Crystal of heterocyclic derivative

Abstract

Disclosed are a type-1 crystal, a type-3 crystal, and a type-4 crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzene sulfonate represented by formula (A-I).

Description

Crystals of heterocyclic derivatives

[0001] The present disclosure relates to crystals of heterocyclic derivatives.

[0002] At the site of inflammation, prostaglandins (PGs) are produced in large quantities and are involved in the progression of inflammation. Among PGs, prostaglandin E2 (PGE2), in particular, is an inflammation-inducing substance in acute and chronic inflammation, inducing fever, hyperalgesia, and the like. PGE2 is known to be synthesized by PGE2 synthase (PGES), which is responsible for the final step in the synthesis pathway of PGE2, an inflammatory mediator. It has been revealed that there are three subtypes of PGES, and among them, membrane-bound prostaglandin E synthase-1 (mPGES-1), like cyclooxygenase 2 (COX2), is primarily induced during inflammation and is deeply involved in PGE2 production in inflammatory lesions. Taking note of this mechanism, mPGES-1 inhibitors are an active ingredient in therapeutic agents for inflammatory diseases. Since mPGES-1 inhibitors inhibit only COX-2-dependent PGE2 production, they are thought to be able to reduce various side effects compared to NSAIDs and COX-2 inhibitors.

[0003] Patent Document 1 discloses N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (hereinafter also referred to as "Compound A") represented by the following formula (I) as an mPGES-1 inhibitor.

[0004] International Publication No. 2013 / 024898

[0005] It is known that physical properties of compounds used as pharmaceuticals, such as storage stability and solubility, which directly and significantly affect their use as active ingredients in pharmaceuticals, can vary depending on their form (e.g., salts, solvates, or crystals thereof).

[0006] The present disclosure aims to provide a crystal of a heterocyclic derivative represented by the following formula (AI): The object of the present invention is to provide a crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate (hereinafter also referred to as "p-TsOH salt of Compound A") represented by the formula:

[0007] The present inventors have discovered a new crystal of the p-TsOH salt of Compound A. Furthermore, the present inventors have found that the discovered crystal of the p-TsOH salt of Compound A is a crystal that is excellent in physical properties, such as storage stability and solubility, which have a direct and significant impact on its use as an active ingredient in pharmaceuticals.

[0008] The present disclosure relates to, for example, the following items <1> to <22>: <1> A compound represented by the following formula (AI): <2> A type 1 crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate represented by the formula (A-I) below, which has an endothermic peak at 265.8±3.0°C in differential scanning calorimetry: <3> A type 1 crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate represented by the formula (A-I) below, which has diffraction peaks at diffraction angles (2θ±0.2°) of 6.3°, 15.0°, 16.4°, 17.9°, and 22.7° in powder X-ray diffraction: <4> A crystalline form 3 of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate represented by the formula (A-I) below, which has an endothermic peak at 247.4±3.0°C in differential thermal analysis: <5> A crystalline form 3 of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by the formula (A-I) below, which has diffraction peaks at diffraction angles (2θ±0.2°) of 7.4°, 8.0°, 14.5°, 16.1°, and 20.6° in powder X-ray diffraction: <6> A 4-type crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate represented by the formula (A-I) below, which has an endothermic peak at 212.5±3.0°C in differential thermal analysis: <7> A composition comprising the crystal according to <1> or <2>, wherein the content of the crystal according to <1> or <2> is 95% by mass or more of the total composition, and wherein the crystal is represented by the following formula (VII): The content of the compound expressed as －４ mass% or less, preferably 50 × 10 －４ <8> A composition comprising the crystal according to <1> or <2> and the compound of the following formula (VII): A composition comprising a compound represented by formula (VII), wherein the content of the crystal according to <1> or <2> is 95% by mass or more of the total composition, and the content of the compound represented by formula (VII) is 100×10 in terms of a free form. －６ mass% or less, preferably 50 × 10 －６ <9> A composition having a moiety of the following formula (XI): The content of the compound expressed as －４% by mass or less, and preferably does not contain the compound represented by formula (XI). <10> The composition according to <7> or <8>, wherein the composition contains N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate represented by formula (A-I) under a temperature condition of 130°C or higher. <13> The composition according to <5> or <6>, wherein the composition contains N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate represented by formula (A-I) <14> A method for producing a compound represented by formula (A-I): N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by formula (A-I), is contacted with acetonitrile, and then exposed to a temperature condition of 90°C or higher. <15> A method for producing the composition according to <7>, <8>, or <9>. <16> A compound represented by formula (A-I): N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate (i.e., represented by the following formula (I): <17> The crystal according to <1> or <2>, produced by the production method according to <10> or <16>. <18> The crystal according to <3> or <4>, produced by the production method according to <11>, <12> or <16>. <19> The crystal according to <5> or <6>, produced by the production method according to <13>, <14> or <16>. <20> The composition according to <7>, <8> or <9>, produced by the production method according to <15> or <16>. <21> A pharmaceutical composition comprising, as an active ingredient, the crystal according to any one of <1> to <6> and <17> to <19> or the composition according to any one of <7> to <9> and <20>. <22> A membrane-bound prostaglandin E synthase-1 inhibitor containing, as an active ingredient, the crystal according to any one of <1> to <6> and <17> to <19> or the composition according to any one of <7> to <9> and <20>.

[0009] In <16>, [1] to

[28] are as follows: [1] The following formula (I): [2] A method for producing a p-toluenesulfonate salt of a compound represented by formula (I) (compound A), comprising a step of converting an N,N-dimethylacetamide solvate of the compound represented by formula (I) (compound A) into a p-toluenesulfonate salt of the compound represented by formula (I) (compound A): (In the formula, R １ represents a protecting group for a carboxyl group or H, R ２ represents a group which forms a protecting group for an aniline amino group together with —O—C(═O)—, [3] The method according to [1], further comprising a step of converting the compound represented by formula (II) into a compound represented by formula (I), wherein the step of converting the compound represented by formula (II) into a compound represented by formula (I) comprises hydrolyzing the compound represented by formula (II) in the presence of a base to obtain a compound represented by formula (III): [4] The method according to [2], wherein the step of converting the compound represented by formula (II) into the compound represented by formula (I) is carried out by reacting a compound represented by the following formula (III): The compound represented by the following formula (VIII): [5] The method according to [2] or [3], wherein the step of converting the compound represented by formula (II) into a compound represented by formula (I) is carried out by converting a compound represented by formula (VIII): The compound represented by the following formula (I): [6] The method according to any one of [2] to [4], comprising converting a compound represented by formula (II) into an N,N-dimethylacetamide solvate. １ and R ２ are each independently C １ ~C ６ [7] The method according to any one of [2] to [5], wherein R in formula (II) represents alkyl. １ and R ２ [8] The method according to any one of [2] to [6], wherein R is a methyl group. (In the formula, R １ is R in formula (II) １ and X represents Cl, Br, I, or OTf, and a protected compound thereof represented by the following formula (V): (In the formula, R ２ is R in formula (II) ２(the same as above). The production method according to any one of [1] to [7], further comprising a step of obtaining the compound represented by formula (II), which comprises contacting a compound represented by formula (IV) with a compound represented by formula (IV), to obtain the compound represented by formula (II) or a protected form thereof. [9] The production method according to [8], wherein X in formula (IV) is Cl, Br, or I.

[10] The production method according to [8] or [9], wherein X in formula (IV) is Br.

[11] The production method according to any one of [8] to

[10] , wherein the contacting of the compound represented by formula (IV) or a protected form thereof with the compound represented by formula (V) in the step of obtaining the compound represented by formula (II) is carried out in the presence of a palladium catalyst.

[12] The production method according to

[11] , wherein the palladium catalyst is a palladium catalyst containing zero-valent palladium.

[13] The production method according to

[11] or

[12] , wherein the palladium catalyst is tris(dibenzylideneacetone)dipalladium(0).

[14] The production method according to any one of

[11] to

[13] , wherein in the step of obtaining the compound represented by formula (II), the compound represented by formula (IV) or a protected form thereof is brought into contact with the compound represented by formula (V) in the presence of a ligand.

[15] The production method according to

[14] , wherein the ligand is 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[16] The production method according to

[14] , wherein the compound represented by formula (IV) or a protected form thereof is represented by the following formula (IX): (In the formula, R １ is R in formula (II) １ and X is the same as X in formula (IV).

[17] The method according to any one of [8] to

[15] , wherein the step of obtaining the compound represented by formula (II), which comprises contacting the compound represented by formula (IV) or a protected form thereof with the compound represented by formula (V), comprises: converting the compound represented by formula (IV) into a compound represented by formula (IX), contacting the compound represented by formula (IX) with the compound represented by formula (V) to obtain a compound represented by formula (X): (In the formula, R １ is R in formula (II) １ is the same as R２ is R in formula (V). ２

[18] The production method according to any one of [8] to

[16] , comprising, in this order, obtaining a compound represented by formula (VI): (In the formula, R １ is R in formula (II) １ and X is the same as X in formula (IV). The production method according to any one of [1] to

[17] , further comprising a step of contacting a compound represented by the following formula (I) with methoxyacetic acid to obtain the compound represented by formula (IV).

[19] The production method according to any one of [1] to

[18] , further comprising a step of purifying the N,N-dimethylacetamide solvate of the compound represented by formula (I) by recrystallization.

[20] The production method according to

[19] , wherein the recrystallization of the N,N-dimethylacetamide solvate of the compound represented by formula (I) is carried out using a mixed solvent of N,N-dimethylacetamide and water.

[21] The production method according to

[19] or

[20] , wherein the recrystallization of the N,N-dimethylacetamide solvate of the compound represented by formula (I) is carried out using a mixed solvent of N,N-dimethylacetamide and water, wherein the N,N-dimethylacetamide content is 75% by volume or more.

[22] The production method according to any one of [1] to

[21] , comprising, after a step of converting the N,N-dimethylacetamide solvate of the compound represented by formula (I) into a p-toluenesulfonate of the compound represented by formula (I), a step of purifying the p-toluenesulfonate of the compound represented by formula (I) by contacting it with activated carbon, and a step of recrystallizing the p-toluenesulfonate of the compound represented by formula (I) after contacting it with activated carbon to obtain Type 1 crystals of the p-toluenesulfonate of the compound represented by formula (I).

[23] The production method according to

[22] , wherein the mass of the activated carbon brought into contact with the p-toluenesulfonate of the compound represented by formula (I) is 0.04 times or more the mass of the p-toluenesulfonate of the compound represented by formula (I).

[24] A compound represented by the following formula (I): The present invention relates to a method for producing a p-toluenesulfonate salt of a compound (Compound A) represented by the following formula (IV): (In the formula, R １ represents a protecting group for a carboxyl group or H, and X represents Cl, Br, I or OTf. (In the formula, R ２ represents a group which forms a protecting group for an aniline amino group together with —O—C(═O)—, (In the formula, R １ is R in the above formula (IV) １ is the same as R ２ is R in the above formula (V) ２ a step of obtaining a compound represented by formula (II), which comprises obtaining a compound represented by formula (II) or a protected form thereof; a step of converting the compound represented by formula (II) into an N,N-dimethylacetamide solvate of the compound represented by formula (I), which comprises hydrolyzing the compound represented by formula (II) in the presence of a base to obtain a compound represented by the following formula (III): and obtaining a compound represented by formula (III) by reacting the compound represented by formula (VIII): and converting the compound represented by formula (VIII) into an N,N-dimethylacetamide solvate of the compound represented by formula (I) (compound A); and converting the N,N-dimethylacetamide solvate of the compound represented by formula (I) (compound A) into a p-toluenesulfonate of the compound represented by formula (I) (compound A), in this order.

[25] A production method comprising the steps of: The present invention relates to a method for producing a p-toluenesulfonate salt of a compound (Compound A) represented by the following formula (VI): (In the formula, R １ represents a protecting group for a carboxyl group or H, and X represents Cl, Br, I or OTf. (In the formula, R １ and X is R in formula (VI). １and X are the same as each other; a step of obtaining a compound represented by formula (IV) by reacting the compound represented by formula (IV) with a compound represented by the following formula (II): (In the formula, R １ is R in formula (VI) １ is the same as R ２ represents a group which forms a protecting group for an aniline amino group together with —O—C(═O)—, (In the formula, R １ and X is R in formula (VI). １ and X are the same as each other, and converting the compound represented by formula (IX) into a compound represented by formula (V): (In the formula, R ２ is R in formula (II) ２ is the same as (In the formula, R １ is R in formula (VI) １ is the same as R ２ is R in formula (II) ２ and hydrolyzing the compound represented by formula (X) in the presence of an acid to obtain a compound represented by formula (II); A step of converting the compound represented by formula (II) into an N,N-dimethylacetamide solvate of the compound represented by formula (I) (Compound A), which comprises hydrolyzing the compound represented by formula (II) in the presence of a base to obtain a compound represented by the following formula (III): and obtaining a compound represented by formula (III) by reacting the compound represented by formula (VIII): and converting the compound represented by formula (VIII): into an N,N-dimethylacetamide solvate of the compound represented by formula (I) (Compound A); converting the N,N-dimethylacetamide solvate of the compound represented by formula (I) (Compound A) into a p-toluenesulfonate of the compound represented by formula (I) (Compound A); purifying the N,N-dimethylacetamide solvate of the compound represented by formula (I) (Compound A) by recrystallization; purifying the p-toluenesulfonate of the compound represented by formula (I) (Compound A) by contacting it with activated carbon; and recrystallizing the p-toluenesulfonate of the compound represented by formula (I) (Compound A) after contacting it with activated carbon to obtain Type 1 crystals of the p-toluenesulfonate of the compound represented by formula (I) (Compound A).

[26] A production method comprising the steps of: １ and the R ２ is C １ ~C ６

[27] The method according to

[24] or

[25] , wherein R is alkyl, preferably methyl, and X is Cl, Br or I, preferably Br. １ and the R ２ is C １ ~C ６the compound represented by formula (IV) or a protected form thereof is contacted with the compound represented by formula (V) in the presence of a palladium catalyst; the recrystallization of the N,N-dimethylacetamide solvate of the compound represented by formula (I) is carried out using a mixed solvent of N,N-dimethylacetamide and water, preferably a mixed solvent of N,N-dimethylacetamide and water having an N,N-dimethylacetamide content of 75% by volume or more; and the mass of activated carbon brought into contact with the p-toluenesulfonate of the compound represented by formula (I) is 0.04 times or more, preferably 0.08 times or more, the mass of the p-toluenesulfonate of the compound represented by formula (I).

[28] The production method according to any one of

[24] to

[27] , wherein the contacting of the compound represented by formula (IV) or a protected form thereof with the compound represented by formula (V) is carried out in the presence of a palladium catalyst containing zero-valent palladium and a ligand, preferably in the presence of tris(dibenzylideneacetone)dipalladium(0) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0010] According to the present disclosure, it is possible to provide new crystals of the p-TsOH salt of Compound A, as well as a pharmaceutical composition and a membrane-bound prostaglandin E synthase-1 inhibitor containing the same. Furthermore, according to the present disclosure, it is possible to provide a method for producing crystals of the p-TsOH salt of Compound A.

[0011] According to one embodiment of the present disclosure, it is possible to provide a type 1 crystal of the p-TsOH salt of compound A. The type 1 crystal of the p-TsOH salt of compound A is a highly stable crystal of the p-TsOH salt of compound A, and according to one embodiment of the present disclosure, it is possible to provide a type 1 crystal of the p-TsOH salt of compound A, which has excellent storage stability, as well as a pharmaceutical composition and a membrane-bound prostaglandin E synthase-1 inhibitor containing the same.

[0012] According to one embodiment of the present disclosure, it is possible to provide Form 3 crystals of the p-TsOH salt of Compound A. The Form 3 crystals of the p-TsOH salt of Compound A are highly soluble crystals of the p-TsOH salt of Compound A, and according to one embodiment of the present disclosure, it is possible to provide Form 3 crystals of the p-TsOH salt of Compound A, which have excellent solubility and absorbability in the body (e.g., bioavailability), as well as a pharmaceutical composition and a membrane-bound prostaglandin E synthase-1 inhibitor containing the same.

