Method for producing dihydropyridazine-3,5-dione derivatives

Abstract

The purpose of the present invention is to provide a method that is for producing p-toluenesulfonate of 7-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-10-hydroxy-6-methy-N-(4-methyl-2-(6-methylpyrimidine-4-yl)phenyl)-8-oxo-6,7-diazaspiro[4.5]deca-9-en-9-carboxamide which is industrially preferable and that makes it possible to obtain a target product more easily and more inexpensively than conventional methods.　For the present invention, a method was found which makes it possible to efficiently obtain a target product via a step for obtaining a wet powder of p-toluenesulfonate of 7-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-10-hydroxy-6-methy-N-(4-methyl-2-(6-methylpyrimidine-4-yl)phenyl)-8-oxo-6,7-diazaspiro[4.5]deca-9-en-9-carboxamide and also a step for drying the wet powder.

Description

[Technical field]

[0001] The present invention relates to a process for producing dihydropyridazine-3,5-dione derivatives. [Background technology]

[0002] It is known that in patients with renal dysfunction such as chronic kidney disease (CKD) and end-stage kidney disease (ESKD), phosphorus accumulates in the body, causing hyperphosphatemia. Calcification of blood vessels due to hyperphosphatemia can cause cardiovascular dysfunction. It also leads to excessive secretion of parathyroid hormone, which causes bone lesions. Thus, hyperphosphatemia can be a factor that worsens the prognosis and QOL of patients with end-stage renal failure and dialysis patients (Non-Patent Document 1).

[0003] CKD is classified into stages 1 to 5 according to the degree of progression (Non-Patent Document 2, Non-Patent Document 3). Blood phosphorus concentration in patients with CKD stages 3 and 4 is related to the morbidity and mortality of cardiovascular disease, and suppression of blood phosphorus concentration in these patients may lead to the alleviation or prevention of cardiovascular disease. Furthermore, controlling the phosphate load of patients at an earlier stage may alleviate and / or prevent the progression of the disease in early stage CDK patients (Non-Patent Document 4).

[0004] In the current treatment of hyperphosphatemia, phosphate binders are used to suppress phosphate absorption in the digestive tract. Phosphate binders include non-metallic polymeric binders such as sevelamer hydrochloride, calcium salt preparations such as precipitated calcium carbonate, and metallic binders such as lanthanum carbonate. However, poor compliance is observed because several grams of the agent must be taken per day, and side effects due to calcium accumulation in the body have been reported. Therefore, there is a strong demand for the development of a new therapeutic agent for hyperphosphatemia that overcomes these problems of phosphate binders (Non-Patent Document 4).

[0005] There are three known families of sodium-dependent phosphate transporters: NaPi-I, NaPi-II, and NaPi-III. These families are further classified into isotypes, and in the case of the NaPi-II family, NaPi-IIa, NaPi-IIb, and NaPi-IIc are known. In particular, phosphate transporters such as NaPi-IIb, PiT-1, and PiT-2 are known to be responsible for phosphate absorption in the digestive tract, and selectively inhibiting only these phosphate transporters involved in phosphate absorption is expected to bring about a strong phosphate absorption inhibitory effect in the digestive tract and reduce blood phosphorus concentration (Non-Patent Document 5, Non-Patent Document 6, Non-Patent Document 7, and Non-Patent Document 8).

[0006] So far, NTX1942 (Patent Document 1) and condensed thiophene derivatives (Patent Document 2, Patent Document 3, Patent Document 4, and Patent Document 5) have been reported as NaPi-IIb inhibitors. Dihydropyridazine-3,5-dione derivatives, such as 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-carboxamide (hereinafter also referred to as compound I) represented by formula 1, have been reported to exhibit NaPi-IIb, PiT-1, and PiT-2 inhibitory effects (Patent Document 6 and Patent Document 7).

[0007] [ka]

[0008] In Patent Document 6 and Patent Document 7, a compound represented by formula 1 is produced using a compound obtained by Suzuki coupling reaction between a phenylboronic acid ester derivative and a chloropyrimidine derivative as an intermediate. In the production of a compound including a Suzuki coupling reaction in a reaction process, the production cost becomes an issue. For example, it is known that palladium used as a catalyst increases the production cost, and that bis-pinacolatodiboron, which is a raw material for boronic acid ester, increases the cost of the raw material (Non-Patent Document 9, Patent Document 8).

[0009] Non-Patent Document 10 describes a method for producing a salt of the compound represented by formula 1 and its crystal. In addition, it is desirable to select the most thermodynamically stable crystal form at around room temperature from among the crystal polymorphs of a solid low molecular weight drug substance, and it is known that selecting the most stable form as the crystal of a development candidate and establishing a robust production method for it are important factors that directly affect 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 literature]

[0011] [Non-licensed document 1] Hruska, KA et al., Kidney Int., 2008, 74(2), 148-157.

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

Non-licensed literature 10

Non-licensed Document 11

[0012] It is considered that dihydropyridazine-3,5-dione derivatives are used as therapeutic drugs for chronic diseases such as hyperphosphatemia, that is, treatment by drug administration is long-term. In order to ensure a stable supply of pharmaceuticals and to reduce manufacturing costs, the present inventors have closely examined the manufacturing method of the pharmaceutical ingredient from the viewpoints of raw material costs and reaction conditions.

[0013] Specifically, a method for producing p-toluenesulfonic acid salt of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-carboxamide represented by formula 1 was investigated. 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (compound II), which is a key intermediate in the production of the compound represented by formula 1:

[0014] [ka] The raw material used in this study, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline, is expensive and has a large impact on the manufacturing cost, which is one of the factors that push up the manufacturing cost of the active pharmaceutical ingredient. In addition, in the process of manufacturing a specific crystalline form of p-toluenesulfonate salt of the compound represented by formula 1, which can be an active ingredient, it was found that problems such as slow crystal formation and oil-out in the reaction solution occurred, resulting in a decrease in the yield of the target product and contamination with another crystalline form. [Means for solving the problem]

[0015] The present inventors have conducted intensive research to solve these problems. Using an alternative raw material to a phenylboronic acid ester derivative, which is expensive among raw materials, the inventors have found a method for obtaining a p-toluenesulfonate salt of the compound represented by formula 1 without increasing the amount of impurities mixed into the drug substance compared to the conventional method. Furthermore, in the conventional method, the p-toluenesulfonate salt of the compound represented by formula 1 is obtained by mixing the compound represented by formula 1 with p-toluenesulfonic acid, whereas the inventors have found that the desired crystals can be obtained in a high yield by obtaining a specific solvate of the p-toluenesulfonate salt of the compound represented by formula 1 and then removing the solvent, and that the desired crystals can be obtained without being mixed with other crystal forms, thereby completing the present invention.

[0016] That is, this specification includes the disclosure of the following inventions. [1-1]Formula 1

[0017] [ka] A method for producing a crystalline powder of a p-toluenesulfonate salt of a compound represented by the following formula: converting the compound represented by formula 1 into said p-toluenesulfonate salt in a solvent and collecting the precipitated solid to obtain a wet powder of said p-toluenesulfonate salt; subjecting the wet powder to drying conditions to obtain a dry powder of the Type 1 crystal of the p-toluenesulfonate salt. The method comprising:

[0018] [1-2] A1) preparing an ethanol solution of a compound represented by formula 1 and p-toluenesulfonic acid; A2) adding a poor solvent to the solution to precipitate a solid; A3) recovering the solid to obtain a wet powder of the p-toluenesulfonate salt; and A4) subjecting the wet powder to drying conditions to obtain a dry powder of the Type 1 crystal of the p-toluenesulfonate salt. The method according to [1-1], comprising:

[0019] [1-3] The method according to [1-2], wherein the poor solvent used in A2 is used in the range of 0.8 parts by weight or more and 3.5 parts by weight or less per part by weight of ethanol used in A1.

[0020] [1-4]B1) dissolving a compound represented by formula 1 in a mixed solvent containing ethanol and a poor 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 to obtain a wet powder of the p-toluenesulfonate salt; and B4) subjecting the wet powder to drying conditions to obtain a dry powder of the Type 1 crystal of the p-toluenesulfonate salt. The method according to [1-1], comprising:

[0021] [1-5] The method according to [1-4], wherein the poor solvent is used in an amount of 0.8 parts by weight or more per part by weight of ethanol used in B1.

[0022] [1-6] The method according to [1-4], wherein the poor solvent is used in an amount of 0.8 parts by weight or more and 3.5 parts by weight or less per part by weight of ethanol used in B1.

[0023] [1-7] The method according to any one of [1-1] to [1-6], further comprising adding a poor solvent to the mixture containing the solid before recovery.

[0024] [1-8] The method according to any one of [1-2] to [1-7], wherein the poor solvent is a solvent containing hexane or heptane; a solvent selected from hexane and heptane; or a mixed solvent containing hexane and heptane.

[0025] [1-9] The dry powder of the 1st type crystal of the p-toluenesulfonate salt contains at least one peak selected from the diffraction angles 2θ of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.5°) in powder X-ray diffraction. The method according to any one of [1-1] to [1-8], having a powder X-ray diffraction pattern comprising:

[0026] [1-10] The method according to any of [1-1] to [1-9], wherein the dry powder of the type 1 crystal of p-toluenesulfonate has a powder X-ray diffraction pattern including at least one peak at a diffraction angle 2θ selected from among 4.9°, 9.4°, 15.8°, 18.9°, and 22.6° (±0.5°) in powder X-ray diffraction.

