Method for producing arylamide derivative

Abstract

The present disclosure provides, for example, a method for producing a sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl] benzamide (compound 3), including a step for mixing 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino) pyridin-4-yl]methyl] benzamide, sodium tert-butoxide, and m-cresol in a solvent so as to obtain a mixture that contains the compound 3. The present disclosure provides a method for producing the compound 3, wherein a product which has a higher content of the compound 3 can be obtained.

Description

Method for producing arylamide derivatives

[0001] The present disclosure relates to a method for producing arylamide derivatives.

[0002] The sodium salt (also referred to as "Compound 3" in this disclosure) of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (also referred to as "Compound 1" or "Compound 1A" in this disclosure) is known to be useful in the treatment or prevention of cancer (see Patent Document 1).

[0003] As a method for producing Compound 3 and its intermediate Compound 1, the method described in Synthesis Example 4 below is known (see Patent Document 2).

[0004] International Publication No. 2021 / 149776 International Publication No. 2023 / 003014

[0005] It has been found that the method described in Synthesis Example 4 below leaves room for improvement in terms of the content of Compound 3 in the resulting product. It has also been found that the method for producing Compound 1 described in Synthesis Example 4 below leaves room for improvement in terms of simplicity.

[0006] An object of the present disclosure is to provide a method for producing compound 3, which can produce a product having a higher content of compound 3. Another object of the present disclosure is to provide a method for producing compound 1, which can more simply produce a product having a higher content of compound 1.

[0007] The present disclosure includes methods described in A1 to A45 below. A1: A method for producing the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 3), the method comprising the following step (A-1): (A-1) A step of mixing the following (a), (b), and (c) in a first solvent to obtain a mixture containing Compound 3: (a) 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1), (b) a sodium base, and (c) at least one organic acid selected from the group consisting of compounds represented by the following general formula (A): [In the formula, X １ is a hydroxy group or a mercapto group, R １ , R ２ , R ３ , R ４ and R ５ are each independently a hydrogen atom, a halogen atom, a C1-6 alkyl group, a hydroxy group, a C1-6 alkoxy group, a phenoxy group, a nitro group, or a cyano group.

[0008] A2: The method according to A1, wherein the sodium base comprises at least one selected from the group consisting of sodium C1-6 alkoxide, sodium hydroxide, sodium hydride, and sodium hexamethyldisilazide. A3: The method according to A1 or A2, wherein the sodium base comprises at least one selected from the group consisting of sodium tert-butoxide, sodium tert-pentoxide, sodium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, and sodium hexamethyldisilazide. A4: The method according to any one of A1 to A3, wherein the sodium base comprises at least one selected from the group consisting of sodium tert-butoxide, sodium tert-pentoxide, and sodium hydroxide. A5: The method according to any one of A1 to A4, wherein the sodium base is sodium tert-butoxide.

[0009] A6: X １ is a hydroxy group, and R １ , R ２ , R ３ , R ４ and R ５ are each independently a hydrogen atom or a C1-6 alkyl group. A7: The method according to any one of A1 to A6, wherein the organic acid is at least one selected from the group consisting of o-cresol, m-cresol, p-cresol, phenol, and dibutylhydroxytoluene. A8: The method according to any one of A1 to A7, wherein the organic acid is at least one selected from the group consisting of m-cresol, phenol, and dibutylhydroxytoluene. A9: The method according to any one of A1 to A8, wherein the organic acid is at least one selected from the group consisting of m-cresol and phenol. A10: The method according to any one of A1 to A9, wherein the organic acid is m-cresol.

[0010] A11: The method according to any one of A1 to A10, wherein the organic acid is a weaker acid than Compound 1. A12: The method according to any one of A1 to A11, wherein the organic acid has a pKa of 7.0 to 12.0 in water at 25°C. A13: The method according to any one of A1 to A12, wherein the organic acid has a pKa of 7.0 to 11.0 in water at 25°C. A14: The method according to any one of A1 to A13, wherein the organic acid has a pKa of 8.0 to 11.0 in water at 25°C.

[0011] A15: The method according to any one of A1 to A14, wherein the solubility of the sodium salt of the organic acid in a mixed solvent of tetrahydrofuran, acetone, tert-butyl methyl ether, and water at 25° C. (the volume ratio of tetrahydrofuran, acetone, and tert-butyl methyl ether is 8:10:5, and the water content is 3 mass% based on the mass of the mixed solvent) is 3 mmol / L or more. A16: The method according to any one of A1 to A15, wherein the solubility of the sodium salt of the organic acid in a mixed solvent of tetrahydrofuran, acetone, tert-butyl methyl ether, and water at 25° C. (the volume ratio of tetrahydrofuran, acetone, and tert-butyl methyl ether is 8:10:5, and the water content is 3 mass% based on the mass of the mixed solvent) is 0.05 mol / L or more. A17: The method according to any one of A1 to A16, wherein the solubility of the sodium salt of the organic acid in a mixed solvent of tetrahydrofuran, acetone, tert-butyl methyl ether, and water at 25°C (the volume ratio of tetrahydrofuran, acetone, and tert-butyl methyl ether is 8:10:5, and the water content is 3 mass% relative to the mass of the mixed solvent) is 0.08 mol / L or more.

[0012] A18: The method according to any one of A1 to A17, wherein the solubility of the organic acid in a mixed solvent of tetrahydrofuran, acetone, tert-butyl methyl ether, and water at 25° C. (wherein the volume ratio of tetrahydrofuran, acetone, and tert-butyl methyl ether is 8:10:5, and the water content is 3 mass% relative to the mass of the mixed solvent) is 0.05 mol / L or more. A19: The method according to any one of A1 to A18, wherein the solubility of the organic acid in a mixed solvent of tetrahydrofuran, acetone, tert-butyl methyl ether, and water at 25° C. (wherein the volume ratio of tetrahydrofuran, acetone, and tert-butyl methyl ether is 8:10:5, and the water content is 3 mass% relative to the mass of the mixed solvent) is 0.08 mol / L or more. A20: The method according to any one of A1 to A19, wherein the solubility of the organic acid in a mixed solvent of tetrahydrofuran, acetone, tert-butyl methyl ether, and water at 25°C (the volume ratio of tetrahydrofuran, acetone, and tert-butyl methyl ether is 8:10:5, and the water content is 3 mass% relative to the mass of the mixed solvent) is 0.10 mol / L or more.

[0013] A21: The method according to any one of A1 to A20, wherein the molar equivalent of the organic acid mixed in step (A-1) relative to the sodium base is 0.1 to 3. A22: The method according to any one of A1 to A21, wherein the molar equivalent of the organic acid mixed in step (A-1) relative to the sodium base is 0.1 to 1.5. A23: The method according to any one of A1 to A22, wherein the molar equivalent of the organic acid mixed in step (A-1) relative to the sodium base is 0.3 to 0.6.

[0014] A24: The method according to any one of A1 to A23, wherein the molar equivalent of the sodium base mixed in step (A-1) is 0.3 to 3 relative to compound 1. A25: The method according to any one of A1 to A24, wherein the molar equivalent of the sodium base mixed in step (A-1) is 0.5 to 1.5 relative to compound 1. A26: The method according to any one of A1 to A25, wherein the molar equivalent of the sodium base mixed in step (A-1) is 0.8 to 1.2 relative to compound 1.

[0015] A27: The method according to any one of A1 to A26, wherein the first solvent comprises at least one selected from the group consisting of ether solvents, ketone solvents, and amide solvents. A28: The method according to any one of A1 to A27, wherein the first solvent comprises at least one selected from the group consisting of tetrahydrofuran, acetone, and 1,3-dimethyl-2-imidazolidinone. A29: The method according to any one of A1 to A28, wherein the first solvent comprises at least one selected from the group consisting of tetrahydrofuran and acetone.

[0016] A30: The method according to any one of A1 to A29, wherein the temperature of the first solvent in step (A-1) is −25° C. to 40° C. A31: The method according to any one of A1 to A30, wherein the temperature of the first solvent in step (A-1) is −10° C. to 10° C.

[0017] A32: The method according to any one of A1 to A31, wherein the volume of the first solvent in step (A-1) is 6 to 16 mL per gram of the mass of compound 3 produced in step (A-1). A33: The method according to any one of A1 to A32, wherein the volume of the first solvent in step (A-1) is 8 to 14 mL per gram of the mass of compound 3 produced in step (A-1). A34: The method according to any one of A1 to A33, wherein the volume of the first solvent in step (A-1) is 10 to 12 mL per gram of the mass of compound 3 produced in step (A-1).

[0018] A35: The method according to any one of A1 to A34, further comprising the following step (A-2): (A-2) a step of mixing the mixture obtained in step (A-1) with a second solvent.

[0019] A36: The method according to A35, wherein the second solvent comprises at least one selected from the group consisting of ether solvents, ketone solvents, and hydrocarbon solvents. A37: The method according to A35 or A36, wherein the second solvent comprises at least one selected from the group consisting of acetone, methyl ethyl ketone, tert-butyl methyl ether, cyclopentyl methyl ether, and n-heptane. A38: The method according to any one of A35 to A37, wherein the second solvent comprises at least one selected from the group consisting of acetone and tert-butyl methyl ether.

[0020] A39: The method according to any one of A35 to A38, wherein the temperature of the second solvent in step (A-2) is −25° C. to 50° C. A40: The method according to any one of A35 to A39, wherein the temperature of the second solvent in step (A-2) is 5° C. to 40° C.

[0021] A41: The method according to any one of A35 to A40, wherein the volume of the second solvent in step (A-2) is 0.3 to 3 times the volume of the first solvent. A42: The method according to any one of A35 to A41, wherein the volume of the second solvent in step (A-2) is 0.5 to 2 times the volume of the first solvent. A43: The method according to any one of A35 to A42, wherein the volume of the second solvent in step (A-2) is 0.7 to 1.3 times the volume of the first solvent.

[0022] A44: The method according to any one of A1 to A43, further comprising the following step (A-3): (A-3) a step of obtaining compound 3 from the mixture obtained in step (A-1) or (A-2). A45: The method according to A44, wherein in step (A-3), compound 3 is obtained from the mixture obtained in step (A-2) by solid-liquid separation.

[0023] In the methods described in A1 to A45 above, an organic acid of general formula (A) is used to convert compound 1 into a sodium salt (compound 3). Compared to the method described in Synthesis Example 4 below, which does not use such an organic acid, the methods described in A1 to A45 above make it possible to obtain a product with a higher content of compound 3.

[0024] The present disclosure also includes methods described in B1 to B16 below. B1: A method for producing 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1), the method comprising the following steps (B-1), (B-2), and (B-3): (B-1) A step of mixing the following (d), (e), and (f) to obtain a mixture containing Compound 1: (d) 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 2); (e) N-methylsulfamoyl chloride; and (f) an aqueous solution of an inorganic salt. (B-2) A step of removing the aqueous layer from the mixture obtained in Step (B-1) by a separation operation. (B-3) A step of mixing the mixture obtained in Step (B-2) with a fourth solvent to remove the inorganic salt.

[0025] B2: The method according to B1, wherein the aqueous solution of an inorganic salt is at least one selected from the group consisting of an aqueous sodium chloride solution, an aqueous ammonium chloride solution, an aqueous sodium dihydrogen phosphate solution, and an aqueous potassium dihydrogen phosphate solution. B3: The method according to B1 or B2, wherein the aqueous solution of an inorganic salt is at least one selected from the group consisting of an aqueous sodium chloride solution and an aqueous ammonium chloride solution. B4: The method according to any one of B1 to B3, wherein the aqueous solution of an inorganic salt is an aqueous sodium chloride solution.

[0026] B5: The method according to any one of B1 to B4, wherein step (B-1) is carried out in a third solvent. B6: The method according to B5, wherein the third solvent comprises at least one selected from the group consisting of ether solvents, ketone solvents, and ester solvents. B7: The method according to B5 or B6, wherein the third solvent comprises at least one selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, acetone, methyl ethyl ketone, ethyl acetate, and isopropyl acetate. B8: The method according to any one of B5 to B7, wherein the third solvent is tetrahydrofuran.

