the dried powder of the aforementioned type I crystal of p-toluenesulfonate has a powder X-ray diffraction pattern, wherein the powder X-ray diffraction pattern contains peaks at 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9° and 22.6° (±0.2°) as diffraction angles 2θ.

[0034] [1-20] [1-1]~[1-19] The method wherein the dried powder of the aforementioned type I crystal of p-toluenesulfonate has a powder X-ray diffraction pattern, wherein the powder X-ray diffraction pattern contains peaks at 4.9°, 9.4°, 15.8°, 18.9° and 22.6° (±0.2°) as diffraction angles 2θ in the powder X-ray diffraction.

[0035] [1-21] [1-1] to [1-20] The amount of solvent used to convert the compound represented by Formula 1 into the aforementioned p-toluenesulfonate is 2 to 15 parts by weight relative to 1 part by weight of the compound represented by Formula 1.

[0036] [1-22] The method described in any one of [1-1] to [1-21], wherein the solution temperature at which the solid precipitates is in the range of -5°C or higher and 70°C or lower. [1-23] The method described in any one of [1-1] to [1-22], wherein the amount of p-toluenesulfonic acid used to convert the compound represented by Formula 1 into the aforementioned p-toluenesulfonate is in the range of 1 equivalent or higher and 1.2 equivalents or lower relative to 1 equivalent of the compound represented by Formula 1.

[0037] [2-1] A method for manufacturing a compound represented by Formula 2, the method comprising:

[0038] [Chemical 4]

[0039] The compound represented by Formula 3 was treated with C1-6 alkyl magnesium halide, C1-6 alkyl lithium, and zinc halide.

[0040] [Chemical 5]

[0041] [where X1 is a decomposing group] reacts with the compound represented by Formula 4 in the presence of a palladium catalyst.

[0042] [Chemical 6]

[0043] [where X2 is the detaching radical] The compound represented by Formula 5 is obtained, and

[0044] [Chemical 7]

[0045] The compound represented by Formula 5 is reacted with an alkali metal salt of dicarboxylic acid nitriloimide, and the compound represented by Formula 2 is obtained by decomposition of the obtained nitriloimide compound.

[0046] [2-2] The method described in [2-1], wherein X1 is a halogen atom. [2-3] The method described in [2-1] or [2-2], wherein X1 is a fluorine atom. [2-4] The method described in any one of [2-1] to [2-3], wherein X2 is a chlorine atom.

[0047] [2-5] The method described in any one of [2-1] to [2-4], wherein the C1-6 alkyl magnesium halide is C1-6 alkyl magnesium chloride. [2-6] The method described in any one of [2-1] to [2-5], wherein the zinc halide is selected from the group consisting of ZnCl2, ZnBr2 and ZnI2.

[0048] [2-7] [2-1]~[2-6] The method thereof, wherein the palladium catalyst is selected from the group consisting of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, bis(triphenylphosphino)palladium(II), dichlorobis(tricyclohexylphosphino)palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl](3-chloropyridine)palladium(II), (1,3-bis(2,6-diisopropylphenyl)imidazolined)(3-chloropyridine)palladium(II), and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-yl](3-chloropyridine)palladium(II).

[0049] [2-8] The method described in any one of [2-1] to [2-7], wherein the alkali metal salt of dicarboxylic acid nitrile is potassium phthalimide. [2-9] The method described in any one of [2-1] to [2-8], wherein the nitrile decomposition reaction is carried out by reacting a nucleophile selected from hydrazine hydrate and methylamine with the nitrile compound.

[0050] [2-10] [2-1]~[2-9] The method wherein the reaction of the compound represented by Formula 5 with the dicarboxylic acid imine alkali metal salt is carried out in a solvent selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidineone, N,N'-dimethylacrylurea, acetonitrile, and dimethyl sulfoxide, or in a mixed solvent of two or more solvents selected from the solvent.

[0051] [2-11] [2-1] to [2-10] The method wherein the reaction to obtain the compound represented by Formula 5 is carried out in a reaction solvent containing a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, 1,4-diane, and 1,3-diane, or two or more solvents selected from the solvent.

[0052] [2-12] The method described in any one of [2-1] to [2-11], wherein the reaction to obtain the compound represented by Formula 5 is carried out in a reaction solvent containing a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, and dimethoxyethane, or two or more solvents selected from the solvent.

[0053] [2-13] The method described in any one of [2-1] to [2-12], wherein the reaction to obtain the compound represented by Formula 5 is carried out in a reaction solvent containing tetrahydrofuran or 2-methyltetrahydrofuran, or a mixed solvent containing the solvent.

[0054] [2-14] [2-1]~[2-13] The method wherein C1-6 alkyl lithium is added dropwise to a reaction system containing a compound represented by Formula 3 and C1-6 alkyl magnesium halide, and then zinc halide is added dropwise to the reaction system.

[0055] [2-15] The method described in any one of [2-1] to [2-14], wherein a solution of palladium catalyst and the compound represented by Formula 4 is added dropwise to a reaction system containing the compound represented by Formula 3 treated with C1-6 alkyl magnesium halide, C1-6 alkyl lithium and zinc halide.

[0056] [3-1] A method for manufacturing a compound represented by Formula 1, the method comprising:

[0057] [Chemical 8]

[0058] 1) Prepare the compound represented by formula 2 by any one of the methods described in [2-1] to [2-15], 2) React the compound represented by formula 2 with a malonic acid derivative to prepare the compound represented by formula 6.

[0059] [Chemical 9]

[0060] 3) React the compound represented by Formula 6 with the compound represented by Formula 7 in the presence of a condensing agent.

[0061] [Chemical 10]

[0062] Preparation of the compound represented by Formula 8, and

[0063] [Chemical 11]

[0064] 4) Prepare the compound represented by Formula 1 by cyclization reaction of the compound represented by Formula 8.

[0065] [3-2] The method described in [3-1] wherein the malonic acid derivative is selected from the group consisting of Meldrum's acid, dialkylmalonic acid, and malonic acid. [3-3] The method described in [3-1] or [3-2] wherein the reaction of the compound represented by Formula 2 with the malonic acid derivative is carried out in a solvent selected from the group consisting of toluene, heptane, acetonitrile, methanol, and ethanol, or in a mixture of two or more solvents selected from the solvent.

[0066] [3-4] [3-1]~[3-3] The method contained therein, wherein the condensing agent is selected from the group consisting of propylphosphonic anhydride (cyclic trimer), diethyl chlorophosphate, and N,N'-diisopropylcarbodiimide.

[0067] [3-5] [3-1]~[3-4] The method wherein the reaction of the compound represented by Formula 6 with the compound represented by Formula 7 is carried out in the presence of a base selected from the group consisting of pyridine, N,N-diisopropylethylamine, and triethylamine, in a solvent selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidineone, N,N'-dimethylacrylurea, acetonitrile, and dimethyl sulfoxide, or in a mixed solvent of two or more solvents selected from the solvent.

[0068] [3-6] [3-1]~[3-5] The method wherein the cyclization reaction of the compound represented by Formula 8 is carried out in a solvent selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and acetonitrile, in the presence of a base selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate and potassium phosphate.

[0069] [4-1] A method for producing crystals of p-toluenesulfonate of a compound represented by Formula 1, the method comprising:

[0070] [Chemical 12]

[0071] In a solvent, the compound represented by Formula 1 is converted into the aforementioned p-toluenesulfonate, and the precipitated solid is recovered to obtain the aforementioned wet p-toluenesulfonate; the aforementioned wet p-toluenesulfonate is subjected to drying conditions to obtain the aforementioned dry type I crystals of p-toluenesulfonate.

[0072] [4-2] The method described in [4-1] wherein the aforementioned wet p-toluenesulfonate is a powder. [4-3] The method described in [4-1] or [4-2] wherein the aforementioned dried type I crystals of p-toluenesulfonate are a powder. [Effects of the Invention]

[0073] This invention provides a method for effectively manufacturing p-toluenesulfonate of 7-[[2,3-difluoro-4-[2-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-sideoxy-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-methoxyamine (compound I), which has a strong inhibitory effect on NaPi-IIb, PiT-1, and PiT-2.

Implementation Method

[0075] The abbreviations used in this specification are as follows: DIC: N,N'-diisopropylcarbodiimide; DIPEA: N,N-diisopropylethylamine; DMA: N,N-dimethylacetamide; DMF: N,N-dimethylformamide; DMI: 1,3-dimethyl-2-imidazolidineone; DMSO: dimethyl sulfoxide; DMPU: N,N'-dimethylacrylamide; EtOH: ethanol; GC: gas chromatography; HPLC: high performance liquid chromatography; MeCN: acetonitrile; MeOH: methanol; MTBE: methyl tributyl ether; NMP: N-methylpyrrolidone; NMR: nuclear magnetic resonance spectroscopy; PDA: photodiode array detector; T3P: propylphosphonic anhydride; t-Bu: tributyl ether; TEA: triethylamine; TFA: trifluoroacetic acid (definition of functional groups, etc.). In this specification, "detaching radical" refers to a group that can be detached by breaking a chemical bond and can generate anionic atoms or anionic molecules by detachment. Examples include halogen groups composed of halogen atoms such as fluorine, chlorine, bromine, or iodine groups, as well as sulfonyl groups such as mesyl, tosyl, trifluoromethanesulfonyl, or nitrobenzenesulfonyl.