[0013] According to one embodiment of the present disclosure, it is possible to provide Form 4 crystals of the p-TsOH salt of Compound A, as well as a pharmaceutical composition and a membrane-bound prostaglandin E synthase-1 inhibitor containing the same.

[0014] According to one embodiment of the present disclosure, it is possible to provide a crystal of the p-TsOH salt of compound A having excellent stability. According to one embodiment of the present disclosure, it is possible to provide a crystal of the p-TsOH salt of compound A having excellent solubility. The crystal of the p-TsOH salt of compound A having such excellent physical properties can be suitably used as an active ingredient in pharmaceutical compositions and membrane-bound prostaglandin E synthase-1 inhibitors.

[0015] FIG. 1 is a diagram showing the results of powder X-ray diffraction of the type 1 crystal of the p-TsOH salt of Compound A in Example 1. FIG. 2 is a diagram showing the results of measurement of thermal properties by differential scanning calorimetry (DSC) of the type 1 crystal of the p-TsOH salt of Compound A in Example 1. FIG. 3 is a diagram showing the results of measurement of thermal properties by differential thermal analysis (DTA) and thermogravimetric analysis (TGA) of the type 1 crystal of the p-TsOH salt of Compound A in Example 1. FIG. 4 is a diagram showing the results of powder X-ray diffraction of the amorphous form of the p-TsOH salt of Compound A in Preparation Example 1. FIG. 5 is an enlarged view showing the results of powder X-ray diffraction of the amorphous form of the p-TsOH salt of Compound A in Preparation Example 1. FIG. 6 is a diagram showing the results of powder X-ray diffraction of the type 3 crystal of the p-TsOH salt of Compound A in Example 2. FIG. 7 shows the results of measuring the thermal properties of the Form 3 crystal of the p-TsOH salt of Compound A by differential thermal analysis (DTA) and thermogravimetric analysis (TGA) in Example 2. FIG. 8 shows the results of powder X-ray diffraction of an intermediate product in the preparation of the Form 4 crystal of the p-TsOH salt of Compound A in Example 3. FIG. 9 shows the results of measuring the thermal properties of the intermediate product in the preparation of the Form 4 crystal of the p-TsOH salt of Compound A in Example 3 by differential thermal analysis (DTA) and thermogravimetric analysis (TGA). FIG. 10 shows the results of powder X-ray diffraction of the Form 4 crystal of the p-TsOH salt of Compound A in Example 3. FIG. 11 shows the results of measuring the thermal properties of the Form 4 crystal of the p-TsOH salt of Compound A in Example 3 by differential thermal analysis (DTA) and thermogravimetric analysis (TGA). Fig. 12 is a diagram showing the results of powder X-ray diffraction of an intermediate product in the production of Type 5 crystals of p-TsOH salt of Compound A in Comparative Example 1. Fig. 13 is a diagram showing the results of measurement of thermal properties by differential thermal analysis (DTA) and thermogravimetric analysis (TGA) of an intermediate product in the production of Type 5 crystals of p-TsOH salt of Compound A in Comparative Example 1. Fig. 14 is a diagram showing the results of powder X-ray diffraction of Type 5 crystals of p-TsOH salt of Compound A in Comparative Example 1. Fig. 15 is a diagram showing the results of measurement of thermal properties by differential thermal analysis (DTA) and thermogravimetric analysis (TGA) of Type 5 crystals of p-TsOH salt of Compound A in Comparative Example 1.FIG. 16 is a graph showing the results of powder X-ray diffraction of an intermediate product in the production of Form 6 crystals of p-TsOH salt of Compound A in Comparative Example 2. FIG. 17 is a graph showing the results of powder X-ray diffraction of Form 6 crystals of p-TsOH salt of Compound A in Comparative Example 2. FIG. 18 is a graph showing the results of measurement of thermal properties by differential thermal analysis (DTA) and thermogravimetric analysis (TGA) of Form 6 crystals of p-TsOH salt of Compound A in Comparative Example 2. FIG. 19 is a graph showing the results of powder X-ray diffraction of an intermediate product in the production of Form 7 crystals of p-TsOH salt of Compound A in Comparative Example 3. FIG. 20 is a graph showing the results of powder X-ray diffraction of Form 7 crystals of p-TsOH salt of Compound A in Comparative Example 3. FIG. 21 is a graph showing the results of measurement of thermal properties by differential thermal analysis (DTA) and thermogravimetric analysis (TGA) of Form 7 crystals of p-TsOH salt of Compound A in Comparative Example 3. FIG. 22 shows the results of powder X-ray diffraction at 20°C for 3, 4, 7, and 8 days after the start of stirring in Example 9. FIG. 23 shows the results of powder X-ray diffraction at 55°C for 3 and 4 days after the start of stirring in Example 9. FIG. 24 shows the results of powder X-ray diffraction for type 1 crystals of p-TsOH salt of Compound A subjected to various treatments in Example 12. FIG. 25 shows the results of powder X-ray diffraction for type 2 crystals of p-TsOH salt of Compound A in Comparative Example 4. FIG. 26 shows the results of measurement of thermal properties by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of type 2 crystals of p-TsOH salt of Compound A in Comparative Example 4. FIG. 27 shows the results of powder X-ray diffraction when type 2 crystals of p-TsOH salt of Compound A are heated and cooled in Example 14. Figure 28 is a diagram showing the results of powder X-ray diffraction in which the stability of type 1 crystals of p-TsOH salt of Compound A in various solvents was evaluated in Example 16. Figure 29 is a diagram showing the results of powder X-ray diffraction of type 1 crystals of p-TsOH salt of Compound A in Reference Example 1. Figure 30 is a diagram showing the results of measurement of thermal properties of type 1 crystals of p-TsOH salt of Compound A by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) in Reference Example 1.

[0016] Hereinafter, embodiments for carrying out the present disclosure will be described, but the present disclosure is not limited to the following examples.

[0017] In this disclosure, unless otherwise specified, the term "compound" includes any form of the compound, including the free form of the compound, salts thereof, and solvates thereof. On the other hand, terms such as "hydrochloride salt of compound," "N,N-dimethylacetamido solvate of compound," and "p-toluenesulfonate of compound" refer to the specified salt or solvate of the compound and do not include other forms of the compound. More specifically, for example, "converting a compound represented by structural formula (1) into a compound represented by structural formula (2)" means converting any form of a compound represented by structural formula (1) into any form of a compound represented by structural formula (2). Furthermore, for example, the statement "hydrolyzing a compound represented by structural formula (1) to obtain an N,N-dimethylacetamido solvate of a compound represented by structural formula (2)" means hydrolyzing any form of a compound represented by structural formula (1) to obtain a compound represented by structural formula (2) in the form of an N,N-dimethylacetamido solvate. For example, the description "the hydrochloride salt of a compound represented by structural formula (1) is contacted with a compound represented by structural formula (3) to obtain a p-toluenesulfonate salt of a compound represented by structural formula (2)" means that the hydrochloride salt form of a compound represented by structural formula (1) is contacted with any form of a compound represented by structural formula (3) to obtain a p-toluenesulfonate salt form of a compound represented by structural formula (2). In the present disclosure, "an N,N-dimethylacetamide solvate of a compound" refers to a solvate in which a compound is solvated with N,N-dimethylacetamide. The p-toluenesulfonate salt of a compound according to the present disclosure may be, for example, a salt in which the number of molecules of the compound and p-toluenesulfonic acid is 1:1. The N,N-dimethylacetamide solvate of a compound according to the present disclosure may be, for example, a solvate in which the number of molecules of the compound and N,N-dimethylacetamide solvate is 1:1.

[0018] The chemical reactions in the present disclosure may be quenched as appropriate by methods commonly used by those skilled in the art, and the products may be recovered by methods commonly used by those skilled in the art, such as evaporation under reduced pressure, filtration, or extraction. The products of the chemical reactions in the present disclosure may be purified by methods commonly used by those skilled in the art, such as recrystallization or column chromatography. In a preferred embodiment, from the perspective of mass production, purification may be performed by recrystallization. The reactions in each step in the present disclosure may be monitored by methods commonly used by those skilled in the art, such as chromatography, including reverse-phase liquid chromatography (HPLC), and the products may be analyzed by methods commonly used by those skilled in the art, such as HPLC, nuclear magnetic resonance (NMR), mass spectrometry, X-ray crystallography, and DSC.

[0019] In this disclosure, 4-methylbenzenesulfonic acid may be referred to as p-toluenesulfonic acid, paratoluenesulfonic acid, tosylic acid, or p-TsOH.

[0020] In the present disclosure, "having a diffraction peak at a diffraction angle (2θ±X°) of Y°" means that the diffraction angle (2θ) is at Y±X°. For example, "having a diffraction peak at a diffraction angle (2θ±0.2°) of 14.5°" means that the diffraction angle (2θ) is in the range of 14.3° to 14.7°. In the present disclosure, the diffraction angle and diffraction pattern of powder X-ray diffraction refer to the diffraction angle and diffraction pattern obtained by irradiation with copper Kα radiation (CuKα).

[0021] <Type 1 Crystal of p-TsOH Salt of Compound A> A first aspect of the present disclosure is a compound having the following formula (AI): The present disclosure relates to a Form 1 crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by the formula:

[0023] That is, a first aspect of the present disclosure relates to a Form 1 crystal of the p-TsOH salt of Compound A. In one embodiment, the first aspect of the present disclosure may also be a Form 1 crystal of the p-TsOH salt of Compound A, produced by a production method according to a fifth aspect of the present disclosure, which will be described later.

[0022] The type 1 crystal of p-TsOH salt of Compound A according to one embodiment of the first aspect of the present disclosure has diffraction peaks in powder X-ray diffraction at diffraction angles (2θ), (2θ±0.1°), (2θ±0.2°), (2θ±0.3°), (2θ±0.4°), or (2θ±0.5°) of 7.1°, 14.3°, 15.8°, and 18.3°. In a preferred embodiment of the first aspect of the present disclosure, the type 1 crystal of p-TsOH salt of Compound A has diffraction peaks in powder X-ray diffraction at diffraction angles (2θ±0.2°) of 7.1°, 14.3°, 15.8°, and 18.3°. In one embodiment of the present disclosure, the Form 1 crystal of p-TsOH salt of Compound A may have diffraction peaks in powder X-ray diffraction at diffraction angles (2θ±0.2°) of 7.1°, 14.3°, 15.8°, 18.3°, and 22.0°. In one embodiment of the present disclosure, the Form 1 crystal of p-TsOH salt of Compound A may have diffraction peaks in powder X-ray diffraction at diffraction angles (2θ±0.2°) of 7.1°, 8.5°, 14.3°, 15.8°, 18.3°, 18.8°, 19.6°, 20.1°, 22.0°, and 25.8°. In one embodiment of the present disclosure, the Form 1 crystal of p-TsOH salt of Compound A may have diffraction peaks in powder X-ray diffraction at diffraction angles (2θ±0.2°) of 7.1°, 8.5°, 11.8°, 14.3°, 14.7°, 15.8°, 16.4°, 17.4°, 18.3°, 18.8°, 19.6°, 20.1°, 22.0°, 23.5°, 24.4°, 25.3°, 25.8°, 27.3°, 28.8°, and 29.0°.

[0023] The type 1 crystal of the p-TsOH salt of compound A according to one embodiment of the first aspect of the present disclosure has an endothermic peak at 265.8±3.0°C in differential scanning calorimetry. The type 1 crystal of the p-TsOH salt of compound A according to one embodiment of the first aspect of the present disclosure has diffraction peaks at diffraction angles (2θ±0.2°) of 7.1°, 14.3°, 15.8°, and 18.4° in powder X-ray diffraction, and also has an endothermic peak at 265.8±3.0°C in differential scanning calorimetry. Furthermore, the type 1 crystal of the p-TsOH salt of compound A according to one embodiment of the first aspect of the present disclosure has an endothermic peak at 263.0±3.0°C in differential thermal analysis. Furthermore, the type 1 crystal of the p-TsOH salt of compound A according to one embodiment of the first aspect of the present disclosure can remain stable for 7 days or more even under conditions of a temperature of 40°C and a relative humidity of 75%.

[0024] The Form 1 crystal of the p-TsOH salt of Compound A according to one embodiment of the first aspect of the present disclosure is a crystal having excellent stability. In the present disclosure, the term "a crystal having excellent stability" means, for example, that the crystal has excellent storage stability, that the crystal is stable to treatment in formulation, or that the crystal is the most stable form among multiple crystalline forms of the same compound.

[0025] "Excellent storage stability" of crystals of p-TsOH salt of Compound A means that when the crystals are left to stand or when the crystals are exposed to a stimulus such as heating, light, or humidity, the p-TsOH salt of Compound A contained in the crystals does not significantly decompose and the crystalline form does not change significantly. Examples of cases where such a significant change is not observed include when, after exposure to a stimulus, the proportion of crystals of p-TsOH salt of Compound A that are in the same crystalline form as before exposure to the stimulus, among substances derived from p-TsOH salt of Compound A contained in the crystals, is 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, or 99.65% or more. Another example of a case in which no significant change is observed is a case in which the rate of decrease in the proportion of p-TsOH salt crystals of Compound A having the same crystalline form as the p-TsOH salt crystals of Compound A between before and after exposure to a stimulus is 10% or less, 5% or less, 3% or less, 1% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.01% or less, or 0.005% or less. In these cases, the proportion (%) may be, for example, the proportion (%) of the peak area in HPLC (e.g., the peak area of ​​absorbance at a wavelength of 230 nm) or may be % by mass, and in a preferred embodiment, it may be the proportion of the peak area in HPLC.

[0026] That the crystals of p-TsOH salt of Compound A are stable to treatments during formulation means that the p-TsOH salt of Compound A contained in the crystals does not significantly decompose and the crystalline form does not significantly change when subjected to treatments performed during formulation, such as mixing the crystals with excipients, grinding the crystals, exposing the crystals to water, tableting the crystals, etc. Examples of cases in which such a significant change is not observed include when the proportion of crystals of p-TsOH salt of Compound A that are in the same crystalline form as before treatment, to the substances derived from p-TsOH salt of Compound A contained in the crystals after treatment, is 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, or 99.65% or more. Another example of a case in which no significant change is observed is a case in which the decrease in the proportion of crystals of p-TsOH salt of Compound A having the same crystalline form as the crystals of p-TsOH salt of Compound A before and after treatment is 10% or less, 5% or less, 3% or less, 1% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.01% or less, or 0.005% or less. In these cases, the proportion may be, for example, the proportion (%) of the peak area in HPLC (e.g., the peak area of ​​absorbance at a wavelength of 230 nm) or may be % by mass, and in a preferred embodiment, it may be the proportion (%) of the peak area in HPLC.

[0027] The phrase "a crystal of the p-TsOH salt of Compound A is the most stable form among multiple crystalline forms of the same compound" may mean, for example, that when multiple crystals of the p-TsOH salt of Compound A are subjected to the above-mentioned storage stability test or formulation stability test, the crystals exhibit the greatest stability among the tested crystals of the p-TsOH salt of Compound A. The phrase "a crystal of the p-TsOH salt of Compound A is the most stable form among multiple crystalline forms of the same compound" may mean, for example, that when equal amounts of multiple crystals of the p-TsOH salt of Compound A are present in a single mixed solution and incubated, the crystal form is the crystalline form that is ultimately present in the largest amount in the mixture.

[0028] <Form 3 Crystal of p-TsOH Salt of Compound A> A second aspect of the present disclosure is a compound having the following formula (AI): That is, a second aspect of the present disclosure relates to a Form 3 crystal of the p-TsOH salt of Compound A. In one embodiment, the second aspect of the present disclosure may also be a Form 3 crystal of the p-TsOH salt of Compound A, produced by a production method according to a sixth aspect of the present disclosure, which will be described later.

[0029] The Form 3 crystal of p-TsOH salt of Compound A according to one embodiment of the second aspect of the present disclosure has diffraction peaks in powder X-ray diffraction at diffraction angles (2θ), (2θ±0.1°), (2θ±0.2°), (2θ±0.3°), (2θ±0.4°), or (2θ±0.5°) of 6.3°, 15.0°, 16.4°, 17.9°, and 22.7°. In a preferred embodiment of the second aspect of the present disclosure, the Form 3 crystal of p-TsOH salt of Compound A has diffraction peaks in powder X-ray diffraction at diffraction angles (2θ±0.2°) of 6.3°, 15.0°, 16.4°, 17.9°, and 22.7°.