[0027] B9: The method according to any one of B5 to B8, wherein the temperature of the third solvent in step (B-1) is −20° C. to 10° C. B10: The method according to any one of B5 to B9, wherein the temperature of the third solvent in step (B-1) is −20° C. to 5° C.

[0028] B11: The method according to any one of B1 to B10, wherein the fourth solvent comprises at least one selected from the group consisting of ketone solvents, ether solvents, ester solvents, hydrocarbon solvents, aromatic solvents, alcohol solvents, and halogenated solvents. B12: The method according to any one of B1 to B11, wherein the fourth solvent comprises at least one selected from the group consisting of ketone solvents and ether solvents. B13: The method according to any one of B1 to B12, wherein the fourth solvent is a solvent that does not dissolve sodium chloride but dissolves Compound 1. B14: The method according to any one of B1 to B13, wherein the fourth solvent comprises at least one selected from the group consisting of acetone, methyl ethyl ketone, and tetrahydrofuran.

[0029] B15: The method according to any one of B1 to B14, wherein the temperature of the fourth solvent in step (B-3) is −20° C. to 25° C. B16: The method according to any one of B1 to B15, wherein the temperature of the fourth solvent in step (B-3) is −10° C. to 15° C.

[0030] The methods described in B1 to B16 above do not require concentration to remove inorganic salts from a mixture containing Compound 1. Compared to the method described in Synthesis Example 4 (4-1) below, in which concentration is performed to remove inorganic salts, the methods described in B1 to B16 above make it possible to more easily obtain a product having a high content of Compound 1.

[0031] Furthermore, the methods described in B1 to B16 above do not require precipitation of Compound 1. Compared with the method described in Synthesis Example 4 (4-2) below, in which precipitation of Compound 1 is performed, the methods described in B1 to B16 above make it possible to more easily obtain a product having a high content of Compound 1.

[0032] The present disclosure also includes the methods described in C1 to C3 below. C1: A method for producing the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 3), the method comprising the following step (C-1): (C-1) a step of producing 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1) by the method described in any of B1 to B16, and C2: a step of producing Compound 3 from Compound 1 obtained in step (C-1) using a sodium base. C3: A method for producing the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 3), comprising the following steps (C-1) and (C-2): (C-1) a step of producing 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1) by the method described in any one of B1 to B16; and (C-2) a step of producing Compound 3 by the method described in any one of A1 to A45 using Compound 1 obtained in step (C-1).

[0033] The present disclosure also includes compositions or methods described in D1 to D7 below. D1: A composition comprising the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound 3), wherein the content of compound 3 is 98.0% by mass or more relative to the mass of the composition. D2: The composition described in D1, wherein the content of compound 3 is 99.0% by mass or more relative to the mass of the composition. D3: The composition described in D1 or D2, wherein the peak area of ​​compound 3 obtained by high performance liquid chromatography (HPLC) analysis of the composition at 278 nm is 99.0% or more relative to the sum of the peak areas of all substances detected in the HPLC analysis.

[0034] D4: A composition comprising the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound 3) and 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid (compound 4), wherein the peak area of ​​compound 4 obtained by high performance liquid chromatography (HPLC) analysis at 278 nm of the composition is 0.20% or less of the peak area of ​​compound 3 obtained by the HPLC analysis. D5: A composition wherein the peak area of ​​compound 4 obtained by high performance liquid chromatography (HPLC) analysis at 278 nm of the composition is 0.05% or less of the peak area of ​​compound 3 obtained by the HPLC analysis.

[0035] D6: The composition according to D4 or D5, which is a pharmaceutical composition. D7: The composition according to D6, which is a pharmaceutical composition for treating or preventing cancer.

[0036] D8: A method according to any one of A1 to A45 and C1 to C3, which is a method for producing the composition according to any one of D1 to D7.

[0037] The present disclosure also includes a method according to E1 below: E1: The method according to any one of A1 to A45 and C1 to C3, wherein a product having an enriched content of Compound 3 is obtained.

[0038] The present disclosure provides a method for producing a specific arylamide derivative useful for the treatment or prevention of cancer, which method enables the production of a product having a higher content of the arylamide derivative, and also provides a method for producing a production intermediate of such an arylamide derivative, which method enables the production of a product having a higher content of the production intermediate to be more simply obtained.

[0039] Figure 1 shows the powder X-ray diffraction pattern of Sample 1a (Form I), Figure 2 shows the powder X-ray diffraction pattern of Sample 1b (Form I), and Figure 3 shows the powder X-ray diffraction pattern of Sample 1c.

[0040] Exemplary embodiments of the present disclosure will now be described.

[0041] In the present disclosure, when a numerical range is indicated by "to", the numerical range includes both end values. For example, "a pKa of 7.0 to 12.0" means that the pKa is 7.0 or more and 12.0 or less.

[0042] In the present disclosure, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0043] In the present disclosure, a C1-6 alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms. Examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, a 1-methylpropyl group, an n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a 1-ethylpropyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, a 3,3-dimethylbutyl group, a 1-ethylbutyl group, and a 2-ethylbutyl group.

[0044] In the present disclosure, a C1-6 alkoxy group refers to an alkoxy group having a linear or branched alkyl group having 1 to 6 carbon atoms. Examples include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a sec-butoxy group, a tert-butoxy group, an n-pentoxy group, a tert-pentoxy group, and an n-hexoxy group.

[0045] In the present disclosure, sodium C1-6 alkoxide refers to a sodium alkoxide having a linear or branched alkyl group having 1 to 6 carbon atoms, such as sodium methoxide, sodium ethoxide, sodium n-propoxide, sodium isopropoxide, sodium n-butoxide, sodium sec-butoxide, sodium tert-butoxide, sodium n-pentoxide, sodium tert-pentoxide, and sodium n-hexoxide.

[0046] A first aspect of the present disclosure provides a method for producing the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 3), the method comprising the following step (A-1): (A-1) mixing the following (a), (b), and (c) in a first solvent to obtain a mixture containing Compound 3: (a) 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1), (b) a sodium base, and (c) at least one organic acid selected from the group consisting of compounds represented by the following general formula (A): [In the formula, X １ is a hydroxy group or a mercapto group, R １ , R ２ , R ３ , R ４ and R ５ are each independently a hydrogen atom, a halogen atom, a C1-6 alkyl group, a hydroxy group, a C1-6 alkoxy group, a phenoxy group, a nitro group, or a cyano group.

[0047] Compound 3 is represented by the following formula:

[0048] Compound 1 (also referred to as "Compound 1A" in this disclosure) is represented by the following formula:

[0049] Compound 1 can be produced, for example, in accordance with the method of the second aspect described below or the method described in Synthesis Example 4 described below. Compound 1 may be obtained in any manner, but is preferably produced, for example, in accordance with the method of the second aspect described below.

[0050] The sodium base is used to convert Compound 1 to a sodium salt (Compound 3). The sodium base is, for example, at least one selected from the group consisting of sodium C1-6 alkoxide, sodium hydroxide, sodium hydride, and sodium hexamethyldisilazide, or includes at least one such base. Preferably, the sodium base is at least one selected from the group consisting of sodium tert-butoxide, sodium tert-pentoxide, sodium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, and sodium hexamethyldisilazide, or includes at least one such base. More preferably, the sodium base is at least one selected from the group consisting of sodium tert-butoxide, sodium tert-pentoxide, and sodium hydroxide, or includes at least one such base. Most preferably, the sodium base is sodium tert-butoxide.

[0051] In general formula (A), X １ is preferably a hydroxy group, and R １ is preferably a hydrogen atom or a C1-6 alkyl group, and R ２ is preferably a hydrogen atom or a C1-6 alkyl group, and R ３ is preferably a hydrogen atom or a C1-6 alkyl group, and R ４ is preferably a hydrogen atom or a C1-6 alkyl group, and R ５ is preferably a hydrogen atom or a C1-6 alkyl group.

[0052] The organic acid is preferably at least one selected from the group consisting of o-cresol, m-cresol, p-cresol, phenol, and dibutylhydroxytoluene, more preferably at least one selected from the group consisting of m-cresol, phenol, and dibutylhydroxytoluene, and most preferably m-cresol.

[0053] The organic acid is preferably an acid weaker than Compound 1. The pKa of the organic acid in water at 25° C. is preferably 7.0 to 12.0, more preferably 7.0 to 11.0, and even more preferably 8.0 to 11.0.

[0054] The solubility of the sodium salt of an organic acid in a mixed solvent of tetrahydrofuran, acetone, tert-butyl methyl ether, and water (the volume ratio of tetrahydrofuran, acetone, and tert-butyl methyl ether is 8:10:5, and the water content is 3 mass% relative to the mass of the mixed solvent) at 25°C is preferably 3 mmol / L or more, more preferably 0.05 mol / L or more, and even more preferably 0.08 mol / L or more.

[0055] The solubility of the organic acid in a mixed solvent of tetrahydrofuran, acetone, tert-butyl methyl ether, and water (the volume ratio of tetrahydrofuran, acetone, and tert-butyl methyl ether is 8:10:5, and the water content is 3 mass% relative to the mass of the mixed solvent) at 25°C is preferably 0.05 mol / L or more, more preferably 0.08 mol / L or more, and even more preferably 0.10 mol / L or more.

[0056] The molar equivalent of the organic acid mixed in step (A-1) is preferably 0.1 to 3, more preferably 0.1 to 1.5, and even more preferably 0.3 to 0.6, relative to the sodium base.

[0057] The molar equivalent of the sodium base to be mixed in step (A-1) is preferably 0.3 to 3, more preferably 0.5 to 1.5, and even more preferably 0.8 to 1.2, relative to Compound 1.

[0058] The first solvent is, or includes, at least one selected from the group consisting of ether solvents, ketone solvents, and amide solvents. Examples of ether solvents include diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane, diisopropyl ether, cyclopentyl methyl ether, tert-butyl methyl ether, 4-methyltetrahydropyran, diglyme, triglyme, and tetraglyme. Examples of ketone solvents include methyl ethyl ketone, acetone, methyl isobutyl ketone, and cyclohexanone. Examples of amide solvents include dimethylformamide, dimethylacetamide, and N-methyl-2-pyrrolidone.

[0059] The first solvent is preferably at least one selected from the group consisting of tetrahydrofuran, acetone, and 1,3-dimethyl-2-imidazolidinone, or contains at least one such solvent, and more preferably at least one selected from the group consisting of tetrahydrofuran and acetone, or contains at least one such solvent.

[0060] The temperature of the first solvent in step (A-1) is, for example, -25°C to 40°C, preferably -15°C to 15°C, more preferably -10°C to 10°C, and even more preferably -5°C to 5°C.

[0061] The volume of the first solvent in step (A-1) is preferably 6 to 16 mL, more preferably 8 to 14 mL, and even more preferably 10 to 12 mL per gram of the mass of compound 3 produced in step (A-1).

[0062] Step (A-1) can be carried out, for example, in a container. For example, when step (A-1) is carried out in a container, the above (a), (b), and (c) and the first solvent may be added to the container in any order, for example, they may be added simultaneously. Alternatively, for example, the above (b) and (c) may be mixed first, and then mixed with the above (a) and the first solvent. Alternatively, for example, the above (a), (b), and (c) may each be in the form of a solution when added.

[0063] In some preferred embodiments, the method of the first aspect of the present disclosure further comprises both or either one of the following steps (A-2) and (A-3): (A-2) mixing the mixture obtained in step (A-1) with a second solvent; and (A-3) obtaining compound 3 from the mixture obtained in step (A-1) or (A-2).