[0076] Examples of "halogen atom" in this specification include fluorine, chlorine, bromine, or iodine atoms. "Alkyl" in this specification refers to a monovalent group derived by removing one arbitrary hydrogen atom from an aliphatic hydrocarbon, whose skeleton does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds, and which has a hydrocarbon group or a subset of hydrocarbon group structures containing hydrogen and carbon atoms. This alkyl group includes straight-chain, branched, or cyclic forms. Examples of alkyl groups include those with 1 to 20 carbon atoms (C1-20, hereinafter "Cp-q" indicates the number of carbon atoms from p to q), preferably C1-6 alkyl groups. Specifically, examples include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, tert-butyl, dibutyl, cyclopentyl, cyclohexyl, etc.

[0077] In this specification, examples of temperatures for processing compounds include temperatures near the ambient temperature of a typical operator's work environment (room temperature), such as a range of 10°C to 30°C, or a range of 15°C to 25°C. Examples of temperatures for processing compounds in a reaction vessel include a range from -100°C using a coolant such as liquid nitrogen to near the boiling point of the solvent. This allows for the selection of a suitable temperature for effectively manufacturing the target compound, taking into account the stability of the compound and the reactivity of the starting material.

[0078] In one aspect of the present invention, 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (compound II) can be produced by means of the reaction scheme shown below (scheme 1).

[0079] [Chemical 13]

[0080] In the formula, X1 and X2 represent detached radicals. The compound represented by Formula 3 as the starting material can be a commercially available compound. Examples of detached radical X1 include, for example, a halogen atom, preferably a fluorine atom or a chlorine atom, with fluorine being a particularly preferred example. Examples of detached radical X2 include, for example, a halogen atom, preferably a chlorine atom, a bromine atom, or an iodine atom, with chlorine being a particularly preferred example.

[0081] In one state, C1-6 alkyl magnesium halide and C1-6 alkyl lithium are added to a solution of the compound represented by Formula 3 at -100 to 10°C, preferably -60 to 0°C, and more preferably -30 to -10°C. The molar ratio of the reagent used [C1-6 alkyl lithium / C1-6 alkyl magnesium halide] can be, for example, 1.5 to 3.0, preferably 1.8 to 2.8, and more preferably 2.0 to 2.5, and can be added in the order of C1-6 alkyl magnesium halide solution followed by C1-6 alkyl lithium solution. In this case, although not particularly limited, the alkyl magnesium halide can be used in, for example, 0.25 to 2.0 equivalents, preferably 0.28 to 1.0 equivalents, and more preferably 0.30 to 0.50 equivalents, relative to the equivalent amount of the compound represented by Formula 4. The compound represented by Formula 3 can be used, for example, in amounts of 0.8 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents, and more preferably 1.3 to 1.7 equivalents, relative to the compound represented by Formula 4. The dropping time can be appropriately set considering the reaction scale or temperature variations of the reaction solution. After the C1-6 alkyllithium solution is added dropwise, the resulting reaction mixture can be stirred at, for example, -100 to 10°C, preferably -60 to 0°C, and more preferably -30 to -10°C. The stirring time can be, for example, 0.1 to 12 hours, preferably 1 to 10 hours, and more preferably 2 to 7 hours.

[0082] Examples of solvents for solutions of compounds represented by Formula 3 include ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, etc.) and hydrocarbons (e.g., pentane, hexane, heptane, benzene, toluene, etc.). Examples of solvents for C1-6 alkyl magnesium halide solutions include ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, etc.) and hydrocarbons (e.g., pentane, hexane, heptane, benzene, toluene, etc.). Examples of solvents for C1-6 alkyl lithium include hydrocarbons (e.g., pentane, hexane, heptane, benzene, toluene, etc.) and ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, etc.).

[0083] Next, the zinc halide solution is added dropwise to the resulting reaction mixture at, for example, -60 to 10°C, preferably -50 to 0°C, and more preferably -30 to -10°C. Here, for example, 0.1 to 2.0 equivalents, preferably 0.6 to 1.5 equivalents, and more preferably 0.8 to 1.3 equivalents of zinc halide can be used relative to the compound represented by Formula 4. The dropping time can be appropriately set considering the reaction scale or the temperature variation of the reaction solution. Examples of solvents used for the zinc halide solution include, for example, ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, tributyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, etc.) and hydrocarbons (e.g., pentane, hexane, heptane, benzene, toluene, etc.).

[0084] After adding the zinc halide solution dropwise, the resulting reaction mixture can be stirred at, for example, -60~10°C, preferably -40~10°C, and more preferably -20~5°C. The stirring time can take, for example, 0.1~4 hours, preferably 0.15~2 hours, and more preferably 0.2~1.5 hours. Next, when adding the compound represented by Formula 4 and the palladium catalyst to the reaction mixture, the addition can be made at, for example, -20~20°C, preferably -20~10°C, and more preferably -10~5°C. Here, relative to the compound represented by Formula 4, the amount of palladium catalyst used can be, for example, 0.001~0.1 equivalents (0.1~10 mol%), preferably 0.003~0.05 equivalents (0.3~5 mol%), and more preferably 0.005~0.02 equivalents (0.5~2 mol%).

[0085] The reaction mixture obtained by adding the compound represented by Formula 4 with a palladium catalyst can be heated at, for example, 25 to 100°C, preferably 40 to 80°C, more preferably 50 to 70°C, and the stirring time can be set to, for example, 0.1 to 12 hours, preferably 0.5 to 8 hours, more preferably 1 to 3 hours.

[0086] The post-processing of the reaction mixture after adding the compound represented by Formula 4 and the palladium catalyst can be carried out after confirming the reduction or disappearance of the compound represented by Formula 4 in the reaction system by analysis using HPLC, GC, etc. The resulting compound represented by Formula 5 can be purified by column chromatography or the like before proceeding to the next step, or it can be proceeded to the next step without special purification.

[0087] Among the samples in the above steps, C1-6 alkyl magnesium halides can be exemplified as C1-6 alkyl magnesium chloride, specifically C3-6 alkyl magnesium chloride, preferably isopropyl magnesium chloride, n-butyl magnesium chloride, cyclopentyl magnesium chloride, and cyclohexyl magnesium chloride. Such C1-6 alkyl magnesium halides can be used in solutions with suitable solvents.

[0088] In the above-described step, the C1-6 alkyl lithium is not particularly limited, but examples of readily available industrial raw materials include methyl lithium, n-butyl lithium, secondary butyl lithium, and tertiary butyl lithium. These C1-6 alkyl lithiums can be used in solutions with appropriate solvents.

[0089] In the above-described step, the zinc halide is not particularly limited, but examples of readily available industrial raw materials include zinc chloride, zinc bromide, or zinc iodide. Such zinc halides can be used in solutions with appropriate solvents.

[0090] In the above-mentioned step, the palladium catalyst is not particularly limited as long as it plays the role of a reaction catalyst. Examples include 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, bis(triphenylphosphino)palladium(II) dichloride, dichlorobis(tricyclohexylphosphino)palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl](3-chloropyridine)palladium(II) dichloride, (1,3-bis(2,6-diisopropylphenyl)imidazolined)(3-chloropyridine)palladium(II) dichloride, or [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-yl](3-chloropyridine)palladium(II) dichloride, etc.

[0091] In one state of the above steps, X1 is a fluorine atom, X2 is a chlorine atom, C1-6 alkyl magnesium halide is C3-6 alkyl magnesium chloride, and zinc halide is zinc chloride. In another state of the above steps, X1 is a fluorine atom, X2 is a chlorine atom, C1-6 alkyl magnesium halide is C3-6 alkyl magnesium chloride, zinc halide is zinc chloride, and the palladium catalyst is a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex or a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex.

[0092] In one state, the compound represented by Formula 5 can be reacted with the alkali metal salt of dicarboxylic acid amide in a suitable solvent at a suitable temperature, for example, 50-150°C, preferably 80-130°C, and more preferably 90-110°C. Here, for example, 0.9-2.0 equivalents, preferably 1.0-1.5 equivalents, and more preferably 1.05-1.2 equivalents of the alkali metal salt of dicarboxylic acid amide can be used relative to the compound represented by Formula 5. The reaction time can be appropriately set considering the reaction scale or temperature variations of the reaction solution. As a solvent, acetonitrile, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), 1,3-dimethyl-2-imidazolidineone (DMI), N,N'-dimethylacrylurea (DMPU), or a mixture of two or more solvents selected from these solvents can be used. Preferably, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc., can be used. As an alkali metal salt of dicarboxylic acid imine, examples include potassium phthalimide or sodium phthalimide, with potassium phthalimide being more preferred.

[0093] After confirming the reduction or disappearance of the compound represented by Formula 5 in the reaction solution by analyzing the reaction mixture using HPLC, GC, etc., a nucleophile is added to the reaction mixture to convert the amide structure to an amine (amide decomposition reaction). Analysis of the amide decomposition reaction can be omitted. The reaction temperature is not particularly limited, but can be, for example, 0-150°C, preferably 25-100°C, and more preferably 40-60°C. Here, as the nucleophile, C1-6 alkylamines, hydrazine, and other amines can be used, preferably C1-6 alkylamines, and more preferably an aqueous solution of methylamine. The amount of the aqueous methylamine solution is not particularly limited as long as it does not produce significant side reactions, but the equivalent of methylamine relative to the compound represented by Formula 5 can be an amount containing, for example, 2-30 equivalents, preferably 3-20 equivalents, and more preferably 5-15 equivalents. The above reaction time can be appropriately set considering the reaction scale or temperature variations of the reaction solution. The crude product of the compound represented by Formula 2 (compound II) can be purified. Examples of purification methods include column chromatography and recrystallization.