[0030] The type 3 crystal of p-TsOH salt of compound A according to one embodiment of the second aspect of the present disclosure has an endothermic peak at 247.4±3.0°C in differential thermal analysis. The type 3 crystal of p-TsOH salt of compound A according to one embodiment of the second aspect of the present disclosure has diffraction peaks at diffraction angles (2θ±0.2°) of 6.3°, 15.0°, 16.4°, 17.9°, and 22.7° in powder X-ray diffraction, and also has an endothermic peak at 247.4±3.0°C in differential thermal analysis. Furthermore, the type 3 crystal of p-TsOH salt of compound A according to one embodiment of the second aspect of the present disclosure can remain stable for 7 days or more even under conditions of a temperature of 40°C and a relative humidity of 75%.

[0031] The Type 3 crystal of the p-TsOH salt of Compound A according to one embodiment of the second aspect of the present disclosure has excellent solubility. Without wishing to be bound by any theory, it is believed that the Type 3 crystal of the p-TsOH salt of Compound A is relatively less stable than the Type 1 crystal, which is the most stable form, and therefore requires less energy to dissolve, resulting in high solubility.

[0032] <Form 4 Crystal of p-TsOH Salt of Compound A> A third aspect of the present disclosure is a compound having the following formula (AI): The present disclosure relates to Form 4 crystals of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by the formula:

[0023] That is, a third aspect of the present disclosure relates to Form 4 crystals of p-TsOH salt of Compound A. In one embodiment, the third aspect of the present disclosure may also be Form 4 crystals of p-TsOH salt of Compound A, produced by the production method according to the seventh aspect of the present disclosure, which will be described later.

[0033] The Form 4 crystal of p-TsOH salt of Compound A according to one embodiment of the third aspect of the present disclosure has diffraction peaks in powder X-ray diffraction at diffraction angles (2θ), (2θ±0.1°), (2θ±0.2°), (2θ±0.3°), (2θ±0.4°), or (2θ±0.5°) of 7.4°, 8.0°, 14.5°, 16.1°, and 20.6°. In a preferred embodiment of the third aspect of the present disclosure, the Form 4 crystal of p-TsOH salt of Compound A has diffraction peaks in powder X-ray diffraction at diffraction angles (2θ±0.2°) of 7.4°, 8.0°, 14.5°, 16.1°, and 20.6°.

[0034] The Form 4 crystal of p-TsOH salt of Compound A according to one embodiment of the third aspect of the present disclosure has an endothermic peak at 212.5±3.0°C in differential thermal analysis. The Form 4 crystal of p-TsOH salt of Compound A according to one embodiment of the third aspect of the present disclosure has diffraction peaks at diffraction angles (2θ±0.2°) of 7.4°, 8.0°, 14.5°, 16.1°, and 20.6° in powder X-ray diffraction, and also has an endothermic peak at 212.5±3.0°C in differential thermal analysis.

[0035] <Composition> A fourth aspect of the present disclosure is a composition comprising type 1 crystals of p-TsOH salt of Compound A according to the first aspect of the present disclosure, wherein the content of type 1 crystals of p-TsOH salt of Compound A in the entire composition is 95% by mass or more, and the composition is represented by the following formula (VII): (hereinafter also referred to as "compound B") is a composition in which the content of the compound represented by the formula (I) is not more than a predetermined upper limit. Another embodiment of the fourth aspect of the present disclosure is a composition comprising type 1 crystals of the p-TsOH salt of compound A according to the first aspect of the present disclosure and compound B, wherein the content of type 1 crystals of the p-TsOH salt of compound A is 95% by mass or more of the total composition, and the content of compound B is not more than a predetermined upper limit. The composition in the fourth aspect of the present disclosure refers to a composition comprising one or more components contained in any materials used in the process of preparing type 1 crystals of the p-TsOH salt of compound A, and products of one-step or multi-step reactions between them.

[0036] Compound B may be involved in mutagenicity and may be generated during the production of type 1 crystals of the p-TsOH salt of compound A. In a composition according to an embodiment of the present disclosure, the amount of compound B is reduced, which can reduce the risk of mutagenicity when the composition is used in the production of a pharmaceutical product, and can also reduce the burden of controlling the amount of contamination of compound B, which must be controlled on the ppm order, in the production of type 1 crystals of the p-TsOH salt of compound A.

[0037] The content of compound B in the composition according to one embodiment of the fourth aspect of the present disclosure is, for example, 1000×10 －４ Mass% or less, 600×10 －４ Mass% or less, 300×10 －４ Mass% or less, 100×10 －４ Mass% or less, 50×10 －４ Mass% or less or 20 x 10 －４ % by mass or less, and as a specific example, the content of Compound B may be 100×10 －４Furthermore, the content of the p-toluenesulfonate salt of compound A in the composition according to one embodiment of the fourth aspect of the present disclosure may be 95% by mass or more, 96% by mass or more, 97% by mass or more, 98% by mass or more, or 99% by mass or more of the total composition.

[0038] The composition according to one embodiment of the fourth aspect of the present disclosure has formula (XI): (hereinafter also referred to as "compound C") is not more than a predetermined upper limit in terms of free form, and the predetermined upper limit is, for example, 1000 × 10 －４ Mass%, 600×10 －４ Mass%, 300×10 －４ Mass%, 100×10 －４ Mass%, 50×10 －４ Mass% or 20 x 10 －４ % by mass, and in a specific example, the content of compound C is 50×10 －４ The composition according to a preferred embodiment of the fourth aspect of the present disclosure does not contain compound C.

[0039] Compound C is a synthetic intermediate when compound A is produced by the production method described in Patent Document 1, and evaluation using multiple in silico testing software programs capable of predicting mutagenicity (genotoxicity) revealed that compound C is highly likely to have mutagenicity (genotoxicity). Therefore, if the content of compound C in a composition according to an embodiment of the fourth aspect of the present disclosure is equal to or less than the above-mentioned predetermined upper limit, or if compound C is not contained, it is possible to reduce the risk of mutagenicity in pharmaceuticals produced using the composition according to an embodiment of the fourth aspect of the present disclosure, and it is also possible to reduce the burden of controlling the amount of compound C contamination, which requires control on the order of ppm, in the production of type 1 crystals of the p-TsOH salt of compound A.

[0040] <Method for Producing Form 1 Crystals of p-TsOH Salt of Compound A or a Composition Comprising the Same> A fifth aspect of the present disclosure is a method for producing Form 1 crystals of p-TsOH salt of Compound A or a composition comprising the same. In one embodiment, the fifth aspect of the present disclosure may be a method for producing Form 1 crystals of p-TsOH salt of Compound A according to an embodiment of the first aspect of the present disclosure or a composition according to an embodiment of the fourth aspect of the present disclosure.

[0041] In one embodiment, the production method according to the fifth aspect of the present disclosure comprises a compound represented by the following formula (AI): N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate (i.e., represented by the following formula (I): One embodiment of such a production method is described below.

[0042] <First Step> The first step is a step of reacting a compound represented by the following formula (IV): (In the formula, R １ represents a protecting group for a carboxyl group or H, and X represents Cl, Br, I or OTf.

[0043] R in the above formula (IV) １ is a protecting group for a carboxyl group or H, preferably a protecting group for a carboxyl group. In the present disclosure, the protecting group for a carboxyl group is a protecting group for a carboxyl group that is not removed in the second and third steps described below and is a protecting group for a carboxyl group represented by the following formula (II): (In the formula, R １ is R in the above formula (VI) １ is the same as R ２ represents a group which forms a protecting group for an aniline amino group together with —O—C(═O)—.) １is not particularly limited as long as it is a group that can provide a compound in which is H, and may be, for example, an alkyl, cycloalkyl, alkenyl, alkoxymethyl or benzyl protecting group. In one embodiment, C １ ~C ６ Alkyl, C ４ ~C ６ Cycloalkyl, C １ ~C ６ Alkenyl, C １ ~C ６ Alkoxymethyl (C １ ~C ６ alkoxylated methyl), benzyl, phenethyl or para-methoxybenzyl, and in a preferred embodiment C １ ~C ６ It may be alkyl, and in another preferred embodiment it may be methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, vinyl, allyl, methoxymethyl, benzyl, or paramethoxybenzyl, and in a more preferred embodiment it may be methyl or ethyl, and in a most preferred embodiment it may be methyl.

[0044] R in the above formula (IV) １ X is Cl, Br, I or OTf(O-SO ２ -CF ３ ), which in a preferred embodiment may be Cl, Br or I, in a more preferred embodiment may be Cl or Br, and in a most preferred embodiment may be Br.

[0045] In a most preferred embodiment, the compound represented by the above formula (IV) is represented by the following formula (IV'): The form of the compound of formula (IV′) obtained in the first step is not particularly limited, but in one embodiment, it may be obtained as a free form.

[0046] In one embodiment, the first step is a reaction of formula (VI): (In the formula, R １and X is R in formula (IV). １ and X are the same as X.) with methoxyacetic acid to obtain a compound represented by formula (IV).

[0047] The temperature at which the compound represented by formula (VI) is contacted with methoxyacetic acid is not particularly limited as long as it is a temperature at which imidazole ring formation occurs in the compound represented by formula (IV), and may be, for example, 50°C to 150°C, 60°C to 120°C, 70°C to 105°C, or 80°C to 95°C. When the compound represented by formula (VI) is contacted with methoxyacetic acid, the contact may be carried out in a solvent, or may be carried out by dissolving the compound represented by formula (VI) in methoxyacetic acid without using a solvent. From the viewpoint of highly efficient reaction, in a preferred embodiment, the contact may be carried out by dissolving the compound represented by formula (VI) in methoxyacetic acid without using a solvent. When a solvent is used, the solvent is an organic solvent in which the compound represented by formula (VI) and methoxyacetic acid are soluble and which has a boiling point below the above temperature range, such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMA).

[0048] The reaction time for contacting the compound represented by formula (VI) with methoxyacetic acid is not particularly limited as long as it is a time that allows the compound represented by formula (IV) to be obtained, and may be, for example, 5 to 20 hours. During this time, the atmosphere inside the reaction vessel may be purged with an inert gas such as nitrogen or argon.

[0049] The equivalent relationship between the compound represented by formula (VI) above and methoxyacetic acid in the contact between them is not particularly limited as long as the compound represented by formula (IV) above can be obtained in a high yield (for example, a yield of 75% or more) relative to the compound represented by formula (VI) above as a raw material. In one embodiment, the equivalent of methoxyacetic acid may be, for example, 1 to 100 equivalents, 2 to 50 equivalents, or 4 to 25 equivalents relative to 1 equivalent of the compound represented by formula (VI) above, and a specific example is 10 equivalents.

[0050] <Step 2 / 3> Step 2 / 3 is a step of reacting a compound represented by the following formula (II): (In the formula, R １ is R in the above formula (VI) １ is the same as R ２ represents a group which forms a protecting group for an aniline amino group together with —O—C(═O)—. The second / third step is a step of obtaining a compound represented by the formula (IV) or a protected form thereof, and a compound represented by the following formula (V): (In the formula, R ２ is R in the above formula (II) ２ (which is the same as the formula (II)) to obtain a compound represented by formula (II) or a protected form thereof.

[0051] R in the above formula (II) ２ represents a group which forms a protecting group for the aniline amino group together with —O—C(═O)—. In this case, the protecting group for the aniline amino group is R １ By removing １ The protecting group R forming such an aniline amino group is not particularly limited as long as it is not removed during the process of converting R to H. ２ The alkyl group may be, for example, an alkyl, cycloalkyl, alkenyl, or a hydrocarbon group having one or more aromatic rings, and in one embodiment, C １ ~C ６ Alkyl, C ４ ~C ６ Cycloalkyl, C １ ~C ６ alkenyl, benzyl, phenethyl, paramethoxybenzyl or 9-fluorenylmethyl, and in one preferred embodiment C １ ~C ６ It may be alkyl, and in another preferred embodiment it may be methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, vinyl, allyl, benzyl, phenethyl, or 9-fluorenylmethyl, and in a more preferred embodiment it may be methyl or ethyl, and in a most preferred embodiment it may be methyl.

[0052] In a most preferred embodiment, the compound represented by formula (II) is represented by the following formula (II'): The form of the compound represented by formula (II') obtained in step 2 / 3 is not particularly limited, but in one embodiment, it may be in the form of a salt of the acid used in the deprotection of the secondary amino group at position 1, which will be described later, for example, in the form of a hydrochloride salt. In the most preferred embodiment described above, the compound represented by formula (V) is represented by the following formula (V'): It is methyl carbamate represented by the formula:

[0053] The protected compound of the compound represented by the formula (II) is a compound represented by the following formula (II″): (In the formula, R １ and X is R in the above formula (VI). １ and X, and R ３ represents a protecting group for an amino group, for example, a tert-butyloxycarbonyl (Boc) group, an allyloxycarbonyl (Alloc) group, a 9-fluorenylmethyloxycarbonyl (Fmoc) group, a trimethylsilyl (TMS) group, or a benzyl group.

[0054] The second / third step involves contacting the compound represented by formula (IV) or a protected form thereof with the compound represented by formula (V) to obtain the compound represented by formula (II) or a protected form thereof. Without wishing to be bound by any theory, in this reaction, the functional group represented by X in the compound represented by formula (IV) or a protected form thereof is substituted with the nitrogen atom in the terminal amide of the compound represented by formula (V) by Buchwald-Hartwig cross-coupling, thereby obtaining the compound represented by formula (II) or a protected form thereof.

[0055] The temperature at which the compound represented by formula (IV) or a protected form thereof is contacted with the compound represented by formula (V) is not particularly limited as long as it allows the compound represented by formula (II) or a protected form thereof to be obtained, and may be, for example, 60° C. to 120° C., 70° C. to 110° C., 80° C. to 105° C., or 88° C. to 97° C. In this case, the solvent used to contact the compound represented by formula (IV) or a protected form thereof with the compound represented by formula (V) is not particularly limited as long as it has a boiling point equal to or higher than the above temperature range or is capable of refluxing (reflux) at the above temperature range, and is not reactive with any of the compound represented by formula (IV) and its protected form and the compound represented by formula (V) in the reaction system. For example, toluene or 1,4-dioxane can be suitably used, and in a preferred embodiment, toluene may be used. The time for contacting the compound represented by formula (IV) or its protected form with the compound represented by formula (V) is not particularly limited and may be, for example, 10 minutes to 168 hours. During this time, the atmosphere in the reaction vessel may be replaced with an inert gas such as nitrogen or argon.

[0056] The equivalent relationship when the compound represented by formula (IV) or a protected form thereof is contacted with the compound represented by formula (V) is not particularly limited as long as the compound represented by formula (II) or a protected form thereof can be obtained in high yield (e.g., a yield of 85% or more) relative to the compound represented by formula (IV) or a protected form thereof as a starting product. For example, the compound represented by formula (V) may be used in an amount of 1 to 5 equivalents, 1.2 to 4 equivalents, or 1.5 to 3 equivalents relative to 1 equivalent of the compound represented by formula (IV) or a protected form thereof, and a specific example is 2 equivalents.

[0057] In one embodiment, the contacting of the compound represented by formula (IV) or a protected form thereof with the compound represented by formula (V) is carried out in the presence of a palladium catalyst. The palladium catalyst is not particularly limited as long as it is capable of obtaining the compound represented by formula (II) or a protected form thereof by contacting the compound represented by formula (IV) or a protected form thereof with the compound represented by formula (V). For example, the palladium catalyst may be a palladium catalyst containing zero-valent palladium (Pd(0)) or a palladium catalyst containing divalent palladium (Pd(2)). In one embodiment, the palladium catalyst may be a palladium catalyst containing zero-valent palladium (Pd(0)). Specific examples of palladium catalysts include tris(dibenzylideneacetone)dipalladium(0) (Pd ２ (dba) ３ ), bis(dibenzylideneacetone)palladium(0) (Pd(dba) ２ Examples of the palladium catalyst include palladium(II) acetate and palladium(II) chloride, and in a preferred embodiment, tris(dibenzylideneacetone)dipalladium(II) may be used. The equivalent amount of the palladium catalyst used in contacting the compound represented by formula (IV) or a protected form thereof with the compound represented by formula (V) may be, for example, 0.0005 to 0.2 equivalents, 0.001 to 0.1 equivalents, or 0.003 to 0.05 equivalents relative to 1 equivalent of the compound represented by formula (IV) or a protected form thereof.

