Method for producing heterocyclic derivative

Abstract

Disclosed is a method for producing a p-toluenesulfonate salt of a compound represented by formula (I), the method including a step for converting an N,N-dimethylacetamide solvate of a compound represented by formula (I) into a p-toluenesulfonate salt of a compound represented by formula (I).

Description

Method for producing heterocyclic derivatives

[0001] The present disclosure relates to a method for producing 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] The method for producing Compound A according to Patent Document 1 goes through a synthetic intermediate represented by the following formula (XI) (hereinafter also referred to as "Compound C"), and it has been revealed that Compound C is highly likely to have mutagenicity (genotoxicity) through evaluation using multiple in silico test software programs capable of predicting mutagenicity (genotoxicity).

[0006] Therefore, when compound A is produced by the method described in Patent Document 1, compound C is isolated as a powder in the process, which poses a problem that worker protection and environmental measures (containment) are required. In contrast, if compound A could be produced by a synthetic route that does not isolate compound C as a powder, it would be possible to avoid the risk of mutagenicity due to the dispersion of compound C isolated as a powder, and it would also be possible to reduce the time and cost required for worker protection and environmental measures (containment).

[0007] An object of the present disclosure is to provide a method for producing a heterocyclic derivative and a method for producing a p-toluenesulfonate salt of Compound A.

[0008] The present inventors have discovered a method for producing a p-toluenesulfonate salt of compound A without isolating powder of compound C. Furthermore, the present inventors have discovered that this production method makes it possible to remove impurities that are generated during the production process and that must be controlled on the ppm level, and have thus completed the present disclosure.

[0009] The present disclosure relates to, for example, the following: [1] A compound of the following formula (I): [2] A method for producing a p-toluenesulfonate salt of 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)—, [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 purifying the p-toluenesulfonate of the compound represented by formula (I) after contacting it with activated carbon by recrystallization.

[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): A method for producing a p-toluenesulfonate salt of a compound represented by the following formula (IV): (In the formula, R１ 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); and converting the N,N-dimethylacetamide solvate of the compound represented by formula (I) into a p-toluenesulfonate salt of the compound represented by formula (I), in this order.

[25] A production method comprising the steps of: The method for producing a p-toluenesulfonate salt of a compound 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). １ and 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 １is 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), comprising 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); purifying the N,N-dimethylacetamide solvate of the compound represented by formula (I) by recrystallization; converting the N,N-dimethylacetamide solvate of the compound represented by formula (I) into a p-toluenesulfonate of the compound represented by formula (I); contacting the p-toluenesulfonate of the compound represented by formula (I) with activated carbon to purify it; and purifying the p-toluenesulfonate of the compound represented by formula (I) after contact with activated carbon by recrystallization, in this order.

[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.

[29] A compound represented by the following formula (I):

[30] An N,N-dimethylacetamide solvate of a compound represented by the following formula (I): The composition contains an N,N-dimethylacetamide solvate of a compound represented by formula (I), wherein the content of the N,N-dimethylacetamide solvate of the compound represented by formula (I) is 95% by mass or more of the total composition, and the composition contains an N,N-dimethylacetamide solvate of a compound represented by formula (VII): The content of the compound represented by the formula (I) is 1800×10 of the total composition in terms of free form. －４ % by mass or less, preferably 200 × 10 －４

[31] A composition having the following formula (I): and an N,N-dimethylacetamide solvate of a compound represented by the following formula (VII): wherein the content of the N,N-dimethylacetamide solvate of the compound represented by formula (I) is 95% by mass or more of the entire composition, and the content of the compound represented by formula (VII) is 1800 × 10 in terms of the free form of the compound of the entire composition. －４ % by mass or less, preferably 200 × 10 －４ % by volume or less.

[32] The salt according to

[29] or the composition according to

[30] or

[31] , which is recrystallized using a mixed solvent of N,N-dimethylacetamide and water.

[33] The salt according to

[29] or the composition according to

[30] or

[31] , which is recrystallized using a mixed solvent of N,N-dimethylacetamide and water, wherein the N,N-dimethylacetamide content is 75% by volume or more.