[0094] The compound II obtained by the above method can be used as a synthetic intermediate in the manufacturing method of compound I as described in the prior art (patent documents 6 and 7, and non-patent document 10).

[0095] As an example of a synthetic intermediate of compound I, more specifically, the compound represented by formula 6 obtained by reacting compound II with a malonic acid derivative in a suitable solvent can be exemplified.

[0096] [Chemical 14]

[0097] Examples of malonic acid derivatives used in the above method include dialkylmalonic acids such as Michaelis-Müller acid, dimethylmalonic acid, and diethylmalonic acid, or malonic acid. Michaelis-Müller acid is preferred. Furthermore, the solvent used in this step is a solvent commonly used in chemical reactions, and is not particularly limited to a range that does not interfere with the reaction. However, it is preferable to use a solvent selected from toluene, heptane, acetonitrile, methanol, and ethanol, or a mixture of two or more solvents selected from such solvents.

[0098] As an example of a synthetic intermediate of compound I, more specifically, a compound represented by formula 8 can be obtained by condensing the compound represented by formula 7 and the compound represented by formula 6 in a suitable solvent, which can be manufactured according to conventional methods (Patent Documents 6 and 7).

[0099] [Chemical 15]

[0100] The condensation reaction of the compound represented by Formula 6 and the compound represented by Formula 7 is carried out by a method commonly used by those skilled in the art for the condensation reaction of carboxyl and amine groups. As an example of a condensation reaction, a condensation reaction using a condensing agent can be cited. Examples of condensing agents include diethyl chlorophosphate, propylphosphonic anhydride (T3P), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI). Diethyl chlorophosphate or propylphosphonic anhydride (T3P) is preferred. Furthermore, the solvent used in this step is a solvent commonly used in chemical reactions, and there is no particular limitation on the range in which it does not interfere with the reaction. However, it is preferable to use a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidineone, N,N'-dimethylacrylurea, acetonitrile, dimethyl sulfoxide, or a mixture of two or more solvents selected from these solvents. Also, the condensation reaction may be carried out in the presence of a base as needed. Specific examples of bases include bases selected from the group consisting of pyridine, dimethylaminepyridine, N,N-diisopropylethylamine, and triethylamine.

[0101] In one aspect of the present invention, a method for manufacturing a crystalline powder of p-toluenesulfonate (TsOH salt) of compound I is provided. The outline of the manufacturing method is shown below.

[0102] [Chemical 16]

[0103] In one embodiment of the present invention, p-toluenesulfonate of compound I is precipitated from a solution in which compound I and p-toluenesulfonic acid are dissolved in a solvent, thereby obtaining p-toluenesulfonate of compound I. The amount of p-toluenesulfonic acid used, relative to compound I, may be, for example, one equivalent or more, specifically one equivalent. The p-toluenesulfonic acid used may be a commercially available product, preferably a p-toluenesulfonate monohydrate.

[0104] Ethanol can be used as the solution solvent for compound I and p-toluenesulfonic acid. Seed crystals can also be added for the precipitation of the target p-toluenesulfonate, and / or other solvents can be added to the ethanol solution. As other solvents, solvents with low solubility in the target substance (unsuitable solvents) can be used to increase the amount of the target substance precipitated or to improve the precipitation rate of the target substance. Examples of such unsuitable solvents include hexane, heptane, or pentane. The mixing ratio of ethanol to other solvents at the time of crystallization from this solution can be set to 0.80 to 3.5 parts by weight of other solvents relative to 1.0 parts by weight of ethanol, preferably 1.0 to 3.0, more preferably 1.2 to 2.5, and most preferably 1.5 to 2.2. Seed crystals can be used, for example, those described in Non-Patent Document 10.

[0105] In this invention, "Type I crystal" refers to a state of crystallization of p-toluenesulfonate of compound I, characterized by the presence of peaks at diffraction angles (2θ) near 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° in the powder X-ray diffraction pattern (Non-Patent Document 9). The diffraction angle (2θ) of the Type I crystal may have at least one peak selected from the group consisting of the following, or may have a powder X-ray diffraction pattern having all of the following peaks: 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0106] Furthermore, it is recorded that in thermogravimetric analysis, the peaks caused by melting are shown at 112.6℃ (interpolation point) and 126.6℃ (peak). After the target p-toluenesulfonate precipitates, other solvents may be added to further increase the precipitation amount. Examples of other solvents include hexane, heptane, or pentane. As for the mixing ratio of ethanol and other solvents after adding other solvents, the weight ratio of other solvents relative to 8.0 parts by weight of ethanol can be set to 7.0~28, preferably 8.0~24, more preferably 10~20, and most preferably 14~20.

[0107] In the above steps, the ethanol solution in which compound I and p-toluenesulfonic acid are dissolved can be set to 22~28°C, specifically 25°C. Subsequently, the temperature at which other solvents are added and crystallization is carried out can be cooled to below the temperature of the solution in which compound I and p-toluenesulfonic acid are dissolved, in order to further increase the amount of precipitation. For example, it can be set to -5~33°C, specifically 25°C. Furthermore, the temperature at which other solvents are added and crystallization is carried out can be set, for example, -5~33°C, specifically 25°C.

[0108] In another embodiment of the present invention, p-toluenesulfonate of compound I is obtained by dissolving compound I in a mixture of ethanol and other solvents, adding an ethanol solution of p-toluenesulfonic acid, and then precipitating the p-toluenesulfonate of compound I. The amount of p-toluenesulfonic acid used is preferably in the range of 1 equivalent or more and 1.2 equivalents or less relative to compound I, more preferably in the range of 1 equivalent or more and 1.1 equivalents or less, and most preferably 1 equivalent. Seed crystals may also be added to precipitate the target p-toluenesulfonate. Other solvents include hexane, heptane, or pentane. Heptane is preferred, and n-heptane is more preferred. The mixing ratio of ethanol and other solvents is preferably 7.0 to 28 parts by weight of other solvents relative to 8.0 parts by weight of ethanol, preferably 8.0 to 24, more preferably 10 to 20, and most preferably 12 to 17. Seed crystals, for example, those described in Non-Patent Document 10, can be used. When seed crystals are added to the reaction solution, solid seed crystals or a suspension of seed crystals dispersed in a suitable solvent can be used. When using a suspension of seed crystals, the dispersing solvent can be a solvent in which the seed crystals are completely insoluble, preferably a solvent containing a poor solvent for precipitating p-toluenesulfonate of compound I, more preferably a solvent containing n-heptane, and even more preferably n-heptane.

[0109] After the p-toluenesulfonate of the target compound I is precipitated by adding an ethanol solution of p-toluenesulfonic acid, other solvents may be added to further increase the precipitation amount. Examples of other solvents include those that precipitate the p-toluenesulfonate of compound I, preferably hexane, heptane, or pentane, more preferably a solvent containing n-heptane, and even more preferably n-heptane. The mixing ratio of ethanol to other solvents after adding other solvents is approximately 7.0 to 28 parts by weight of other solvents relative to 8.0 parts by weight of ethanol, preferably 8.0 to 24, more preferably 10 to 20, and most preferably 12 to 17.

[0110] In the above steps, the ethanol solution in which compound I is dissolved can be set to 22~28°C, specifically 25°C. Then, the temperature for adding other solvents and crystallizing can be set, for example, -5~33°C, specifically 25°C. Furthermore, the temperature for adding other solvents and crystallizing can be set, for example, -5~33°C, specifically 25°C.

[0111] The precipitated crystals can be separated and purified from the solution or mixed solution by solid-liquid separation operations, such as separating the solid and liquid components by filtration or centrifugation, washing with a cleaning solvent for the solid components, or drying under reduced pressure with a cleaning solvent adhering to the solid components. As a cleaning solvent for the solid components, it is preferable to use a solvent that does not cause the target crystal of p-toluenesulfonate of compound I to convert into other crystals, a solvent with low solubility of p-toluenesulfonate of compound I, and / or a solvent that does not decompose p-toluenesulfonate of compound I. Examples of such solvents include hexane, heptane, isopropyl acetate, n-butyl acetate, tributyl methyl ether, or mixtures of such solvents.

[0112] In this specification, "wet" refers to the state in which a solid contains a solvent. For example, a solid recovered by a solid-liquid separation operation that contains a portion of the separated liquid can be called a wet solid. In one embodiment of the present invention, the p-toluenesulfonate of compound I precipitated from the solvent is recovered as a wet solid (i.e., a wet solid), which may be a wet powder and / or a wet solid.

[0113] In this specification, "powder" refers to a solid with a particle size of 0.5 to 20 μm, for example, 1.0 to 10 μm. The particle size distribution of the powder can be determined by information such as laser diffraction and scattering methods.

[0114] In this specification, "wet powder" refers to a mixture of powder recovered by a solid-liquid separation operation, a solvent used in the solid-liquid separation operation, and / or a solvent used for powder cleaning. The mixing ratio of powder to solvent can be arbitrary.

[0115] In this specification, "wet crystallization" refers to a mixture of crystals precipitated by a crystallization operation, a solvent used in the crystallization operation, and / or a solvent used for crystallization cleaning. The mixing ratio of crystals to solvent can be arbitrary.