[0064] The second solvent is, for example, at least one selected from the group consisting of ether solvents, ketone solvents, and hydrocarbon solvents, or includes at least one such solvent. Examples of ether solvents include tert-butyl methyl ether, cyclopentyl methyl ether, 4-methyltetrahydropyran, tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane, diisopropyl ether, diglyme, triglyme, and tetraglyme. Examples of ketone solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone. Examples of hydrocarbon solvents include n-hexane, n-heptane, n-octane, n-decane, n-dodecane, 2,3-dimethylhexane, 2-methylheptane, 2-methylhexane, 3-methylhexane, and cyclohexane.

[0065] The second solvent is preferably at least one selected from the group consisting of acetone, methyl ethyl ketone, tert-butyl methyl ether, cyclopentyl methyl ether, and n-heptane, or contains at least one such solvent, and more preferably at least one selected from the group consisting of acetone and tert-butyl methyl ether, or contains at least one such solvent.

[0066] The temperature of the second solvent in step (A-2) is, for example, -25°C to 50°C, preferably 0°C to 45°C, more preferably 5°C to 40°C, and even more preferably 25°C to 40°C.

[0067] The volume of the second solvent in step (A-2) is preferably 0.3 to 3 times, more preferably 0.5 to 2 times, and even more preferably 0.7 to 1.3 times the volume of the first solvent.

[0068] In step (A-3), the compound 3 is obtained, for example, by solid-liquid separation from the mixture obtained in step (A-2). The solid-liquid separation can be carried out, for example, by filtration or centrifugation.

[0069] A second aspect of the present disclosure provides a method for producing 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1), the method comprising the following steps (B-1), (B-2), and (B-3): (B-1) A step of mixing the following (d), (e), and (f) to obtain a mixture containing Compound 1: (d) 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 2); (e) N-methylsulfamoyl chloride; and (f) an aqueous solution of an inorganic salt. (B-2) A step of removing the aqueous layer from the mixture obtained in Step (B-1) by a separation operation. (B-3) A step of mixing the mixture obtained in Step (B-2) with a fourth solvent to remove the inorganic salt.

[0070] Compound 2 (also referred to as "compound 5A" in this disclosure) is represented by the following formula:

[0071] Compound 2 can be produced, for example, according to the method described in Synthesis Example 3 (3-1) or 4 (4-2) below. Compound 2 may be obtained in any manner.

[0072] N-methylsulfamoyl chloride is available, for example, as a commercially available reagent.

[0073] The aqueous solution of the inorganic salt is preferably at least one selected from the group consisting of an aqueous sodium chloride solution, an aqueous ammonium chloride solution, an aqueous sodium dihydrogen phosphate solution, and an aqueous potassium dihydrogen phosphate solution, more preferably at least one selected from the group consisting of an aqueous sodium chloride solution and an aqueous ammonium chloride solution, and most preferably an aqueous sodium chloride solution.

[0074] The concentration of the inorganic salt in the aqueous solution is, for example, 5 to 25% by mass, preferably 8 to 23% by mass.

[0075] Step (B-1) is preferably carried out in a third solvent.

[0076] The third solvent is, for example, at least one selected from the group consisting of ether solvents, ketone solvents, and ester solvents, or includes at least one such solvent. Examples of ether solvents include tert-butyl methyl ether, cyclopentyl methyl ether, 4-methyltetrahydropyran, tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane, diisopropyl ether, diglyme, triglyme, and tetraglyme. Examples of ketone solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone. Examples of ester solvents include ethyl acetate, butyl acetate, isopropyl acetate, ethylene glycol diacetate, and propylene glycol monomethyl ether acetate.

[0077] The third solvent is preferably at least one selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, 4-methyltetrahydropyran, acetone, methyl ethyl ketone, ethyl acetate, and isopropyl acetate, or contains at least one such solvent, and is most preferably tetrahydrofuran.

[0078] The temperature of the third solvent in step (B-1) is, for example, -20°C to 10°C, preferably -20°C to 8°C, more preferably -20°C to 5°C, and even more preferably -20°C to 0°C.

[0079] Step (B-1) can be carried out, for example, in a container. For example, when step (B-1) is carried out in a container in a third solvent, the above (d), (e), and (f) and the third solvent may be added to the container in any order, for example, they may be added simultaneously. Alternatively, for example, the above (e) and (f) may be mixed first, and then mixed with the above (d) and the third solvent. Alternatively, for example, the above (d) and (e) may each be in the form of a solution when added.

[0080] The fourth solvent is, for example, at least one selected from the group consisting of ketone solvents, ether solvents, ester solvents, hydrocarbon solvents, aromatic solvents, alcohol solvents, and halogenated solvents, or includes at least one such solvent. Preferably, the fourth solvent is, or includes at least one selected from the group consisting of ketone solvents and ether solvents. Examples of ketone solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, and cyclohexanone. Examples of ether solvents include tert-butyl methyl ether, cyclopentyl methyl ether, 4-methyltetrahydropyran, tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, 1,2-dimethoxyethane, diisopropyl ether, diglyme, triglyme, and tetraglyme. Examples of ester solvents include ethyl acetate, butyl acetate, isopropyl acetate, ethylene glycol diacetate, and propylene glycol monomethyl ether acetate. Examples of hydrocarbon solvents include n-hexane, n-heptane, n-octane, n-decane, n-dodecane, 2,3-dimethylhexane, 2-methylheptane, 2-methylhexane, 3-methylhexane, and cyclohexane. Examples of aromatic solvents include toluene and xylene. Examples of alcohol solvents include methanol, ethanol, propanol, isopropanol, and butanol. Examples of halogen-based solvents include dichloromethane and chloroform.

[0081] The fourth solvent is more preferably a solvent that does not dissolve sodium chloride but dissolves Compound 1, and even more preferably is at least one selected from the group consisting of acetone, methyl ethyl ketone, and tetrahydrofuran, or contains at least one such solvent.

[0082] The temperature of the fourth solvent in step (B-3) is, for example, -20°C to 25°C, preferably -15°C to 20°C, more preferably -10°C to 15°C, and even more preferably -5°C to 10°C.

[0083] Step (B-3) can be carried out, for example, in a vessel. For example, when step (B-3) is carried out in a vessel, the mixture obtained in step (B-2) and the fourth solvent may be added to the vessel in any order, for example, they may be added simultaneously.

[0084] In the step (B-3), the inorganic salt can be removed by, for example, a separation operation.

[0085] The process of the second aspect may be carried out as one step in a process for producing compound 3.

[0086] That is, a third aspect of the present disclosure provides a method for producing the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 3), which includes the following step (C-1): (C-1) A step of producing 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1) by the method of the second aspect.

[0087] In a preferred embodiment, the method of the third aspect further comprises a step of producing compound 3 from compound 1 obtained in step (C-1) using a sodium base. This step can be carried out, for example, in accordance with the method described in Synthesis Example 4 below.

[0088] The sodium base is used to convert Compound 1 to a sodium salt (Compound 3). The sodium base is, for example, at least one selected from the group consisting of sodium C1-6 alkoxide, sodium hydroxide, sodium hydride, and sodium hexamethyldisilazide, or includes at least one such base. Preferably, the sodium base is at least one selected from the group consisting of sodium tert-butoxide, sodium tert-pentoxide, sodium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, and sodium hexamethyldisilazide, or includes at least one such base. More preferably, the sodium base is at least one selected from the group consisting of sodium tert-butoxide, sodium tert-pentoxide, and sodium hydroxide, or includes at least one such base. Most preferably, the sodium base is sodium tert-butoxide.

[0089] The molar equivalent of the sodium base used in the above step is preferably 0.3 to 3, more preferably 0.5 to 1.5, and even more preferably 0.8 to 1.2 relative to Compound 1.

[0090] In another preferred embodiment, the method of the third aspect further comprises the following step (C-2): (C-2) a step of producing compound 3 by the method of the first aspect using compound 1 obtained in step (C-1).

[0091] The method of the first or third aspect allows for obtaining a product with a high content of compound 3 (for example, 97.0% by weight or more, 98.0% by weight or more, or 99.0% by weight or more).

[0092] That is, a fourth aspect of the present disclosure provides a composition comprising the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound 3), wherein the content of compound 3 is 98.0% by mass or more relative to the mass of the composition.

[0093] In a preferred embodiment, the composition of the fourth aspect is a composition in which the content of compound 3 is 99.0% by mass or more based on the mass of the composition.

[0094] In another preferred embodiment, the composition of the fourth aspect is a composition in which the peak area of ​​compound 3 obtained by high performance liquid chromatography (HPLC) analysis of the composition at 278 nm is 99.0% or more of the total peak area of ​​all substances detected in the HPLC analysis.

[0095] When compound 3 is produced by the method of the first or third aspect, 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid (compound 4) may be produced, but the amount of compound 4 produced is small, and the peak area of ​​compound 4 obtained by high performance liquid chromatography (HPLC) analysis at 278 nm is, for example, 0.20% or less of the peak area of ​​compound 3 obtained by the HPLC analysis.

[0096] That is, a fifth aspect of the present disclosure provides a composition comprising sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (compound 3) and 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid (compound 4), wherein the peak area of ​​compound 4 obtained by high performance liquid chromatography (HPLC) analysis of the composition at 278 nm is 0.20% or less of the peak area of ​​compound 3 obtained by the HPLC analysis.

[0097] In a preferred embodiment, the composition of the fifth aspect is a composition in which the peak area of ​​compound 4 obtained by high performance liquid chromatography (HPLC) analysis at 278 nm of the composition is 0.05% or less of the peak area of ​​compound 3 obtained by the HPLC analysis.

[0098] Compound 4 is represented by the following formula:

[0099] Compound 3 is useful for treating or preventing cancer. That is, in one embodiment, the composition of the fifth aspect is a pharmaceutical composition. Also, in one embodiment, the pharmaceutical composition is a pharmaceutical composition for treating or preventing cancer.

[0100] The method of the first or third aspect is also a method for producing the composition of the fourth or fifth aspect.

[0101] The method of the first or third embodiment is also a method that can yield a product with a high content of compound 3.

[0102] The content of Compound 3 in the product can be determined by quantitative NMR using a commercially available internal standard (e.g., dimethyl sulfone). Quantitative NMR measurement can be performed, for example, under the following conditions: Deuterated solvent: dimethyl sulfoxide-d ６ and heavy water (D ２ O) were used in a volume ratio of 9:1. １ H Pulse angle: 90° Delay time: 60 seconds Digital resolution: 0.25Hz Spinning: Off Number of accumulations: 32

[0103] The content of compound 3 in the product can also be determined by HPLC analysis when the content of compound 3 in a standard sample is known. HPLC analysis can be performed, for example, using analysis condition 1 described in Table 1 below. The content of compound 3 in the product can be calculated according to the following formula: Content of compound 3 in the product (% by mass) = [mass (mg) of standard sample subjected to HPLC analysis / mass (mg) of product sample subjected to HPLC analysis] × [peak area of ​​compound 3 obtained by HPLC analysis of the product / peak area of ​​compound 3 obtained by HPLC analysis of the standard sample] × content of compound 3 in the standard sample (% by mass).

[0104] In connection with the practice of the presently disclosed invention, seed crystals of a certain compound or its salt may be used. Generally, seed crystals can be obtained by methods well known to those skilled in the art, such as cooling a solution of the compound or salt, adding a solvent (antisolvent) in which the compound or salt has low solubility, scraping the wall of a container containing a solution of the compound or salt with a spatula, or purifying the compound or salt by silica gel column chromatography and then concentrating the solution of the compound or salt under reduced pressure.

[0105] Examples of abbreviations used in the present specification are listed below together with their meanings: AA: Ammonium acetate BHT: Dibutylhydroxytoluene DCM: Dichloromethane DIPEA: N,N-diisopropylethylamine DMA: N,N-dimethylacetamide DMAP: N,N-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide EDC.HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOH: Ethanol FA: Formic acid HOOBt: 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine 2-MeTHF: 2-methyltetrahydrofuran MeCN: Acetonitrile MeOH: Methanol NMP: N-methyl-2-pyrrolidone RuPhos-Pd-G3: (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TBME: tert-butyl methyl ether TFA: trifluoroacetic acid THF: tetrahydrofuran Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos-Pd-G3: (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0106] In this disclosure, "room temperature" means a temperature of about 20°C to about 25°C.