[34] A compound represented by the following formula (I): The content of the p-toluenesulfonate of the compound represented by formula (I) is 95 mass % or more of the total composition, and the p-toluenesulfonate of the compound represented by formula (VII): The content of the compound expressed as －４ mass% or less, preferably 50 × 10 －４

[35] A composition having the following formula (I): and p-toluenesulfonic acid salts of compounds represented by the following formula (VII): wherein the content of the p-toluenesulfonate salt of the compound represented by formula (I) 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 free form. －４ mass% or less, preferably 50 × 10 －４% by mass or less.

[36] The composition according to

[34] or

[35] , which is purified by contact with activated carbon and then purified by recrystallization.

[37] The composition according to

[34] or

[35] , which is purified by contact with activated carbon in an amount of 0.04 times or more, preferably 0.08 times or more, by mass of the p-toluenesulfonate salt of the compound represented by formula (I), and then purified by recrystallization.

[38] The salt or composition according to any one of

[29] to

[37] , which is produced by the production method according to any one of [1] to

[28] or a production method comprising part of the steps thereof.

[39] The salt or composition according to any one of

[29] to

[37] , which is produced by the production method according to any one of [1] to

[28] or a production method comprising part of the steps thereof. a method for purifying a compound represented by formula (I) or a p-toluenesulfonate thereof, the method comprising the steps of: recrystallizing an N,N-dimethylacetamide solvate of the compound represented by formula (I) using a mixed solvent of N,N-dimethylacetamide and water, the mixed solvent having an N,N-dimethylacetamide content of 75% by volume or more; contacting the p-toluenesulfonate of the compound represented by formula (I) with activated carbon in an amount of 0.04 times or more by mass the p-toluenesulfonate of the compound represented by formula (I); and recrystallizing the p-toluenesulfonate of the compound represented by formula (I) after contact with activated carbon, in this order.

[0010] According to one embodiment of the present disclosure, a method for producing a heterocyclic derivative can be provided. Also, according to one embodiment of the present disclosure, a method for producing a p-toluenesulfonate salt of compound A can be provided.

[0011] According to a production method according to an embodiment of the present disclosure, it is possible to produce p-toluenesulfonate of compound A or a composition containing the same without isolating compound C as a powder.

[0012] According to a production method according to one embodiment of the present disclosure, a compound represented by the following formula (VII): It is possible to produce a p-toluenesulfonate of compound A or a composition containing the same, in which the content of a compound represented by the formula (hereinafter also referred to as "compound B") is reduced. Although compound B may also be involved in mutagenicity and may be generated during the production process, the production method according to one embodiment of the present disclosure can reduce the amount of compound B, and further, in one embodiment, can remove compound B with high efficiency.

[0013] According to a production method according to an embodiment of the present disclosure, it is possible to produce a p-toluenesulfonate of compound A or a composition containing the same, in which the inclusion of mutagenic impurities is suppressed. According to a production method according to an embodiment of the present disclosure, it is possible to produce a p-toluenesulfonate of compound A or a composition containing the same, in which the content of compound B is suppressed.

[0014] Furthermore, the method described in Patent Document 1 includes a step of nitration in concentrated sulfuric acid / concentrated nitric acid and a catalytic reduction step with hydrogen to introduce a primary amino group, which raises concerns about explosiveness when produced on an industrial scale. In contrast, the production method according to an embodiment of the present disclosure introduces a primary amino group through a step that involves a mild coupling reaction, thereby avoiding steps that may be explosive and enabling the safe production of p-toluenesulfonate of compound A or a composition containing the same.

[0015] According to one embodiment of the present disclosure, an N,N-dimethylacetamide solvate of compound A or a composition containing the same can be provided. By using the N,N-dimethylacetamide solvate of compound A, it is possible to produce a p-toluenesulfonic acid of compound A or a composition containing the same, in which the inclusion of mutagenic impurities is suppressed. Furthermore, by using the N,N-dimethylacetamide solvate of compound A, it is possible to produce a p-toluenesulfonic acid of compound A or a composition containing the same, in which the content of compound B is reduced. That is, in one embodiment of the present disclosure, a p-toluenesulfonic acid of compound A or a composition containing the same is provided, in which the content of compound B is reduced, and in another embodiment of the present disclosure, an N,N-dimethylacetamide solvate of compound A or a composition containing the same is provided.