[0116] In this specification, "dry powder" refers to a state in which the solvent components have vaporized and decreased in quantity compared to the wet powder described above. The amount of solvent remaining relative to the powder can be arbitrary, but it refers to a state in which the solvent has decreased from the powder, resulting in reduced adhesion between powder particles and increased flowability.

[0117] The term "drying conditions" in this specification, while not specifically limited, refers to conditions under which a wet solid (e.g., wet powder) is converted into a dry solid (e.g., dry powder). A wet powder mixed with a solvent that readily vaporizes at room temperature can be converted into a dry powder by allowing the solvent to evaporate under normal temperature and pressure. The wet powder can also be heated to promote solvent vaporization. If the properties of the powder-forming substance are unsuitable for heating, the wet powder can be subjected to reduced pressure to promote solvent vaporization. Heating and reduced pressure can also be performed simultaneously or separately.

[0118] In one aspect of the present invention, a dried powder of type I crystals of p-toluenesulfonate of compound I can be obtained by subjecting a wet powder of p-toluenesulfonate of compound I to drying conditions. In one state sample, a dried powder of type I crystals of p-toluenesulfonate of compound I is obtained by phase transfer of the p-toluenesulfonate crystals of compound I contained in the wet powder under drying conditions.

[0119] The term "powder X-ray diffraction" in this specification refers to a value obtained using X-ray diffraction phenomena for the identification and structural analysis of crystalline substances, and is inherent to any powder. This value is usually expressed as one or more diffraction angles (2θ values). It can be measured using CuKα1 radiometrics. Those skilled in the art can use commercially available powder X-ray diffraction measuring instruments and follow their instruction manuals. More specifically, the 2θ value can be determined by irradiating the sample with X-rays of CuKα1 and measuring the diffracted X-rays relative to the incident X-rays. For example, it can be performed using conventional methods such as the "Powder X-ray Diffraction Measurement Method" as described in the Japanese Pharmacopoeia (17th or 18th revision).

[0120] The diffraction angle (2θ value) of powder X-ray diffraction spectra may have some error due to measurement conditions such as the measuring instrument or the reading conditions of the diffraction angle. The diffraction angle in this manual has a measurement error in the range of approximately ±0.5° to ±0.2°.

[0121] In the markings of the diffraction angle 2θ in this specification, when "(±0.2°)" is written at the end of the listed diffraction angle 2θ, it means that a range of ±0.2° is allowed for each of the listed diffraction angles 2θ. When "(±0.5°)" is written at the end of the listed diffraction angle 2θ, it means that a range of ±0.5° is allowed for each of the listed diffraction angles 2θ.

[0122] The “powder X-ray diffraction pattern” in this specification refers to a graph plotted on the horizontal and vertical axes, showing the diffraction angle and intensity of the diffraction obtained by powder X-ray diffraction spectroscopy. Those skilled in the art can use a commercially available powder X-ray diffraction measuring machine and follow its instruction manual to plot the pattern.

[0123] "Thermogravimetric analysis" in this specification refers to a method for thermally analyzing changes in the physical and chemical properties of a sample, and is an analytical means of measuring the weight change caused by heating the sample. Those skilled in the art can use commercially available thermogravimetric analysis equipment and follow its instruction manual to perform the measurement.

[0124] In this specification, "differential thermal analysis" refers to an analytical method used to detect and measure the exothermic or endothermic effects of heating a sample. Those skilled in the art can use commercially available differential thermal analysis equipment and follow its instruction manual to perform the measurement. By using thermogravimetric analysis and / or differential thermal analysis, information about the physical phenomena of a sample, such as sublimation, melting, solidification, condensation, evaporation, decomposition, adsorption, or desorption, can be obtained.

[0125] In thermogravimetric analysis, the measured endothermic peak (peak value) may vary due to changes in the temperature rise per minute or the purity of the sample. The interpolation points or peak values ​​in this specification may have a measurement error within the range of approximately ±5.0℃.

[0126] The crystalline powder obtained by the method according to the present invention may or may not be pulverized to form various forms of pharmaceutical compositions, such as oral preparations like lozenges, capsules, granules, fine granules, powders, and dry syrups, or it may be processed into injections, but oral preparations are preferred. These pharmaceutical compositions can be manufactured using pharmaceutically acceptable carriers and by formulation methods commonly known to those skilled in the art. When preparing oral solid preparations, excipients may be added to the active ingredient, or binders, disintegrants, lubricants, colorants, flavoring agents, etc., may be added as needed, and then lozenges, coated lozenges, granules, powders, dry syrups, capsules, etc., can be manufactured according to conventional methods. When preparing oral liquid preparations, flavoring agents, buffers, stabilizers, flavoring agents, etc., may be added to the active ingredient and oral liquids, syrups, etc., can be manufactured according to conventional methods. When preparing injectable preparations, pH adjusters, buffers, stabilizers, tension agents, local anesthetics, etc., can be added to the active ingredient and manufactured into subcutaneous, intramuscular, and intravenous injections according to conventional methods.

[0127] The amount of p-toluenesulfonate of compound I formulated in the above-described pharmaceutical composition is not fixed and depends on the symptoms of the patient using it or its dosage form, but it is generally desirable to administer approximately 10 to 700 mg of oral dosage or approximately 10 to 700 mg of injectable dosage per unit form. Furthermore, the daily dosage of type I crystals in the above-described pharmaceutical composition is also determined based on the physician's prescription, not on the symptoms, route of administration, or patient's age, and is generally preferred to be approximately 10 to 500 mg.

[0128] In this specification, the term "and / or" includes all appropriate combinations of "and" and "or". Specifically, for example, "A, B, and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B, and C. [Example]

[0129] Hereinafter, the present invention will be described in further detail with reference to embodiments, but the present invention is not limited to these embodiments. The solvents exemplified by DMF, DMA, NMP, DMI, or DMPU used in the implementation of the present invention can be commercially available products without purification. Furthermore, for reactions in which water is not added as a solvent, commercially available products such as dehydrated solvents, ultradehydrated solvents, or anhydrous solvents can be used without purification.

[0130] Unless otherwise specified, reagents used in the implementation of this invention are commercially available products without purification. ¹H-NMR spectroscopy was performed using a JNM-ECP500 nuclear magnetic resonance apparatus (manufactured by Nippon Electron Ltd.), with the chemical shift of Me₄Si, used as an internal standard, set to 0 ppm, and referenced to the deuterium-locked signal from the sample solvent. The chemical shift of the analyte compound's signal is indicated in ppm. Abbreviations for signal separation are used: s = singleline, brs = broad singleline, d = doubleline, t = tripleline, q = quadrupleline, dd = double doubleline, and m = multipleline. The signal width is expressed in J value (Hz). The integral value of each signal is calculated based on the signal area intensity ratio.

[0131] Powder X-ray diffraction (XRPD) was measured under the following conditions, and the 2θ value of the scanning range was calculated. The X-ray diffraction pattern was plotted with the diffraction angle (2θ value) on the horizontal axis and the line intensity on the vertical axis. Measurement apparatus: SmartLab System (manufactured by Rigaku Corporation) Radiation source: Cukα1 Tube voltage: 45kV Tube current: 200mA Scanning range: 3~35° Sampling width: 0.02° Thermogravimetric analysis (TGA) was performed using an EXSTAR TG / DTA6200R system (manufactured by SEIKO INSTRUMENTS (now HITACHI HIGHTECH SCIENCE)). 1~3 mg of sample was added to an aluminum container. The analysis temperature was performed in the range of 30°C to 350°C. The sample was analyzed under a nitrogen flow at a heating rate of 10°C / min.

[0132] HPLC analysis was performed using a Waters H-Class system with a PDA detector at 225 nm. GC analysis was performed using a Shimadzu GC2010 with FID detection.

[0133] The products of each step were evaluated using the analytical methods shown in Table 1 below.

[0134] [Table 1]

[0135] (Example 1-1) 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline was manufactured according to the manufacturing route shown below.

[0136] [Chemistry 17]

[0137] [Step 1] Manufacturing of 4-(2-fluoro-5-(trifluoromethyl)phenyl)-6-(trifluoromethyl)pyrimidine

[0138] [Chemical 18]

[0139] 1-Fluoro-(4-trifluoromethyl)benzene (150 g, 912 mmol) and tetrahydrofuran (700 mL) were added to a 3 L flask purged with nitrogen. The resulting solution was stirred and cooled until the internal temperature reached -17.8 °C. Then, n-butylmagnesium chloride (2.13 M, tetrahydrofuran solution, 100 mL, 213 mmol) was added dropwise over 12 minutes. Subsequently, n-butyllithium (1.63 M, hexane solution, 298 mL, 486 mmol) was added dropwise to the reaction solution over 1 hour and 21 minutes. After stirring for 4 hours and 30 minutes within the internal temperature range of -10.5 °C to -17.6 °C, zinc chloride (2.03 M, 2-methyltetrahydrofuran solution, 300 mL, 608 mmol) was added dropwise to the reaction solution over 35 minutes. Subsequently, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (4.9717 g, 6.08 mmol) and 4-chloro-6-(trifluoromethyl)pyrimidine (111.033 g, 608 mmol) were added to the reaction solution using tetrahydrofuran (45 mL) at an internal temperature of 0 °C. The internal temperature of the reaction solution was heated to 60 °C over a period of more than 30 minutes. One hour after reaching 60 °C, samples were taken, and the disappearance of 4-chloro-6-(trifluoromethyl)pyrimidine was confirmed by GC analysis. The internal temperature of the reaction solution was then cooled to 25 °C. Citric acid (10% aqueous solution, 555 mL) was added to the reaction solution, stirred for 20 minutes, allowed to stand, and the aqueous layer was removed. EDTA-4 sodium dihydrate (10% aqueous solution, 555 mL) was added to the reaction solution, stirred for 20 minutes, allowed to stand, and the aqueous layer was removed. Add 555 mL of water to the reaction mixture, stir for 10 minutes, allow to stand, and drain the aqueous layer. Concentrate the resulting organic layer under reduced pressure, add toluene (555 mL), and concentrate again under reduced pressure to obtain the crude product of 4-(2-fluoro-5-(trifluoromethyl)phenyl)-6-(trifluoromethyl)pyrimidine. The crude product is used directly in the next step.