[0027] [1-11] The method according to any of [1-1] to [1-10], wherein the dry powder of the type 1 crystal of p-toluenesulfonate has a powder X-ray diffraction pattern including a peak at a diffraction angle 2θ of 15.8° (±0.5°) in powder X-ray diffraction.

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

[0029] [1-13] The method according to any one of [1-1] to [1-12], wherein the wet powder is a wet crystal. [1-14] The method according to [1-13], wherein the wet crystals contain ethanol.

[0030] [1-15] The method according to any one of [1-2] to [1-14], wherein the poor solvent comprises heptane, hexane, or pentane.

[0031] [1-16] The method according to any of [1-1] to [1-15], wherein the dry powder of the type 1 crystal of p-toluenesulfonate has a powder X-ray diffraction pattern including peaks at diffraction angles 2θ of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.5°) in powder X-ray diffraction.

[0032] [1-17] The method according to any of [1-1] to [1-16], wherein the dry powder of the type 1 crystal of p-toluenesulfonate has a powder X-ray diffraction pattern including peaks at diffraction angles 2θ of 4.9°, 9.4°, 15.8°, 18.9°, and 22.6° (±0.5°) in powder X-ray diffraction.

[0033] [1-18] The method according to any of [1-1] to [1-17], wherein the dry powder of the type 1 crystal of p-toluenesulfonate has a powder X-ray diffraction pattern including a peak at a diffraction angle 2θ of 15.8° (±0.5°) in powder X-ray diffraction.

[0034] [1-19] The method according to any of [1-1] to [1-18], wherein the dry powder of the type 1 crystal of p-toluenesulfonate has a powder X-ray diffraction pattern including peaks at diffraction angles 2θ of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°) in powder X-ray diffraction.

[0035] [1-20] The method according to any of [1-1] to [1-19], wherein the dry powder of the type 1 crystal of p-toluenesulfonate has a powder X-ray diffraction pattern including peaks at diffraction angles 2θ of 4.9°, 9.4°, 15.8°, 18.9°, and 22.6° (±0.2°) in powder X-ray diffraction.

[0036] [1-21] The method according to any one of [1-1] to [1-20], wherein the amount of the solvent used in converting the compound represented by formula 1 to the p-toluenesulfonate is 2 to 15 parts by weight relative to 1 part by weight of the compound represented by formula 1.

[0037] [1-22] The method according to any one of [1-1] to [1-21], wherein the temperature of the solution when precipitating the solid is in the range of −5° C. or more and 70° C. or less.

[0038] [1-23] The method according to any one of [1-1] to [1-22], wherein the amount of p-toluenesulfonic acid used in converting the compound represented by formula 1 to the p-toluenesulfonic acid salt is in the range of 1 equivalent or more and 1.2 equivalents or less relative to 1 equivalent of the compound represented by formula 1.

[0039] [2-1]Formula 2:

[0040] [ka] A method for producing a compound represented by the following formula: formula 3

[0041] [ka] [where, X 1 is a leaving group] The compound represented by C 1-6 Alkyl magnesium halide, C 1-6 Treatment with alkyllithium and zinc halide affords the compound of formula 4.

[0042] [ka] [where, X 2 is a leaving group] and a compound represented by the formula 5 in the presence of a palladium catalyst.

[0043] [ka] and obtaining a compound represented by the formula: The compound represented by formula 5 is reacted with an alkali metal salt of a dicarboxylic acid imide, and the resulting imide compound is decomposed to obtain the compound represented by formula 2. The method comprising:

[0044] [2-2]X 1 The method according to [2-1], wherein

[0045] [2-3]X 1 The method according to [2-1] or [2-2], wherein

[0046] [2-4]X 2 The method according to any one of [2-1] to [2-3], wherein

[0047] [2-5]C 1-6 Alkyl magnesium halide, C 1-6 The method according to any one of [2-1] to [2-4], wherein the compound is an alkyl magnesium chloride.

[0048] [2-6] The method according to any one of [2-1] to [2-5], wherein the zinc halide is selected from the group consisting of ZnCl2, ZnBr2, and ZnI2.

[0049] [2-7] Palladium catalysts include 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, bis(triphenylphosphine)palladium(II) dichloride, dichlorobis(tricyclohexylphosphine)palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazo] The method according to any one of [2-1] to [2-6], wherein the compound is selected from the group consisting of [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride, and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride.

[0050] [2-8] The method according to any one of [2-1] to [2-7], wherein the alkali metal dicarboxylic acid imide salt is potassium phthalimide.

[0051] [2-9] The method according to any one of [2-1] to [2-8], wherein the imide decomposition reaction is carried out by reacting an imide compound with a nucleophile selected from hydrazine hydrate and methylamine.

[0052] [2-10] The method according to any one of [2-1] to [2-9], wherein the reaction of the compound represented by formula 5 with the dicarboxylic acid imide 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-imidazolidinone, N,N'-dimethylpropyleneurea, acetonitrile, and dimethylsulfoxide, or in a mixed solvent of two or more solvents selected from the above solvents.

[0053] [2-11] The method according to any one of [2-1] to [2-10], wherein the reaction to obtain the compound represented by formula 5 is carried out in a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane, 1,4-dioxane, and 1,3-dioxane, or in a reaction solvent containing two or more solvents selected from the solvents.

[0054] [2-12] The method according to any one of [2-1] to [2-11], wherein the reaction to obtain the compound represented by formula 5 is carried out in a solvent selected from tetrahydrofuran, 2-methyltetrahydrofuran, and dimethoxyethane, or in a reaction solvent containing two or more solvents selected from the above solvents.

[0055] [2-13] The method according to 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 mixture of these solvents.

[0056] [2-14] Compound represented by formula 3 and C 1-6In a reaction system in which alkyl magnesium halide is present, C 1-6 The method according to any one of [2-1] to [2-13], wherein an alkyl lithium is added dropwise, and then a zinc halide is added dropwise to the reaction system.

[0057] [2-15]C 1-6 Alkyl magnesium halide, C 1-6 The method according to any one of [2-1] to [2-14], wherein a solution of a palladium catalyst and a compound represented by formula 4 is added dropwise to a reaction system containing an alkyl lithium and a compound represented by formula 3 treated with a zinc halide.

[0058] [3-1]Formula 1: [ka] A method for producing a compound represented by the formula: 1) preparing a compound represented by formula 2 by a method according to any one of [2-1] to [2-15]; 2) Reacting the compound represented by formula 2 with a malonic acid derivative to obtain a compound represented by formula 6:

[0059] [ka] preparing a compound represented by 3) A compound represented by formula 6 and a compound represented by formula 7:

[0060] [ka] In the presence of a condensing agent, a compound represented by formula 8:

[0061] [ka] preparing a compound represented by 4) preparing a compound of formula 1 by cyclization of a compound of formula 8; The method comprising:

[0062] [3-2] The method according to [3-1], wherein the malonic acid derivative is selected from the group consisting of Meldrum's acid, dialkylmalonic acid, and malonic acid.

[0063] [3-3] The method according to [3-1] or [3-2], wherein the reaction of the compound represented by formula 2 with a malonic acid derivative is carried out in a solvent selected from the group consisting of toluene, heptane, acetonitrile, methanol, and ethanol, or in a mixed solvent of two or more solvents selected from the above solvents.

[0064] [3-4] The method according to any one of [3-1] to [3-3], wherein the condensing agent is selected from the group consisting of propylphosphonic anhydride (cyclic trimer), diethyl chlorophosphate, and N,N'-diisopropylcarbodiimide.

[0065] [3-5] The method according to any one of [3-1] to [3-4], 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-imidazolidinone, N,N'-dimethylpropyleneurea, acetonitrile, and dimethylsulfoxide, or in a mixed solvent of two or more solvents selected from the solvents.

[0066] [3-6] The method according to any one of [3-1] to [3-5], 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.

[0067] [4-1] Formula 1 [ka] A method for producing a crystal of a p-toluenesulfonate salt of a compound represented by the following formula: converting the compound of formula 1 to said p-toluenesulfonic acid salt in a solvent and collecting the precipitated solid to obtain said wet p-toluenesulfonic acid salt; subjecting the wet p-toluenesulfonate to drying conditions to obtain dried Form 1 crystals of the p-toluenesulfonate. The method comprising:

[0068] [4-2] The method according to [4-1], wherein the wet p-toluenesulfonate salt is a powder.