[0016] FIG. 1 is a diagram showing the results of powder X-ray crystallography of the powder obtained in step 8 of Example 1. FIG. 2 is a diagram showing the results of DSC of the powder obtained in step 8 of Example 1. FIG. 3 is a diagram showing the results of TG-DTA of the powder obtained in step 8 of Example 1. FIG. 4 is a diagram showing the results of powder X-ray crystallography of the powder obtained in step 5 of Example 4. FIG. 5 is a diagram showing the results of powder X-ray crystallography of the powder obtained in step 6 of Example 4. FIG. 6 is a diagram showing the results of measurement of thermophysical properties by DSC of the powder obtained in step 6 of Example 4. FIG. 7 is a diagram showing the results of powder X-ray crystallography of the powder obtained in step 7 of Example 4. FIG. 8 is a diagram showing the results of TG-DTA of the powder obtained in step 7 of Example 4. FIG. 9 is a diagram showing the results of powder X-ray diffraction of the powder obtained in Reference Example 1. FIG. 10 is a diagram showing the results of DSC-TGA of the powder obtained in Reference Example 1.

[0017] Hereinafter, embodiments for carrying out the present disclosure will be described, but the present disclosure is not limited to the following embodiments.

[0018] 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.

[0019] The chemical reactions in the present disclosure may be quenched as appropriate by a method commonly used by those skilled in the art, and the product may be recovered by a method 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 a method commonly used by those skilled in the art, such as recrystallization or column chromatography, although 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 a method commonly used by those skilled in the art, such as chromatography, including reverse-phase liquid chromatography (HPLC), and the products may be analyzed by a method commonly used by those skilled in the art, such as HPLC, nuclear magnetic resonance (NMR), mass spectrometry, X-ray crystallography, DSC, and TG-DTA.

[0020] <First Aspect: Method for Producing p-Toluenesulfonate of Compound A> A method for producing p-toluenesulfonate of Compound A according to the first aspect of the present disclosure, comprising the steps of: An embodiment of each step in the method for producing a p-toluenesulfonate salt of a compound represented by the following formula (hereinafter may be referred to as "Compound A") is described below.

[0021] <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.

[0022] 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 give a compound in which R １ may be, for example, alkyl, cycloalkyl, alkenyl, alkoxymethyl, or aralkyl, and 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, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-hexyl, cyclopentyl, cyclohexyl, vinyl, allyl, methoxymethyl, benzyl, phenethyl, or paramethoxybenzyl, and in a more preferred embodiment, it may be methyl or ethyl, and in a most preferred embodiment, it may be methyl.

[0023] X in the above formula (IV) 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.

[0024] 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.

[0025] 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).

[0026] 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 the imidazole ring of the compound represented by formula (IV) is formed, 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. Alternatively, in a preferred embodiment, from the viewpoint of highly efficient reaction, 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, a solvent in which the compound represented by formula (VI) and methoxyacetic acid are soluble and which has a boiling point equal to or higher than the above-mentioned temperature range is suitable, and examples of suitable solvents include N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMA).

[0027] 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.

[0028] 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.

[0029] <Step 2 / 3> Step 2 / 3 is a step of reacting a compound represented by the following formula (II): (In the formula, R １is 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.

[0030] 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, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, n-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.

[0031] 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:

[0032] The protected compound of the compound represented by the above formula (IV) is a compound represented by the following formula (IV″): (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 t-butoxycarbonyl (Boc) group, an allyloxycarbonyl (Alloc) group, a 9-fluorenylmethyloxycarbonyl (Fmoc) group, a trimethylsilyl (TMS) group, or a benzyl group.

[0033] 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.

[0034] 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. 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-mentioned temperature range or is capable of refluxing (reflux) at the above-mentioned temperature range, and is unreactive with the compound represented by formula (IV) or a protected form thereof, 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 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, and may be, for example, 10 minutes to 168 hours. During this time, the atmosphere inside the reaction vessel may be replaced with an inert gas such as nitrogen or argon.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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-butoxide, 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.

[0039] 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.

[0040] 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.

[0041] 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-t-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).

[0042] 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.

[0043] 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.

[0044] <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:

[0045] 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).

[0046] 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.

[0047] 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.

[0048] 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.