[0140] GC purity: 91.17% Determination method: GC, retention time: 7.4 minutes [Step 2] Preparation of 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline

[0141] [Chemistry 19]

[0142] The crude product of 4-(2-fluoro-5-(trifluoromethyl)phenyl)-6-(trifluoromethyl)pyrimidine obtained in step 1 was transferred to a 5L flask, and N,N-dimethylformamide (1.71L) was added. The solution obtained by adding N,N-dimethylformamide (190mL) to potassium phthalimide (124.051g, 670mmol) was added to the aforementioned solution. Stirring of the reaction mixture was started, and the external temperature of the flask was set to 110°C and heating was initiated. After 3 hours when the internal temperature of the reaction mixture reached 100°C, a sample was taken, and HPLC analysis confirmed a reaction conversion rate of 99.3%. The reaction mixture was then cooled to an internal temperature of 53°C. The reaction mixture was added to an aqueous methylamine solution (40% w / w, 567mL). The reaction mixture was stirred at an internal temperature of 48°C–53°C for 4 hours, and a sample was taken, and HPLC analysis confirmed a reaction conversion rate of 100%. A solution of N,N-dimethylformamide (38 mL) containing N-acetylg-L-cysteine ​​(9.9449 g, 60.9 mmol) was added and stirred for 1 hour. Water (1134 mL) was added dropwise to the reaction mixture in six portions (189 mL × 6) over approximately 1 hour and 20 minutes. Crystals precipitated from the added water, forming a suspension. After the water addition was complete, the mixture was stirred for 1 hour, then cooled to 25°C. The suspension was filtered, and the resulting crystals were washed twice with water (1980 mL × 2). The resulting wet powder was dried under reduced pressure at an external temperature of 35°C to obtain 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (169.62 g, 90.7% yield in step 2).

[0143] HPLC purity: 96.42% Determination method: HPLC method A, retention time: 8.8 min 1H-NMR (500MHz, CDCl3) δ: 6.71 (2H, brs), 6.83 (1H, d, J=9.0Hz), 7.49 (1H, d, J=8.5Hz), 7.95 (1H, s), 8.04 (1H, s), 9.34 (1H, s).

[0144] (Examples 1-2) [Step 1] Preparation of 4-(2-fluoro-5-(trifluoromethyl)phenyl)-6-(trifluoromethyl)pyrimidine

[0145] [Chemical 20]

[0146] 1-Fluoro-(4-trifluoromethyl)benzene (150 g, 912 mmol) and tetrahydrofuran (720 mL) were added to a 3 L flask purged with nitrogen. The solution was stirred and cooled to an internal temperature of -20.3 °C, and then n-butylmagnesium chloride (2.13 M, tetrahydrofuran solution, 100 mL, 213 mmol) was added dropwise over 28 minutes. Next, n-butyllithium (1.63 M, hexane solution, 299 mL, 487 mmol) was added dropwise to the reaction solution over 47 minutes. The container was then rinsed with tetrahydrofuran (30 mL), and the rinsing solution was added to the reaction solution. The reaction solution was stirred for 4 hours within an internal temperature range of -8.6 °C to -10.2 °C, and then cooled to -20.1 °C. Zinc chloride (1.0 M tetrahydrofuran solution, 609 mL, 609 mmol) was added dropwise over 61 minutes. The internal temperature of the reaction solution was raised to 0°C, and after stirring for 17 minutes, 4.98 g (6.09 mmol) of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex and 4-chloro-6-(trifluoromethyl)pyrimidine (111.084 g, 609 mmol) were added to the reaction solution. The internal temperature of the reaction solution was raised to 60°C over 25 minutes, and after stirring at the same temperature for 1 hour, a sample was taken. A portion of the reaction solution was analyzed by GC to confirm the disappearance of 4-chloro-6-(trifluoromethyl)pyrimidine. The internal temperature of the reaction solution was cooled to below 10°C, and 750 mL of 1M hydrochloric acid and 750 mL of toluene were added. After stirring for 10 minutes, the aqueous layer was removed. Then, 300 mL of 1M hydrochloric acid was added to the organic layer, and after stirring for 10 minutes, the aqueous layer was removed. A 10% aqueous solution of N-(2-hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid trisodium dihydrate (750 mL) was added to the organic layer, and the mixture was stirred for 30 minutes. The aqueous layer was then removed. A 10% aqueous solution of sodium chloride (750 mL) was added to the organic layer, and the mixture was stirred for 10 minutes. The aqueous layer was then removed. The resulting organic layer was concentrated under reduced pressure to obtain a crude product of 4-(2-trifluoro-5-(trifluoromethyl)phenyl)-6-(trifluoromethyl)pyrimidine. The crude product was used directly in the next step.

[0147] GC purity: 94.35% (calculated only from the peak after a residence time of 3.1 minutes) Determination method: GC, residence time: 7.4 minutes [Step 2] Preparation of 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline

[0148] [Chemistry 21]

[0149] The crude product of 4-(2-trifluoro-5-(trifluoromethyl)phenyl)-6-(trifluoromethyl)pyrimidine obtained in step 1 of Examples 1-2 was transferred to a 5L flask, and N,N-dimethylformamide (1.5L) was added. Potassium phthalimide (124.022g, 670mmol) was added to this solution using N,N-dimethylformamide (378mL). The reaction solution was stirred while the external temperature of the reaction vessel was set to 103°C and heated. After the internal temperature of the reaction solution reached 100°C for 3 hours, the reaction solution was sampled, and the reaction conversion rate was confirmed to be 98.6% by HPLC analysis. After stirring the reaction solution at 100°C for another 3 hours, the reaction solution was sampled again, and the reaction conversion rate was confirmed to be 99.9% by HPLC analysis. Then the internal temperature of the reaction solution was cooled to 50°C. A methylamine aqueous solution (40% w / w, 567 mL) was added to the reaction solution. After stirring at an internal temperature of approximately 50 °C for 3 hours, the reaction solution was sampled, and HPLC analysis confirmed that the conversion rate was 100%. N-acetycysteine ​​(9.9447 g, 60.9 mmol) was added to the reaction solution using N,N-dimethylformamide (18.9 mL), and the mixture was stirred for 1 hour. Water (1134 mL) was added dropwise to the reaction solution in 6 portions (189 mL × 6) over approximately 1 hour and 20 minutes. Crystals precipitated upon the addition of water, forming a suspension. After the water addition was complete, the mixture was stirred for 1 hour, and then cooled to 25 °C. The suspension was filtered, and the obtained crystals were washed twice with water (1890 mL × 2). The resulting wet powder was dried under reduced pressure at an external temperature of 30-40°C to obtain 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (169.73 g, yield of 90.8% in step 2).

[0150] HPLC purity: 96.95% Determination method: HPLC method A, retention time: 8.8 minutes. (Refer to Example 1) Production of 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (conventional method) Produced by the following manufacturing route.

[0151] [Chemistry 22]

[0152] 86.2 kg of N,N-dimethylacetamide solution of 2-(4,4,5,5-tetramethyl-1,3,2-diborane-2-yl)-4-(trifluoromethyl)aniline (Boron molecular (catalog number: BM1088), 30.0 kg) and N,N-dimethylacetamide (22.2 L) were added to the reaction vessel under a nitrogen flow. Next, 20.6 kg of 4-chloro-6-(trifluoromethyl)pyrimidine and 38.2 L of N,N-dimethylacetamide were added, followed by 166 L of N,N-dimethylacetamide solution of 0.408 kg of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex and 9.55 L of water. The reaction vessel was then degassed under reduced pressure for 15 minutes, followed by purging with nitrogen. A tripotassium phosphate aqueous solution was prepared by adding 38.2 L of water to 25.3 kg of tripotassium phosphate while bubbling with nitrogen. The reaction vessel was then degassed under reduced pressure for 5 minutes, followed by purging with nitrogen. After stirring the reaction solution at 50–60 °C for 2 hours, N,N-dimethylacetamide (95.5 L) was added to a solution prepared from N-acetyl-L-cysteine ​​(1.63 kg), and the mixture was further stirred at 54.4–57.6 °C for 1 hour. Water (28.7 L) was added to the reaction solution in 10 portions at 52.0–56.4 °C. The reaction solution was stirred at 55.8–56.3 °C for 30 minutes, then cooled to 25 °C and stirred for another 19 hours and 45 minutes. The resulting precipitate was filtered off and washed twice with water (287 L). The wet powder was dried at 40 °C under reduced pressure (0.08–0.10 MPa) for 70 hours to obtain 31.52 kg (98.2% yield) of the title compound. The 1H-NMR spectra and HPLC retention times of the obtained compound were consistent with those in Example 1.