[0107] The present disclosure will be described in more detail below based on examples, but the present disclosure is not limited to the following examples.

[0108] Unless otherwise specified, starting materials and reagents used in the following examples were either commercially available or prepared by known methods.

[0109] In the following examples, high performance liquid chromatography (HPLC) analysis was carried out using one of the analytical conditions listed in Table 1 below.

[0110] The water content in the solvent was measured by the Karl Fischer method (electrolysis method) using a water content measuring device CA-200 manufactured by Mitsubishi Chemical Analytech.

[0111] NMR was measured using a nuclear magnetic resonance spectrometer JNM-ECZ-500R manufactured by JEOL.

[0112] (Example 1) Synthesis of 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide A reaction vessel containing a 24% lithium bis(trimethylsilyl)amide THF solution (94.7 kg, 136 mol) was cooled to an external temperature of -15°C, and a solution of 4-cyclopropyl-2-fluoroaniline (8.1 kg, 53.5 mol) in THF (18.7 kg) was added dropwise at an internal temperature of 5°C or below. The reaction vessel was then rinsed with THF (4.7 kg), and a solution of 5-bromo-2,3,4-trifluorobenzoic acid (10.5 kg, 41.2 mol) in THF (65.3 kg) was added dropwise while maintaining the internal temperature at 5°C or below, followed by stirring for 30 minutes. 5M hydrochloric acid (88.7 kg) was added to the reaction mixture, which was then warmed to room temperature and extracted with isopropyl acetate (45.9 kg). The organic layer was washed once with 2M hydrochloric acid (42.8 kg) and twice with 15% aqueous sodium chloride solution (52.5 kg), and then concentrated under reduced pressure. THF (74.8 kg) was added to the resulting concentrate, and the mixture was concentrated until the total volume reached 75 L. THF (74.8 kg) was again added to the concentrate, and the mixture was concentrated until the total volume reached 75 L. Acetonitrile (100 kg) and THF (31.6 kg) were then sequentially added to the concentrate. 1,1'-carbonyldiimidazole (10.0 kg, 48.8 mmol) was added to the resulting solution, and the mixture was stirred at room temperature for 1 hour. 28% aqueous ammonia (14.5 kg) was added to the reaction mixture, and the mixture was stirred at room temperature for 1.5 hours. The resulting suspension was heated to 60°C. After confirming dissolution of the suspended matter, the solution was cooled to 25°C, and seed crystals (80 g) of 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide and water (191 kg) were sequentially added. The precipitated crystals were collected by filtration, and the filter cake was washed twice with a mixed liquid of acetonitrile (18.7 kg) and water (23.9 kg) and then dried under reduced pressure at an external temperature of 40°C to obtain the title compound (13.84 kg, yield 87.3%).

[0113] The seed crystals were produced according to the method described in Synthesis Example 2 (2-2) below.

[0114] Example 2: Preparation of sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 3)

[0115] (2-1) Effect of Various Additives 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 2) (1.00 g, 2.32 mmol) and THF (10.0 mL) were added to a reaction vessel, and the reaction vessel was degassed under reduced pressure while stirring and purged with nitrogen. Pyridine (0.564 mL, 6.97 mmol) was added to the resulting solution, and the mixture was cooled to a temperature of -20°C to 0°C. N-methylsulfamoyl chloride was then added stepwise while the reaction rate was monitored by HPLC (analysis condition 1). After confirming that the reaction rate had reached 95% or higher, 10% aqueous sodium chloride solution (5.00 g) was added while maintaining the temperature of the reaction solution below 10°C. The organic layer obtained by layer separation was washed sequentially with 10% aqueous sodium chloride solution (5.0 g) and 20% aqueous sodium chloride solution (5.00 g). While maintaining the resulting solution at 10°C or below, acetone (3.7 mL) was added, and THF was added to the mixture to adjust the volume ratio of acetone to THF in the solution to 3:8. The resulting suspension was then filtered to obtain a clear solution. Water was added to adjust the water content in the solution to approximately 5% by mass, and 2 M sodium tert-butoxide (1.11 mL, 2.21 mmol) was added dropwise with or without an additive (acetaminophen, BHT, phenol, or m-cresol) while maintaining the temperature of the reaction solution in the range of 20°C to 40°C. Subsequently, a suspension of seed crystals of Compound 3 (12 mg) in acetone (0.24 mL) was added at 40°C. Acetone (2.2 mL) was added over 30 minutes, followed by stirring for 1 hour. Acetone (6.1 mL) was then added over 20 minutes, followed by stirring for 30 minutes. TBME (6.1 mL) was then added over 20 minutes, followed by stirring for an additional 30 minutes. The resulting suspension was cooled to 25°C over 30 minutes and stirred for an additional 30 minutes. The precipitated solid was collected by filtration, washed twice with a mixed solvent of acetone (3.7 mL) and TBME (3.7 mL), and then dried under reduced pressure to obtain compound 3. A sample of the resulting compound 3 (hereinafter referred to as "sample 3a") was subjected to HPLC analysis using analytical condition 1.

[0116] The above compound 2 was produced from 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide obtained in the above Example 1 according to the method described in Synthesis Example 3 (3-1) below.

[0117] The seed crystals were produced from 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide obtained in Example 1 above according to the methods described in Synthesis Examples 3 (3-1) and 4 (4-1) below.

[0118] The reaction rate was calculated according to the following formula: Reaction rate (%) = [(Peak area of ​​compound 1 + Peak area of ​​compound X + Peak area of ​​compound Y) / (Peak area of ​​compound 1 + Peak area of ​​compound 2 + Peak area of ​​compound X + Peak area of ​​compound Y)] × 100 (%)

[0119] The HPLC retention times were about 3.26 minutes for compound 1, 1.02 minutes for compound 2, 3.54 minutes for compound X, and 4.05 minutes for compound Y.

[0120] The structural formulae of Compound X and Compound Y are as follows:

[0121] The results of the HPLC analysis of Sample 3a are shown in Table 2. Table 2 shows the content of Compound 3 in Sample 3a, the HPLC purity of Compound 3 in Sample 3a (the percentage of the peak area of ​​Compound 3 relative to the sum of the peak areas of all substances detected in the HPLC analysis of Sample 3a), and the amount of the impurity 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid (Compound 4) in Sample 3a (relative amount to Compound 3).

[0122] The content of Compound 3 in Sample 3a was calculated from the content of Compound 3 in a standard sample of Compound 3 (hereinafter referred to as "Standard 3") according to the following formula: Content of Compound 3 in Sample 3a (% by mass) = [mass (mg) of Standard 3 subjected to HPLC analysis / mass (mg) of Sample 3a subjected to HPLC analysis] × [peak area of ​​Compound 3 obtained by HPLC analysis of Sample 3a / peak area of ​​Compound 3 obtained by HPLC analysis of Standard 3] × content of Compound 3 in Standard 3 (% by mass).

[0123] Sample 3 was obtained by jet milling a sample produced from 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide obtained in Example 1 according to the methods described in Synthesis Examples 3(3-1) and 4(4-1) below. HPLC analysis of Sample 3 was carried out under Analysis Condition 1.

[0124] The content of Compound 3 in Sample 3 was determined by quantitative NMR using dimethyl sulfone as an internal standard. The quantitative NMR measurement was carried out under the following conditions: Deuterated solvent: dimethyl sulfoxide-d ６ and heavy water (D ２ O) were used in a volume ratio of 9:1. １ H Pulse angle: 90° Delay time: 60 seconds Digital resolution: 0.25Hz Spinning: Off Number of accumulations: 32

[0125] The HPLC purity of Compound 3 in Sample 3a was calculated according to the following formula: HPLC purity of Compound 3 in Sample 3a (%) = 100 (%) - [total peak areas of all impurities detected in HPLC analysis of Sample 3a / total peak areas of all substances detected in HPLC analysis of Sample 3a] × 100 (%)

[0126] The amount of compound 4 in sample 3a (relative to compound 3) was calculated according to the following formula: Amount of compound 4 in sample 3a (%) = [peak area of ​​compound 4 obtained by HPLC analysis of sample 3a / peak area of ​​compound 3 obtained by HPLC analysis of sample 3a] × 100 (%)

[0127] The structural formula of compound 4 is as follows:

[0128] Table 2 also shows the pKa of the additive, the solubility of the sodium salt of the additive, and the solubility of the additive.

[0129] The pKa values ​​shown in Table 2 are pKa values ​​in water described in the following documents. The pKa values ​​of acetaminophen, phenol, and m-cresol are pKa values ​​in water at 25°C. Acetaminophen: Org. Biomol. Chem., 2009, 7, 5103. BHT: IUPAC Chemical Data Series, No. 23; Pergamon Press: Oxford, UK, 1979. Phenol: Handbook of Biochemistry and Selected Data for Molecular Biology, 2nd ed.; CRC: Cleveland, OH, 1970. m-Cresol: Handbook of Chemistry and Physics, 85th ed. ;CRC: Boca Raton, FL, 2004-2005.

[0130] The solubility of the additive or its sodium salt was measured as follows. A mixed solvent of tetrahydrofuran, acetone, tert-butyl methyl ether, and water (the volume ratio of tetrahydrofuran, acetone, and tert-butyl methyl ether was 8:10:5, and the water content was 3 mass% relative to the mass of the mixed solvent) was prepared. The temperature of the solvent was brought to 25°C, and an additive (acetaminophen, BHT, phenol, or m-cresol) or its sodium salt was added, and the resulting suspension was stirred for 6 hours or more. The supernatant was subjected to HPLC analysis using analysis condition 1.

[0131]

[0132] As is evident from the above results, the addition of BHT, phenol or m-cresol results in a product with a higher content of Compound 3 compared to the product without additive or the product with the addition of acetaminophen.

[0133] When acetaminophen was added, residual impurities were confirmed in Sample 3a, and when phenol was added, the peak of Compound 4 was not detected.

[0134] (2-2) Investigation of inorganic salt removal method (1) Inorganic salt removal by concentration 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (compound 2) (1.00 g, 2.32 mmol) and THF (10.0 mL) were added to a reaction vessel, and the reaction vessel was degassed under reduced pressure while stirring and purged with nitrogen. Pyridine (0.564 mL, 6.97 mmol) was added to the resulting solution, and the mixture was cooled to a temperature of -20°C to 0°C. N-methylsulfamoyl chloride was then added stepwise while the reaction rate was monitored by HPLC (analysis condition 2). After confirming that the reaction rate had reached 95% or higher, 10% aqueous sodium chloride solution (5.00 g) was added while maintaining the temperature of the reaction solution at 10°C or below. The organic layer obtained by layer separation was washed sequentially with a 10% aqueous sodium chloride solution (5.0 g) and a 20% aqueous sodium chloride solution (5.00 g). THF (15.0 mL) was added and the mixture was concentrated to a total volume of 5 mL twice at 40°C. The resulting suspension was filtered to obtain a clear solution. Acetone (3.7 mL) and THF were added to adjust the volume ratio of acetone to THF in the solution to 3:8. Water was added to adjust the water content in the solution to approximately 5% by mass, followed by the addition of m-cresol, and 2 M sodium tert-butoxide (1.10 mL, 2.21 mmol) dropwise while maintaining the temperature of the reaction solution between 20°C and 40°C. Subsequently, a suspension of seed crystals (12 mg) of Compound 3 in acetone (0.20 mL) was added at 40°C. Acetone (2.5 mL) was added over 30 minutes, followed by stirring for 1 hour. Further, acetone (6.0 mL) was added over 20 minutes, followed by stirring for 30 minutes. Thereafter, TBME (6.0 mL) was added over 20 minutes, followed by stirring for an additional 30 minutes. The resulting suspension was cooled to 25°C over 30 minutes, followed by stirring for an additional 30 minutes. The precipitated solid was collected by filtration, and the filter cake was washed twice with a mixed solvent of acetone (3.5 mL) and TBME (3.5 mL), followed by drying under reduced pressure to obtain compound 3. A sample of the obtained compound 3 (hereinafter referred to as "sample 3c") was subjected to HPLC analysis using analytical condition 2.