[0058] In one embodiment, the contacting of the compound represented by formula (IV) or a protected form thereof with the compound represented by formula (V) is carried out in the presence of a ligand in addition to a palladium catalyst. The ligand is not particularly limited as long as it can provide the compound represented by formula (II) or a protected form thereof by contacting the compound represented by formula (IV) or a protected form thereof with the compound represented by formula (V). Examples of the ligand include 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 1,1'-bis(diphenylphosphino)ferrocene (DPPF), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos). In a preferred embodiment, the ligand may be 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos). The equivalent amount of the ligand used in contacting the compound represented by formula (IV) or a protected form thereof with the compound represented by formula (V) may be, for example, 0.005 to 0.08 equivalents, 0.008 to 0.05 equivalents, or 0.01 to 0.04 equivalents relative to 1 equivalent of the compound represented by formula (IV) or a protected form thereof.

[0059] In one embodiment, the contacting of the compound represented by formula (IV) or a protected form thereof with the compound represented by formula (V) is carried out in the presence of a base in addition to a palladium catalyst and a ligand. The base is not particularly limited as long as it can be used to obtain the compound represented by formula (II) or a protected form thereof by contacting the compound represented by formula (IV) or a protected form thereof with the compound represented by formula (V), and may be, for example, potassium carbonate, cesium carbonate, potassium hydroxide, sodium tert-butyloxide, or sodium methoxide. The equivalent amount of the base used in contacting the compound represented by formula (IV) or a protected form thereof with the compound represented by formula (V) may be, for example, 1.5 to 20 equivalents, 2.0 to 10 equivalents, or 3.0 to 7.0 equivalents relative to 1 equivalent of the compound represented by formula (IV) or a protected form thereof.

[0060] In one embodiment, the second / third step comprises reacting a compound represented by formula (IV) with a compound represented by formula (IX): (In the formula, R １ is R in the above formula (II) １ and X is the same as X in the above formula (IV). (In the formula, R １ is R in the above formula (II) １ is the same as R ２ is R in the above formula (V) ２ and hydrolyzing the compound represented by formula (X) in the presence of an acid to obtain a compound represented by formula (II), in this order.

[0061] In this case, the compound represented by the formula (IV) can be converted into the compound represented by the formula (IX) by a method commonly used by those skilled in the art. For example, for one equivalent of the compound represented by the formula (IV) dissolved in an organic solvent such as toluene, about 1.1 to 3 equivalents of di-tert-butyl dicarbonate ((Boc) ２O), and in this case, about 1.2 to 5 equivalents of a base (for example, potassium carbonate) may further be present in the system.

[0062] In one embodiment, in Step 2 / 3, converting the compound represented by formula (IV) to the compound represented by formula (IX) and contacting the compound represented by formula (IX) with the compound represented by formula (V) to obtain the compound represented by formula (X) may be performed in one reaction vessel (one-pod). A specific example includes a case in which the compound represented by formula (IV) is contacted with di-tert-butyl dicarbonate in an organic solvent such as toluene in which a base may be dissolved, and then the compound represented by formula (V), a palladium catalyst, a ligand, and a base are further added to the reaction vessel, and the reaction solution is heated to obtain the compound represented by formula (X).

[0063] The compound represented by formula (X) above can be hydrolyzed in the presence of an acid to obtain the compound represented by formula (II) above by a method commonly used by those skilled in the art, for example, by contacting the compound represented by formula (X) above with an excess amount of an acid such as concentrated hydrochloric acid or trifluoroacetic acid in isopropanol (2-propanol), methanol, or acetonitrile, and in this case, the reaction solution may be heated to about 50 to 60°C, if necessary.

[0064] In one embodiment, obtaining a compound represented by formula (II) by hydrolyzing a compound represented by formula (X) in the presence of an acid may be carried out without purification after contacting a compound represented by formula (IX) with a compound represented by formula (V) to obtain a compound represented by formula (X). In this case, the reaction solution obtained by contacting a compound represented by formula (IX) with a compound represented by formula (V) to obtain a compound represented by formula (X) is filtered to remove insoluble matter such as a base such as potassium carbonate, and the solvent is removed by distillation under reduced pressure as necessary to reduce or dry the solvent, followed by adding the solvent and acid used for hydrolysis in the presence of an acid and incubating.

[0065] <Fourth Step> The fourth step is a step of reacting a compound represented by the following formula (II): (In the formula, R １ represents a protecting group for a carboxyl group or H, R ２ represents a group which forms a protecting group for an aniline amino group together with —O—C(═O)—, This is a process for converting the compound represented by the formula:

[0066] In one embodiment, the step of converting the compound represented by formula (II) into the compound represented by formula (VIII) comprises converting the compound represented by formula (II) into the compound represented by formula (III): In a preferred embodiment, the step of converting the compound represented by formula (II) into the compound represented by formula (VIII) comprises hydrolyzing the compound represented by formula (II) in the presence of a base to obtain the compound represented by formula (III).

[0067] The compound represented by formula (II) above can be converted into the compound represented by formula (III) above by a method commonly used by those skilled in the art. In a method including such a step, a compound represented by formula (XI) below, which has a concern of mutagenicity, can be obtained.

[0023] This method can avoid isolating the compound represented by formula (II) (compound C) as a powder, thereby avoiding the risk of mutagenicity due to scattering of compound C isolated as a powder, and reducing the time and cost required for worker protection and environmental measures (containment). In one embodiment, the step of converting the compound represented by formula (II) to the compound represented by formula (VIII) comprises converting the compound represented by formula (II) to the compound represented by formula (III), wherein the compound represented by formula (III) is obtained as a solution. In one embodiment, the step of converting the compound represented by formula (II) to the compound represented by formula (VIII) comprises hydrolyzing the compound represented by formula (II) in the presence of a base to obtain the compound represented by formula (III) as a solution. In one embodiment, the step of converting the compound represented by formula (II) to the compound represented by formula (VIII) does not include isolating the compound represented by formula (III) as a powder. In one embodiment, the step of converting the compound represented by formula (II) to the compound represented by formula (VIII) does not include handling the compound represented by formula (III) in a state other than its solution.

[0068] The hydrolysis of the compound represented by formula (II) with a base can be carried out under conditions commonly used by those skilled in the art, and examples of such a method include adding the compound represented by formula (II) or a salt thereof (e.g., hydrochloride) to an aqueous sodium hydroxide solution having a concentration of about 5 to 30% by mass or about 10 to 25% by mass, and stirring the mixture at a temperature of about 40 to 70° C. or about 50 to 60° C. The reaction time is not particularly limited and may be, for example, 10 minutes to 72 hours, 1 hour to 24 hours, or 2 hours to 12 hours, and may be 6 hours.

[0069] In one embodiment of the present disclosure, the step of converting the compound represented by formula (II) into the compound represented by formula (VIII) includes converting the compound represented by formula (II) into the compound represented by formula (III), and then converting the compound represented by formula (III) into the compound represented by formula (VIII). The conversion of the compound represented by formula (III) above into the compound represented by formula (VIII) above can be carried out by a method that is usually carried out by a person skilled in the art. For example, the conversion may be carried out by a method in which an acid halide such as an acid chloride or acid bromide of 2-(trifluoromethyl)benzoic acid is contacted with the compound represented by formula (VIII) above to amidate the anilinic amino group in the compound represented by formula (VIII) above, or by a method in which 2-(trifluoromethyl)benzoic acid is contacted with the compound represented by formula (VIII) above in the presence of a condensing agent such as HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) to amidate the anilinic amino group in the compound represented by formula (VIII) above. Among these, from the viewpoint of avoiding a decrease in yield due to the generation of by-products caused by the participation of the carboxyl group of the compound represented by formula (VIII) in amide formation, the conversion of the compound represented by formula (III) to the compound represented by formula (VIII) is preferably carried out by a method in which an acid halide such as an acid chloride or acid bromide of 2-(trifluoromethyl)benzoic acid is brought into contact with the compound represented by formula (VIII) to amidate the anilinic amino group in the compound represented by formula (VIII), and for example, this may be carried out by contacting the compound represented by formula (VIII) with 2-(trifluoromethyl)benzoyl chloride.

[0070] In the above case, the solvent used in contacting the acid halide of 2-(trifluoromethyl)benzoic acid with the compound represented by formula (VIII) can be one that would normally be selected by a person skilled in the art, and may be, for example, acetonitrile or a mixed solvent of acetonitrile and water. The reaction temperature is not particularly limited as long as it is a temperature at which the compound represented by formula (VIII) is produced, and may be, for example, −10° C. to 20° C., −10° C. to 10° C., or −5° C. to 5° C. The reaction time is also not particularly limited as long as it is a time at which the compound represented by formula (VIII) is produced, and may be, for example, 1 minute to 3 hours, 5 minutes to 1 hour, or 10 minutes to 30 minutes. From the viewpoint of increasing the yield by decomposing the compound formed by the reaction of multiple by-products of 2-(trifluoromethyl)benzoic acid acid halide, the reaction solution may be further incubated, after the reaction under the above conditions, at a temperature of, for example, 50 to 80° C. or 60 to 70° C., for example, 5 minutes to 12 hours, 15 minutes to 6 hours, or 30 minutes to 4 hours. The equivalent relationship between the acid halide of 2-(trifluoromethyl)benzoic acid and the compound represented by formula (VIII) is not particularly limited as long as the compound represented by formula (VIII) can be obtained in high yield (e.g., 80% or higher) relative to the compound represented by formula (VIII), and may be, for example, 0.90 to 1.50 equivalents, 0.95 to 1.30 equivalents, 0.97 to 1.10 equivalents, or 0.99 to 1.01 equivalents relative to 1 equivalent of the compound represented by formula (VIII). Furthermore, the reaction system may further contain about 1 equivalent (e.g., 0.7 to 1.5 equivalents, or 0.9 to 1.1 equivalents) of a compound having a carboxyl group, such as acetic acid, relative to the compound represented by formula (VIII).

[0071] In one embodiment, the conversion of the compound represented by formula (II) to the compound represented by formula (III) and the conversion of the compound represented by formula (III) to the compound represented by formula (VIII) may be carried out in one reaction vessel (one-pot). In this case, for example, after the compound represented by formula (II) is converted to the compound represented by formula (III), acetonitrile, water, acetic acid, and an acid halide of 2-(trifluoromethyl)benzoic acid may be further added to the reaction solution.

[0072] <Fifth Step> The fifth step is a step of reacting a compound represented by the following formula (VIII): The compound represented by the following formula (I): In one embodiment, the fifth step comprises converting the compound represented by formula (VIII) into the compound represented by formula (I), and contacting the compound represented by formula (I) with N,N-dimethylacetamide to obtain the N,N-dimethylacetamide solvate of the compound represented by formula (I).

[0073] The compound represented by formula (VIII) above can be converted into the compound represented by formula (I) above according to a method commonly used by those skilled in the art. For example, the compound represented by formula (VIII) above can be brought into contact with 1,1'-carbonyldiimidazole (CDI) or the like to give the compound represented by formula (XII) below: or a compound represented by the following formula (XIII) obtained by contacting a compound represented by the above formula (VIII) with thionyl chloride or the like: and 3-chloro-2-methylaniline, and for example, the reaction can also be carried out by contacting the compound represented by formula (VIII) above with 3-chloro-2-methylaniline in the presence of a condensing agent such as HATU or DMTMM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride). In a preferred embodiment, the reaction can be carried out by contacting the compound represented by formula (VIII) above with CDI, which is obtained by contacting the compound represented by formula (XII) above with 3-chloro-2-methylaniline.

[0074] The solvent used in contacting the compound represented by formula (VIII) with CDI is a solvent that is unreactive with the compound represented by formula (VIII) and CDI, and examples of such a solvent include N,N-dimethylformamide and N,N-dimethylacetamide. The temperature and time for contacting the compound represented by formula (VIII) with CDI are not particularly limited as long as they allow the compound represented by formula (XII) to be obtained. For example, the reaction may be carried out at a temperature of about 5 to 50°C, 10 to 40°C, or 20 to 30°C for 10 minutes to 24 hours, 20 minutes to 6 hours, or 30 minutes to 2 hours. The equivalent relationship in contacting the compound represented by formula (VIII) with CDI is not particularly limited as long as the compound represented by formula (VIII) can be used to obtain the compound represented by formula (XII) in high yield (e.g., a yield of 90% or more). For example, the amount of CDI relative to 1 equivalent of the compound represented by formula (VIII) may be 1.00 to 2.00 equivalents, 1.05 to 1.40 equivalents, or 1.10 to 1.20 equivalents.

[0075] The solvent used in contacting the compound represented by formula (XII) with 3-chloro-2-methylaniline is a solvent that is unreactive with the compound represented by formula (XII) and 3-chloro-2-methylaniline, and examples of such a solvent include N,N-dimethylformamide and N,N-dimethylacetamide. The temperature and time for contacting the compound represented by formula (XII) with 3-chloro-2-methylaniline are not particularly limited as long as the compound represented by formula (I) can be obtained. For example, the reaction may be carried out at a temperature of about 40 to 70°C or about 50 to 60°C for 10 minutes to 168 hours, 1 hour to 72 hours, or 6 hours to 30 hours. The equivalent relationship in contacting the compound represented by formula (XII) with 3-chloro-2-methylaniline is not particularly limited as long as it allows the compound represented by formula (I) to be obtained in high yield (e.g., 90% or higher) relative to the compound represented by formula (XII), and the amount of 3-chloro-2-methylaniline relative to 1 equivalent of the compound represented by formula (XII) may be, for example, 1.1 to 10 equivalents, 1.5 to 5.0 equivalents, or 2.0 to 3.0 equivalents. The contacting of the compound represented by formula (XII) with 3-chloro-2-methylaniline may be carried out in the presence of a compound having a carboxyl group, such as benzoic acid.

[0076] The contacting of the compound represented by formula (VIII) with CDI and the contacting of the compound represented by formula (XII) with 3-chloro-2-methylaniline may be carried out in one reaction vessel (one-pot). In this case, for example, the compound represented by formula (VIII) and CDI may be contacted in N,N-dimethylformamide, and then 3-chloro-2-methylaniline and benzoic acid may be added to the reaction solution.

[0077] Contacting the compound represented by formula (I) with N,N-dimethylacetamide to obtain an N,N-dimethylacetamide solvate of the compound represented by formula (I) can be carried out by a method commonly used by those skilled in the art, for example, by adding DMA or a mixture containing DMA (e.g., a mixture of DMA and water) to a solvent in which any form of the compound represented by formula (I) (e.g., the free form of the compound represented by formula (I)) is dissolved, and incubating the mixture. In one embodiment, the reaction may be carried out by adding a mixture of DMA and water to a solution obtained after contacting the compound represented by formula (XII) with 3-chloro-2-methylaniline. The temperature conditions for this reaction may be, for example, 40 to 70°C or 50 to 60°C, and the incubation time may be, for example, 10 minutes to 24 hours.

[0078] By the above-described fourth and fifth steps, an N,N-dimethylacetamide solvate of the compound represented by formula (I) is obtained using the compound represented by formula (II) as a starting material. That is, in one embodiment, the fourth and fifth steps can be combined to perform a step of converting the compound represented by formula (II) into the N,N-dimethylacetamide solvate of the compound represented by formula (I).