[0069] [4-3] The method according to [4-1] or [4-2], wherein the dried type 1 crystals of the p-toluenesulfonate salt are powder. Effect of the Invention

[0070] The present invention provides an efficient method for preparing p-toluenesulfonate of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-carboxamide (Compound I), which has strong inhibitory activity against NaPi-IIb, PiT-1, and PiT-2. [Brief description of the drawings]

[0071] [Figure 1] FIG. 1 shows an example of a synthesis scheme for compound I. [Diagram 2] 2 shows the results of powder X-ray diffraction measurement 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 the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Diagram 3] 3 shows the results of thermogravimetric analysis of the dry 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] 4 shows the results of powder X-ray diffraction measurement 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 the diffraction intensity, and the horizontal axis represents the diffraction angle 2θ (°). [Diagram 5] 5 shows the results of thermogravimetric analysis of the dry powder of Example 8. The horizontal axis represents temperature (° C.), and the vertical axis represents the heat flow observed in the thermal analysis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0072] The abbreviations used in this specification are listed below. DIC: N,N'-diisopropylcarbodiimide DIPEA: N,N-diisopropylethylamine DMA: N,N-Dimethylacetamide DMF: N,N-dimethylformamide DMI: 1,3-Dimethyl-2-imidazolidinone DMSO: Dimethyl sulfoxide DMPU: N,N'-Dimethylpropylene urea EtOH: Ethanol GC: Gas chromatography HPLC: High-performance liquid chromatography MeCN: Acetonitrile MeOH: Methanol MTBE: Methyl tert-butyl ether NMP: N-methylpyrrolidone NMR: Nuclear magnetic resonance spectroscopy PDA: Photodiode array detector T3P: Propylphosphonic anhydride t-Bu: t-Butyl TEA: Triethylamine TFA: Trifluoroacetic acid

[0073] (Definition of functional groups, etc.) The term "leaving group" as used herein refers to a group which can be eliminated by cleavage of a chemical bond and which can generate an anionic atom or an anionic molecule upon elimination. Examples of such a group include halogeno groups consisting of halogen atoms such as a fluoro group, a chloro group, a bromo group, or an iodo group, as well as sulfonyl groups such as a mesyl group, a tosyl group, a trifluoromethanesulfonyl group, or a nitrophenylsulfonyl group.

[0074] As used herein, the term "halogen atom" is exemplified by a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. In this specification, "alkyl" refers to a monovalent group derived by removing any one hydrogen atom from an aliphatic hydrocarbon, does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in the skeleton, and has a subset of hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. The alkyl group includes linear, branched, and cyclic alkyl groups. The alkyl group may have 1 to 20 carbon atoms (C 1-20 , hereinafter referred to as “C p-q " means that the number of carbon atoms is p to q.) 1-6 Examples of the alkyl group include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, tert-butyl, sec-butyl, cyclopentyl, and cyclohexyl.

[0075] In the present specification, the temperature at which the compound is handled is, for example, a temperature near the room temperature in the working environment of a normal worker (room temperature), for example, in the range of 10°C to 30°C, or in the range of 15°C to 25°C. The temperature at which the compound is handled in the reaction vessel is, for example, in the range of -100°C by using a refrigerant such as liquid nitrogen to near the boiling point of the solvent. A temperature suitable for efficiently producing the target product can be selected depending on the stability of the compound and the reactivity of the starting material.

[0076] In one aspect of the present invention, 4-( trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (compound II) can be prepared.

[0077] [ka]

[0078] In the formula, X 1 and X 2 Each represents a leaving group. The compound represented by formula 3, which is the starting material, can be a commercially available compound. 1 Examples of the leaving group X include a halogen atom, preferably a fluorine atom or a chlorine atom, and a fluorine atom is particularly preferred. 2 Examples of the halogen atom include a halogen atom, preferably a chlorine atom, a bromine atom, or an iodine atom, and a particularly preferred example is a chlorine atom.

[0079] In one embodiment, a solution of the compound represented by formula 3 is subjected to, for example, C at −100 to 10° C., preferably −60 to 0° C., more preferably −30 to −10° C. 1-6 Alkyl magnesium halides and C 1-6 Add alkyl lithium. The molar ratio of the reagent used [C 1-6 Alkyl lithium / C 1-6 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; 1-6 A solution of alkyl magnesium halide, followed by C 1-6The alkyl lithium solution can be added in that order. In this case, the amount of alkyl magnesium halide relative to the compound represented by formula 4 is not particularly limited, but can be, for example, 0.25 to 2.0 equivalents, preferably 0.28 to 1.0 equivalents, more preferably 0.30 to 0.50 equivalents. The compound represented by formula 3 can be used in an amount of, for example, 0.8 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents, more preferably 1.3 to 1.7 equivalents relative to the compound represented by formula 4. The drop time can be appropriately set taking into consideration the reaction scale and the change in temperature of the reaction solution. C 1-6 After the alkyllithium solution is added dropwise, the resulting reaction mixture can be stirred, for example, at −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.

[0080] Examples of the solvent used for the solution of the compound represented by formula 3 include ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, etc.), and hydrocarbons (e.g., pentane, hexane, heptane, benzene, toluene, etc.). 1-6 Examples of the solvent for the alkyl magnesium halide solution include ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, etc.), and hydrocarbons (e.g., pentane, hexane, heptane, benzene, toluene, etc.). 1-6 Examples of the solvent for the alkyllithium solution include hydrocarbons (e.g., pentane, hexane, heptane, benzene, toluene, etc.) and ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, etc.).

[0081] Subsequently, a zinc halide solution is dropped into the obtained reaction mixture at, for example, -60 to 10°C, preferably -50 to 0°C, more preferably -30 to -10°C. Here, for example, 0.1 to 2.0 equivalents, preferably 0.6 to 1.5 equivalents, more preferably 0.8 to 1.3 equivalents of zinc halide can be used relative to the compound represented by formula 4. The drop time can be appropriately set in consideration of the reaction scale and the change in temperature of the reaction solution. Examples of the solvent used for the zinc halide solution include ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran, diethyl ether, t-butyl methyl ether, diisopropyl ether, cyclopentyl methyl ether, 1,2-dimethoxyethane, etc.), hydrocarbons (e.g., pentane, hexane, heptane, benzene, toluene, etc.), etc.

[0082] After the zinc halide solution is dropped, the resulting reaction mixture can be stirred at, for example, -60 to 10°C, preferably -40 to 10°C, and more preferably -20 to 5°C. The stirring time can be, for example, 0.1 to 4 hours, preferably 0.15 to 2 hours, and more preferably 0.2 to 1.5 hours. Subsequently, when the compound represented by formula 4 and the palladium catalyst are added to the reaction mixture, they can be added at a temperature of, for example, -20 to 20°C, preferably -20 to 10°C, and more preferably -10 to 5°C. Here, the amount of the palladium catalyst that can be used is, for example, 0.001 to 0.1 equivalents (0.1 to 10 mol%), preferably 0.003 to 0.05 equivalents (0.3 to 5 mol%), and more preferably 0.005 to 0.02 equivalents (0.5 to 2 mol%) relative to the compound represented by formula 4.

[0083] The reaction mixture obtained by adding the compound represented by formula 4 and the palladium catalyst is heated, for example, at 25 to 100°C, preferably 40 to 80°C, and more preferably 50 to 70°C, and the stirring at that time can be performed, for example, for 0.1 to 12 hours, preferably 0.5 to 8 hours, and more preferably 1 to 3 hours.

[0084] The post-treatment of the reaction mixture after addition of the compound represented by formula 4 and the palladium catalyst can be carried out after confirming the decrease or disappearance of the compound represented by formula 4 in the reaction system by analysis using HPLC, GC, etc. The obtained compound represented by formula 5 may be subjected to the next step after purification by column chromatography, etc., or may be subjected to the next step without any particular purification.

[0085] In one embodiment of the above process, 1-6 Examples of alkyl magnesium halides include C 1-6 Alkyl magnesium chloride, specifically C 3-6 Examples of the alkyl magnesium chloride include i-propyl magnesium chloride, n-butyl magnesium chloride, cyclopentyl magnesium chloride, and cyclohexyl magnesium chloride. 1-6 The alkyl magnesium halide can be used as a solution in a suitable solvent.

[0086] In one embodiment of the above process, 1-6 The alkyl lithium is not particularly limited, and for example, C 1-6 Alkyl lithium, specifically methyl lithium, n-butyl lithium, s-butyl lithium, and t-butyl lithium, etc. 1-6 The alkyllithium can be used as a solution in a suitable solvent.

[0087] In one embodiment of the above process, the zinc halide is not particularly limited and may be, for example, a zinc halide that is easily available as an industrial raw material, specifically, zinc chloride, zinc bromide, zinc iodide, etc. These zinc halides may be used in the form of a solution in a suitable solvent.

[0088] In one embodiment of the above-mentioned step, the palladium catalyst is not particularly limited as long as it acts as a catalyst for the reaction, and examples thereof include 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, bis(triphenylphosphine)palladium(II) dichloride, dichlorobis(tricyclohexylphosphine)palladium(II) dichloride, and the like. palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride, or [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride.

[0089] In one embodiment of the above process, X 1 is a fluorine atom, and X 2 is a chlorine atom, C 1-6 Alkyl magnesium halide is C 3-6 In another embodiment of the above process, X is an alkyl magnesium chloride and the zinc halide is zinc chloride. 1 is a fluorine atom, and X 2 is a chlorine atom, C 1-6 Alkyl magnesium halide is C 3-6 The alkyl magnesium chloride is the zinc halide, the zinc halide is zinc chloride, and the palladium catalyst is 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex or 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex.

[0090] In one embodiment, the compound represented by formula 5 can be reacted with a dicarboxylic acid imide alkali metal salt in a suitable solvent at a suitable temperature, for example, 50 to 150°C, preferably 80 to 130°C, more preferably 90 to 110°C. Here, for example, 0.9 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents, more preferably 1.05 to 1.2 equivalents of a dicarboxylic acid imide alkali metal salt can be used relative to the compound represented by formula 5. The reaction time can be appropriately set in consideration of the reaction scale and the change in temperature of the reaction solution. As the solvent, for example, acetonitrile, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone (DMI), N,N'-dimethylpropyleneurea (DMPU), or a mixed solvent of two or more solvents selected from the above solvents can be used. Preferably, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc. can be used. Examples of the dicarboxylic acid imide alkali metal salt include potassium phthalimide and sodium phthalimide, and potassium phthalimide is preferred.