[0049] In the above case, the solvent used in contacting the acid halide of 2-(trifluoromethyl)benzoic acid with the compound represented by formula (III) above 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 temperature in the reaction is not particularly limited as long as it is a temperature at which the compound represented by formula (VIII) above 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) above is produced, and may be, for example, 1 minute to 3 hours, 5 minutes to 1 hour, or 10 minutes to 30 minutes. Furthermore, from the viewpoint of increasing the yield by decomposing a compound resulting from the reaction of a plurality of by-products of acid halides of 2-(trifluoromethyl)benzoic acid (an acylated product resulting from the reaction of an NH of an imidazole ring or an OH of a carboxylic acid bonded to benzimidazole with a halide of 2-(trifluoromethyl)benzoic acid), 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, for 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 (III) 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 (III), 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 (III). 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 (III).

[0050] 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.

[0051] <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) above into the compound represented by formula (I) above (compound A), and contacting the compound represented by formula (I) above (compound A) with N,N-dimethylacetamide to obtain the N,N-dimethylacetamide solvate of the compound represented by formula (I) above (compound A).

[0052] The compound represented by formula (VIII) above can be converted into the compound represented by formula (I) above (compound A) 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.

[0053] 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.

[0054] 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) (compound A) 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) (compound A) to be obtained in high yield (e.g., a yield of 90% or more) 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.

[0055] 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.

[0056] The compound represented by formula (I) (Compound A) can be contacted with N,N-dimethylacetamide to obtain an N,N-dimethylacetamide solvate of the compound represented by formula (I) (Compound A) by a method commonly used by those skilled in the art. For example, this can be carried out by adding DMA or a mixture containing DMA (for example, a mixture of DMA and water) to a solvent in which any form of the compound represented by formula (I) (for example, the free form of the compound represented by formula (I)) is dissolved, followed by incubation. In one embodiment, this can 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 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.

[0057] By the above-described fourth and fifth steps, an N,N-dimethylacetamide solvate of the compound represented by formula (I) (compound A) 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 an N,N-dimethylacetamide solvate of the compound represented by formula (I) (compound A).

[0058] <Step 6> Step 6 is a step of purifying by recrystallization the crude product of the N,N-dimethylacetamide solvate of the compound represented by formula (I) above (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) above (Compound A) obtained in Step 5. Recrystallization of the crude product of the N,N-dimethylacetamide solvate of the compound represented by formula (I) above (Compound A) 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) above (Compound A) 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. When recrystallization is carried out in such a solvent, the N,N-dimethylacetamide solvate of the compound represented by formula (I) above (Compound A) can be obtained in high yield and high purity. Furthermore, when recrystallization is carried out in such a solvent, the N,N-dimethylacetamide solvate of the compound represented by formula (VII) below, which is generated during the production process and may be involved in mutagenicity, may be obtained. It is possible to obtain a purified product of the N,N-dimethylacetamide solvate of the compound represented by formula (I) above (Compound A) in which the content of the compound represented by formula (I) (hereinafter also referred to as "Compound B") is reduced, and 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 (Compound A) in which the content of Compound B is further reduced. In these cases, "reduced content of Compound B" means that the content of Compound B in the purified product (crystals) obtained by recrystallization is, for example, 1800 x 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.

[0059] <Step 7> Step 7 is a step of converting the N,N-dimethylacetamide solvate of the compound represented by formula (I) above (Compound A) into a p-toluenesulfonate of the compound represented by formula (I) above (Compound A). 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) above (Compound A) obtained in Step 6 into a p-toluenesulfonate of the compound represented by formula (I) above (Compound A). Step 7 is typically carried out by contacting the N,N-dimethylacetamide solvate of the compound represented by formula (I) above (Compound A) 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) (Compound A) with p-toluenesulfonic acid are not particularly limited, as long as the N,N-dimethylacetamide solvate of the compound represented by formula (I) (Compound A) is converted to the p-toluenesulfonic acid salt of the compound represented by formula (I) (Compound A). 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 (for example, a mixed solvent with a mass ratio of about 1:6). The temperature for contact may be, for example, 30 to 70°C or 45 to 60°C. The time for contact 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) above (compound A).

[0060] <Step 8> Step 8 is a step of purifying the crude product of p-toluenesulfonate of the compound represented by formula (I) (compound A). In one embodiment, Step 8 is a step of purifying the crude product of p-toluenesulfonate of the compound represented by formula (I) (compound A) obtained in Step 7. Step 8 comprises, in this order, purifying the p-toluenesulfonate of the compound represented by formula (I) (compound A) by contacting it with activated carbon, and purifying the p-toluenesulfonate of the compound represented by formula (I) (compound A) after contacting it with activated carbon by recrystallization.