[0079] <Step 6> Step 6 is a step of purifying by recrystallization the crude N,N-dimethylacetamide solvate of the compound represented by formula (I) (Compound A), and in one embodiment, is a step of purifying by recrystallization the N,N-dimethylacetamide solvate of the compound represented by formula (I) obtained in Step 5. The recrystallization of the crude N,N-dimethylacetamide solvate of the compound represented by formula (I) may be carried out in N,N-dimethylacetamide or a mixed solvent containing it, and in one embodiment, may be carried out in a mixed solvent of N,N-dimethylacetamide and water. Furthermore, in a preferred embodiment, recrystallization of the crude product of the N,N-dimethylacetamide solvate of the compound represented by formula (I) may be carried out in a mixed solvent of N,N-dimethylacetamide and water, in which the N,N-dimethylacetamide content is 50 vol% or more, 60 vol% or more, 70 vol% or more, 75 vol% or more, or 78 vol% or more, and 99 vol% or less, 95 vol% or less, 90 vol% or less, or 80 vol% or less. For example, recrystallization may be carried out in a mixed solvent of N,N-dimethylacetamide and water, in which the N,N-dimethylacetamide content is 75 vol% or more, or 75 vol% or more and 99 vol% or less. Recrystallization in such a solvent can produce the N,N-dimethylacetamide solvate of the compound represented by formula (I) in high yield and high purity. Furthermore, recrystallization in such a solvent can prevent the formation of a compound represented by formula (VII) below, which may be generated during the production process and may be involved in mutagenicity: It is possible to obtain a purified product of the N,N-dimethylacetamide solvate of the compound represented by formula (I) above, in which the content of the compound represented by formula (I) (hereinafter also referred to as "compound B") is reduced. In particular, by using a mixed solvent of N,N-dimethylacetamide and water, in which the content of N,N-dimethylacetamide is 70 vol% or more, 75 vol% or more, or 78 vol% or more, it is possible to obtain a purified product of the N,N-dimethylacetamide solvate of the compound represented by formula (I) above, in which the content of compound B is further reduced. In these cases, the reduced content of compound B means that the content of compound B in the purified product (crystals) obtained by recrystallization is, for example, 1800×10 －４ Mass% or less, 1000×10－４ Mass% or less, 500×10 －４ Mass% or less, 400×10 －４ Mass% or less, 300×10 －４ Mass% or less, 200×10 －４ Mass% or less or 170 x 10 －４ % by mass or less, and in particular, when a mixed solvent of N,N-dimethylacetamide and water is used, in which the content of N,N-dimethylacetamide is 70% by volume or more, 75% by volume or more, or 78% by volume or more, the content of compound B can be, for example, 1000×10 －４ Mass% or less, 500×10 －４ Mass% or less, 400×10 －４ Mass% or less, 300×10 －４ Mass% or less, 200×10 －４ Mass% or less or 170 x 10 －４ A purified product (crystal) having a molecular weight of less than 100% by mass can be obtained.

[0080] <Step 7> Step 7 is a step of converting the N,N-dimethylacetamide solvate of the compound represented by formula (I) (Compound A) into a p-toluenesulfonate of the compound represented by formula (I). In one embodiment, Step 7 is a step of converting the purified product (crystals) of the N,N-dimethylacetamide solvate of the compound represented by formula (I) obtained in Step 6 into a p-toluenesulfonate of the compound represented by formula (I). Step 7 is typically carried out by contacting the N,N-dimethylacetamide solvate of the compound represented by formula (I) with p-toluenesulfonic acid (tosylic acid, 4-methylbenzenesulfonic acid). The conditions for contacting the N,N-dimethylacetamide solvate of the compound represented by formula (I) with p-toluenesulfonic acid are not particularly limited as long as the N,N-dimethylacetamide solvate of the compound represented by formula (I) is converted to the p-toluenesulfonic acid salt of the compound represented by formula (I). The solvent may be, for example, N,N-dimethylformamide, acetonitrile, or a mixed solvent thereof. A specific example is a mixed solvent of N,N-dimethylformamide and acetonitrile (e.g., a mixed solvent with a mass ratio of about 1:6). The contact temperature may be, for example, 30 to 70°C or 45 to 60°C. The contact time may be, for example, 10 minutes to 24 hours or 1 hour to 12 hours. The form of the p-toluenesulfonic acid to be added is not particularly limited, and it may be added to the solvent as a hydrate, for example. The equivalent relationship in the reaction system may be, for example, 1.01 to 2.00 equivalents, 1.03 to 1.50 equivalents, or 1.05 to 1.20 equivalents of p-toluenesulfonic acid or a hydrate thereof relative to 1 equivalent of the N,N-dimethylacetamide solvate of the compound represented by formula (I).

[0081] <Step 8> Step 8 is a step of obtaining Type 1 crystals of the p-TsOH salt of Compound A from a crude product of p-toluenesulfonate (p-TsOH salt) of the compound represented by formula (I) (Compound A). In one embodiment, Step 8 is a step of obtaining Type 1 crystals of the p-TsOH salt of Compound A from the crude product of the p-toluenesulfonate salt of the compound represented by formula (I) obtained in Step 7. In one embodiment, Step 8 comprises, in this order, purifying the p-toluenesulfonate salt of the compound represented by formula (I) by contacting it with activated carbon, and recrystallizing the p-toluenesulfonate salt of the compound represented by formula (I) after contacting it with activated carbon to obtain Type 1 crystals of the p-TsOH salt of Compound A.

[0082] The purification of the p-toluenesulfonate salt of the compound represented by formula (I) by contacting it with activated carbon is carried out by adding activated carbon to a solution of the p-toluenesulfonate salt of the compound represented by formula (I), incubating the mixture, and then removing the activated carbon by filtration or the like. The solvent is not particularly limited as long as it dissolves the p-toluenesulfonate salt of the compound represented by formula (I) and maintains the salt form; for example, N,N-dimethylformamide is preferably used. The contact may be carried out at a temperature of about 30 to 60°C or 40 to 50°C for about 5 minutes to 24 hours or 10 minutes to 6 hours; a specific example is one hour. The amount of activated carbon to be contacted with the p-toluenesulfonate salt of the compound represented by formula (I) may be, for example, at least 0.04 times, at least 0.05 times, at least 0.08 times, at least 0.09 times, at least 0.10 times, at least 0.14 times, or at least 0.15 times the mass of the p-toluenesulfonate salt of the compound, or at most 1.00 times, at most 0.50 times, or at most 0.20 times the mass of the p-toluenesulfonate salt of the compound, and in a preferred embodiment, at least 0.08 times the mass. When the amount of activated carbon to be contacted with the p-toluenesulfonate salt of the compound represented by formula (I) is at least the above lower limit, compound B, an impurity that may be involved in mutagenicity, can be efficiently removed.

[0083] The recrystallization of the p-toluenesulfonate salt of the compound represented by formula (I) after contact with activated carbon to obtain Type 1 crystals of the p-TsOH salt of Compound A can be carried out by a method commonly used by a person skilled in the art. In one embodiment, the recrystallization may be carried out by contacting the p-toluenesulfonate salt of the compound represented by formula (I) with activated carbon to purify it, and then filtering the filtrate to remove the activated carbon. If necessary, seed crystals of the p-toluenesulfonate salt of the compound represented by formula (I) are added to the filtrate, and the filtrate is then heated and cooled.

[0084] When the eighth step comprises, in this order, purifying the p-toluenesulfonate of the compound represented by formula (I) by contacting it with activated carbon, and recrystallizing the p-toluenesulfonate of the compound represented by formula (I) after contacting it with activated carbon to obtain type 1 crystals of the p-TsOH salt of Compound A, the content of Compound B, an impurity that may be involved in mutagenicity, in the purified product obtained by recrystallization (type 1 crystals of the p-TsOH salt of Compound A) can be significantly reduced compared to the case where only recrystallization is performed. More specifically, the content of Compound B in the purified product obtained by recrystallization (type 1 crystals of the p-TsOH salt of Compound A) can be significantly reduced by 100×10 －４ Mass% or less, 70×10 －４ Mass% or less, 50×10 －４ Mass% or less, 40×10 －４ Mass% or less, 30×10 －４ Mass% or less, 20×10 －４ Mass% or less, 15×10 －４ Mass% or less, 12×10 －４ mass% or less or 10 x 10 －４ The content can be reduced to % by mass or less.

[0085] <Embodiments of the Manufacturing Method According to the Fifth Aspect> One embodiment of the fifth aspect of the present disclosure may be a method for manufacturing a type 1 crystal of a p-TsOH salt of Compound A or a composition comprising the same, comprising at least one of the steps described above. A specific embodiment of the fifth aspect of the present disclosure may be a method for manufacturing a type 1 crystal of a p-TsOH salt of Compound A or a composition comprising the same, comprising step 7. One embodiment of the fifth aspect of the present disclosure may be a method for manufacturing a type 1 crystal of a p-TsOH salt of Compound A or a composition comprising the same, comprising step 4 and step 7, in this order. One embodiment of the fifth aspect of the present disclosure may be a method for manufacturing a type 1 crystal of a p-TsOH salt of Compound A or a composition comprising the same, comprising step 2 / 3, step 4, and step 7, in this order. One embodiment of the fifth aspect of the present disclosure may be a method for manufacturing a type 1 crystal of a p-TsOH salt of Compound A or a composition comprising the same, comprising step 4, step 5, and step 7, in this order. An embodiment of the fifth aspect of the present disclosure may be a method for producing a Form 1 crystal of a p-TsOH salt of Compound A or a composition comprising the same, comprising, in this order, Steps 2 / 3, 4, 5, and 7. An embodiment of the fifth aspect of the present disclosure may be a method for producing a Form 1 crystal of a p-TsOH salt of Compound A or a composition comprising the same, comprising, in this order, Step 1, Steps 2 / 3, 4, 5, and 7. An embodiment of the fifth aspect of the present disclosure may be a method for producing a Form 1 crystal of a p-TsOH salt of Compound A or a composition comprising the same, further comprising Step 6 immediately before Step 7 in these embodiments. An embodiment of the fifth aspect of the present disclosure may be a method for producing a Form 1 crystal of a p-TsOH salt of Compound A or a composition comprising the same, further comprising Step 8 immediately after Step 7 in these embodiments.

[0086] <Method for Producing Form 3 Crystals of p-TsOH Salt of Compound A> A sixth aspect of the present disclosure is a method for producing Form 3 crystals of p-TsOH salt of Compound A. In one embodiment, the sixth aspect of the present disclosure may be a method for producing Form 3 crystals of p-TsOH salt of Compound A according to an embodiment of the second aspect of the present disclosure. In one embodiment, the sixth aspect of the present disclosure may be a method for producing Form 3 crystals of p-TsOH salt of Compound A, comprising a step of producing Form 1 crystals of p-TsOH salt of Compound A by a production method according to an embodiment of the fifth aspect of the present disclosure.

[0087] The sixth aspect of the present disclosure may, in one embodiment, comprise a step of exposing p-TsOH salt of Compound A to a temperature condition equal to or higher than a predetermined lower limit. In a preferred embodiment, the method may comprise a step of exposing Type 1 crystals of p-TsOH salt of Compound A to a temperature condition equal to or higher than a predetermined lower limit. In a more preferred embodiment, the method may comprise a step of exposing Type 1 crystals of p-TsOH salt of Compound A in a solid state to a temperature condition equal to or higher than a predetermined lower limit. In these cases, the predetermined lower limit may be, for example, 130°C, 140°C, 150°C, or 160°C. In a preferred embodiment, the Type 1 crystals of p-TsOH salt of Compound A exposed to a temperature condition equal to or higher than the predetermined lower limit may be produced by a production method according to an embodiment of the fifth aspect of the present disclosure. That is, a production method according to a preferred embodiment of the sixth aspect of the present disclosure may be a method for producing Type 3 crystals of the p-TsOH salt of Compound A, comprising the steps of producing Type 1 crystals of the p-TsOH salt of Compound A by the production method according to an embodiment of the fifth aspect of the present disclosure, and exposing the obtained Type 1 crystals of the p-TsOH salt of Compound A to a temperature condition equal to or higher than a predetermined lower limit. In another embodiment, the p-TsOH salt of Compound A exposed to a temperature condition equal to or higher than a predetermined lower limit may be amorphous obtained from the p-TsOH salt of Compound A produced by a production method including at least step 7 of the production method according to the fifth aspect of the present disclosure. That is, the production method according to an embodiment of the seventh aspect of the present disclosure may be a method for producing Type 3 crystals of p-TsOH salt of Compound A, comprising: a step of producing an amorphous form obtained from p-TsOH salt of Compound A produced by a production method including at least step 7 of the steps of the production method according to an embodiment of the fifth aspect of the present disclosure; and a step of exposing the obtained amorphous form of p-TsOH salt of Compound A to a temperature condition that is equal to or higher than a predetermined lower limit.

[0088] <Method for Producing Form 4 Crystals of p-TsOH Salt of Compound A> A seventh aspect of the present disclosure is a method for producing Form 4 crystals of p-TsOH salt of Compound A. In one embodiment, the seventh aspect of the present disclosure may be a method for producing Form 4 crystals of p-TsOH salt of Compound A according to an embodiment of the third aspect of the present disclosure. In one embodiment, the seventh aspect of the present disclosure may be a method for producing Form 4 crystals of p-TsOH salt of Compound A, comprising a step of producing Form 1 crystals of p-TsOH salt of Compound A by a production method according to an embodiment of the fifth aspect of the present disclosure. In one embodiment, the seventh aspect of the present disclosure may be a method for producing Form 4 crystals of p-TsOH salt of Compound A, comprising a step of producing amorphous p-TsOH salt of Compound A by a production method including at least step 7 of the steps of the production method according to the fifth aspect of the present disclosure.

[0089] In one embodiment, the seventh aspect of the present disclosure may include a step of contacting the p-TsOH salt of Compound A with acetonitrile and then exposing it to a temperature condition equal to or higher than a predetermined lower limit, or a step of contacting the Type 1 crystals of the p-TsOH salt of Compound A with acetonitrile and then exposing it to a temperature condition equal to or higher than a predetermined lower limit. In these cases, the predetermined lower limit may be, for example, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, or 160°C. In one embodiment, the Type 1 crystals of the p-TsOH salt of Compound A exposed to a temperature condition equal to or higher than a predetermined lower limit may be produced by a production method according to one embodiment of the fifth aspect of the present disclosure. That is, the production method according to one embodiment of the seventh aspect of the present disclosure may be a method for producing Type 4 crystals of the p-TsOH salt of Compound A, comprising the steps of producing Type 1 crystals of the p-TsOH salt of Compound A by the production method according to one embodiment of the fifth aspect of the present disclosure, and contacting the obtained Type 1 crystals of the p-TsOH salt of Compound A with acetonitrile, followed by exposing the resulting crystals to a temperature condition equal to or higher than a predetermined lower limit. In another embodiment, the p-TsOH salt of Compound A exposed to a temperature condition equal to or higher than a predetermined lower limit may be amorphous obtained from the p-TsOH salt of Compound A produced by a production method including at least step 7 of the production method according to the fifth aspect of the present disclosure. That is, the production method according to one embodiment of the seventh aspect of the present disclosure may be a method for producing Type 4 crystals of p-TsOH salt of Compound A, comprising: a step of producing an amorphous form obtained from p-TsOH salt of Compound A produced by a production method including at least step 7 of the steps of the production method according to one embodiment of the fifth aspect of the present disclosure; and a step of contacting the obtained amorphous form of p-TsOH salt of Compound A with acetonitrile, followed by exposing it to a temperature condition equal to or higher than a predetermined lower limit.

[0090] <Pharmaceutical Composition / Inhibitor> An eighth aspect of the present disclosure is a pharmaceutical composition comprising, as an active ingredient, a crystal according to an embodiment of the first aspect of the present disclosure, a crystal according to an embodiment of the second aspect of the present disclosure, a crystal according to an embodiment of the third aspect of the present disclosure, or a composition according to an embodiment of the fourth aspect of the present disclosure. In the present disclosure, a pharmaceutical composition refers to a composition that is administered for the purpose of treatment and / or prevention in a subject to which it is administered. A ninth aspect of the present disclosure is a membrane-bound prostaglandin E synthase-1 inhibitor (mPGES-1 inhibitor) comprising, as an active ingredient, a crystal according to an embodiment of the first aspect of the present disclosure, a crystal according to an embodiment of the second aspect of the present disclosure, a crystal according to an embodiment of the third aspect of the present disclosure, or a composition according to an embodiment of the fourth aspect of the present disclosure.