[0091] After confirming the decrease 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 imide structure into an amine (imide decomposition reaction). The reaction analysis of the imide decomposition reaction can be omitted. The reaction temperature is not particularly limited, but can be, for example, 0 to 150°C, preferably 25 to 100°C, and more preferably 40 to 60°C. Here, the nucleophile can be, for example, C 1-6 Amines such as alkylamines and hydrazines can be used, and preferably C 1-6An aqueous solution of alkylamine, more preferably methylamine, can be used. The amount of the aqueous solution of methylamine is not particularly limited as long as no significant side reaction occurs, but for example, an amount of methylamine that is 2 to 30 equivalents, preferably 3 to 20 equivalents, more preferably 5 to 15 equivalents relative to the compound represented by formula 5 can be used. The reaction time can be appropriately set in consideration of the reaction scale and the change in temperature of the reaction solution. The crude product of the compound represented by formula 2 (compound II) can be purified. Examples of the purification method include column chromatography and recrystallization.

[0092] Compound II obtained by the above method can be used as a synthetic intermediate in the production method of compound I described in known documents (Patent Documents 6 and 7, and Non-Patent Document 10).

[0093] More specifically, an example of a synthetic intermediate of compound I is a compound represented by formula 6, which is obtained by reacting compound II with a malonic acid derivative in an appropriate solvent.

[0094] [ka]

[0095] One embodiment of the malonic acid derivative used in the above method is exemplified by dialkylmalonic acids such as Meldrum's acid, dimethylmalonic acid, and diethylmalonic acid, or malonic acid. Meldrum's acid is preferred. The solvent used in this step is not particularly limited as long as it is a solvent used in normal chemical reactions and does not interfere with the reaction, but it is preferred to carry out the step in a solvent selected from toluene, heptane, acetonitrile, methanol, and ethanol, or a mixed solvent of two or more solvents selected from the above solvents.

[0096] More specifically, an example of a synthetic intermediate of compound I is a compound represented by formula 8, which is obtained by condensing a compound represented by formula 7, which can be produced by a known method (Patent Documents 6 and 7), with a compound represented by formula 6 in an appropriate solvent.

[0097] [ka]

[0098] The condensation reaction between the compound represented by formula 6 and the compound represented by formula 7 can be carried out by a method that is commonly used by those skilled in the art for the condensation reaction between a carboxyl group and an amino group. One embodiment of the condensation reaction is a condensation reaction using a condensing agent. Examples of the condensing agent include diethyl chlorophosphate, propylphosphonic anhydride (T3P), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI). Diethyl chlorophosphate or propylphosphonic anhydride (T3P) is preferred. The solvent used in this step is not particularly limited as long as it is a solvent used in ordinary chemical reactions and does not interfere with the reaction, but it is preferable to carry out the step in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone, N,N'-dimethylpropyleneurea, acetonitrile, and dimethylsulfoxide, or in a mixed solvent of two or more solvents selected from the above solvents. If necessary, the condensation reaction is carried out in the presence of a base. Specific examples of the base include bases selected from the group consisting of pyridine, dimethylaminopyridine, N,N-diisopropylethylamine, and triethylamine.

[0099] In one aspect of the present invention, there is provided a method for producing a crystalline powder of p-toluenesulfonate (TsOH salt) of Compound I. The outline of the production method is shown in the following scheme.

[0100] [ka]

[0101] In one embodiment of the present invention, the p-toluenesulfonic acid salt of compound I can be obtained by precipitating the p-toluenesulfonic acid salt of compound I from a solution in which compound I and p-toluenesulfonic acid are dissolved in a solvent. The amount of p-toluenesulfonic acid used can be, for example, 1 equivalent or more, specifically 1 equivalent, relative to compound I. The p-toluenesulfonic acid used can be a commercially available product, preferably p-toluenesulfonic acid salt monohydrate.

[0102] Ethanol can be used as a solvent for the solution of compound I and p-toluenesulfonic acid. For the precipitation of the desired p-toluenesulfonic acid salt, seed crystals may be added and / or other solvents may be added to the ethanol solution. As the other solvent, a solvent (poor solvent) in which the desired substance has low solubility can be used for the purpose of increasing the amount of precipitation of the desired substance or for the purpose of increasing the precipitation rate of the desired substance. Examples of such poor solvents include hexane, heptane, and pentane. The mixing ratio of ethanol and other solvents when precipitating crystals from the solution can be 0.80 to 3.5, preferably 1.0 to 3.0, more preferably 1.2 to 2.5, and most preferably 1.5 to 2.2, in terms of the ratio of parts by weight of the other solvent to 1.0 part by weight of ethanol. As the seed crystal, for example, the crystals described in Non-Patent Document 10 can be used.

[0103] The "type 1 crystal" in the present invention is one embodiment of the crystal of p-toluenesulfonate salt of Compound I, and it is described that this type 1 crystal is characterized by having peaks at diffraction angles (2θ) of about 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° in a powder X-ray diffraction pattern (Non-Patent Document 9). The diffraction angles (2θ) of the type 1 crystal may have a powder X-ray diffraction pattern including at least one peak selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°), or may have all of them.

[0104] It is also described that thermogravimetric analysis shows peaks at 112.6°C (extrapolation point) and 126.6°C (peak top) due to melting. After the desired p-toluenesulfonate is precipitated, another solvent may be added to further increase the amount of precipitate. Examples of the other solvent include hexane, heptane, and pentane. The mixing ratio of ethanol and the other solvent after the re-addition of the other solvent is 7.0 to 28 parts by weight of the other solvent to 8.0 parts by weight of ethanol, preferably 8.0 to 24 parts by weight, more preferably 10 to 20 parts by weight, and most preferably 14 to 20 parts by weight.

[0105] In the above process, the ethanol solution for dissolving compound I and p-toluenesulfonic acid can be, for example, at 22 to 28°C, specifically at 25°C. Thereafter, the temperature when another solvent is added to cause crystallization may be lowered 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 -5 to 33°C, specifically at 25°C. Furthermore, the temperature when another solvent is added to cause crystallization can be, for example, -5 to 33°C, specifically at 25°C.

[0106] In another embodiment of the present invention, the p-toluenesulfonate of compound I can be obtained by dissolving compound I in a mixed solvent of ethanol and another solvent, adding an ethanol solution of p-toluenesulfonic acid thereto, 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, more preferably in the range of 1 equivalent or more and 1.1 equivalents or less, and most preferably 1 equivalent, relative to compound I. Seed crystals may be added to precipitate the desired p-toluenesulfonate. Examples of other solvents include hexane, heptane, and pentane, and are preferably heptane, and more preferably n-heptane. The mixing ratio of ethanol and other solvents can be 7.0 to 28 parts by weight of other solvent to 8.0 parts by weight of ethanol, preferably 8.0 to 24, more preferably 10 to 20, and most preferably 12 to 17. For example, the crystals described in Non-Patent Document 10 can be used as the seed crystals. When the seed crystals are added to the reaction solution, solid seed crystals or a suspension of seed crystals dispersed in a suitable solvent may be used. When a suspension of seed crystals is used, the solvent for dispersion may be any solvent in which the seed crystals are not completely dissolved, and is preferably a solvent containing a poor solvent used to precipitate the p-toluenesulfonate of Compound I, more preferably a solvent containing n-heptane, and even more preferably n-heptane.

[0107] After the desired p-toluenesulfonate of compound I is precipitated by adding an ethanol solution of p-toluenesulfonic acid, another solvent may be added to further increase the amount of precipitate. The other solvent may be any solvent capable of precipitating p-toluenesulfonate of compound I, and preferably includes hexane, heptane, or pentane, more preferably a solvent containing n-heptane, and even more preferably n-heptane. The mixing ratio of ethanol and the other solvent after re-addition of the other solvent may be 7.0 to 28, preferably 8.0 to 24, more preferably 10 to 20, and most preferably 12 to 17 parts by weight of the other solvent to 8.0 parts by weight of ethanol.

[0108] In the above process, the ethanol solution for dissolving Compound I can be at, for example, 22 to 28° C., specifically 25° C. Thereafter, the temperature when another solvent is added to cause crystallization can be, for example, −5 to 33° C., specifically 25° C. Furthermore, the temperature when another solvent is added to cause crystallization can be, for example, −5 to 33° C., specifically 25° C.

[0109] The precipitated crystals can be isolated and purified from the dissolved solution or mixed solution by known separation and purification means such as solid-liquid separation, for example, separation of solid and liquid components by filtration or centrifugation, washing of the solid components with a washing solvent, drying of the washing solvent attached to the solid components under reduced pressure, etc. As the washing solvent for the solid components, a solvent that does not cause the target crystals of p-toluenesulfonate of Compound I to transition to another crystal, a solvent in which p-toluenesulfonate of Compound I has low solubility, and / or a solvent in which p-toluenesulfonate of Compound I is not decomposed, is preferable, and examples thereof include hexane, heptane, isopropyl acetate, n-butyl acetate, t-butyl methyl ether, etc., or a mixture of these solvents.

[0110] In this specification, "wet" means that the solid contains a solvent. For example, when the solid recovered by solid-liquid separation operation contains a part of the separated liquid, it can be called a wet solid. In one embodiment of the present invention, the p-toluenesulfonate salt of compound I precipitated in a solvent is recovered as a wet solid (i.e., a wet solid), and the wet solid can be a wet powder and / or a wet solid.

[0111] In this specification, the term "powder" refers to a solid having 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 measured based on information obtained, for example, by a laser diffraction / scattering method.