[0135] The compound 2 and the seed crystals were prepared in the same manner as in (2-1) above. The reaction rate was calculated in the same manner as in (2-1) above.

[0136] The content of Compound 3 in Sample 3c was 99.5% by mass, which was calculated in the same manner as the content of Compound 3 in Sample 3a.

[0137] (2) Removal of inorganic salts by adding solvent 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 2) (1.00 g, 2.32 mmol) and THF (10.0 mL) were added to a reaction vessel, and the reaction vessel was degassed under reduced pressure while stirring and purged with nitrogen. Pyridine (0.564 mL, 6.97 mmol) was added to the resulting solution, and the mixture was cooled to a temperature of -20°C to 0°C. N-methylsulfamoyl chloride was then added stepwise while the reaction rate was monitored by HPLC (analysis condition 2). After confirming that the reaction rate had reached 95% or higher, 10% aqueous sodium chloride solution (5.00 g) was added while maintaining the temperature of the reaction solution below 10°C. The organic layer obtained by layer separation was washed sequentially with 10% aqueous sodium chloride solution (5.0 g) and 20% aqueous sodium chloride solution (5.00 g). While maintaining the resulting solution at 10°C or below, methyl ethyl ketone (3.7 mL) or 2-MeTHF (3.7 mL) was added, and THF was added to the mixture to adjust the volume ratio of methyl ethyl ketone or 2-MeTHF to THF in the solution to 3:8. The resulting suspension was then filtered to obtain a clear solution. Water was added to adjust the water content in the solution to approximately 5% by mass, followed by the addition of m-cresol, and 2 M sodium tert-butoxide (1.10 mL, 2.21 mmol) dropwise while maintaining the temperature of the reaction solution in the range of 20°C to 40°C. Subsequently, a suspension of seed crystals of Compound 3 (12 mg) in acetone (0.20 mL) was added at 40°C. Acetone (2.5 mL) was added over 30 minutes, followed by stirring for 1 hour. Furthermore, acetone (6.0 mL) was added over 20 minutes, followed by stirring for 30 minutes. Thereafter, TBME (6.0 mL) was added over 20 minutes, and the mixture was stirred for an additional 30 minutes. The resulting suspension was cooled to 25°C over 30 minutes, and the mixture was stirred for an additional 30 minutes. The precipitated solid was collected by filtration, and the residue was washed twice with a mixed solvent of acetone (3.5 mL) and TBME (3.5 mL), and then dried under reduced pressure to obtain compound 3. A sample of the resulting compound 3 (hereinafter referred to as "sample 3d") was subjected to HPLC analysis using analytical condition 2.

[0138] The compound 2 and the seed crystals were prepared in the same manner as in (2-1) above. The reaction rate was calculated in the same manner as in (2-1) above.

[0139] The content of compound 3 in sample 3d was as follows (shown together with the solvent initially added in the inorganic salt removal step). The content of compound 3 in sample 3d was calculated in the same manner as the content of compound 3 in sample 3a. Methyl ethyl ketone: 99.4% by mass 2-MeTHF: 97.4% by mass

[0140] (3) Discussion It was shown that whether inorganic salts were removed by concentration or by adding a solvent, a product with a high content of Compound 3 could be obtained. Furthermore, when inorganic salts were removed by adding a solvent, it was shown that acetone or methyl ethyl ketone, for example, was particularly excellent as the solvent (see Table 2 (m-cresol) above for acetone).

[0141] Although inorganic salts can be removed by any of the above methods, the method of adding a solvent is superior in terms of simplicity.

[0142] Since removal of inorganic salts by concentration is carried out at a relatively high temperature (e.g., 40°C), if the concentration takes a long time, there is a possibility that Compound 1 may be decomposed during the concentration process. The method using solvent addition is advantageous in that it allows removal of inorganic salts at a low temperature (e.g., 10°C or lower).

[0143] (2-3) Preparation of Compound 3 Under a nitrogen atmosphere, THF (21.32 kg) was added to a reaction vessel, followed by the addition of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 2) (3.00 kg, 6.97 mol). While rinsing the weighing vessel, THF (5.34 kg) was added to the reaction vessel, followed by the dropwise addition of pyridine (1.65 kg, 20.9 mol). The solution obtained after stirring was cooled to a temperature of -20°C to -10°C, and N-methylsulfamoyl chloride (total 0.942 kg, 7.27 mol) was added stepwise while maintaining the solution temperature within this range. While maintaining the temperature of the reaction solution below 10°C, a 10% aqueous sodium chloride solution (15.0 kg) was added. While maintaining the temperature of the organic layer obtained by layer separation in the range of -5°C to 5°C, the organic layer was washed successively with a 10% aqueous sodium chloride solution (15.0 kg), a 20% aqueous sodium chloride solution (15.1 kg), and a 20% aqueous sodium chloride solution (15.0 kg). While maintaining the temperature of the organic layer after washing in the range of -5°C to 5°C, acetone (8.63 kg) and THF (8.59 kg) were added successively to the organic layer. The resulting suspension was filtered to obtain a clear solution. The reaction vessel was washed and filtered with THF (3.24 kg), and the obtained filtrate was combined with the above-mentioned clear solution and cooled to a temperature of -5°C to 5°C in a crystallization vessel. Water was added to this solution to adjust the water content in the solution to approximately 5% by mass, and then, while maintaining the temperature of the solution in the range of -5°C to 5°C, 2 M sodium tert-butoxide THF solution (2.89 kg, 6.66 mol) and m-cresol (0.38 kg, 3.51 mol) (which had been mixed in advance under a nitrogen atmosphere) were added dropwise. The vessel used to mix the 2 M sodium tert-butoxide THF solution and m-cresol was washed with THF (8.28 kg), and the resulting mixture was added to a crystallization vessel, and the resulting mixture was heated to a temperature of 25°C to 35°C. Subsequently, seed crystals of Compound 3 (18.0 g) were suspended in acetone (0.57 kg) and added to the crystallization vessel. The resulting suspension was heated to a temperature of 30°C to 40°C and stirred for 30 minutes. The suspension was heated to a temperature of 35°C to 45°C and stirred for 30 minutes, after which acetone (5.2 kg) was added dropwise to the crystallization vessel over 1 hour and the mixture was stirred for another 1 hour.Acetone (14.4 kg) was added dropwise over 30 minutes or more, and the mixture was stirred for an additional 30 minutes. Thereafter, TBME (13.5 kg) was added over 30 minutes or more, and the mixture was stirred for an additional 30 minutes. The resulting suspension was cooled to a temperature of 20°C to 30°C, and the mixture was stirred for an additional 30 minutes. The precipitated solid was filtered, and the filter cake was washed twice with a mixture of acetone (8.64 kg) and TBME (8.10 kg), and then dried under reduced pressure to obtain compound 3 (3.10 kg, yield 81.1%). A sample of the resulting compound 3 (hereinafter referred to as "sample 3b") was subjected to HPLC analysis using analytical condition 2.

[0144] The above compound 2 was produced from 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide obtained in the above Example 1 according to the method described in Synthesis Example 3 (3-1) below.

[0145] The seed crystals were obtained by pulverizing, in a jet mill, samples produced from 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide obtained in Example 1 according to the methods described in Synthesis Examples 3 (3-1) and 4 (4-1) below.

[0146] The content and HPLC purity of Compound 3 in Sample 3b (the percentage of the peak area of ​​Compound 3 relative to the total peak area of ​​all substances detected in the HPLC analysis of Sample 3b) were as follows: The content and HPLC purity of Compound 3 in Sample 3b were calculated in the same manner as the content and HPLC purity of Compound 3 in Sample 3a above. Content: 99.8% by mass HPLC purity: 99.7%

[0147] Reference Examples Below are Reference Examples (Synthesis Examples and Production Examples) relating to the production of Compounds 1 and 3. In the following Reference Examples, Compound 1 is also referred to as "Compound 1A" and Compound 2 is also referred to as "Compound 5A".

[0148] In the following Reference Examples, "HPLC purity" means the percentage of the peak area of ​​the compound in question relative to the total peak area of ​​all substances detected in HPLC analysis.

[0149] [Synthesis Examples] In the following synthesis examples, high performance liquid chromatography (HPLC) analysis was performed using one of the analysis conditions listed in Table 3. Each compound was detected using a photodiode array detector or a mass spectrometer, but other techniques such as evaporative light scattering detection may also be used.

[0150] NMR was measured using a nuclear magnetic resonance spectrometer JNM-ECZ500R (manufactured by JEOL Ltd.) NMR data are shown in ppm (parts per million) (δ) and referenced to the deuterium lock signal from the sample solvent.

[0151] Commercially available reagents were used without further purification. All non-aqueous reactions were carried out in anhydrous solvents. Concentration under reduced pressure or solvent evaporation was performed using a rotary evaporator.

[0152] (Synthesis Example 1) Synthesis of (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate (Compound 4A) (1-1) Synthesis of (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate (Compound 4A) (2-amino-3-fluoropyridin-4-yl)methanol (Compound 2A) (30.0 g, 211 mmol) and DMAP (28.4 g, 232 mmol) were added to a reaction vessel, and then the atmosphere was replaced with nitrogen. MeCN (885 mL) was added, and after confirming that the reaction solution was homogenous, methyl chloroformate (Compound 3A) (16.2 mL, 211 mmol) was added dropwise over 1 hour. MeCN (15 mL) was added, and the mixture was stirred at 25°C for 2 hours. The solvent was distilled off under reduced pressure at 40°C until the volume of the solution was 90 mL, and then isopropyl acetate (900 mL) was added. This solution was washed once with a 15% aqueous sodium chloride solution (300 mL), once with a 15% aqueous ammonium chloride solution (300 mL), and twice with water (150 mL), and the solvent was distilled off under reduced pressure at 40°C until the solution volume reached 90 mL. Toluene (300 mL) was added to the resulting solution, and the solvent was distilled off under reduced pressure at 40°C until the solution volume reached 90 mL. Toluene (300 mL) was added again, and the solvent was distilled off under reduced pressure at 40°C until the solution volume reached 90 mL. Further toluene (30 mL) was added, and the internal temperature of the solution was raised to 60°C to dissolve the precipitated solid, and then the temperature was lowered to 40°C over 30 minutes. Seed crystals (75 mg) obtained in (1-2) below were added, and the solution was stirred for 30 minutes. Thereafter, the internal temperature of the solution was lowered to 25°C over 30 minutes, and the solution was stirred for 30 minutes. n-Heptane (60 mL) was added over 30 minutes, and the solution was stirred for 30 minutes. Again, n-heptane (60 mL) was added over 30 minutes, and the mixture was stirred for 1 hour and 30 minutes. Further, n-heptane (120 mL) was added over 30 minutes, and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration, washed with a mixed solvent of n-heptane (45 mL) and toluene (15 mL), and then dried under reduced pressure to obtain compound 4A (35.1 g, yield 83%). HPLC purity: 98.86% (analysis condition A). １ H-NMR (DMSO-d ６ ) δ: 7.69 (1H, d, J=5.2Hz), 6.47 (1H, t, J=4.9Hz), 6.26 (2H, s), 5.15 (2H, s), 3.73 (3H, s). MS(ESI) ＋ ) m / z: 201 [M+H] ＋