[0091] The pharmaceutical composition according to an embodiment of the eighth aspect of the present disclosure and the inhibitor according to an embodiment of the ninth aspect of the present disclosure may be formulated as a therapeutic and / or prophylactic preparation, and the dosage form is not particularly limited and may be, for example, a tablet, capsule, powder, granules, or fine granules. Furthermore, the pharmaceutical composition according to an embodiment of the eighth aspect of the present disclosure and the inhibitor according to an embodiment of the ninth aspect, as well as preparations containing them, may be administered orally or parenterally. The dosage of the pharmaceutical composition according to an embodiment of the eighth aspect of the present disclosure and the inhibitor according to an embodiment of the ninth aspect, as well as preparations containing them, is preferably adjusted taking into consideration the patient's condition, such as age, body weight, type and severity of disease, and the route of administration. Generally, for an adult, the amount of the active ingredient of the p-TsOH salt of Compound A in oral administration is in the range of 0.01 mg to 5 g per adult, preferably 1 mg to 500 mg per adult, per day. In some cases, a lower dose may be sufficient, or conversely, a higher dose may be required. Generally, the drug is administered once a day or in divided doses several times a day, or in the case of intravenous administration, it can be administered as a bolus or continuously for up to 24 hours.

[0092] The pharmaceutical composition according to an embodiment of the eighth aspect of the present disclosure and the inhibitor according to an embodiment of the ninth aspect of the present disclosure may contain, in addition to the active ingredient, the crystal according to an embodiment of the first aspect of the present disclosure, the crystal according to an embodiment of the second aspect of the present disclosure, the crystal according to an embodiment of the third aspect of the present disclosure, or the composition according to an embodiment of the fourth aspect of the present disclosure, a pharmaceutically acceptable additive, such as an excipient, a buffer, a stabilizer, an antioxidant, a binder, a disintegrant, a filler, an emulsifier, or a flow additive, or at least one additive selected from the group consisting of these.

[0093] The pharmaceutical composition according to an embodiment of the eighth aspect of the present disclosure, the inhibitor according to an embodiment of the ninth aspect, and formulations containing them are effective in treating, by virtue of the mPGES-1 inhibitory activity of the p-TsOH salt of Compound A, various conditions, such as inflammatory bowel syndrome, irritable bowel syndrome, migraine, headache, lower back pain, lumbar spinal stenosis, herniated disc, temporomandibular joint disorder, cervicobrachial syndrome, cervical spondylosis, endometriosis, adenomyosis, premature labor, threatened premature labor, dysmenorrhea, overactive bladder, and nocturia. , interstitial cystitis, neurodegenerative diseases (e.g., Alzheimer's disease, multiple sclerosis), psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, neuralgia, complex regional pain syndrome, fascial disorders, viral infections (e.g., influenza, colds, shingles, AIDS), bacterial infections, fungal infections, burns, inflammation and pain after surgery, trauma, and tooth extraction, malignant tumors (e.g., leukemia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome, Head and neck cancer, esophageal cancer, esophageal adenocarcinoma, stomach cancer, duodenal cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer, gallbladder and bile duct cancer, biliary tract cancer, pancreatic cancer, thyroid cancer, breast cancer, lung cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, vaginal cancer, vulvar cancer, kidney cancer, renal pelvis and ureter cancer, urothelial carcinoma, penile cancer, prostate cancer, testicular tumor, bone and soft tissue sarcoma, malignant bone tumor, skin cancer, thymoma, mesothelioma, and cancer of unknown primary origin, etc.), atherosclerosis, stroke, gout, arthritis, The compound can be used as a preventive or therapeutic agent for pain in osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ossification of ligaments, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, chronic prostatitis, chronic pelvic pain syndrome, conjunctivitis, iritis, scleritis, uveitis, wound treatment, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic disease, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids, and cancer.

[0094] The present disclosure will be described in more detail below using examples, but the present disclosure is not limited to the following examples.

[0095] The following abbreviations are used in the following examples: IPC = In-Process Control, dba = Dibenzylideneacetone, XPhos = 2-Dicyclohexylphosphono-2',4',6'-triisopropylbiphenyl, IPA = 2-Propanol, CDI = 1,1'-Carbonyldiimidazole, DMF = N,N-dimethylformamide, DMAc, DMA = N,N-dimethylacetamide, pTsOH-H ２ O = p-toluenesulfonic acid monohydrate MeCN = acetonitrile HPLC = high performance liquid chromatography

[0096] In the examples １ H-NMR spectra were measured using a JNM-ECS400 nuclear magnetic resonance spectrometer (manufactured by JEOL RESONANCE Co., Ltd.) and observed peaks are expressed as chemical shift values ​​δ (ppm) (s = singlet, d = doublet, t = triplet, q = quartet, brs = broad singlet, m = multiplet, dd = double doublet, dt = double triplet).

[0097] Unless otherwise specified, the powder X-ray diffraction spectra in Examples 1 to 11 were measured using a MiniFlex 600 (manufactured by Rigaku Corporation) (voltage: 40 kV, current: 15 mA, wavelength: CuKα, solar slit: 5.0 degrees, scanning range: 4 to 40 degrees; scan speed / counting time: 20.0).

[0098] Unless otherwise specified, DSC in Examples 1 to 11 was measured using a DSC-60A (manufactured by Shimadzu Corporation) (cell: alumina (open), gas: nitrogen (20.0 mL / min), heating rate: 10.0°C / min, hold temperature: 300°C, hold time: 0 min).

[0099] Unless otherwise specified, TG / DTA in Examples 1 to 11 were measured using a TG-8120 (manufactured by Rigaku Corporation) (cell: alumina (open), gas: nitrogen, heating rate: 10.0°C / min, hold temperature: 300°C, hold time: 0 min).

[0100] Example 1: Preparation of type 1 crystals of p-TsOH salt of Compound A Type 1 crystals of p-TsOH salt of Compound A were prepared by the preparation method outlined below.

[0101] Step 1: Synthesis of methyl 6-bromo-2-(methoxymethyl)-1H-benzimidazole-4-carboxylate (Compound 1) A nitrogen-purged stirring vessel was charged with 80.0 kg of methyl 2,3-diamino-5-bromobenzoate and 294 kg of methoxyacetic acid. The temperature inside the stirring vessel was heated to 85°C or higher, and the reaction was carried out for 10 hours while maintaining the internal temperature at 80-95°C. Completion of the reaction was confirmed by HPLC when the peak area of ​​the starting material, methyl 2,3-diamino-5-bromobenzoate, was 1% or less of the total area of ​​all detected peaks. The reaction mixture was then cooled to 20-30°C. Acetone (506 kg) was added and stirred, followed by the addition of 8.0 kg of diatomaceous earth, 16.0 kg of activated carbon, and 129 kg of acetone. The mixture was then stirred for at least 1 hour while maintaining the temperature at 20-30°C. The insoluble matter was filtered off, and the trapped insoluble matter was washed with acetone (378 kg). The solvent was then removed from the recovered filtrate by distillation under reduced pressure while maintaining the temperature outside the vessel at 50° C. or less, and the filtrate was concentrated to 390 L. Water (800 L) was added thereto while maintaining the temperature of the reaction solution at 20 to 50° C., and the temperature of the reaction solution was then cooled to 15° C. or less. Then, while maintaining the temperature at 20° C. or less, about 1,100 kg of a 10% aqueous sodium hydroxide solution was added so that the pH of the solution was 5.5 to 7.5. While maintaining the temperature of the reaction liquid at 20 to 30°C, the solution was stirred for 30 minutes or more, and then the slurry was filtered to recover the insoluble matter. The recovered insoluble matter was washed with water (602 kg), and the recovered insoluble matter was then dried under reduced pressure while maintaining the temperature outside the container at 60°C or less, to obtain 91.6 kg of a crude product of the target product, methyl 6-bromo-2-(methoxymethyl)-1H-benzimidazole-4-carboxylate (Compound 1), as a powder (yield 94%).

[0102] The resulting crude product of Compound 1 (91.5 kg) and acetone (1,011 kg) were added to a stirring vessel that had been purged with nitrogen. The temperature inside the stirring vessel was raised to 35-45°C, and Compound 1 was dissolved in acetone. Activated carbon (9.2 kg) and acetone (73.2 kg) were then added, and the reaction mixture was stirred for at least 1 hour while maintaining the temperature at 35-45°C. The insoluble matter, including activated carbon, was removed by filtration, and the trapped insoluble matter was washed with acetone (434 kg). The solvent was then distilled off while the temperature was raised, and the filtrate was concentrated to 640 L. The resulting solution was cooled to 20-30°C and stirred for at least 12 hours while maintaining the temperature at 20-30°C. The solution was then cooled to below 10°C over at least 1 hour, and stirred for at least 1 hour while maintaining the temperature at 0-10°C. The slurry was filtered to recover the insoluble matter, and the recovered insoluble matter (cake) was washed with cooled acetone (73.1 kg). The recovered insoluble matter was then dried under reduced pressure while maintaining the temperature outside the container at 60°C or lower, thereby obtaining 79.3 kg of methyl 6-bromo-2-(methoxymethyl)-1H-benzimidazole-4-carboxylate (Compound 1) as a powder (yield 87%).

[0103] The spectral data of the obtained Compound 1 were as follows: ESI-MS (-): calculated value 297.0, measured value 297.0 (M-H) 1H NMR (Chloroform-d, δ in ppm) 10.47 (br, 1H), 8.04 (d, J = 1.3 Hz, 1H), 8.00 (d, J = 1.9 Hz, 1H), 4.76 (s, 2H), 4.00 (s, 3H), 3.51 (s, 3H)

[0104] Step 2 / 3: Synthesis of methyl 6-[(methoxycarbonyl)amino]-2-(methoxymethyl)-1H-benzimidazole-4-carboxylate hydrochloride (Compound 4) Compound 1 (79.2 kg), potassium carbonate (54.9 kg), and toluene (688 kg) obtained in step 1 were added to a stirring vessel that had been purged with nitrogen gas. Di-t-butyl dicarbonate (86.8 kg) was then added at a temperature of 15-30°C, and the temperature of the reaction solution was then raised to 40-50°C, and the reaction was allowed to proceed for 20 hours or more. The completion of the reaction was confirmed by HPLC when the peak area of ​​the raw material Compound 1 was 0.6% or less of the total area of ​​all detected peaks. The temperature of the reaction solution was then cooled to 30°C or less, and a solution containing Compound 2 (Compound 2 solution) was obtained. Methyl carbamate (39.8 kg), potassium carbonate (73.3 kg), and toluene (138 kg) were added to another stirring vessel that had been purged with nitrogen gas, and the mixture was then degassed under reduced pressure. Compound 2 solution and toluene (550 kg) were then added, and the mixture was then degassed under reduced pressure. 64.7%-Pd ２ (dba) ３(1.88 kg) and XPhos (2.54 kg) were added, and degassing was carried out under reduced pressure. The reaction solution was heated to 88-97°C and reacted at 88-97°C for 4 hours. The completion of the reaction was confirmed by HPLC when the peak area of ​​the raw material Compound 2 was 1.0% or less of the total area of ​​all detected peaks, and then the temperature of the reaction solution was cooled to 20-30°C. Insoluble matter was removed by filtration, and the trapped insoluble matter was washed with acetonitrile (437 kg). 2-propanol (310 kg) was added to the recovered filtrate containing Compound 3, and concentrated hydrochloric acid (81.6 kg) was further added while maintaining the temperature of the solution at 30°C or less. The temperature of the reaction solution was raised to 50-60°C, and the reaction was carried out for at least 1 hour while maintaining it at 50-60°C. After confirming the completion of the reaction by HPLC when the peak area of ​​the starting compound 3 was 0.1% or less of the total area of ​​all detected peaks, the reaction mixture was cooled to 25°C or less and incubated at 15-25°C for 1 hour. The slurry was filtered to recover the insoluble matter, and the recovered insoluble matter (cake) was washed with acetonitrile (683 kg). The recovered insoluble matter was then dried under reduced pressure while maintaining the temperature outside the vessel at 60°C or less, yielding 76.0 kg of powder (87% yield) of methyl 6-[(methoxycarbonyl)amino]-2-(methoxymethyl)-1H-benzimidazole-4-carboxylate hydrochloride (compound 4).

[0105] The spectral data of the obtained compound 4 were as follows: ESI-MS (+): calculated value 294.1, measured value 294.0 (M+H) 1H NMR (DMSO-d6, δ in ppm) 10.19 (s, 1H), 8.24 (d, J = 1.9 Hz, 1H), 8.13 (d, J = 1.9 Hz, 1H), 4.94 (s, 2H), 3.96 (s, 3H), 3.68 (s, 3H), 3.44 (s, 3H)

[0106] Step 4: Synthesis of 2-(methoxymethyl)-6-(2-(trifluoromethyl)benzamido)-1H-benzimidazole-4-carboxylic acid (Compound 7) Water (76.2 kg) and 30% aqueous sodium hydroxide solution (153 kg) were added to a stirring vessel that had been purged with nitrogen gas and mixed. Compound 4 (75.6 kg) obtained in step 2 / 3 was added thereto, and degassing was performed with nitrogen gas. The reaction solution was heated to 50-60 ° C and allowed to react for 6 hours or more while maintaining the temperature at 50-60 ° C. After confirming the completion of the reaction by HPLC based on the peak area of ​​the reaction intermediate compound 5 being 1.0% or less of the total area of ​​all detected peaks, the temperature of the reaction solution was cooled to 30 ° C or less, and water (756 L) and acetic acid (13.7 kg) were added. Acetonitrile (356 kg) was added thereto, and the solution was cooled to 0 ° C or less. 47.9 kg of 2-(trifluoromethyl)benzoyl chloride was added dropwise at -5 to 5 ° C, and the reaction was allowed to proceed for 15 minutes or more while maintaining the temperature at -5 to 5 ° C. After confirming the completion of the reaction by HPLC, when the peak area of ​​the reaction intermediate, compound 6, was 1.0% or less of the total area of ​​all detected peaks, the reaction solution was heated to 60°C or higher and allowed to react for 2 hours or more while maintaining the temperature at 60-70°C. After confirming the completion of the reaction by HPLC, when the total peak area of ​​the compound obtained by reacting two or three of 2-(trifluoromethyl)benzoyl chloride, a by-product of the previous reaction, with compound 6 was 0.1% or less of the total area of ​​all detected peaks, acetonitrile (238 kg) was added at a temperature of 70°C or less, and acetic acid (55.0 kg) was added over 30 minutes or more while maintaining the temperature at 60-70°C. The reaction solution was stirred for 1 hour or more while maintaining the temperature at 60-70°C, then cooled to 30°C or less and stirred for another 1 hour or more while maintaining the temperature at 20-30°C. The slurry was filtered to recover the insoluble matter, and the recovered insoluble matter (cake) was washed successively with a mixture of MeCN (142 kg) and water (182 kg), water (183 kg), and 2-propanol (144 kg).The recovered insoluble matter was then dried under reduced pressure while maintaining the temperature outside the container at 60°C or lower, thereby obtaining 85.1 kg of powder (yield 94%) of 2-(methoxymethyl)-6-(2-(trifluoromethyl)benzamido)-1H-benzimidazole-4-carboxylic acid (Compound 7).

[0107] The spectral data of the obtained compound 7 were as follows: ESI-MS (+): calculated value 394.1, measured value 394.0 (M+H) 1H NMR (Methanol-d4, δ in ppm) 8.28 (d, J = 2.6 Hz, 1H), 8.12 (d, J = 1.9 Hz, 1H), 7.64-7.81 (m, 4H), 4.72 (s, 2H), 3.46 (s, 3H)

[0108] Step 5: Synthesis of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide DMA solvate (Compound 8) Compound 7 (82.8 kg) obtained in Step 4 and DMF (235 kg) were added to a stirring vessel that had been purged with nitrogen gas. While stirring the solution at 30°C or less, 1,1'-carbonyldiimidazole (38.8 kg) was added, and the reaction was allowed to proceed for at least 1 hour while maintaining the temperature of the reaction solution at 20-30°C. After confirming the completion of the reaction by HPLC when the peak area of ​​the starting compound 7 was 1.0% or less of the total area of ​​all detected peaks, the reaction solution was cooled to 20-30°C, and 74.3 kg of 3-chloro-2-methylaniline and benzoic acid (1.28 kg) were added. The reaction solution was heated to a higher temperature and allowed to react at 50-60°C for at least 20 hours. After confirming the completion of the reaction by HPLC when the peak area of ​​the reaction intermediate having a carbonylimidazole structure was 2.0% or less of the total area of ​​all detected peaks, DMAc (465 kg) was added to the reaction solution at 50-60°C. Water (331 kg) was added dropwise while maintaining the temperature of the reaction solution at 50-60°C, and the mixture was stirred at 50-60°C for at least 1 hour. The reaction solution was cooled to 25°C or less, and stirred for at least 2 hours while maintaining the temperature of the reaction solution at 20-25°C. The slurry was filtered to recover the insoluble matter, and the recovered insoluble matter (cake) was washed sequentially with a mixture of DMAc (183 kg) and water (195 kg), and then with water (293 kg). The recovered insoluble matter was then dried under reduced pressure while maintaining the temperature outside the container at 60°C or lower, thereby obtaining 115 kg of a crude powder product of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide DMA solvate (N-(3-Chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide DMA solvate, Compound 8 (yield: 91%)).