[0112] In this specification, the term "wet powder" refers to a mixture of powder recovered by solid-liquid separation and the solvent used in the solid-liquid separation and / or the solvent used to wash the powder. The mixture ratio of powder to solvent can be arbitrary.

[0113] In this specification, the term "wet crystals" refers to a mixture of crystals precipitated by a crystallization operation and a solvent used in the crystallization operation and / or a solvent used for washing the crystals. The mixture ratio of the crystals and the solvent can be any ratio.

[0114] In this specification, the term "dry powder" refers to a powder in which the solvent component has evaporated and the amount of the solvent has been reduced, as compared with the above-mentioned wet powder. The amount of solvent remaining in the powder may be arbitrary, but the term refers to a powder in which the amount of the solvent has been reduced, resulting in less adhesion between powder particles and improved fluidity.

[0115] The "drying conditions" in this specification are not particularly limited, but refer to, for example, conditions for converting a wet solid (e.g., wet powder) into a dry solid (e.g., dry powder). A wet powder mixed with a solvent that is easily vaporized at room temperature can be converted into a dry powder by leaving it at room temperature and normal pressure, whereby the solvent evaporates. The wet powder may be heated to promote evaporation of the solvent. If heating is not suitable due to the nature of the substance forming the powder, the wet powder may be subjected to reduced pressure to promote evaporation of the solvent. Heating and decompression may be performed simultaneously or separately.

[0116] In one aspect of the present invention, a dry powder of the Form 1 crystal 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 embodiment, a dry powder of the Form 1 crystal of p-toluenesulfonate of Compound I is obtained by phase transition of the crystal of p-toluenesulfonate of Compound I contained in the wet powder under drying conditions.

[0117] In this specification, "powder X-ray diffraction" refers to a value that can be obtained using the diffraction phenomenon of X-rays, which is used for identification and structural analysis of crystalline substances, and is a value specific to any powder. This value is usually expressed as one or more diffraction angles (2θ values). It can be measured using CuKα1 radiation, and a person skilled in the art can measure it using a commercially available powder X-ray diffraction measurement device and following the instruction manual. More specifically, the 2θ value can be measured by irradiating the sample to be measured with CuKα1 X-rays and measuring the diffracted X-rays relative to the incident X-rays. For example, it can be performed according to a conventional method such as the "powder X-ray diffraction measurement method" described in the Japanese Pharmacopoeia (17th or 18th revision).

[0118] The diffraction angle (2θ value) in the powder X-ray diffraction spectrum may have some error depending on the measuring device or the measurement conditions such as the reading conditions of the diffraction angle. In this specification, the diffraction angle may have a measurement error in the range of about ±0.5° to ±0.2°.

[0119] In the description 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 listed value for all 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 listed value for all listed diffraction angles 2θ.

[0120] In this specification, the term "powder X-ray diffraction pattern" refers to a plot of diffraction angles and their intensities obtained by measuring a powder X-ray diffraction spectrum on the horizontal and vertical axes, respectively. A person skilled in the art can plot such a pattern using a commercially available powder X-ray diffraction measurement device and following the instructions for use with the device.

[0121] In this specification, "thermogravimetric analysis" refers to a method for thermally analyzing changes in the physical and chemical properties of a sample, and is an analytical means for measuring changes in weight caused by heating the sample. Those skilled in the art can perform measurements using a commercially available thermogravimetric analysis device and following the instructions for use.

[0122] In this specification, "differential thermal analysis" is an analytical means for detecting and measuring heat generation or endotherm caused by heating a sample. Those skilled in the art can measure using a commercially available device for differential thermal analysis measurement and following the instruction manual. By using "thermogravimetric analysis" and / or "differential thermal analysis", information on physical phenomena such as sublimation, melting, solidification, condensation, evaporation, decomposition, adsorption, or desorption of a sample can be obtained.

[0123] In thermogravimetric analysis, the measured endothermic peak (peak top value) may vary in measurement temperature depending on the rate of temperature rise per minute, the purity of the sample, etc. In this specification, the measured values ​​of the extrapolation point and peak top may have a measurement error within a range of about ±5.0°C.

[0124] The crystalline powder obtained by the method of the present invention can be processed into various forms of pharmaceutical compositions, such as tablets, capsules, granules, fine granules, powders, dry syrups, and other oral preparations or injections, with or without grinding, but is preferably used as an oral preparation. These pharmaceutical compositions can be produced by known and conventional preparation methods using pharma- ceutical acceptable carriers. When preparing oral solid preparations, tablets, coated tablets, granules, powders, dry syrups, capsules, and the like can be produced by adding excipients, and if necessary, binders, disintegrants, lubricants, colorants, flavorings, odorants, and the like, to the active ingredient, and then tablets, coated tablets, granules, powders, dry syrups, capsules, and the like can be produced by conventional methods. When preparing oral liquid preparations, flavorings, buffers, stabilizers, odorants, and the like can be added to the active ingredient to produce oral liquids, syrups, and the like by conventional methods. When preparing injections, pH adjusters, buffers, stabilizers, isotonicity agents, local anesthetics, and the like can be added to the active ingredient to produce subcutaneous, intramuscular, and intravenous injections by conventional methods.

[0125] The amount of p-toluenesulfonate of Compound I to be incorporated in the above pharmaceutical composition varies depending on the symptoms of the patient to which it is to be administered or on the dosage form, but is generally about 10 to 700 mg per dosage unit for oral preparations and about 10 to 700 mg per dosage unit for injections. The daily dose of the 1st type crystal in the above pharmaceutical composition is also determined by a doctor's prescription and cannot be determined in general depending on the symptoms, administration route, age of the patient, etc., and is generally preferably about 10 to 500 mg.

[0126] In this specification, the meaning of the term "and / or" includes any combination of "and" and "or" appropriately combined. 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. EXAMPLES

[0127] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. Solvents used in the practice of the invention, such as DMF, DMA, NMP, DMI, or DMPU, were obtained from commercial suppliers without further purification, and in reactions in which water was not added as a solvent, dehydrated, ultradehydrated, or anhydrous solvents were obtained from commercial suppliers without further purification.

[0128] Reagents used in the practice of the present invention were obtained from commercial suppliers without purification unless otherwise noted. 1H-NMR spectra were measured using a nuclear magnetic resonance spectrometer JNM-ECP500 (manufactured by JEOL Ltd.), and the chemical shift of Me4Si used as an internal standard was set to 0 ppm, and the deuterium lock signal from the sample solvent was used as a reference. The chemical shift of the signal of the analyte compound was expressed in ppm. The abbreviations for signal splitting are s = singlet, brs = broad singlet, d = doublet, t = triplet, q = quartet, dd = double doublet, and m = multiplet, and the signal splitting width was expressed in J value (Hz). The signal integral value was calculated based on the ratio of the signal area intensity of each signal.

[0129] Powder X-ray diffraction (XRPD) measurements were performed under the following conditions, and the 2θ values ​​in the scanning range were calculated. X-ray diffraction patterns were plotted with the angle of diffraction (2θ value) on the horizontal axis and line intensity on the vertical axis. Measurement device: SmartLab System (manufactured by Rigaku Corporation) Source: Cukα1 Tube voltage: 45kV Tube current: 200mA Scanning range: 3~35° Sampling width: 0.02°

[0130] Thermogravimetric analysis (TGA) was performed using an EXSTAR TG / DTA6200R instrument (Seiko Instruments (currently Hitachi High-Tech Science)). 1-3 mg of sample was placed in an aluminum container. The analysis was performed at temperatures ranging from 30°C to 350°C. The sample was analyzed under a nitrogen stream at a heating rate of 10°C / min.

[0131] The HPLC analysis was performed using a Waters H-Class system with a PDA detector at 225 nm, while the GC analysis was performed using a Shimadzu GC2010 with FID detection.

[0132] The products of each step were evaluated by the analytical methods shown in Table 1 below. [Table 1]

[0133] (Example 1-1) Preparation of 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline It was produced according to the production route shown below.

[0134] [ka]

[0135] [Process 1] Preparation of 4-(2-fluoro-5-(trifluoromethyl)phenyl)-6-(trifluoromethyl)pyrimidine

[0136] [ka]

[0137] 1-Fluoro-(4-trifluoromethyl)benzene (150g, 912mmol) and tetrahydrofuran (700mL) were added to a 3L flask purged with nitrogen. The resulting solution was cooled with stirring until the internal temperature reached -17.8°C, and n-butylmagnesium chloride (2.13M, tetrahydrofuran solution, 100mL, 213mmol) was added dropwise over 12 minutes. Then, n-butyllithium (1.63M, hexane solution, 298mL, 486mmol) was added dropwise to the reaction solution over 1 hour and 21 minutes. After stirring for 4 hours and 30 minutes at an internal temperature range of -10.5°C to -17.6°C, zinc chloride (2.03M, 2-methyltetrahydrofuran solution, 300mL, 608mmol) was added dropwise to the reaction solution over 35 minutes. Then, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (4.9717g, 6.08mmol) and 4-chloro-6-(trifluoromethyl)pyrimidine (111.033g, 608mmol) were added to the reaction solution at an internal temperature of 0°C using tetrahydrofuran (45mL). The reaction solution was heated to an internal temperature of 60°C over 30 minutes, sampled 1 hour after reaching 60°C, and the disappearance of 4-chloro-6-(trifluoromethyl)pyrimidine was confirmed by GC analysis. The reaction solution was then cooled to an internal temperature of 25°C. Citric acid (10% aqueous solution, 555mL) was added to the reaction solution, stirred for 20 minutes, allowed to stand, and the aqueous layer was discharged. EDTA-tetrasodium dihydrate (10% aqueous solution, 555mL) was added to the reaction solution, stirred for 20 minutes, allowed to stand, and the aqueous layer was discharged. Water (555 mL) was added to the reaction solution, and the mixture was stirred for 10 minutes, then allowed to stand, and the aqueous layer was drained. The resulting organic layer was concentrated under reduced pressure, and toluene (555 mL) was added, and the mixture was concentrated under reduced pressure again to obtain a crude product of 4-(2-fluoro-5-(trifluoromethyl)phenyl)-6-(trifluoromethyl)pyrimidine. The resulting crude product was used as it was in the next step.