[0153] (1-2) Synthesis of seed crystals of (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate (Compound 4A) Under a nitrogen atmosphere, (2-amino-3-fluoropyridin-4-yl)methanol (Compound 2A) (10.0 g, 70.4 mmol) and DMAP (12.9 g, 106 mmol) were added to a reaction vessel, and the atmosphere was then replaced with nitrogen. MeCN (300 mL) was added, and the mixture was stirred to obtain a homogeneous solution. To this solution, methyl chloroformate (Compound 3A) (5.4 mL, 70 mmol) was added dropwise over 1 hour at an external temperature of 25°C. The resulting reaction solution was stirred for 3 hours and then concentrated under reduced pressure. 2-MeTHF (100 mL) was added to the concentrated residue, and the mixture was concentrated under reduced pressure. 2-MeTHF (100 mL) was added to the residue, and the mixture was concentrated again. 2-MeTHF (50 mL) was added to the concentrated residue, and the precipitated solid was filtered off. The filter cake was then washed with 2-MeTHF (30 mL) (the resulting washing solution is referred to as washing solution 1). The remaining filter cake was again washed with 2-MeTHF (100 mL) (the resulting washing solution is referred to as washing solution 2). The filtrate and washing solution 1 were combined and concentrated under reduced pressure to a total volume of 25 mL. 2-MeTHF (5 mL) was then added, and the mixture was heated and stirred at an external temperature of 40°C to obtain a homogeneous solution. n-Heptane (30 mL) was added to this solution over 1 hour, and the mixture was then cooled to an external temperature of 35°C. n-Heptane (30 mL) was added again to the resulting mixture over 1 hour, and the mixture was then cooled to an external temperature of 25°C. The precipitated solid was filtered off, and the filter cake was washed with an n-heptane / 2-MeTHF mixture (3:1, 28 mL). The filtrate and washing solution were combined and concentrated under reduced pressure. This concentrated residue, the residue remaining in the reaction vessel after filtration, and the residue obtained by concentrating Washing Solution 2 under reduced pressure were combined and purified by silica gel column chromatography using ethyl acetate and n-heptane as the mobile phase. The resulting ethyl acetate / n-heptane solution of Compound 4A was concentrated under reduced pressure. The colorless solid obtained by concentration was dried under reduced pressure at an external temperature of 40°C to obtain Compound 4A (4.2 g, yield 30%) as crystals. HPLC purity: 99.99% (analysis condition A).

[0154] (Synthesis Example 2) Synthesis of 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 9A) (2-1) Synthesis of 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoic acid (Compound 8A) A reaction vessel containing a 1M lithium bis(trimethylsilyl)amide THF solution (206 mL, 206 mmol) was cooled to an external temperature of -15°C, and a solution of 4-cyclopropyl-2-fluoroaniline (11.6 g, 76.5 mmol) in THF (30 mL) was added dropwise. Furthermore, a solution of 5-bromo-2,3,4-trifluorobenzoic acid (15.0 g, 58.8 mmol) in THF (120 mL) was added dropwise over 30 minutes, followed by stirring for 30 minutes. 5M hydrochloric acid (118 mL) was added to the reaction mixture, which was then warmed to room temperature and extracted with isopropyl acetate (75 mL). The organic layer was washed twice with water (75 mL) and once with 15% aqueous sodium chloride solution (75 mL), followed by concentration under reduced pressure. Acetone (120 mL) was added to the resulting concentrated residue, which was then dissolved by heating. Water (45 mL) and seed crystals (150 mg) were then added to precipitate crystals. Water (45 mL) was added to the resulting slurry, and the crystals were collected by filtration. The crystals were washed with a mixture of acetone and water (1 / 2) and dried under reduced pressure at an external temperature of 40° C. to obtain Compound 8A (19.4 g, yield 85%). LCMS m / z: 386 [M+H] ＋ HPLC retention time: 0.62 minutes (Analysis conditions B)

[0155] (2-2) Synthesis of 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 9A) MeCN (104 mL), THF (26 mL), and 1,1'-carbonyldiimidazole (8.2 g, 50.5 mmol) were added to a reaction vessel containing 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzoic acid (Compound 8A) (13.0 g, 33.7 mmol), and the mixture was stirred at room temperature for 2 hours. 28% aqueous ammonia (13 mL) was added to the reaction mixture, which was then stirred at room temperature for 30 minutes. Water (117 mL) was then added over 1 hour. The crystals were collected by filtration, washed with water, and dried under reduced pressure at an external temperature of 40°C to obtain Compound 9A (12.0 g, 93% yield). LCMS m / z: 385 [M+H] ＋ HPLC retention time: 0.52 minutes (Analysis conditions B)

[0156] (Synthesis Example 3) Synthesis of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 5A) (3-1) Synthesis of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 5A) 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 9A) (15.00 g, 38.9 mmol), potassium acetate (11.47 g, 117 mmol), bispinacoldiboron (10.88 g, 42.8 mmol), and 2-MeTHF (113 mL) were added to a reaction vessel, and the atmosphere inside the reaction vessel was then purged with nitrogen. XPhos-Pd-G3 (659 mg, 0.779 mmol) was added to this reaction solution, and the atmosphere inside the reaction vessel was then purged with nitrogen. The internal temperature of the reaction solution was raised to 80°C, and the mixture was stirred for 4 hours. After the internal temperature of the reaction solution was lowered to 25°C, (2-amino-3-fluoropyridin-4-yl)methyl methyl carbonate (compound 4A) (11.69 g, 58.4 mmol), potassium carbonate (16.15 g, 117 mmol), and RuPhos-Pd-G3 (1.629 g, 1.947 mmol) were added. After the atmosphere in the reaction vessel was replaced with nitrogen (oxygen concentration in the reaction vessel ≦0.1%), the internal temperature of the reaction solution was raised to 75°C. EtOH (52 mL, 900 mmol) was slowly added dropwise (so that the internal temperature of the solution did not fall below 60°C), followed by stirring for 4 hours and 30 minutes. After confirming the decomposition of compound 4A (less than 1%), 2-MeTHF (113 mL) and an aqueous solution of N-acetyl-L-cysteine ​​(1.271 g, 113 mL) were added and the mixture was stirred for 1 hour. The internal temperature of the reaction solution was lowered to 40°C, and then extraction was performed. The organic layer was washed successively with 0.1 M hydrochloric acid (113 mL), 0.1 M aqueous potassium phosphate solution (113 mL), and 2% aqueous sodium chloride solution (113 mL), and the obtained organic layer was filtered. The filtrate was concentrated under reduced pressure to a total volume of 75 mL, and toluene (225 mL) was added to the concentrated residue. The solvent was distilled off under reduced pressure until the solution volume was 75 mL, and then toluene (225 mL) was added again. The solvent was distilled off under reduced pressure until the solution volume was 75 mL, and then 1-butanol (12 mL) was added as an internal standard, １The toluene content was calculated by H-NMR measurement, and toluene was added to make a solution with a toluene volume of 240 mL. The internal temperature of the reaction solution was raised to 110°C, and after confirming complete dissolution of the solid, the temperature was lowered to 90°C. After adding the seed crystals (75 mg) obtained in (4-2)(5) described below, the internal temperature of the reaction solution was lowered to 80°C and stirred for 1 hour. The solution temperature was lowered to 60°C and stirred for 30 minutes. The solution temperature was lowered to 40°C and stirred for 30 minutes. The solution temperature was lowered to 25°C and stirred for 30 minutes. The solution temperature was lowered to 5°C and stirred for 30 minutes. The precipitated solid was collected by filtration, washed with toluene (45 mL), and then filtered under reduced pressure to obtain Compound 5A (12.6 g, yield 75%). HPLC purity: 99.69% (analysis condition A). １ H-NMR (DMSO-d ６ ) δ: 9.38 (1H, brs), 8.19 (1H, brs), 7.70 (1H, brs), 7.65 (1H, d, J = 5.2Hz), 7.58 (1H, d, J = 6.9Hz), 6.90 (1H, d, J = 13.2), 6.81-6 76 (2H, m), 6.38 (1H, t, J=5.2Hz), 6.14 (2H, brs), 3.91 (2H, s), 1.90-1.84 (1H, m), 0.92-0.88 (2H, m), 0.64-0.61 (2H, m). MS(ESI) ＋ ) m / z: 431 [M+H] ＋

[0157] Synthesis Example 4: Synthesis of sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1A) (4-1) Preparation of Sample 1a (Form I) 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 5A) (3.00 g, 6.97 mmol) was added to a reaction vessel, followed by the addition of 1,3-dimethyl-2-imidazolidinone (12 mL) and THF (6 mL) for dissolution. The reaction vessel was purged with nitrogen, and then pyridine (1.69 mL, 20.91 mmol) was added and cooled to 0°C. N-methylsulfamoyl chloride (0.67 mL, 7.67 mmol) was added and the mixture was stirred for 45 minutes. After that, pyridine (0.10 mL, 1.26 mmol) and N-methylsulfamoyl chloride (0.30 mL, 3.42 mmol) were added and the mixture was stirred for 35 minutes. Subsequently, pyridine (0.24 mL, 2.93 mmol) and N-methylsulfamoyl chloride (0.13 mL, 1.46 mmol) were added and the mixture was stirred for 35 minutes. Then, pyridine (0.09 mL, 1.12 mmol) and N-methylsulfamoyl chloride (0.05 mL, 0.56 mmol) were added and the mixture was stirred for 3 hours. The reaction mixture was diluted with THF (18 mL) and TBME (24 mL), and then 10% aqueous sodium chloride solution (15 g) was added to terminate the reaction. The temperature was raised to 25°C. The reaction mixture was separated, and the upper layer (organic layer) was washed with 10% aqueous sodium chloride solution (24 g). The resulting organic layer was concentrated under reduced pressure to 15 mL and diluted with THF (45 mL). This procedure was repeated two more times, after which the precipitated inorganic salts were filtered off. The separated inorganic salts were washed with THF (15 mL), combined with the filtrate, and concentrated under reduced pressure to 15 mL. The residue was diluted with acetone (11 mL), and THF (9.3 mL) was added. The resulting solution was heated to 40°C, and then a 5 M aqueous sodium hydroxide solution (1.32 mL, 6.62 mmol) and a suspension of seed crystals (1.82 mg) of the sodium salt of Compound 1A (Sample 1b described below) in acetone (0.7 mL) were added sequentially, followed by stirring for 2 hours and 30 minutes. Acetone (6.6 mL) was added over 30 minutes, followed by stirring for 2 hours. Acetone (18.2 mL) was added over 20 minutes, followed by stirring for 45 minutes. TBME (24 mL) was added over 20 minutes, followed by stirring for 50 minutes. The resulting suspension was cooled to 25°C over 30 minutes, stirred for 1 hour, and then allowed to stand at room temperature overnight.After standing overnight, the suspension was stirred at 25° C. for 2 hours and 30 minutes. The precipitated solid was collected by filtration, washed with a mixed solvent of acetone (11.0 mL) and TBME (11.0 mL), and then dried under reduced pressure to obtain the sodium salt of compound 1A (2.77 g, yield 73%) (Sample 1a (Form I)). HPLC purity: 99.49% (analysis condition C). HPLC retention time: 7.02 minutes (analysis condition C). １ H-NMR (DMSO-d ６ ) δ: 9.36 (1H, brs), 8.21 (1H, brs), 7.68 (1H, brs), 7.60-7.55 (2H, m), 6.89 (1H, brd, J = 13.5Hz), 6.82-6.75 (2H, m), 6.17 (1H, t, J = 5.0Hz), 5.50 (1H, q, J = 6.0Hz), 3.85 (2H, s), 2.28 (3H, d, J = 6.0Hz), 1.90-1.83 (1H, m), 0.92-0.87 (2H, m), 0.64-0.60 (2H, m). MS(ESI) ＋ ) m / z: 524 [M+2H-Na] ＋