[0109] Step 6: Purification of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide DMA solvate (Compound 8) The crude product of compound 8 (105 kg) obtained in Step 5 and DMAc (322 kg) were added to a stirring tank. The mixture was heated to 70-80°C, and water (90.3 kg) was added to the solution at 70-80°C. The mixture was cooled to 25°C or below over 90 minutes, and the mixture was stirred at 20-30°C for 30 minutes or more. The slurry was filtered to recover the insoluble matter, and the recovered insoluble matter (cake) was washed with a mixture of DMAc (98.4 kg) and water (105 kg), and then with water (211 kg). The recovered insoluble matter was then dried under reduced pressure while maintaining the temperature outside the container at 60°C or lower, thereby obtaining 98.7 kg of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide DMA solvate (Compound 8) as a powder (yield: 94%).

[0110] The spectral data of the obtained Compound 8 was as follows: ESI-MS (+): Calculated value of the desolvated free form: 517.1, Measured value: 517.0 (M+H) 1 H NMR (DMSO-d6, δ in ppm) 11.88 (s, 1H), 10.80 (s, 1H), 8.35 (d, J = 2.3 Hz, 1H), 8.24 (dd, J = 6.9 and 2.3 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 7.67-7.84 (m, 4H), 7.21-7.27 (m, 2H), 4.75 (s, 2H), 3.40 (s, 3H), 2.90 (s, 3H), 2.74 (s, 3H), 2.53 (s, 3H),1.92 (s, 3H)

[0111] Step 7: Synthesis of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonic acid (Compound 9 (synonymous with “p-TsOH salt of Compound A”)) Compound 8 (98.0 kg) obtained in Step 6 and DMF (231 kg) were added to a stirring tank. The solution was heated to 50-60°C, and compound 8 was dissolved in DMF. Then, MeCN (576 kg) was added to the solution at 45-60°C. While maintaining the temperature at 45-60°C, pTsOH-H ２ A solution of 200 (33.9 kg) dissolved in MeCN (307 kg) was added dropwise, and MeCN (461 kg) was further added while maintaining the temperature at 45 to 60°C. Thereafter, the reaction solution was stirred for 5 hours or more while maintaining the temperature at 50 to 60°C. The slurry was filtered to recover the insoluble matter, and the recovered insoluble matter (cake) was washed with a mixture of DMF (23.1 kg) and MeCN (134 kg), and then with MeCN (230 kg). The recovered insoluble matter was then dried under reduced pressure while maintaining the temperature outside the container at 60°C or lower, thereby obtaining 96.5 kg of a crude product of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate (Compound 9) as a powder (yield: 86%).

[0112] Step 8: Preparation of Form 1 Crystals of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonic acid (p-TsOH Salt of Compound A) The crude product of Compound 9 (48.0 kg) obtained in Step 7 and DMF (113 kg) were added to a stirring vessel, and the temperature inside the stirring vessel was raised to 35-40°C to dissolve the compound. Activated carbon (4.8 kg) was then added, and the reaction mixture was heated to 40-50°C and stirred for 1 hour while maintaining the temperature at 40-50°C. The slurry was filtered to remove insoluble matter, and the trapped insoluble matter was washed with a mixture of DMF (22.6 kg) and toluene (41.5 kg). To the resulting filtrate, toluene (208 kg) was added at a temperature of 20-30°C. Form 1 crystals of Compound 9 (48.0 g) were added thereto, and then toluene (872 kg) was added dropwise at a temperature of 20-30°C, followed by stirring for 5 hours or more while maintaining the temperature at 20-30°C. After adding seed crystals (240 g) of Compound 9 to the mixture, the solution was heated to 50-60°C and stirred at 50-60°C for 5 hours or more. The solution was cooled to 20-30°C and then stirred at 20-30°C for an additional 12 hours or more. The slurry was filtered to recover the insoluble matter, and the recovered insoluble matter (cake) was washed with toluene (125 kg) and then with MeCN (75.2 kg). The recovered insoluble matter was then dried under reduced pressure while maintaining the temperature outside the vessel at 60°C or less, to obtain 44.9 kg of type 1 crystals of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonic acid (Compound 9), i.e., type 1 crystals of the p-TsOH salt of Compound A, as a powder (yield 94%). The results of powder X-ray diffraction of the obtained Type 1 crystals of p-TsOH salt of Compound A are shown in Figure 1. According to Figure 1, peaks were observed at 2θ = 7.1°, 14.3°, 15.8°, and 18.3°. Furthermore, when the obtained powder was analyzed by HPLC, the purity of Compound 9 was 99.95% based on the peak area at 230 nm. Furthermore, the amount of residual solvent toluene in the obtained Type 1 crystals of p-TsOH salt of Compound A was 460 ppm, N,N-dimethylformamide was 514 ppm, and acetonitrile was not detected.

[0113] The results of differential scanning calorimetry (DSC) of the type 1 crystal of the p-TsOH salt of Compound A are shown in Figure 2. The results of measurement of the thermal properties of the type 1 crystal of the p-TsOH salt of Compound A by differential scanning calorimetry (DTA) and thermogravimetric analysis (TGA) are shown in Figure 3. According to Figure 2, the type 1 crystal of the p-TsOH salt of Compound A had an endothermic peak at 265.76°C in DSC. According to Figure 3, the type 1 crystal of the p-TsOH salt of Compound A had an endothermic peak at 263.0°C in DTA, and was stable with no change in weight or endothermic / heat-generating reaction until decomposition at temperatures above 200°C.

[0114] <Test Example 1: Purification efficiency and impurity removal efficiency in step 6> Before carrying out the purification in step 6, the purification in step 6 was carried out using DMA and H ２ The purification in step 6 was carried out using a solvent with a volume ratio of 79:21 DMA and H2O. ２ After the reaction was carried out in a solvent having a volume ratio of 69:31, the powder of Compound 8 or its crude product was measured for the content of Compound B represented by the following formula, which is an impurity that requires content control on the order of ppm.

[0115] The results are shown in Table 1 below. As shown in Table 1, when recrystallization was performed under any solvent conditions, a purified product of Compound 8 was obtained in high yield, and the content of Compound B, an impurity, was reduced. Furthermore, when comparing the solvent conditions, the results were similar between DMA and H ２ When the volume ratio of DMA to H was 79:21, the content of compound B was significantly reduced. ２ The condition where the volume ratio of N to O was 79:21 showed a higher removal efficiency of compound B. This indicates that by obtaining N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, a synthetic intermediate of compound 9, as a DMA solvate (compound 8), impurities that require control on the ppm order can be removed with high efficiency by recrystallization.

[0116]

[0117] Test Example 2: Purification efficiency and impurity removal efficiency in Step 8 The content of Compound B, an impurity, was measured for Compound 9 obtained before purification in Step 8, after purification by recrystallization alone without contact with activated carbon in Step 8, and after purification by recrystallization after contact with activated carbon in an amount 0.05 times, 0.10 times, or 0.15 times the mass of the crude product of Compound 9 as in Step 8.

[0118] The results are shown in Table 2 below. Unexpectedly, recrystallization of compound 9 alone was unable to effectively remove compound B. On the other hand, contacting compound 9 with activated carbon prior to recrystallization effectively removed compound B, and compound B was more efficiently removed when the mass of the contacted activated carbon was 0.10 and 0.15 times the mass of the crude product of compound 9.

[0119]

[0120] Preparation Example 1: Preparation of amorphous p-TsOH salt of Compound A Type 1 crystals (10 g) of the p-TsOH salt of Compound A obtained in Example 1 were suspended in methanol (1 L) and concentrated to dryness under reduced pressure at an external temperature of 55°C to obtain amorphous p-TsOH salt of Compound A. The powder X-ray diffraction results of the obtained amorphous are shown in FIG. 4, and the enlarged view in the vertical direction is shown in FIG. 5. No peaks were observed in the analysis results, confirming that the obtained product was amorphous p-TsOH salt of Compound A.

[0121] Example 2: Preparation 1 of Form 3 Crystals of p-TsOH Salt of Compound A Amorphous form (14 g) of p-TsOH salt of Compound A obtained in Preparation Example 1 was placed in an electric furnace and heated at 210°C for 1 hour, resulting in Form 3 crystals of p-TsOH salt of Compound A (13.5 g) in a 96% yield. The powder X-ray diffraction results of the obtained Form 3 crystals of p-TsOH salt of Compound A are shown in Figure 6. The thermal property measurements of the obtained Form 3 crystals of p-TsOH salt of Compound A by differential scanning calorimetry (DTA) and thermogravimetric analysis (TGA) are shown in Figure 7. According to Figure 6, peaks were observed at 2θ = 6.3°, 15.0°, 16.4°, 17.9°, and 22.7°. Furthermore, according to Figure 7, Form 3 crystals of p-TsOH salt of Compound A had an endothermic peak at 247.4°C in DTA.

[0122] Example 3: Preparation 1 of Form 4 Crystal of p-TsOH Salt of Compound A Amorphous form (14 g) of p-TsOH salt of Compound A obtained in Preparation Example 1 was added to acetonitrile (1 L) and stirred, resulting in precipitation of crystals. After stirring the mixture overnight, the crystals were collected by filtration and dried overnight at room temperature and atmospheric pressure to obtain, as an intermediate product, a crystal whose powder X-ray diffraction results are shown in FIG. 8 and whose thermal property measurements by differential scanning calorimetry (DTA) and thermogravimetric analysis (TGA) results are shown in FIG. 9. This crystal is １ The results of H-NMR revealed that the crystals were an acetonitrile solvate in which one molecule of Compound A was solvated with 1 / 2 molecules of acetonitrile (hereinafter, the crystals obtained here will also be referred to as "crystals of the 1 / 2 acetonitrile solvate of the p-TsOH salt of Compound A obtained in Example 3"). The obtained crystals were placed in an electric furnace and heated at 160°C for 1.5 hours, yielding Form 4 crystals of the p-TsOH salt of Compound A (12.7 g) in a 91% yield. The result of powder X-ray diffraction of the obtained Form 4 crystals of the p-TsOH salt of Compound A is shown in Figure 10. The results of measurement of the thermal properties of the obtained Form 4 crystals of the p-TsOH salt of Compound A by differential scanning calorimetry (DTA) and thermogravimetric analysis (TGA) are shown in Figure 11. According to Figure 10, peaks were observed at 2θ = 7.4°, 8.0°, 14.5°, 16.1°, and 20.6°. Furthermore, according to FIG. 11, the type 4 crystal of p-TsOH salt of Compound A had an endothermic peak at 212.5° C. in DTA.

[0123] Comparative Example 1: Preparation of Form 5 Crystal of p-TsOH Salt of Compound A When the amorphous form of p-TsOH salt of Compound A (14 g) obtained in Preparation Example 1 was added to chloroform (0.8 L) and stirred, crystals precipitated. The mixture was stirred overnight, and the crystals were collected by filtration to obtain, as an intermediate product, crystals whose powder X-ray diffraction results are shown in FIG. 12 and whose thermal property measurements by differential scanning calorimetry (DTA) and thermogravimetric analysis (TGA) results are shown in FIG. 13. The crystals were １ The results of H-NMR revealed that the product was a chloroform solvate. The obtained crystals were placed in an electric furnace and heated at 170°C for 1.5 hours, resulting in type 5 crystals of the p-TsOH salt of Compound A (12.9 g) in a 92% yield. The results of powder X-ray diffraction of the obtained type 5 crystals of the p-TsOH salt of Compound A are shown in Figure 14. The results of measurement of the thermal properties of the obtained type 5 crystals of the p-TsOH salt of Compound A by differential scanning calorimetry (DTA) and thermogravimetric analysis (TGA) are shown in Figure 15.

[0124] Comparative Example 2: Preparation of Form 6 Crystal of p-TsOH Salt of Compound A When the amorphous form of p-TsOH salt of Compound A (15 g) obtained in Preparation Example 1 was added to 2,2,2-trifluoroethanol (TFE, 60 mL) cooled to 5°C and stirred, crystals were precipitated. After stirring the mixture for 5 days, the crystals were collected by filtration to obtain, as an intermediate product, crystals whose powder X-ray diffraction results are shown in Figure 16. These crystals were １ The results of H-NMR revealed that the crystals were trifluoroethanol solvate. The obtained crystals were placed in an electric furnace and heated at 150°C for 30 minutes, yielding Form 6 crystals of p-TsOH salt of Compound A (12.5 g) in a yield of 83%. The results of powder X-ray diffraction of the obtained Form 6 crystals of p-TsOH salt of Compound A are shown in Figure 17. The results of measurement of the thermal properties of the obtained Form 6 crystals of p-TsOH salt of Compound A by differential scanning calorimetry (DTA) and thermogravimetric analysis (TGA) are shown in Figure 18.

[0125] Comparative Example 3: Preparation of Form 7 Crystal of p-TsOH Salt of Compound A When the amorphous form of p-TsOH salt of Compound A (15 g) obtained in Preparation Example 1 was added to 2,2,2-trifluoroethanol (TFE, 60 mL) cooled to 5°C and stirred, crystals precipitated. After stirring the mixture for 6 days, the crystals were collected by filtration to obtain, as an intermediate product, crystals whose powder X-ray diffraction results are shown in Figure 16. The collected crystals were then left overnight on a separatory funnel to obtain crystals whose powder X-ray diffraction results are shown in Figure 19. These crystals were １ The results of H-NMR revealed that the crystals were trifluoroethanol solvate. The obtained crystals were placed in an electric furnace and heated at 150°C for 1 hour, yielding type 7 crystals of p-TsOH salt of Compound A (12.7 g) in a yield of 85%. The results of powder X-ray diffraction of the obtained type 7 crystals of p-TsOH salt of Compound A are shown in Figure 20. The results of measurement of the thermal properties of the obtained type 7 crystals of p-TsOH salt of Compound A by differential scanning calorimetry (DTA) and thermogravimetric analysis (TGA) are shown in Figure 21.

[0126] Example 4: Preparation 2 of Form 3 crystals of p-TsOH salt of Compound A When the Form 4 crystals of p-TsOH salt of Compound A obtained in Example 3 were heated at 205°C, Form 3 crystals of p-TsOH salt of Compound A were obtained.

[0127] Example 5: Preparation 3 of Form 3 crystals of p-TsOH salt of Compound A When the Form 5 crystals of p-TsOH salt of Compound A obtained in Comparative Example 1 were heated at 205°C for 10 minutes, Form 3 crystals of p-TsOH salt of Compound A were obtained. Furthermore, this result revealed that the Form 3 crystals of p-TsOH salt of Compound A are more stable than the Form 5 crystals.

[0128] Example 6: Preparation 4 of Form 3 crystals of p-TsOH salt of Compound A When the Form 6 crystals of p-TsOH salt of Compound A obtained in Comparative Example 2 were heated at 190°C for 10 minutes, Form 3 crystals of p-TsOH salt of Compound A were obtained. Furthermore, this result revealed that the Form 3 crystals of p-TsOH salt of Compound A are more stable than the Form 6 crystals.

[0129] Example 7: Preparation of Form 3 crystals of p-TsOH salt of Compound A Approximately 10 mg of the 1 / 2 acetonitrile solvate crystals of p-TsOH salt of Compound A obtained in Example 3 was placed in a 100 μL open pan and heated to a temperature just above the desolvation temperature using a TG / DTA apparatus and maintained at this temperature until the weight loss stabilized (10 minutes) to desolvate. The sample was then cooled to ambient temperature and analyzed by XRPD, which revealed that Form 3 crystals of p-TsOH salt of Compound A had been obtained.