[0138] GC purity: 91.17% Measurement method: GC, retention time: 7.4 minutes [Process 2] Preparation of 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline

[0139] [ka]

[0140] 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. A solution obtained by adding N,N-dimethylformamide (190mL) to potassium phthalimide (124.051g, 670mmol) was added to the above solution. Stirring of the reaction solution was started, and the external temperature of the flask was set to 110°C and heating was started. The reaction solution was sampled 3 hours after the internal temperature of the reaction solution reached 100°C, and the reaction conversion rate was confirmed to be 99.3% by HPLC analysis, and then the reaction solution was cooled to an internal temperature of 53°C. A methylamine aqueous solution (40%w / w, 567mL) was added to the reaction solution. The reaction solution was sampled after stirring at an internal temperature of 48°C to 53°C for 4 hours, and the reaction conversion rate was confirmed to be 100% by HPLC analysis. A solution of N-acetyl-L-cysteine ​​(9.9449 g, 60.9 mmol) in N,N-dimethylformamide (38 mL) was added and stirred for 1 hour. Water (1134 mL) was added dropwise in 6 portions over about 1 hour and 20 minutes (189 mL x 6). Crystals precipitated during the dropwise addition of water to form a suspension. After stirring for 1 hour after the dropwise addition of water, the reaction solution was cooled to 25°C. The suspension was filtered, and the obtained crystals were washed twice with water (1980 mL x 2). The obtained 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, 2-step yield 90.7%).

[0141] HPLC purity: 96.42% Measurement method: HPLC method A, retention time: 8.8 minutes 1 H-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).

[0142] (Example 1-2) [Project 1] Preparation of 4-(2-fluoro-5-(trifluoromethyl)phenyl)-6-(trifluoromethyl)pyrimidine

[0143]

change

[0144] 1-Fluoro-(4-trifluoromethyl)benzene (150g, 912mmol) and tetrahydrofuran (720mL) were added to a 3L flask purged with nitrogen. The solution was cooled to -20.3°C while stirring, and n-butylmagnesium chloride (2.13M, tetrahydrofuran solution, 100mL, 213mmol) was added dropwise over 28 minutes. Next, n-butyllithium (1.63M, hexane solution, 299mL, 487mmol) was added dropwise to the reaction solution over 47 minutes, and the inside of the dropping container was washed with tetrahydrofuran (30mL), and the washings were added to the reaction solution. The reaction solution was stirred at an internal temperature of -8.6°C to -10.2°C for 4 hours, and then cooled to -20.1°C, and zinc chloride (1.0M tetrahydrofuran solution, 609mL, 609mmol) was added dropwise over 61 minutes. The internal temperature of the reaction solution was raised to 0°C, and after stirring for 17 minutes, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex (4.98g, 6.09mmol) and 4-chloro-6-(trifluoromethyl)pyrimidine (111.084g, 609mmol) 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, and a part of the reaction solution was analyzed by GC analysis to confirm the disappearance of 4-chloro-6-(trifluoromethyl)pyrimidine. The internal temperature of the reaction solution was cooled to below 10°C, 1M hydrochloric acid (750mL) and toluene (750mL) were added, and after stirring for 10 minutes, the aqueous layer was discharged. Subsequently, 1M hydrochloric acid (300mL) was added to the organic layer, and after stirring for 10 minutes, the aqueous layer was discharged. A 10% N-(2-hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid trisodium dihydrate aqueous solution (750 mL) was added to the organic layer, and after stirring for 30 minutes, the aqueous layer was discharged. A 10% sodium chloride aqueous solution (750 mL) was added to the organic layer, and after stirring for 10 minutes, the aqueous layer was discharged. The obtained organic layer was concentrated under reduced pressure to obtain a crude product of 4-(2-trifluoro-5-(trifluoromethyl)phenyl)-6-(trifluoromethyl)pyrimidine. The obtained crude product was used as it was in the next step.

[0145] GC purity: 94.35% (calculated only from peaks with retention times of 3.1 minutes and later) Measurement method: GC, retention time: 7.4 minutes [Process 2] Preparation of 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline

[0146] [ka]

[0147] The crude product of 4-(2-trifluoro-5-(trifluoromethyl)phenyl)-6-(trifluoromethyl)pyrimidine obtained in step 1 of Example 1-2 was transferred to a 5L flask, and N,N-dimethylformamide (1.5L) was added. To this solution, potassium phthalimide (124.022g, 670mmol) was added using N,N-dimethylformamide (378mL). While stirring the reaction solution, the external temperature of the reaction vessel was set to 103°C and heating was started. The reaction solution was sampled 3 hours after the internal temperature of the reaction solution reached 100°C, and the reaction conversion rate was confirmed to be 98.6% by HPLC analysis. The reaction solution was further stirred at 100°C for 3 hours, and then the reaction solution was sampled again, and the reaction conversion rate was confirmed to be 99.9% by HPLC, after which 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, and after stirring for 3 hours at an internal temperature of about 50°C, the reaction solution was sampled and confirmed to have a 100% reaction conversion rate by HPLC analysis. N-acetylcysteine ​​(9.9447 g, 60.9 mmol) was added to the reaction solution using N,N-dimethylformamide (18.9 mL) and stirred for 1 hour. Water (1134 mL) was added dropwise to the reaction solution in 6 portions over about 1 hour and 20 minutes (189 mL x 6). Crystals precipitated in the reaction solution during the dropwise addition of water, forming a suspension. After stirring for 1 hour from the end of the dropwise addition of water, the reaction solution was cooled to 25°C. The suspension was filtered, and the obtained crystals were washed twice with water (1890 mL x 2). The obtained wet powder was dried at an external temperature of 30 to 40° C. under reduced pressure to obtain 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (169.73 g, two-step yield 90.8%).

[0148] HPLC purity: 96.95% Measurement method: HPLC method A, retention time: 8.8 minutes. (Reference Example 1) Preparation of 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (conventional method) It was produced according to the production route shown below.

[0149] [ka]

[0150] Into the reaction vessel, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (Boron molecular (catalog number: BM1088), 30.0 kg) in N,N-dimethylacetamide solution (86.2 kg) and N,N-dimethylacetamide (22.2 L) were added under a nitrogen stream. Next, 4-chloro-6-(trifluoromethyl)pyrimidine (20.6 kg) and N,N-dimethylacetamide (38.2 L) were added, and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.408 kg) in N,N-dimethylacetamide solution (166 L) and water (9.55 L) were added, and the reaction vessel was degassed under reduced pressure for 15 minutes and then replaced with nitrogen. While bubbling with nitrogen, an aqueous solution of tripotassium phosphate prepared by adding water (38.2 L) to tripotassium phosphate (25.3 kg) was added so that the internal temperature of the reaction solution did not exceed 50°C, and then the reaction vessel was degassed under reduced pressure for 5 minutes and replaced with nitrogen. The reaction solution was stirred for 2 hours at an internal temperature range of 50 to 60°C, and then a solution prepared by adding N,N-dimethylacetamide (95.5 L) to N-acetyl-L-cysteine ​​(1.63 kg) was added, and the mixture was further stirred for 1 hour at an internal temperature range of 54.4 to 57.6°C. Water (28.7 L) was added in 10 portions to the reaction solution at an internal temperature range of 52.0 to 56.4°C. The reaction solution was stirred for 30 minutes at an internal temperature range of 55.8 to 56.3°C, cooled to 25°C, and further stirred for 19 hours and 45 minutes. The resulting precipitate was collected by filtration and washed twice with water (287 L). The wet powder was dried at 40°C under reduced pressure of 0.08 to 0.10 MPa for 70 hours to obtain 31.52 kg (yield 98.2%) of the title compound. 1The 1 H-NMR spectrum data and the retention time in HPLC analysis were consistent with those in Example 1.

[0151] A comparison between Examples 1-2 and Reference Example 1 is shown in Table 2 below. The purity of the compounds was calculated by HPLC analysis.

[0152] [Table 2]

[0153] It was found that in Example 1-2, the target product was obtained with the same purity as in Reference Example 1. (Reference Example 2) Production of 1-(2-chloroethoxy)-2,3-difluorobenzene

[0154] [ka]

[0155] This compound was prepared using 2,3-difluorophenol and 1,2-dichloroethane according to the method described in the literature (Williamson, AW et al., J. Chem. Soc. 1852, 106, 229-239).

[0156] (Reference Example 3) Preparation of 2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzaldehyde

[0157] [ka]

[0158] Using 1-(2-chloroethoxy)-2,3-difluorobenzene obtained in Reference Example 2, this was produced according to the production route shown below described in WO 2014 / 142273.