[0158] (4-2) Preparation of Sample 1b (Form I) (1) Synthesis of N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide. tert-Butyl-[(2-chloro-3-fluoropyridin-4-yl)methoxy]-dimethylsilane (180 g, 653 mmol), Xantphos (22.7 g, 39.2 mmol), potassium carbonate (135 g, 979 mmol), acetamide (77.1 g, 1.31 mol), and 2-methyl-2-butanol (540 mL) were placed in a reaction vessel, degassed under reduced pressure, and purged with nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (14.9 g, 16.3 mmol) and toluene (540 mL) were added, and the mixture was further degassed under reduced pressure and purged with nitrogen. Under a nitrogen atmosphere, the mixture was heated to an external temperature of 120°C and stirred for 7 hours. The external temperature was cooled to room temperature, and the reaction mixture was filtered and washed with toluene (450 mL). Activated carbon (9.00 g, 749 mmol) was added to the filtrate, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and washed twice with toluene (270 mL for the first time and 180 mL for the second time) to obtain a crude product of N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide as a toluene solution. LCMS m / z: 299 [M+H] ＋ HPLC retention time: 0.81 minutes (Analysis conditions B)

[0159] (2) Synthesis of N-[3-fluoro-4-(hydroxymethyl)pyridin-2-yl]acetamide methanesulfonate (Compound 13A) The resulting toluene solution of N-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-fluoropyridin-2-yl]acetamide, toluene (175 mL), and MeOH (195 mL) were added to a reaction vessel, followed by degassing under reduced pressure and purging with nitrogen. Methanesulfonic acid (188 g, 1.96 mol) was added dropwise at an external temperature of 10°C, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to an external temperature of 0°C and stirred for 3 hours. The precipitate was collected by filtration and washed with a cooled mixture of toluene (312 mL) and MeOH (78 mL). The collected solid and a mixture of toluene (1.1 L) and EtOH (492 mL) were added to a reaction vessel, and the mixture was stirred at an external temperature of 0°C for 1 hour. The solid was collected by filtration, washed with a mixture of toluene (281 mL) and EtOH (117 mL), and dried under reduced pressure at an external temperature of 40° C. to obtain Compound 13A (149 g, yield 81%). LCMS m / z: 185 [M+H] ＋ HPLC retention time: 0.30 minutes (Analysis conditions D)

[0160] (3) Synthesis of (2-acetamido-3-fluoropyridin-4-yl)methyl methyl carbonate (compound 14A) DMAP (52.3 g, 428 mmol) was added to a reaction vessel containing N-[3-fluoro-4-(hydroxymethyl)pyridin-2-yl]acetamide methanesulfonate (compound 13A) (50.0 g, 178 mmol) and 2-MeTHF (750 mL) at room temperature. The external temperature was cooled to 0 ° C., and methyl chloroformate (21.9 g, 232 mmol) was added. The mixture was then warmed to room temperature and stirred. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure at an external temperature of 40 ° C. Ethyl acetate (300 mL) was added to the concentrated residue, which was then dissolved at room temperature. DIPEA (31.2 mL, 178 mmol), n-heptane (150 mL), and seed crystals were then added. After confirming the precipitation of crystals, n-heptane (1 L) was added. After the slurry was cooled to an external temperature of 0°C, the crystals were collected by filtration and washed with a mixture of ethyl acetate / n-heptane (2 / 7). The crystals were dried under reduced pressure at an external temperature of 40°C to obtain Compound 14A (31.3 g, yield 72%) as a colorless solid. LCMS m / z: 243 [M+H] ＋ HPLC retention time: 0.37 minutes (Analysis conditions B)

[0161] (4) Synthesis of 5-[(2-acetamido-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 15A) A reaction vessel was charged with 5-bromo-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 9A) (10.0 g, 26.0 mmol), bis(pinacolato)diboron (7.3 g, 28.6 mmol), potassium acetate (7.6 g, 77.9 mmol), and 2-MeTHF (150 mL), followed by degassing under reduced pressure and purging with nitrogen. (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (440 mg, 0.52 mmol) was added, followed by further degassing under reduced pressure and purging with nitrogen. Under a nitrogen atmosphere, the mixture was heated to an external temperature of 80°C and stirred for 6 hours. The external temperature was cooled to room temperature, potassium carbonate (10.8 g, 77.9 mmol) was added, the mixture was degassed under reduced pressure, and the atmosphere was replaced with nitrogen. (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (1.1 g, 1.3 mmol) was added, the mixture was further degassed under reduced pressure, and the atmosphere was replaced with nitrogen. Then, a solution of (2-acetamido-3-fluoropyridin-4-yl)methyl methyl carbonate (Compound 14A) (12.6 g, 51.9 mmol) in 2-MeTHF (150 mL) was added. Under a nitrogen atmosphere, the mixture was heated to an external temperature of 70°C, and water (935 μL, 51.9 mmol) was added three times every 20 minutes, followed by stirring for 20 minutes. Further, water (7.0 mL) was added dropwise and stirred for 2 hours. A solution prepared from N-acetylcysteine ​​(847 mg, 5.2 mmol) and water (150 mL) was added and stirred for 1 hour. After cooling to an external temperature of 40°C, the aqueous layer was discharged. The organic layer was washed with a 15% aqueous sodium chloride solution (150 mL), insoluble matter was filtered off, and the mixture was concentrated under reduced pressure. MeCN (500 mL) was added to the resulting concentrated residue, and the mixture was heated to an external temperature of 100°C to dissolve the solids, followed by cooling to room temperature. The crystals were collected by filtration, washed with MeCN (200 mL), and dried under reduced pressure at an external temperature of 40°C to obtain compound 15A (8.34 g, yield 68%). LCMS m / z: 471 [M-H] － HPLC retention time: 0.74 minutes (Analysis conditions B)

[0162] (5) Synthesis of 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 5A) MeOH (3 mL) and 5M hydrochloric acid (0.42 mL, 2.1 mmol) were added to a reaction vessel containing 5-[(2-acetamido-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (compound 15A) (100 mg, 0.21 mmol), and the mixture was stirred at an external temperature of 50°C for 6 hours. The reaction mixture was cooled to room temperature, and 2M aqueous sodium hydroxide solution (1.1 mL, 2.1 mmol) was added. Water (0.5 mL) was added to the resulting slurry, and the crystals were collected by filtration. The mixture was washed with a mixture of MeOH / water (3 / 2) and dried under reduced pressure at an external temperature of 40°C to obtain compound 5A (77.7 mg, 85% yield) as a colorless solid. LCMS m / z: 431 [M+H] ＋ HPLC retention time: 0.61 minutes (Analysis conditions B)

[0163] (6) Synthesis of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1A) 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (Compound 5A) (100 mg, 0.232 mmol) was dissolved in anhydrous DMA (1 mL), and pyridine (56.4 μL, 0.697 mmol) was added. After cooling to 0°C, methylsulfamoyl chloride (30.2 μL, 0.349 mmol) was added and stirred for 1 hour. MeCN (0.6 mL), water (0.3 mL), and seed crystals (obtained in Production Example 1A-1 described below) (1 mg) were added to the reaction mixture, and the mixture was warmed to room temperature. Water (0.7 mL) and MeCN (0.4 mL) were added, and the mixture was stirred for 20 hours. The precipitate was collected by filtration and washed with a mixture of MeCN / water (1 / 1) to obtain Compound 1A (93.1 mg, yield 77%) as a colorless solid. LCMS m / z: 524 [M+H] ＋ HPLC retention time: 1.13 minutes (analysis condition E)

[0164] (7) Preparation of sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1A) (i) Preparation of Sample 1b (Form I) 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1A) (3.03 g) was dissolved in acetone (10.6 mL) and DMSO (1.51 mL) at room temperature. To this solution, 20% sodium ethoxide in EtOH (3.03 mL) and seed crystals of the sodium salt of Compound 1A (Sample 1c described below) were added, and the mixture was stirred at room temperature for 1 hour. EtOH (15.1 mL) was then added, and the mixture was stirred at room temperature for 4 hours. Thereafter, EtOH (15.1 mL) was further added, and the mixture was stirred at room temperature for 4 hours to obtain the sodium salt of Compound 1A (2.74 g) as powdery crystals (Sample 1b (Form I)).

[0165] (ii) Preparation of Sample 1c Compound 1A (53.6 mg) was added with 20% sodium ethoxide EtOH solution (0.054 mL) and methyl isobutyl ketone (0.161 mL), and the mixture was stirred at room temperature for 30 minutes. Methyl isobutyl ketone (0.161 mL) was then added, and the mixture was stirred for 4 days at 60° C. DMSO (0.054 mL) was then added, and the mixture was stirred at 60° C. for 5 hours to obtain the sodium salt of Compound 1A (25.6 mg) as powdery crystals (Sample 1c).

[0166] (4-3) Powder X-ray Diffraction Measurement Sample 1a (Form I) was subjected to powder X-ray diffraction measurement under the following conditions: Measurement apparatus: Empyrean (manufactured by PANalytical) Anticathode: Cu Tube voltage: 45 kV Tube current: 40 mA Scanning method: Continuous Step width: 0.0262606° Scanning axis: 2θ Sampling time per step: 5.100 seconds Scanning range: 3 to 25°

[0167] Sample 1b (Form I) and Sample 1c were subjected to powder X-ray diffraction measurement under the following conditions: Measurement device: SmartLab, D / Tex Ultra detector (manufactured by Rigaku Corporation) Anticathode: Cu Tube voltage: 45 kV Tube current: 200 mA Sampling width: 0.02°

[0168] The results of the powder X-ray diffraction measurements are shown in Figures 1 to 3. Figure 1 shows the powder X-ray diffraction pattern of Sample 1a (Form I). Figure 2 shows the powder X-ray diffraction pattern of Sample 1b (Form I). Figure 3 shows the powder X-ray diffraction pattern of Sample 1c. In Figures 1 to 3, the horizontal axis (X axis) represents the diffraction angle 2θ (°), and the vertical axis (Y axis) represents the diffraction intensity.

[0169] (4-4) Ion Chromatography The proportion of sodium ions in the crystals of Sample 1b (Form I) was measured by ion chromatography, and the molar ratio of sodium ions to Compound 1A was found to be 0.99. This confirmed that Sample 1b was a monosodium salt. Ion chromatography was performed under the following conditions. Measurement equipment: Dionex ICS-1600, AS-AP (manufactured by Thermo Fisher Scientific) Column: Dionex IonPac CG16 (5 x 50 mm) / CS16 (5 x 250 mm) (manufactured by Thermo Fisher Scientific) Eluent: 30 mmol / L methanesulfonic acid solution Suppressor: Dionex CERS-500 4 mm, 88 mA (manufactured by Thermo Fisher Scientific) Column temperature: 40°C Eluent flow rate: 1.00 mL / min Sample injection volume: 10 μL Detector: Electrical conductivity detector Sample treatment: Sample 1b was dissolved in 20 mmol / L The sample was suspended in a methanesulfonic acid solution at a concentration of 0.5 mg / mL, and the suspension was shaken and stirred for 17 hours to extract sodium ions, and the supernatant was measured.

[0170] [Preparation Examples] In the following preparation examples, NMR analyses were carried out using an AVANCE III HD400 (400 MHz) manufactured by BRUKER Corp. NMR data are given in ppm (parts per million) (δ) and were referenced to the deuterium lock signal from the sample solvent.

[0171] Mass spectral data were obtained using a Shimadzu single quadrupole mass spectrometer (LCMS-2020) equipped with an ultra-high performance liquid chromatograph (Nexera UC) or a Waters single quadrupole mass spectrometer (SQD or SQD2) equipped with an Acquity ultra-high performance liquid chromatograph (UPLC or UPLC I-Class).

[0172] High performance liquid chromatography (HPLC) analysis was carried out using one of the analytical conditions listed in Table 4 below.

[0173] Commercially available reagents were used without further purification. All non-aqueous reactions were carried out in anhydrous solvents. Concentration under reduced pressure or solvent evaporation was performed using a rotary evaporator.