[0153] The comparison between Examples 1-2 and Reference Example 1 is shown in Table 2 below. The purity of the compounds was calculated based on HPLC analysis.

[0154] [Table 2]

[0155] In Examples 1-2, it was found that the target compound was obtained with the same purity as in Reference Example 1. (Reference Example 2) Preparation of 1-(2-chloroethoxy)-2,3-difluorobenzene

[0156] [Chemistry 23]

[0157] Prepared using 2,3-difluorophenol and 1,2-dichloroethane, based on a method described in the literature (Williamson, AW et al., J. Chem. Soc. 1852, 106, 229-239). (Ref. Example 3) Preparation of 2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzaldehyde

[0158] [Chemical 24]

[0159] Using 1-(2-chloroethoxy)-2,3-difluorobenzene obtained in Reference Example 2, it was manufactured according to the manufacturing route shown below as set out in International Publication No. 2014 / 142273.

[0160] [Chemistry 25]

[0161] (Ref. Example 4) Preparation of (E)-1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-1-methylhydrazine)cyclopentane-1-carboxylic acid methyl oxalate

[0162] [Chemical 26]

[0163] [Step 1] Using methyl 1-(methylamino)cyclopentane-1-carboxylic acid as a starting material, 2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzaldehyde of Reference Example 3 was obtained by manufacturing via the manufacturing route shown below as disclosed in International Publication No. 2014 / 142273.

[0164] [Chemical 27]

[0165] [Step 2] Under a nitrogen atmosphere, (E)-1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-1-methylhydrazyl)cyclopentane-1-carboxylic acid methyl ester hydrochloride (60.0 g, 129 mmol) and toluene (360 mL) were added to the reaction vessel to suspend them. The resulting slurry was cooled while maintaining the internal temperature at -5 °C, and an aqueous solution of sodium bicarbonate (prepared by dissolving 21.7 g of sodium bicarbonate in 300 mL of water) was added dropwise. The temperature was raised to room temperature and stirred for another 0.5 hours. After separating the organic layer, the resulting aqueous layer was further extracted with toluene (60 mL). The combined organic layers were concentrated to obtain a toluene solution (131.9 g) of (E)-1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-1-methylhydrazyl)cyclopentane-1-carboxylic acid ester (free form). Toluene was added to the concentrate in 330 mL increments, and the mixture was kept at room temperature overnight. After 13 hours, the external temperature of the reaction vessel was set to 50 °C, and a methanol solution of oxalic acid (prepared by dissolving 11.6 g of oxalic acid in 27.6 mL of methanol) was added at an internal temperature of 48 °C. The mixture was stirred for another 20 minutes. The external temperature of the reaction vessel was set to 25 °C, and n-heptane (138 mL) was added to the resulting solution. The external temperature of the reaction vessel was set to 0 °C, and the mixture was stirred for another 1.5 hours at a temperature below 1 °C. The precipitated solid was filtered off, and the resulting wet powder was washed with toluene (166 mL). The wet powder was dried under reduced pressure at an external temperature of 40 °C to obtain the target compound (56.7 g) (yield: 85%).

[0166] HPLC purity: 99.52% Determination method: HPLC method A, retention time: 6.7 minutes 1H-NMR (DMSO-D6) δ: 7.45-7.41 (1H, m), 7.27 (1H, s), 7.06 (1H, t, J = 8.2 Hz), 4.42 (2H, t, J = 5.3 Hz), 3.65 (2H, t, J = 5.3 Hz), 3.61 (3H, s), 3.42 (2H, t, J = 5.0 Hz), 3.29 (3H, s), 3.22 (2H, t, J = 5.3 Hz), 2.85 (3H, s), 2.76 (3H, s), 2.28-2.23 (2H, m), 2.17-2.11 (2H, m), 1.73-1.67 (4H, m).

[0167] (Example 2) Preparation of methyl 1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-1-methylhydrazyl)cyclopentane-1-carboxylic acid

[0168] [Chemistry 28]

[0169] Under a nitrogen atmosphere, toluene (375 mL) was added to (E)-1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-1-methylhydrazyl)cyclopentane-1-carboxylic acid methyl oxalate (50.0 g, 97 mmol) and 2-picoline borane (8.7 g, 77 mmol) obtained in Reference Example 4 to suspend the mixture. An aqueous solution of oxalic acid (prepared by dissolving 17.4 g of oxalic acid in 235 mL of water) was added dropwise to this suspension while maintaining an internal temperature below 25°C, and the mixture was stirred for 8.5 hours. The organic layer was discarded, and toluene (375 mL) was added to the aqueous layer, and the mixture was maintained at room temperature overnight. After 12 hours, an aqueous solution of potassium hydroxide (prepared by dissolving 39.5 g of potassium hydroxide in 150 mL of water) was added dropwise while maintaining an internal temperature below 0°C. After stirring at 20°C for 0.5 hours, the aqueous layer was discarded. An aqueous sodium chloride solution (prepared by dissolving 30.1 g of sodium chloride in 150 mL of water) was added to the organic layer, and the mixture was stirred for 15 minutes. The aqueous layer was then removed, and the organic layer was concentrated to obtain a toluene solution of the target compound. Ethyl acetate (290 mL) was added to the resulting solution, and the mixture was kept at room temperature overnight.

[0170] HPLC purity: 97.91% Determination method: HPLC method A, retention time: 4.3 minutes. (Example 3) Preparation of 3-side-oxy-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propionic acid

[0171] [Chemistry 29]

[0172] Under a nitrogen atmosphere, 2.0 g (6.5 mmol) of 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline obtained in Examples 1-2 and 0.94 g (6.5 mol) of Michaelis-Menten acid were added to a reaction vessel, and toluene (10 mL) and n-heptane (10 mL) were further added to suspend the mixture. The external temperature of the reaction vessel was set to 110 °C, and the internal temperature of the reaction solution was raised to 100 °C and stirred for 5 hours. After confirming the completion of the reaction by HPLC, the internal temperature of the reaction solution was cooled to 25 °C and stirred for another 2 hours. The precipitated crystals were filtered and washed with a mixture prepared from toluene (4 mL) and n-heptane (4 mL). The wet powder was dried under reduced pressure at an external temperature of 35 °C to obtain the target product (2.1 g) (yield: 80%).

[0173] HPLC purity: 99.67% Determination method: HPLC method A, retention time: 7.5 minutes 1H-NMR (DMSO-D6) δ: 11.01 (1H,s), 9.53 (1H,s), 8.47 (1H,s), 8.25 (1H,d,J=8.6Hz), 8.22-8.21 (1H,m), 7.96-7.94 (1H,m), 3.42 (2H,s).

[0174] (Refer to Example 5) Preparation of 3-side-oxy-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propionic acid (conventional method)

[0175] [Chemical 30]

[0176] Under a nitrogen atmosphere, 54.88 kg of 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline and 25.76 kg of Michaelis-Menten acid obtained in Example 1 were added to a reaction vessel, and toluene (274 L) and n-heptane (274 L) were further added to suspend them. The internal temperature of the reaction solution was raised to above 90°C and stirred for 5 hours. After confirming the completion of the reaction by HPLC, the internal temperature of the reaction solution was cooled to 25°C, and stirred for more than 1 hour at an internal temperature of 15-25°C. The precipitated crystals were filtered and washed with a mixture prepared from toluene (110 L) and n-heptane (110 L). The wet powder was dried under reduced pressure at an external temperature of 40°C to obtain the target product (61.82 kg) (yield: 88%).

[0177] HPLC purity: 99.9%. Determination method: HPLC method A, retention time: 7.5 minutes. A comparison of Example 3 and Reference Example 5 is shown below. The purity of the compound was calculated based on HPLC analysis.

[0178] [Table 3]

[0179] In Example 3, it was found that the target compound was obtained with the same purity as that of Reference Example 5. (Example 4-1) Preparation of methyl 1-((2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)phenyl)methyl)-1-methyl-2-(3-sideoxy-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propionic)hydrazyl)cyclopentane-1-carboxylic acid

[0180] [Chemistry 31]