[0130] Example 8: Preparation 2 of Form 4 crystals of p-TsOH salt of Compound A About 10 mg of the crystals of the hemiacetonitrile solvate of p-TsOH salt of Compound A obtained in Example 3 was allowed to stand for 7 days under conditions of 40°C and a relative humidity of 75%, yielding Form 4 crystals of p-TsOH salt of Compound A. Furthermore, this result revealed that Form 4 crystals of p-TsOH salt of Compound A are more stable than the crystals of the hemiacetonitrile solvate of p-TsOH salt of Compound A obtained in Example 3.

[0131] Example 9: Relative stability among crystals of p-TsOH salt of Compound A 100 mg of each of the crystals of p-TsOH salt of Compound A prepared in Examples 1 to 3 and Comparative Examples 1 to 3 was weighed out, and a total of 600 mg was added to 30 mL of a mixed solvent of DMF and toluene in a volume ratio of 1:9, and the mixture was stirred at 20°C or 55°C. The crystalline form of p-TsOH salt of Compound A in the mixture was measured by powder X-ray diffraction 3, 4, 7, and 8 days after the start of stirring at 20°C, and 3 and 4 days after the start of stirring at 55°C. The results at 20°C are shown in Figure 22. The results at 55°C are shown in Figure 23. As shown in Figures 22 and 23, the crystals in the mixture all became Type 1 crystals of p-TsOH salt of Compound A after 8 days at 20°C and after 3 days at 55°C, respectively, demonstrating that Type 1 crystals are the most stable form of p-TsOH salt of Compound A.

[0132] Example 10: Stability test of type 1 crystals of p-TsOH salt of Compound A when mixed with excipients Type 1 crystals of p-TsOH salt of Compound A and various excipients were mixed in a mortar at a mass ratio of 1:1, and the mixture was left to stand in an open system in a thermo-hygrostat at a temperature of 40°C and a relative humidity of 75% for 2 weeks or 1 month, after which the presence or absence of decomposition was evaluated using HPLC and a change in color was visually confirmed. As a reference, the stability of type 1 crystals of p-TsOH salt of Compound A alone was also evaluated. The HPLC conditions were as follows: Apparatus: Shimadzu LC-2010 CHT Column: COSMOSIL 3C18-MSII 4.6 x 100 mm Column temperature: 40°C Mobile phase: Solution A: MeCN / H2O / MsOH = 600 / 400 / 1 Solution B: MeCN / H2O / MsOH = 900 / 100 / 1 Gradient: 0-8 min; A = 100% 8-10 min; A to B 10-20 min; B = 100% 20-21 min; B to A Flow rate: 0.5 mL / min Wavelength: 230 nm

[0133] The percentage (%) of the area occupied by the peaks of type 1 crystals of p-TsOH salt of Compound A among the observed peaks in HPLC, and the results of observing the color of the crystals are shown in Table 3. As shown in Table 3, no decomposition of type 1 crystals of p-TsOH salt of Compound A was observed under any of the conditions of mixing with any of the excipients, and no change in color occurred. This demonstrates that type 1 crystals of p-TsOH salt of Compound A are highly stable crystals of p-TsOH salt of Compound A.

[0134]

[0135] Example 11: Evaluation of stability of type 1 crystals of p-TsOH salt of Compound A upon exposure to various stimuli Type 1 crystals of the p-TsOH salt of Compound A and crystals of the free form of Compound A prepared according to the method described in Patent Document 1 were exposed to a heat stimulus (standing at 60°C for 24 hours), a light stimulus (light source D65 lamp, total illuminance 1.2 million lx hr), or a humidity stimulus (standing at 30°C and a relative humidity of 90% for 24 hours), and their stability was evaluated based on the percentage area (%) of the peaks of the free form of Compound A or type 1 crystals of the p-TsOH salt of Compound A among the peaks observed in HPLC, with or without exposure to the stimuli. The results are shown in Table 4. According to Table 4, the type 1 crystals of the p-TsOH salt of Compound A showed no decrease in purity after exposure to any of the stimuli, and no change in the color of the crystals was observed. This demonstrates that the type 1 crystal of p-TsOH salt of Compound A is a stable crystal of p-TsOH salt of Compound A.

[0136]

[0137] Example 12: Stability of Form 1 Crystals of p-TsOH Salt of Compound A Upon Exposure to Mechanical Stimuli and Water Powder X-ray diffraction measurements were performed on the following samples of Form 1 crystals of p-TsOH salt of Compound A: crystals obtained by pulverizing in a mortar (pulverization), crystals obtained by adding water and then kneading (water treatment), a sample stored under humidified stimulation conditions (30°C, relative humidity 90%), and a sample prepared by tableting (2,000 kgf x 30 min). The results are shown in Figure 24, alongside Form 1 crystals of p-TsOH salt of Compound A that had not been subjected to any treatment (untreated). As shown in Figure 24, no change in crystal form was observed under any of the conditions. This demonstrated that Form 1 crystals of p-TsOH salt of Compound A are stable crystals of p-TsOH salt of Compound A. In the present examples, the powder X-ray diffraction spectrum was measured using a RINT-Ultima III (manufactured by Rigaku Corporation) (target: Cu, voltage: 40 kV, current: 40 mA, scan speed: 4 degrees / min).

[0138] Example 13: Stability test of type 3 crystals of p-TsOH salt of Compound A When about 10 mg of type 3 crystals of p-TsOH salt of Compound A obtained in Example 2 was allowed to stand for 7 days or more under conditions of 40°C and a relative humidity of 75%, the type 3 crystals of p-TsOH salt of Compound A were able to exist stably for 7 days or more. This demonstrated that the type 3 crystals of p-TsOH salt of Compound A are crystals that can exist stably.

[0139] Comparative Example 4: Preparation of Form 2 Crystals of p-TsOH Salt of Compound A The free form of Compound A (50 mg) obtained according to the method described in Patent Document 1 was added to ethyl acetate (1.0 mL). ２ When O was added and stirred, gum precipitated on the bottom wall, followed by precipitation of crystals in the form of cloudiness overall. The crystals were collected, and the powder X-ray diffraction results were as shown in Figure 25, and the thermal property measurement results by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were as shown in Figure 26. Form 2 crystals of p-TsOH salt of Compound A were obtained.

[0140] Example 14: Examination of thermal stability of type 2 crystals of p-TsOH salt of Compound A According to the results in FIG. 26, although type 2 crystals of p-TsOH salt of Compound A showed an endothermic peak in DSC at 177°C, no mass change was observed in TGA, suggesting that a crystal form transition occurred around 177°C. Therefore, the crystal form of type 2 crystals of p-TsOH salt of Compound A was examined by powder X-ray diffraction while heating the crystals to 30°C, 150°C, and 200°C, and then further examined by powder X-ray diffraction while cooling the crystals to 150°C and 30°C. The results are shown in FIG. 27. According to FIG. 27, type 2 crystals of p-TsOH salt of Compound A were unstable to heat. Furthermore, since the type 2 crystal of the p-TsOH salt of Compound A was transformed into the type 3 crystal of the p-TsOH salt of Compound A at 200°C, it was revealed that the type 3 crystal of the p-TsOH salt of Compound A is more stable against heat.

[0141] Example 15: Examination of relative stability of Forms 1 to 3 crystals of p-TsOH salt of Compound A As in Example 4, Forms 1 and 2 crystals of p-TsOH salt of Compound A, Forms 1 and 3 crystals of p-TsOH salt of Compound A, or Forms 2 and 3 crystals of p-TsOH salt of Compound A were stirred in a single solution, and the most stable form of these crystals was examined based on the crystalline form of p-TsOH salt of Compound A in the solution. Forms 1 and 2 crystals of p-TsOH salt of Compound A, Forms 1 and 3 crystals of p-TsOH salt of Compound A, or Forms 2 and 3 crystals of p-TsOH salt of Compound A were added to acetone in a mass ratio of 1:1, and the mixture was stirred at 30°C for 42 hours. Thereafter, the crystalline form of the p-TsOH salt of Compound A in the solution was examined by powder X-ray diffraction, and it was found that under all three conditions, the p-TsOH salt of Compound A in the solution was transformed into crystal form 1. Therefore, it was shown that among these three crystalline forms, crystal form 1 is the most stable form.

[0142] Example 16: Confirmation of stability of type 1 crystals of p-TsOH salt of Compound A in various solvents To facilitate solvent-induced crystal form transition, type 1 crystals of p-TsOH salt of Compound A were pulverized in a mortar. The resulting pulverized product was added to methanol, ethyl acetate, or methyl ethyl ketone, and stirred at 40°C for 115 hours. The crystalline form of p-TsOH salt of Compound A in the solution after stirring was examined by powder X-ray diffraction. The results are shown in Figure 28. As shown in Figure 28, no change in crystalline form was observed under any of the conditions, demonstrating that type 1 crystals of p-TsOH salt of Compound A are an extremely stable crystalline form.

[0143] Example 17: Preparation 1 of crystals of p-TsOH salt of Compound A under various conditions Amount of 22 mg of the amorphous p-TsOH salt of Compound A obtained in Preparation Example 1 was added to 1.4 mL of solvent at room temperature. Subsequently, while stirring at 600 rpm using a stirrer, the mixture was heated to a temperature within ±3°C of the boiling point of the solvent or to 100°C, whichever is lower, and then cooled to 20°C at a rate of 0.2°C per minute, repeating two cycles, and then the crystal form was evaluated. As a result, Type 1 crystals of p-TsOH salt of Compound A were obtained using acetone, acetonitrile, anisole, chloroform, cyclohexane, dichloromethane, 1,4-dioxane, ethanol, n-heptane, isopropyl acetate, methyl ethyl ketone, methyl tert-butyl ether (MTBE), 2-propanol, tetrahydrofuran, 2-methyltetrahydrofuran, or toluene as a solvent.

[0144] Example 18: Preparation of crystals of p-TsOH salt of Compound A under various conditions 2. The amorphous p-TsOH salt of Compound A obtained in Preparation Example 1 was added to acetic acid in a vial, and the vial was left to stand at room temperature in a draft chamber with the lid open to evaporate the acetic acid. As a result, type 1 crystals of p-TsOH salt of Compound A were obtained.

[0145] Example 19: Preparation 3 of crystals of p-TsOH salt of Compound A under various conditions Amorphous p-TsOH salt of Compound A obtained in Preparation Example 1 was added to a solvent, and the resulting slurry was stirred at 5°C. When a mixed solution of DMF and toluene in a volume ratio of 1:9, acetone, ethanol, or tetrahydrofuran was used as the solvent, Type 1 crystals of p-TsOH salt of Compound A were obtained.

[0146] Example 20: Preparation of crystals of p-TsOH salt of Compound A under various conditions 4 Amorphous p-TsOH salt of Compound A obtained in Preparation Example 1 was added to a solvent, and the resulting slurry was stirred at 20°C. When acetone, ethanol, methyl tertiary butyl ether (MTBE), or tetrahydrofuran was used as the solvent, type 1 crystals of p-TsOH salt of Compound A were obtained.

[0147] Example 21 Preparation 5 of Crystals of p-TsOH Salt of Compound A Under Various Conditions Amorphous p-TsOH salt of Compound A obtained in Preparation Example 1 was added to a solvent, and the resulting slurry was stirred at 50°C. When a mixed solution of DMF and toluene in a volume ratio of 1:1, 1:2, 1:3, 1:4, or 1:9, a mixed solution of DMF and acetonitrile in a volume ratio of 1:1, 1:2, 1:3, or 1:4, a mixed solution of acetonitrile and toluene in a volume ratio of 1:1, acetone, chloroform, ethanol, methyl tertiary butyl ether (MTBE), tetrahydrofuran, or toluene was used as the solvent, Type 1 crystals of p-TsOH salt of Compound A were obtained.

[0148] Example 22: Preparation of crystals of p-TsOH salt of Compound A under various conditions 6 The amorphous p-TsOH salt of Compound A obtained in Preparation Example 1 was dissolved in DMF at a concentration of 350 mg / mL (for room temperature) or 500 mg / mL (for 50°C), and filtered through a 0.2 μm polytetrafluoroethylene filter. A poor solvent was added to 275 μL (for room temperature) or 250 μL (for 50°C) of the filtrate while stirring at 300 rpm, and the mixture was stirred for 2 hours. Thereafter, when toluene was used as the poor solvent, the mixture was stirred for an additional 70 hours. When a solvent other than toluene was used as the poor solvent, seed crystals of p-TsOH salt of Compound A were added, and the mixture was stirred for an additional 70 hours. As a result, Type 1 crystals of p-TsOH salt of Compound A were obtained when acetonitrile was used as the poor solvent and the mixture was stirred at 50°C, when 2-propanol was used as the poor solvent and the mixture was stirred at 50°C, when methyl ethyl ketone was used as the poor solvent and the mixture was stirred at room temperature or 50°C, or when toluene was used as the poor solvent and the mixture was stirred at room temperature or 50°C. The amounts of the poor solvents added were 1.93 ml (room temperature) or 1.75 ml (50°C) for acetonitrile, 2.20 ml (room temperature) or 2.00 ml (50°C) for 2-propanol, 2.20 ml (room temperature) or 2.00 ml (50°C) for methyl ethyl ketone, and 2.48 ml (room temperature) or 2.25 ml (50°C) for toluene.

[0149] Reference Example 1: Obtaining Type 1 Crystals of Compound 9 without Using Seed Crystals N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide can be obtained by the method described in Example 11 of Patent Document 1. 480 ml of THF was added to 80 g of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, and the mixture was heated to 50°C to dissolve. 32.4 g of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at the same temperature for at least 1 hour, and 960 ml of acetone was added while heating at 55°C. The mixture was further stirred for at least 2 hours while heating at 50°C, cooled to room temperature, and stirred at the same temperature for 30 minutes. The slurry was filtered and washed with 50 ml of chilled acetone. The mixture was dried under reduced pressure while heating at an external temperature of 50°C or less, yielding 98.1 g of white crystals in a 92% yield. A portion of the white crystals obtained in the same manner as the above-described method can be used as seed crystals for Compound 9. The results of powder X-ray diffraction of the resulting Type 1 crystals of Compound 9 are shown in Figure 29. The results of measurement of the thermal properties of the resulting Type 1 crystals of Compound 9 by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are shown in Figure 30. The powder X-ray diffraction spectrum in Reference Example 1 was measured using a RINT-Ultima III (manufactured by Rigaku Corporation) (target: Cu, voltage: 40 kV, current: 40 mA, scan speed: 4 degrees / min). DSC in Reference Example 1 was measured using a DSC-50 (manufactured by Shimadzu Corporation) (cell: alumina (open), gas: nitrogen (20.0 mL / min), heating rate: 10.0°C / min, hold temperature: 400°C, hold time: 0 min).

Claims

1. A compound represented by the following formula (A-I), which has diffraction peaks at diffraction angles (2θ±0.2°) of 7.1°, 14.3°, 15.8°, and 18.3° in powder X-ray diffraction: The present invention relates to a type 1 crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate represented by the formula:

2. A compound represented by the following formula (A-I), which has an endothermic peak of 265.8±3.0° C. in differential scanning calorimetry: The present invention relates to a type 1 crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate represented by the formula:

3. A compound represented by the following formula (A-I), which has diffraction peaks at diffraction angles (2θ±0.2°) of 6.3°, 15.0°, 16.4°, 17.9°, and 22.7° in powder X-ray diffraction: The 3rd type crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate represented by the formula:

4. A compound represented by the following formula (A-I): having an endothermic peak of 247.4±3.0° C. in differential thermal analysis: The 3rd type crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate represented by the formula:

5. A compound represented by the following formula (A-I), which has diffraction peaks at diffraction angles (2θ±0.2°) of 7.4°, 8.0°, 14.5°, 16.1°, and 20.6° in powder X-ray diffraction: The 4th type crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate represented by the formula:

6. A compound represented by the following formula (A-I): having an endothermic peak at 212.5±3.0° C. in differential thermal analysis: The 4th type crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate represented by the formula:

7. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 6 as an active ingredient.

8. A membrane-bound prostaglandin E synthase-1 inhibitor comprising the crystal according to any one of claims 1 to 6 as an active ingredient.

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