[0159] [ka]

[0160] (Reference Example 4) Preparation of methyl (E)-1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzylidene)-1-methylhydrazinyl)cyclopentane-1-carboxylate oxalate

[0161] [ka]

[0162] [Process 1] This was produced using methyl 1-(methylamino)cyclopentane-1-carboxylate as a starting material and 2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzaldehyde obtained in Reference Example 3, according to the production route shown below and described in WO 2014 / 142273.

[0163] [ka]

[0164] [Process 2] In a reaction vessel, methyl (E)-1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzylidene)-1-methylhydrazinyl)cyclopentane-1-carboxylate hydrochloride (60.0 g, 129 mmol) and toluene (360 mL) were added and suspended under a nitrogen atmosphere. The resulting slurry was cooled and, while maintaining the internal temperature at -5°C, an aqueous sodium hydrogen carbonate solution (prepared by dissolving 21.7 g of sodium hydrogen carbonate in 300 mL of water) was added dropwise, the temperature was raised to room temperature, and the mixture was stirred for another 0.5 hours. After separating the organic layer, the obtained aqueous layer was further extracted with toluene (60 mL), and the combined organic layer was concentrated to obtain a toluene solution (131.9 g) of (E)-1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzylidene)-1-methylhydrazinyl)cyclopentane-1-carboxylate (free form). Toluene was added to the concentrated solution so that the liquid volume was 330 mL, and the mixture was stored overnight at room temperature. 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 the reaction liquid of 48 ° C., and 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 obtained solution. The external temperature of the reaction vessel was set to 0 ° C., and the mixture was stirred for another 1.5 hours at an internal temperature of the reaction liquid of 1 ° C. or less. The precipitated solid was collected by filtration, and the obtained wet powder was washed with toluene (166 mL). This wet powder was dried under reduced pressure at an external temperature of 40° C. to obtain the target product (56.7 g) (yield: 85%).

[0165] HPLC purity: 99.52% Measurement 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=8.2Hz),4.42(2H,t,J=5.3Hz),3.65(2H,t,J=5.3Hz),3.61(3H,s),3.42 (2H,t,J=5.0Hz),3.29(3H,s),3.22(2H,t,J=5.3Hz),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).

[0166] Example 2 Preparation of methyl 1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-1-methylhydrazinyl)cyclopentane-1-carboxylate

[0167] [ka]

[0168] Under a nitrogen atmosphere, methyl (E)-1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzylidene)-1-methylhydrazinyl)cyclopentane-1-carboxylate oxalate (50.0 g, 97 mmol) obtained in Reference Example 4 and 2-picoline borane (8.7 g, 77 mmol) were added with toluene (375 ml) and suspended. 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 keeping the internal temperature at 25° C. or less, and then the mixture was stirred for 8.5 hours. The organic layer was discarded, and toluene (375 mL) was added to the aqueous layer, which was then stored 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 keeping the internal temperature at 0° C. or less. After stirring at 20°C for 0.5 hours, the aqueous layer was discarded. 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 stirred for 15 minutes. The aqueous layer was discarded and the organic layer was concentrated to obtain a toluene solution of the target product. Ethyl acetate (290 mL) was added to the obtained solution and stored at room temperature overnight.

[0169] HPLC purity: 97.91% Measurement method: HPLC method A, retention time: 4.3 minutes.

[0170] Example 3 Preparation of 3-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propanoic acid

[0171] [ka]

[0172] In a reaction vessel, 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (2.0 g, 6.5 mmol) obtained in Example 1-2 and Meldrum's acid (0.94 g, 6.5 mol) were added under a nitrogen atmosphere, and toluene (10 mL) and n-heptane (10 mL) were 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 mixed solution prepared from toluene (4 mL) and n-heptane (4 mL). This 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% Measurement method: HPLC method A, retention time: 7.5 minutes 1 H-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] (Reference Example 5) Preparation of 3-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propanoic acid (conventional method)

[0175] [ka]

[0176] In a reaction vessel, 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)aniline (54.88 kg) obtained in Reference Example 1 and Meldrum's acid (25.76 kg) were added under a nitrogen atmosphere, and toluene (274 L) and n-heptane (274 L) were added to suspend the mixture. The internal temperature of the reaction solution was raised to 90°C or higher 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 or lower and further stirred at an internal temperature of 15 to 25°C for 1 hour or more. The precipitated crystals were collected by filtration and washed with a mixed solution prepared from toluene (110 L) and n-heptane (110 L). This 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%. Measurement method: HPLC method A, retention time: 7.5 minutes. A comparison between Example 3 and Reference Example 5 is shown below. The purity of the compound was calculated by HPLC analysis.

[0178] [Table 3]

[0179] It was found that in Example 3, the target product was obtained with the same purity as in 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-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propanoyl)hydrazinyl)cyclopentane-1-carboxylate

[0180] [ka]

[0181] In a reaction vessel, under a nitrogen atmosphere, a solution of 1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-1-methylhydrazinyl)cyclopentane-1-carboxylate methyl obtained in Example 2 and a solution of 3-oxo-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. Pyridine (41.5 mL, 513 mmol) was added dropwise to the resulting solution while maintaining the internal temperature at -5°C. Subsequently, 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 solution at 5° C. for 15 minutes, 3-oxo-3-((4-(trifluoromethyl)2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propionic acid (1.9 g, 4.8 mmol) was added and the mixture was stirred for another 3.5 hours. Aqueous sodium chloride solution (prepared by dissolving 12.5 g of sodium chloride in 124 mL of water) was added to the reaction solution at 25° C., and the mixture was stirred for 20 minutes. The aqueous layer was discarded, and an aqueous sodium chloride solution (prepared by dissolving 12.5 g of sodium chloride in 124 mL of water) was further added to the organic layer, and the mixture was stirred for 20 minutes. The aqueous layer was discarded, and then an aqueous dipotassium hydrogen phosphate solution (prepared by dissolving 45.7 g of dipotassium hydrogen phosphate in 249 mL of water) was added to the organic layer, and the mixture was stirred for 15 minutes, after which the aqueous layer was discharged. The organic layer was concentrated, and the precipitated inorganic salt was removed by filtration using a Kiriyama funnel, and the filtrate was stored overnight at room temperature. After 13 hours, the filtrate was concentrated to dryness, and 2-propanol (116 mL) was added to the residue. The resulting solution was stirred for 10 minutes, and then 2-propanol (382 mL) was added. The external temperature of the reaction vessel was set to 35°C, and the reaction solution was stirred for 1 hour at an internal temperature of 31°C to 33°C, and then the external temperature of the reaction vessel was lowered to 10°C over 1.25 hours. The reaction solution was stirred for 30 minutes at an internal temperature of 12°C to 14°C, and then the external temperature of the reaction vessel was raised to 35°C. The reaction solution was stirred for 30 minutes while maintaining the internal temperature at 30°C to 35°C, and then the external temperature of the reaction vessel was lowered to 0°C over 1.75 hours. The internal temperature of the reaction solution was cooled to 5°C or less, and the precipitated solid was collected by filtration.The obtained wet powder was washed with 2-propanol (207 mL) cooled to 0° C. This wet powder was dried under reduced pressure at an external temperature of 35 to 40° C. to obtain the target product (65.7 g) (total yield for two steps: 84%).

[0182] HPLC purity: 99.49% Measurement conditions: HPLC method B, HPLC retention time: 3.9 minutes. 1 H NMR(500MHz,DMSO-D6)δ:11.15(1H,s),9.5 1(1H,d,J=0.9Hz),8.54(1H,d,J=1.4Hz),8.32(1H,d,J=8.6Hz),8.25(1H,d,J=1.4Hz),7.97-7. 95(1H,m),7.00-6.98(1H,m),6.93-6.91(1H,m),4.70(1H,d,J=16.3Hz),4.41(1H,d,J=16.3Hz) ,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= 5.9Hz),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) (EtO) 2 Synthesis of methyl 1-(2-((2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)phenyl)methyl)-1-methyl-2-(3-oxo-3-((4-(trifluoromethyl)2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propanoyl)hydrazinyl)cyclopentane-1-carboxylate using POCl

[0184] [ka]

[0185] Methyl 1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-1-methylhydrazinyl)cyclopentane-1-carboxylate (0.109g, 0.254mmol) in N,N-dimethylformamide solution (1.0mL) and 3-oxo-3-((4-(trifluoromethyl)2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propionic acid (0.101g, 0.257mmol) were mixed, and the atmosphere in the reaction vessel was replaced with nitrogen. The internal temperature of the reaction solution was -10°C, and pyridine (0.031mL, 0.381mmol) and (EtO)2POCl (0.073mL, 0.509mmol) were added in sequence. The reaction mixture was stirred at an internal temperature of -10°C for 1.5 hours, and the yield of the target compound was determined by HPLC area ratio.

[0186] Generation rate: 76.49%. Measurement conditions HPLC method A, retention time: 8.4 minutes.