[0181] Under a nitrogen atmosphere, a solution of methyl 1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-1-methylhydrazyl)cyclopentane-1-carboxylic acid obtained in Example 2, and a solution of 3-sideoxy-3-((4-(trifluoromethyl)2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propionic acid (39.9 g, 101 mmol) in N,N-dimethylformamide (145 mL) obtained in Reference Example 5 were added to the reaction vessel. Pyridine (41.5 mL, 513 mmol) was added dropwise to the resulting solution while maintaining the internal temperature at -5°C. Next, a 50% ethyl acetate solution of propylphosphonic anhydride (43.0 g, 135 mmol) was added dropwise to the reaction solution while maintaining the internal temperature of the reaction solution at -5°C. After stirring the reaction mixture at 5°C for 15 minutes, 1.9 g (4.8 mmol) of 3-side-oxy-3-((4-(trifluoromethyl)2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propionic acid was added, and the mixture was stirred for another 3.5 hours. At 25°C, an aqueous solution of sodium chloride (prepared by dissolving 12.5 g of sodium chloride in 124 mL of water) was added to the reaction mixture, and the mixture was stirred for 20 minutes. The aqueous layer was discarded, and an aqueous solution of sodium chloride (prepared by dissolving 12.5 g of sodium chloride in 124 mL of water) was added to the organic layer, and the mixture was stirred for 20 minutes. The aqueous layer was then discarded, and an aqueous solution of dipotassium hydrogen phosphate (prepared by dissolving 45.7 g of dipotassium hydrogen phosphate in 249 mL of water) was added, and the mixture was stirred for 15 minutes before the aqueous layer was discharged. The organic layer was concentrated, and the precipitated inorganic salts were removed using a Kiriyama funnel. The filtrate was kept at room temperature overnight. After 13 hours, the filtrate was concentrated and dried, and 116 mL of 2-propanol was added to the residue. The resulting solution was stirred for 10 minutes, and then 382 mL of 2-propanol was added. The external temperature of the reaction vessel was set to 35°C, and the internal temperature of the reaction solution was maintained at 31°C–33°C. After stirring for 1 hour, the external temperature of the reaction vessel was lowered to 10°C over 1.25 hours. The internal temperature of the reaction solution was maintained at 12°C–14°C and stirred for 30 minutes, after which the external temperature of the reaction vessel was raised to 35°C. The internal temperature of the reaction solution was maintained at 30°C–35°C and stirred for 30 minutes, after which the external temperature of the reaction vessel was lowered to 0°C over 1.75 hours. After cooling the internal temperature of the reactor to below 5°C, the precipitated solid was filtered off. The resulting wet powder was washed with 207 mL of 2-propanol cooled to 0°C. This wet powder was dried under reduced pressure at an external temperature of 35–40°C to obtain the target product (65.7 g) (total yield of 2 steps: 84%).

[0182] HPLC purity: 99.49% Determination conditions: HPLC method B, HPLC retention time: 3.9 min. ¹H NMR (500MHz, DMSO-D6) δ: 11.15 (¹H, s), 9.51 (¹H, d, J = 0.9 Hz), 8.54 (¹H, d, J = 1.4 Hz), 8.32 (¹H, d, J = 8.6 Hz), 8.25 (¹H, d, J = 1.4 Hz), 7.97–7.95 (¹H, m), 7.00–6.98 (¹H, m), 6.93–6.91 (¹H, m), 4.70 (¹H, d, J = 16.3 Hz), 4.41 (¹H, d, J = 16.3 Hz), 4.14–4. 08(2H,m),3.96(1H,d,J=15.4Hz),3.69(1H,d,J=15.4Hz),3.61(3H,s),3.40(2H,t,J=5.9H z),3.22(3H,s),2.76(2H,t,J=5.7Hz),2.59-2.57(5H,m),2.27(3H,s),2.04-1.97(2H,m), 1.85-1.48(6H,m).

[0183] (Example 4-2) Synthesis of methyl 1-(2-((2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)phenyl)methyl)-1-methyl-2-(3-sideoxy-3-((4-(trifluoromethyl)2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propionic)hydrazyl)cyclopentane-1-carboxylic acid using (EtO)2POCl

[0184] [Chemistry 32]

[0185] A solution of methyl 1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-1-methylhydrazyl)cyclopentane-1-carboxylic acid (0.109 g, 0.254 mmol) in N,N-dimethylformamide (1.0 mL) and 3-sideoxy-3-((4-(trifluoromethyl)2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propionic acid (0.101 g, 0.257 mmol) was mixed, and the reaction vessel was purged with nitrogen. Pyridine (0.031 mL, 0.381 mmol) and (EtO)₂POCl (0.073 mL, 0.509 mmol) were added sequentially while the internal temperature of the reaction solution was -10 °C. After stirring at -10 °C for 1.5 hours, the formation rate of the target analyte was determined by HPLC area ratio.

[0186] Generation rate: 76.49%. Determination conditions: HPLC method A, retention time: 8.4 minutes. (Example 5) Preparation of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-sideoxy-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-methylamine

[0187] [Chemistry 33]

[0188] Methyl 1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-1-methyl-2-(3-sideoxy-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propionic)hydrazino)cyclopentane-1-carboxylic acid (34 kg, 42 mol), potassium carbonate (11.7 kg, 85 mol), and ethanol (268 kg) were added to a reaction vessel and fluorinated. Stirring and heating were then initiated. The reaction mixture was stirred for 2 hours from reflux, and the conversion rate was confirmed to be 100% by HPLC analysis. The resulting suspension was concentrated under reduced pressure, and ethyl acetate (170 L) was added. 1 M hydrochloric acid aqueous solution (85 kg) was added to the reaction mixture, stirred for 15 minutes, and then allowed to stand. The aqueous layer was then removed. Add 170 kg of a 10% potassium dihydrogen phosphate aqueous solution to the reaction mixture, stir for 15 minutes, allow to stand, and drain the aqueous layer. Add 170 kg of a 10% sodium chloride aqueous solution to the reaction mixture, stir for 15 minutes, allow to stand, and drain the aqueous layer. Concentrate the organic layer under reduced pressure, add 80 L of ethyl acetate to the resulting concentrate, and filter. During filtration, use 80 L of ethyl acetate to clean the container and piping. Concentrate the filtered solution again under reduced pressure, and confirm by 1H-NMR analysis that the molar ratio of ethyl acetate to the target compound is less than 3. Add 52 kg of ethanol and 52 kg of n-heptane to the crude product of the title compound, and proceed to the next step.

[0189] HPLC purity: 99.24%. Determination conditions: HPLC method A, retention time: 9.4 minutes. (Example 6) Preparation of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-sideoxy-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-methylamine p-toluenesulfonate

[0190] [Chemistry 34]

[0191] Under a nitrogen atmosphere, 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-sideoxy-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-en-9-methylamine (33 kg, 42 mol) obtained in Example 5 was added to a mixed solvent (52 kg of ethanol, 56 kg of n-heptane), and the resulting solution was stirred at an internal temperature of 25°C. Then, p-toluenesulfonic acid monohydrate (8 kg, 42 mol) dissolved in ethanol (13 kg) was added. Crystals of the title compound (0.03 kg, 0.035 mol) prepared by the method described in Non-Patent Document 10 were suspended in n-heptane (0.5 L) as seed crystals. The container of the suspension was then cleaned with n-heptane (0.5 L) and a cleaning solution was added. After stirring for 1 hour and confirming crystallization, n-heptane (56 kg) was added, and the crystallization solution was heated to an internal temperature of 33°C. The mixture was stirred at an internal temperature above 30°C for at least 30 minutes, then cooled to an external temperature of 15°C and stirred at an internal temperature below 25°C for at least 30 minutes. Next, n-heptane (56 kg) was added, and the mixture was stirred for at least 1 hour. The resulting suspension was filtered, and the wet powder was washed twice with n-heptane (67 kg). The wet powder was dried under reduced pressure at an external temperature of 40°C to obtain the title compound (36.7 kg) (yield 89%).

[0192] HPLC purity: 99.92%. Determination conditions: HPLC method A, retention time 9.4 min. ¹H-NMR (CDCl₃) δ: 16.60 (¹H, s), 12.82 (¹H, s), 11.40 (¹H, brs), 9.60 (¹H, s), 8.49 (¹H, d, J = 8.6 Hz), 7.95 (¹H, s), 7.90 (¹H, d, J = 1.5 Hz), 7.79 (¹H, dd, J = 8.6, 1.5 Hz), 7.75 (2H, d, J = 8.0 Hz), 7.16 (2H, d, J = 8.0 Hz), 7.06 (¹H, dd, J = 7.6, 7.7 Hz), 6.73 (¹H, dd, J = 7.6, 7.8), 5 .05(1H,d,J=14.3Hz),4.56(2H,m),4.21(1H,d,J=14.3Hz),3.86(2H,m),3.80(1H,m),3.60(1H,m),3.54(1H,m),3.40(1H,m),3.36(3 H,s),3.08(3H,d,J=4.3Hz),2.48(3H,s),2.35(3H,s),2.16(1H,m),1.74(2H,m),1.57(1H,m),1.53(1H,m),1.48(2H,m),1.31(1H,m).

[0193] (Example 7) Preparation of 7-[[2,3-difluoro-4-[2-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-sideoxy-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-methylamine p-toluenesulfonate was prepared by applying p-toluenesulfonic acid to an ethanol solution (0.5M, 0. 935 mL of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-sideoxy-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-en-9-methylamine (311.6 mg) was added and dissolved at 60 °C. Seed crystals were then added while stirring at room temperature, and most crystals were observed to precipitate after 30 minutes. After 24 hours, the resulting crystals were filtered off, and powder X-ray diffraction (PXRD) of the wet powder was performed. The results are shown in Figure 2. Further PXRD of the dried powder was performed after standing at room temperature for 1 hour. The latter powder had the same known crystal morphology, but the former showed a different PXRD pattern, confirming rapid crystal transfer during the drying step. The yield was 298.0 mg.

[0194] The powder X-ray diffraction pattern in Figure 2 shows the following powder X-ray diffraction patterns in the following order: crystals obtained by the method described in the document (Non-Patent Document 10, Technical Report No. 2017-501666) (using ethyl acetate), crystals obtained by the method described in the aforementioned document (using acetone), wet powder obtained in Example 7, and dry powder obtained in Example 7.

[0195] 2θ values ​​of wet powder: diffraction peaks at 3.7°, 5.0°, 7.4°, 7.9°, 14.8°, and 18.4° (±0.2°). 2θ values ​​of dry powder: diffraction peaks at 4.9°, 9.4°, 9.9°, 15.2°, 15.9°, 18.9°, and 22.7° (±0.2°).