[0174] Compound a1: methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-formylbenzoate A suspension of 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-5-formylbenzoic acid (5.50 g, 13.1 mmol) in toluene (44 mL) and MeOH (11 mL) was cooled to 0°C, and 10% diazomethyltrimethylsilane hexane solution (21.8 mL, 13.1 mmol) was added, followed by stirring at room temperature for 64 hours. To the reaction mixture was added acetic acid (0.748 mL), and the mixture was concentrated under reduced pressure. The resulting residue was purified by trituration (hexane / ethyl acetate) to give the title compound (5.01 g, 88%) as a colorless solid. LCMS m / z: 436 [M+H] ＋ HPLC retention time: 1.00 minutes (Analysis conditions I)

[0175] Compound a2: methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate 4-Methylbenzenesulfonyl hydrazide (2.14 g, 11.5 mmol) was added to a suspension of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-formylbenzoate (compound a1, 5.00 g, 11.5 mmol) in EtOH (100 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then hexane (150 mL) was added. The mixture was cooled to 0°C, filtered, and washed with hexane (30 mL) to obtain the title compound (7.05 g, quant.) as a solid. LCMS m / z: 604 [M+H] ＋ HPLC retention time: 1.06 minutes (Analysis conditions I)

[0176] Compound a3: N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridin-2-amine Triethylamine (3.63 mL, 26.0 mmol) and 1-(2,4-dimethoxyphenyl)methanamine (3.26 mL, 21.7 mmol) were added to a solution of 2,3-difluoro-4-iodopyridine (2.09 g, 8.67 mmol) in NMP (32 mL), and the mixture was stirred at 100° C. for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 13% brine, dried over anhydrous sodium sulfate, and the drying agent was removed by filtration, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.20 g, 95%) as an oily substance. LCMS m / z: 389 [M+H] ＋ HPLC retention time: 0.94 minutes (Analysis conditions B)

[0177] Compound a4: [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid A 1,4-dioxane solution (27 mL) of N-(2,4-dimethoxybenzyl)-3-fluoro-4-iodopyridin-2-amine (compound a3, 2.70 g, 6.96 mmol), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (568 mg, 0.696 mmol), potassium acetate (2.05 g, 20.9 mmol), and bis(pinacolato)diboron (2.65 g, 10.4 mmol) was stirred at 90° C. for 5 hours and then at 110° C. for 19 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.1% formic acid aqueous solution / 0.1% formic acid acetonitrile solution) to give the title compound (2.07 g, 97%) as an oil. LCMS m / z: 307 [M+H] ＋ HPLC retention time: 0.44 minutes (Analysis conditions B)

[0178] Compound a5: 5-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate methyl A suspension of methyl 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[(E)-[(4-methylphenyl)sulfonylhydrazinylidene]methyl]benzoate (Compound a2, 1.30 g, 2.16 mmol), [2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]boronic acid (Compound a4, 1.98 g, 6.46 mmol), and potassium carbonate (357 mg, 2.59 mmol) in 1,4-dioxane (59 mL) was stirred under a nitrogen atmosphere at 100°C for 2.5 hours and then at 110°C for 3 hours. Ethyl acetate was added to the reaction mixture, which was washed with water and 13% brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (524 mg, 36%) as a foam. LCMS m / z: 682 [M+H] ＋ HPLC retention time: 1.03 minutes (Analysis conditions I)

[0179] Compound a6: methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate A DCM solution (16 mL) of methyl 5-[[2-[(2,4-dimethoxyphenyl)methylamino]-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a5, 523 mg, 0.768 mmol) was cooled to 0°C, trifluoroacetic acid (15.7 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase column chromatography (0.05% aqueous trifluoroacetic acid / 0.05% acetonitrile trifluoroacetic acid solution) to give the title compound (321 mg, 79%) as an oil. LCMS m / z: 532 [M+H] ＋ HPLC retention time: 0.55 minutes (Analysis conditions I)

[0180] Compound a7: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride A solution of methyl 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzoate (Compound a6, 4.00 g, 7.53 mmol) in THF (64 mL) and water (32 mL) was cooled to 0°C, lithium hydroxide monohydrate (948 mg, 22.6 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. After cooling to 0°C, 5M hydrochloric acid (15.1 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue was washed with water and TBME to give the title compound (4.20 g, quant.) as a purple solid. LCMS m / z: 518 [M+H] ＋ HPLC retention time: 0.68 minutes (Analysis conditions B)

[0181] Compound a8: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide A solution of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid hydrochloride (compound a7, 200 mg, 0.361 mmol) in anhydrous DMF (3.6 mL) was cooled to 0 ° C., and HOOBt (67.8 mg, 0.415 mmol) and EDC·HCl (80.0 mg, 0.415 mmol) were added, followed by stirring at room temperature for 1.5 hours. Further, HOOBt (8.8 mg, 0.054 mmol) and EDC·HCl (10.4 mg, 0.054 mmol) were added, followed by stirring at room temperature for 1 hour. After stirring at room temperature, 7M ammonia in MeOH (0.103 mL, 0.722 mmol) and DIPEA (0.189 mL, 1.08 mmol) were added at 0 ° C., followed by stirring at room temperature for 30 minutes. Water and saturated aqueous sodium bicarbonate solution were added to the reaction mixture in a 1:1 ratio, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (1 mL), and hexane (10 mL) was added. The resulting solid was collected by filtration and washed with hexane to give the title compound (162 mg, 87%) as a colorless solid. LCMS m / z: 517 [M+H] ＋ HPLC retention time: 0.64 minutes (Analysis conditions B)

[0182] Compound a9: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzamide Preparation Example a9-1: Tetrakis(triphenylphosphine)palladium(0) (11.2 mg, 9.68 μmol) and 0.5 M cyclopropylzinc bromide (1.94 mL, 0.969 mmol) were added to an anhydrous THF solution (1.9 mL) of 5-((2-amino-3-fluoropyridin-4-yl)methyl)-3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzamide (Compound a8, 100 mg, 0.194 mmol), and the mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. Ethyl acetate (5 mL) was added to the reaction mixture, which was then filtered through Celite and washed with ethyl acetate (3 mL). The filtrate was washed with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the mixture was concentrated under reduced pressure. Dichloromethane / hexane (1 / 10, 11 mL) was added to the obtained residue, and the solid was collected by filtration and washed with hexane (3 mL) to obtain compound a9 (63.4 mg, 76%) as a colorless solid. LCMS m / z: 431 [M+H] ＋ HPLC retention time: 0.61 minutes (Analysis conditions B)

[0183] Compound r1: 4-nitrophenyl methylsulfamate A dichloromethane solution (60 mL) of 4-nitrophenol (5.00 g, 35.9 mmol) and triethylamine (11.3 mL, 81.0 mmol) was cooled to -78°C, and a dichloromethane solution (15 mL) of methylsulfamoyl chloride (5.82 g, 44.9 mmol) was added, followed by stirring at -78°C for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) and reverse-phase column chromatography (0.1% aqueous formic acid / 0.1% formic acid in acetonitrile) to give the title compound (5.51 g, 66%) as a colorless solid. HPLC retention time: 0.63 minutes (analysis condition B). １ H-NMR (400MHz, CDCl ３ ) δ: 8.31 (2H, m), 7.46 (2H, m), 4.68 (1H, m), 3.00 (3H, d, J=5.4Hz).

[0184] Compound 1A: 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide Preparation Example 1A-1: 5-((2-amino-3-fluoropyridin-4-yl)methyl)-2-((4-cyclopropyl-2-fluorophenyl)amino)-3,4-difluorobenzamide (Compound a9, 2.47 g, 5.74 mmol) was dissolved in anhydrous DMF (28.7 mL), pyridine (2.78 mL, 34.4 mmol) and 4-nitrophenyl methylsulfamate (Compound r1, 4.00 g, 17.2 mmol) were added, and the mixture was stirred at 40° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and water (24.7 mL) was added. Acetonitrile (3 mL) and water (19.8 mL) were added, and the mixture was stirred for 10 minutes, and the solid was collected by filtration. The obtained solid was washed with water / acetonitrile (1 / 1, 49.4 mL) to obtain Compound 1A (2.56 g, 85%) as a colorless solid. LCMS m / z: 524 [M+H] ＋ HPLC retention time: 1.13 minutes (analysis condition E)

Claims

1. A method for producing the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (hereinafter also referred to as "Compound 3"), comprising the following step (A-1): (A-1) A step of mixing the following (a), (b) and (c) in a first solvent to obtain a mixture containing Compound 3: (a) 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (hereinafter also referred to as "Compound 1"); (b) a sodium base; and (c) at least one organic acid selected from the group consisting of compounds represented by the following general formula (A): [In the formula, X １ is a hydroxy group or a mercapto group, R １ , R ２ , R ３ , R ４ and R ５ are each independently a hydrogen atom, a halogen atom, a C1-6 alkyl group, a hydroxyl group, a C1-6 alkoxy group, a phenoxy group, a nitro group, or a cyano group.

2. The method of claim 1, wherein the sodium base comprises at least one selected from the group consisting of sodium C1-6 alkoxide, sodium hydroxide, sodium hydride, and sodium hexamethyldisilazide.

3. X １ is a hydroxy group; R １ , R ２ , R ３ , R ４ and R ５ The method according to claim 1 or 2, wherein each independently represents a hydrogen atom or a C1-6 alkyl group.

4. The method according to any one of claims 1 to 3, wherein the organic acid is at least one selected from the group consisting of o-cresol, m-cresol, p-cresol, phenol, and dibutylhydroxytoluene.

5. The method of any one of claims 1 to 4, wherein the organic acid is a weaker acid than compound 1.

6. The method according to any one of claims 1 to 5, wherein the solubility of the sodium salt of the organic acid in a mixed solvent of tetrahydrofuran, acetone, tert-butyl methyl ether and water at 25°C (the volume ratio of tetrahydrofuran, acetone and tert-butyl methyl ether is 8:10:5, and the water content is 3 mass% relative to the mass of the mixed solvent) is 3 mmol / L or more.

7. The method according to any one of claims 1 to 6, wherein the solubility of the organic acid in a mixed solvent of tetrahydrofuran, acetone, tert-butyl methyl ether and water at 25°C (the volume ratio of tetrahydrofuran, acetone and tert-butyl methyl ether is 8:10:5, and the water content is 3 mass% relative to the mass of the mixed solvent) is 0.05 mol / L or more.

8. The method according to any one of claims 1 to 7, wherein the molar equivalent of the organic acid mixed in step (A-1) is 0.1 to 3 relative to the sodium base.

9. The method according to any one of claims 1 to 8, further comprising the following step (A-3): (A-3) obtaining compound 3 from the mixture obtained in step (A-1).

10. A method for producing 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (hereinafter also referred to as "Compound 1"), comprising the following steps (B-1), (B-2) and (B-3): (B-1) A step of mixing the following (d), (e), and (f) to obtain a mixture containing Compound 1: (d) 5-[(2-amino-3-fluoropyridin-4-yl)methyl]-2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluorobenzamide (hereinafter also referred to as "Compound 2"); (e) N-methylsulfamoyl chloride; and (f) an aqueous solution of an inorganic salt. (B-2) A step of removing an aqueous layer from the mixture obtained in step (B-1) by a separation operation. (B-3) A step of mixing the mixture obtained in step (B-2) with a fourth solvent to remove the inorganic salt.

11. A method for producing the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (hereinafter also referred to as "Compound 3"), comprising the following step (C-1): (C-1) A step for producing 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (Compound 1) by the method according to claim 10.

12. A composition comprising the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (hereinafter also referred to as "Compound 3"), wherein the content of Compound 3 is 98.0% by mass or more relative to the mass of the composition.

13. A composition comprising the sodium salt of 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide (hereinafter also referred to as "compound 3") and 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzoic acid (hereinafter also referred to as "compound 4"), wherein the peak area of ​​compound 4 obtained by high performance liquid chromatography (HPLC) analysis of the composition at 278 nm is 0.20% or less of the peak area of ​​compound 3 obtained by the HPLC analysis.

14. The composition of claim 13 which is a pharmaceutical composition.

15. The process according to any one of claims 1 to 9 and 11, which results in a product having a high content of compound 3.

Images