[0187] Example 5 Preparation of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-carboxamide

[0188] [ka]

[0189] 1-(2-(2,3-difluoro-4-(2-((2-methoxyethyl)(methyl)amino)ethoxy)benzyl)-1-methyl-2-(3-oxo-3-((4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)amino)propanoyl)hydrazinyl)methyl cyclopentane-1-carboxylate (34 kg, 42 mol), potassium carbonate (11.7 kg, 85 mol), and ethanol (268 kg) were added to a reaction vessel and suspended, and stirring and heating were started. The reaction solution was stirred for 2 hours from the start of reflux, and the reaction 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. 1M aqueous hydrochloric acid solution (85 kg) was added to the reaction solution, which was stirred for 15 minutes and then allowed to stand, and the aqueous layer was discharged. A 10% aqueous solution of potassium dihydrogen phosphate (170 kg) was added to the reaction solution, which was stirred for 15 minutes, then allowed to stand, and the aqueous layer was discharged. A 10% aqueous solution of sodium chloride (170 kg) was added to the reaction solution, which was stirred for 15 minutes, then allowed to stand, and the aqueous layer was discharged. The organic layer was concentrated under reduced pressure, and ethyl acetate (80 L) was added to the resulting concentrated solution, which was then filtered. During the filtration operation, ethyl acetate (80 L) was used to wash the container and piping. The filtered solution was concentrated under reduced pressure again, 1 H-NMR analysis confirmed that the molar ratio of ethyl acetate to the target product was less than 3. Ethanol (52 kg) and n-heptane (52 kg) were added to the obtained crude product of the title compound, and the mixture was subjected to the next step.

[0190] HPLC purity: 99.24%. Measurement conditions: HPLC method A, retention time: 9.4 minutes.

[0191] Example 6 Preparation of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-carboxamide p-toluenesulfonate

[0192] [ka]

[0193] Under a nitrogen atmosphere, 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-carboxamide (33 kg, 42 mol) obtained in Example 5 was added with a mixed solvent (ethanol 52 kg, n-heptane 56 kg), and the resulting solution was stirred at an internal temperature of 25° C. 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) and added as seed crystals, and then the suspension container was washed with n-heptane (0.5 L) and the washing liquid was added. After stirring for 1 hour and confirming the precipitation of crystals, n-heptane (56 kg) was added and the crystallization liquid was heated to an internal temperature of 33 ° C. After stirring at an internal temperature of 30 ° C or higher for 30 minutes or more, it was cooled to an external temperature of 15 ° C. and stirred at an internal temperature of 25 ° C. or lower for 30 minutes or more. Subsequently, n-heptane (56 kg) was added and stirred for 1 hour or more. The obtained 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%).

[0194] HPLC purity: 99.92%. Measurement conditions: HPLC method A, retention time 9.4 minutes. 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=8.6Hz),7.95(1H,s),7.90(1H,d,J=1.5Hz) ,7.79(1H,dd,J=8.6,1.5Hz),7.75(2H,d,J=8.0Hz),7.16(2H,d,J=8.0Hz),7.06(1H,dd,J=7.6,7.7Hz),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(3H ,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).

[0195] Example 7 Preparation of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-carboxamide p-toluenesulfonate 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-carboxamide (311.6 mg) was added with p-toluenesulfonic acid ethanol solution (0.5 M, 0.935 mL) and dissolved at 60 ° C. Then, seed crystals were added while stirring at room temperature, and many crystals were precipitated after 30 minutes. After 24 hours, the obtained crystals were filtered and powder X-ray diffraction measurement of the wet powder was performed. The measurement results are shown in Figure 2. After leaving it at room temperature for another hour, powder X-ray diffraction measurement of the dry powder was performed. The latter powder was identical to the known crystalline form, but the former showed a different powder X-ray diffraction pattern, confirming that a crystal transition occurred rapidly during the drying process. The yield was 298.0 mg.

[0196] The powder X-ray diffraction patterns in Figure 2 show, from the bottom, the powder X-ray diffraction patterns of crystals obtained by the method described in the literature (Non-Patent Document 10, Technical Report No. 2017-501666) (obtained using ethyl acetate), crystals obtained by the method described in the aforementioned literature (obtained using acetone), the wet powder obtained in Example 7, and the dry powder obtained in Example 7.

[0197] The wet powder had diffraction peaks at 2θ values ​​of 3.7°, 5.0°, 7.4°, 7.9°, 14.8°, and 18.4° (±0.2°). The dry powder had diffraction peaks at 2θ values ​​of 4.9°, 9.4°, 9.9°, 15.2°, 15.9°, 18.9°, and 22.7° (±0.2°).

[0198] The dry powder of Example 7 was subjected to thermogravimetric analysis, and the measurement results are shown in Figure 3. Peaks due to melting were observed at 112.6°C (extrapolation point) and 126.6°C (peak top).

[0199] Example 8 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-carboxamide Preparation of samide p-toluenesulfonate 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-carboxamide (311.9 mg) was added with p-toluenesulfonic acid ethanol solution (0.5 M, 0.936 mL) and dissolved at 60 ° C. Then, seed crystals and n-heptane (0.936 mL) were added with stirring at room temperature, and after 30 minutes, many crystals were precipitated. Further, n-heptane (1.871 mL) was added, and after 24 hours, the obtained crystals were filtered and powder X-ray diffraction measurement of the wet powder was performed. After leaving it at room temperature for another hour, X-ray diffraction measurement of the dry powder was performed. The measurement results are shown in Figure 4. The powder X-ray diffraction pattern of the dry powder was the same as that of the type 1 crystal, but the powder X-ray diffraction pattern of the wet powder was different from that of the dry powder, confirming that a rapid crystal phase transition occurred during the drying process. The yield was 257.1 mg.

[0200] The powder X-ray diffraction patterns in Figure 4 show, from the bottom, the powder X-ray diffraction patterns of crystals obtained by the method described in the literature (Non-Patent Document 10, Technical Report No. 2017-501666) (obtained using ethyl acetate), crystals obtained by the method described in the aforementioned literature (obtained using acetone), the wet powder obtained in Example 8, and the dry powder obtained in Example 8.

[0201] The wet powder had diffraction peaks at 2θ values ​​of 3.7°, 4.9°, 7.3°, 7.7°, 14.2°, and 18.7° (±0.2°), and the dry powder had diffraction peaks at 2θ values ​​of 4.9°, 9.4°, 9.9°, 15.2°, 15.9°, 18.9°, and 22.6° (±0.2°).

[0202] Thermogravimetric analysis was performed on the dried powder of Example 8. The analysis results are shown in FIG. Peaks due to melting were observed at 119.6°C (extrapolation point) and 130.2°C (peak top). [Industrial Applicability]

[0203] The present invention provides a method for producing p-toluenesulfonic acid salt 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-oxo-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide, which is useful as an active ingredient of pharmaceuticals. By using the production method of the present invention, p-toluenesulfonic acid salt 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-oxo-6,7-diazaspiro[4.5]dec-9-ene-9-carboxamide can be efficiently produced and supplied.

Claims

1. Formula 1 【Chemistry 1】 A method for producing a crystalline powder of a p-toluenesulfonate salt of a compound represented by the following formula: converting the compound represented by formula 1 into the p-toluenesulfonate salt in a solvent and recovering the precipitated solid to obtain a powder of the p-toluenesulfonate salt containing the solvent (wet powder); subjecting the wet powder to drying conditions to obtain a crystalline powder of the Form 1 crystal of the p-toluenesulfonate salt; the crystalline powder of the type 1 crystal of the p-toluenesulfonate salt has a powder X-ray diffraction pattern including peaks at diffraction angles 2θ of 4.9°, 9.4°, 15.8°, 18.9°, and 22.6° (±0.5°) in powder X-ray diffraction; The process wherein the solvent is ethanol.

2. 10. The method of claim 1 further comprising adding an anti-solvent to the mixture containing the solids prior to recovery.

3. The method according to claim 1 or 2, wherein the anti-solvent is heptane.

4. 3. The method of claim 1, wherein the wet powder of p-toluenesulfonate and the crystalline powder of the Form 1 crystal of p-toluenesulfonate have different powder X-ray diffraction patterns.

5. Formula 2: 【Chemistry 2】 A method for producing a compound represented by the following formula: Formula 3 【Chemistry 3】 [In the formula, X １ is a leaving group]. １－６ Alkyl magnesium halide, C １－６ Treatment with alkyllithium and zinc halide affords the compound of formula 4 【Chemistry 4】 [In the formula, X ２ is a leaving group] in the presence of a palladium catalyst to obtain a compound represented by the formula 5 【Chemistry 5】 and obtaining a compound represented by the formula: The method includes reacting a compound represented by formula 5 with an alkali metal salt of a dicarboxylic acid imide, and obtaining a compound represented by formula 2 by decomposition reaction of the resulting imide compound.

6. X １ The method of claim 5 , wherein is a halogen atom.

7. X ２ The method of claim 5 , wherein is a chlorine atom.

8. 8. The method of any one of claims 5 to 7, 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(triphenylphosphine)palladium(II) dichloride, dichlorobis(tricyclohexylphosphine)palladium(II), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride, (1,3-bis(2,6-diisopropylphenyl)imidazolidene)(3-chloropyridyl)palladium(II) dichloride, and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride.

9. 8. The method according to claim 5, wherein the dicarboxylic acid imide alkali metal salt is potassium phthalimide or sodium phthalimide.

10. Formula 1: 【Chemistry 6】 A method for producing a compound represented by the formula: 1) Preparing a compound represented by formula 2 by the method according to any one of claims 5 to 7. thing, 2) Formula 2: 【Chemistry 7】 and a malonic acid derivative to obtain a compound represented by formula 6: 【Chemistry 8】 preparing a compound represented by 3) A compound represented by formula 6 and a compound represented by formula 7: 【Chemistry 9】 In the presence of a condensing agent, a compound represented by formula 8: 【Chemistry 10】 preparing a compound represented by 4) preparing a compound of formula 1 by cyclization of a compound of formula 8, The process, wherein the malonic acid derivative is selected from the group consisting of Meldrum's acid and malonic acid.

11. The method of claim 10, wherein the malonic acid derivative is Meldrum's acid.

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