[0196] Thermogravimetric analysis was performed on the dried powder of Example 7, and the results are shown in Figure 3. Peaks caused by melting are shown at 112.6°C (extrapolation point) and 126.6°C (peak). (Example 8) Preparation of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-sideoxy-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-methylamine p-toluenesulfonate: p-Toluenesulfonic acid ethanol solution (0.5M, 0. 936 mL of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-sideoxy-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-en-9-methylamine (311.9 mg) was added and dissolved at 60 °C. Then, while stirring at room temperature, seed crystals and n-heptane (0.936 mL) were added. After 30 minutes, most of the crystals were observed to precipitate. After further adding n-heptane (1.871 mL) for 24 hours, the resulting crystals were filtered off, and powder X-ray diffraction (PXRD) of the wet powder was performed. After further standing at room temperature for 1 hour, PXRD of the dry powder was performed. The results are shown in Figure 4. The powder X-ray diffraction pattern of the dried powder was the same as that of the type I crystals, but the powder X-ray diffraction pattern of the wet powder was different from that of the dried powder, confirming a rapid phase transfer of crystals during the drying step. The yield was 257.1 mg.

[0197] The powder X-ray diffraction pattern in Figure 4 shows the following powder X-ray diffraction patterns in the following order: crystals obtained by the method described in the document (Non-Patent Document 10, Technical Report No. 2017-501666) (using ethyl acetate), crystals obtained by the method described in the aforementioned document (using acetone), wet powder obtained in Example 8, and dry powder obtained in Example 8.

[0198] 2θ values ​​of wet powder: diffraction peaks at 3.7°, 4.9°, 7.3°, 7.7°, 14.2°, and 18.7° (±0.2°). 2θ values ​​of dry powder: diffraction peaks at 4.9°, 9.4°, 9.9°, 15.2°, 15.9°, 18.9°, and 22.6° (±0.2°).

[0199] Thermogravimetric analysis was performed on the dried powder of Example 8, and the results are shown in Figure 5. Melting peaks are shown at 119.6°C (interpolation point) and 130.2°C (peak). [Industrial Applicability]

[0200] This invention provides a method for manufacturing p-toluenesulfonate of 7-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-10-hydroxy-6-methyl-N-(4-methyl-2-(6-methylpyrimidin-4-yl)phenyl)-8-sideoxy-6,7-diazaspiro[4.5]dec-9-ene-9-carboxylamine, which is useful as an active ingredient in pharmaceuticals. By using the manufacturing method of this invention, p-toluenesulfonate of 7-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-10-hydroxy-6-methyl-N-(4-methyl-2-(6-methylpyrimidin-4-yl)phenyl)-8-sideoxy-6,7-diazaspiro[4.5]dec-9-ene-9-carboxylamine can be manufactured and supplied efficiently and well. [Simplified Explanation of the Diagram]

[0074] Figure 1 shows an example of the synthesis scheme of Compound I. Figure 2 shows the results of powder X-ray diffraction of the crystalline powder obtained in Example 7, and the powder X-ray diffraction patterns of crystals obtained by other methods. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 3 shows the thermogravimetric analysis results of the dried powder of Example 7. The horizontal axis represents temperature (°C), and the vertical axis represents the heat flow observed in the thermal analysis. Figure 4 shows the results of powder X-ray diffraction of the crystalline powder obtained in Example 8, and the powder X-ray diffraction patterns of crystals obtained by other methods. The vertical axis represents diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). Figure 5 shows the thermogravimetric analysis results of the dried powder of Example 8. The horizontal axis represents temperature (°C), and the vertical axis represents the heat flow observed in the thermal analysis.

Claims

1. A method for manufacturing a crystalline powder of a p-toluenesulfonate of a compound represented by Formula 1, the method comprising: converting the compound represented by Formula 1 into the aforementioned p-toluenesulfonate in a solvent, recovering the precipitated solid, and obtaining a wet powder of the aforementioned p-toluenesulfonate; subjecting the aforementioned wet powder to drying conditions to obtain a type I crystalline dry powder of the aforementioned p-toluenesulfonate, wherein the type I crystalline dry powder of the aforementioned p-toluenesulfonate has a powder X-ray diffraction pattern, the powder X-ray diffraction pattern comprising at least one peak selected from 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.5°) as a diffraction angle 2θ in powder X-ray diffraction; and the powder X-ray diffraction pattern of the aforementioned wet powder is different from the powder X-ray diffraction pattern of the dry powder.

2. The method as described in claim 1, wherein a poor solvent is further added to the mixture containing the solids prior to recovery, wherein the poor solvent is a solvent with low solubility for the p-toluenesulfonate of the compound represented by Formula 1.

3. The method as described in claim 2, wherein the aforementioned undesirable solvent is a solvent containing hexane or heptane.

4. The method as described in claim 2, wherein the aforementioned undesirable solvent is selected from hexane and heptane.

5. The method as described in claim 2, wherein the aforementioned undesirable solvent is a mixed solvent comprising hexane and heptane.

6. The method as claimed in any one of claims 1 to 5, wherein the dried powder of the aforementioned type I crystals of p-toluenesulfonate has a powder X-ray diffraction pattern, wherein the powder X-ray diffraction pattern includes at least one peak selected from 4.9°, 9.4°, 18.9° and 22.6° (±0.5°) as a diffraction angle 2θ in the powder X-ray diffraction.

7. The method as described in any one of claims 1 to 5, wherein the dried powder of the aforementioned type I crystals of p-toluenesulfonate has a powder X-ray diffraction pattern, wherein the powder X-ray diffraction pattern comprises peaks of 4.9°, 9.4°, 18.9° and 22.6° (±0.5°) as diffraction angles 2θ in the powder X-ray diffraction.

8. The method as described in any one of claims 1 to 5, wherein the dried powder of the aforementioned type I crystals of p-toluenesulfonate has a powder X-ray diffraction pattern, wherein the powder X-ray diffraction pattern comprises peaks of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.5°) as diffraction angles 2θ in the powder X-ray diffraction.

9. The method as claimed in any one of claims 1 to 5, wherein the dried powder of the aforementioned type I crystals of p-toluenesulfonate has a powder X-ray diffraction pattern, the powder X-ray diffraction pattern comprising at least one peak selected from 4.9°, 9.4°, 18.9° and 22.6° (±0.2°) as a diffraction angle 2θ in the powder X-ray diffraction.

10. The method as claimed in any one of claims 1 to 5, wherein the dried powder of the aforementioned type I crystals of p-toluenesulfonate has a powder X-ray diffraction pattern, wherein the powder X-ray diffraction pattern comprises peaks of 4.9°, 9.4°, 18.9° and 22.6° (±0.2°) as diffraction angles 2θ in the powder X-ray diffraction.

11. The method as claimed in any one of claims 1 to 5, wherein the dried powder of the aforementioned type I crystals of p-toluenesulfonate has a powder X-ray diffraction pattern, wherein the powder X-ray diffraction pattern comprises peaks of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9° and 22.6° (±0.2°) as diffraction angles 2θ in the powder X-ray diffraction.

12. A method for manufacturing a crystalline powder of a p-toluenesulfonate of a compound represented by Formula 1, the method comprising: 1) preparing a compound represented by Formula 2 by the following method, the method comprising: a) treating a compound represented by Formula 3 with C1-6 alkyl magnesium halide, C1-6 alkyl lithium, and zinc halide, [where X1 is a detaching group] and reacting it with a compound represented by Formula 4 in the presence of a palladium catalyst, [where X2 is a detaching group] b) obtaining a compound represented by Formula 5, and reacting the compound represented by Formula 5 with an alkali metal salt of dicarboxylic acid nitrileimine, thereby obtaining a compound represented by Formula 2 by decomposition of the obtained nitrileimine compound; 2) preparing a compound represented by Formula 1 by the compound represented by Formula 2; and 3) preparing a crystalline powder of a p-toluenesulfonate of a compound represented by Formula 1 by the method described in any one of claims 1 to 11.

13. The method as described in claim 12, wherein X1 is a halogen atom.

14. The method as described in claim 12, wherein X2 is a chlorine atom.

15. The method as described in claim 12, wherein the palladium catalyst is selected from the group consisting of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, bis(triphenylphosphino)palladium(II) dichloride, dichlorobis(tricyclohexylphosphino)palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-yl](3-chloropyridine)palladium(II) dichloride, (1,3-bis(2,6-diisopropylphenyl)imidazolinidine)(3-chloropyridine)palladium(II) dichloride, and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-yl](3-chloropyridine)palladium(II) dichloride.

16. The method as described in claim 12, wherein the alkali metal salt of dicarboxylic acid amide is potassium phthalimide or sodium phthalimide.

17. The method as described in any one of claims 12 to 16, wherein step 2) of preparing the compound represented by formula 1 from the compound represented by formula 2 comprises: i) reacting the compound represented by formula 2 with a malonic acid derivative to prepare the compound represented by formula 6, ii) reacting the compound represented by formula 6 with the compound represented by formula 7 in the presence of a condensing agent to prepare the compound represented by formula 8, and iii) preparing the compound represented by formula 1 by a cyclization reaction of the compound represented by formula 8.

18. The method as described in claim 17, wherein the malonic acid derivative is selected from the group consisting of Meldrum's acid, dialkylmalonic acid, and malonic acid.

Images