[0061] The purification of the p-toluenesulfonate salt of the compound represented by formula (I) (Compound A) 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) (Compound A), 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) (Compound A) 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) above (compound A) 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) above (compound A) is at least the above lower limit, compound B, an impurity that may be involved in mutagenicity, can be efficiently removed.

[0062] The p-toluenesulfonate of the compound represented by formula (I) (Compound A) after contact with activated carbon can be purified by a method commonly used by a person skilled in the art. In one embodiment, the purification may be performed by bringing the p-toluenesulfonate of the compound represented by formula (I) (Compound A) into contact with activated carbon for purification, and then filtering the filtrate to remove the activated carbon. If necessary, seed crystals of the p-toluenesulfonate of the compound represented by formula (I) (Compound A) are added to the filtrate, and the filtrate is then heated and cooled.

[0063] When the eighth step includes purifying the p-toluenesulfonate of the compound represented by formula (I) (compound A) by contacting it with activated carbon, and purifying the p-toluenesulfonate of the compound represented by formula (I) (compound A) after contacting it with activated carbon by recrystallization, in this order, the content of compound B, an impurity that may be involved in mutagenicity, in the purified product (crystals) obtained by recrystallization can be significantly reduced compared to purification by recrystallization alone. More specifically, the content of compound B in the purified product (crystals) obtained by recrystallization 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.

[0064] <Embodiments of the Production Method According to the First Aspect> One embodiment of the first aspect of the present disclosure may be a method for producing a p-toluenesulfonate of a compound represented by formula (I) above (compound A), comprising at least one of the steps described above. A specific embodiment of the first aspect of the present disclosure may be a method for producing a p-toluenesulfonate of a compound represented by formula (I) above (compound A), comprising step 7. One embodiment of the first aspect of the present disclosure may be a method for producing a p-toluenesulfonate of a compound represented by formula (I) above (compound A), comprising step 4 and step 7, in this order. One embodiment of the first aspect of the present disclosure may be a method for producing a p-toluenesulfonate of a compound represented by formula (I) above (compound A), comprising step 2 / 3, step 4, and step 7, in this order. One embodiment of the first aspect of the present disclosure may be a method for producing a p-toluenesulfonate of a compound represented by formula (I) above (compound A), comprising step 4, step 5, and step 7, in this order. One embodiment of the first aspect of the present disclosure may be a method for producing a p-toluenesulfonate salt of a compound represented by formula (I) above (compound A), comprising, in this order, steps 2 / 3, 4, 5, and 7. One embodiment of the first aspect of the present disclosure may be a method for producing a p-toluenesulfonate salt of a compound represented by formula (I) above (compound A), comprising, in this order, steps 1, 2 / 3, 4, 5, and 7. One embodiment of the first aspect of the present disclosure may be a method for producing a p-toluenesulfonate salt of a compound represented by formula (I) above (compound A), further comprising step 6 immediately before step 7 in these embodiments. One embodiment of the first aspect of the present disclosure may be a method for producing a p-toluenesulfonate salt of a compound represented by formula (I) above (compound A), further comprising step 8 immediately after step 7 in these embodiments.

[0065] <Second Aspect: N,N-Dimethylacetamido Solvate of Compound A> One embodiment of the second aspect of the present disclosure is an N,N-dimethylacetamido solvate of compound A. Another embodiment of the second aspect of the present disclosure may be a composition containing the N,N-dimethylacetamido solvate of compound A, in which the content of the N,N-dimethylacetamido solvate of the compound represented by formula (I) above (compound A) is 95% by mass or more of the total composition, and the content of compound B is a predetermined upper limit or less. The composition in the second aspect of the present disclosure refers to a composition comprising one or more components contained in any materials used in the process of preparing the N,N-dimethylacetamido solvate of compound A, and products of one-step or multi-step reactions between these components.

[0066] Examples of a method for producing a p-toluenesulfonate salt of the compound represented by formula (I) (Compound A) from a compound represented by formula (VIII) include a method for producing a p-toluenesulfonate salt of the compound represented by formula (I) (Compound A) via an N,N-dimethylacetamide solvate of the compound represented by formula (I) (Compound A) as in the present application (a method via an N,N-dimethylacetamide solvate of Compound A), and a method for producing a p-toluenesulfonate salt of the compound represented by formula (I) (Compound A) without via an N,N-dimethylacetamide solvate of the compound represented by formula (I) (Compound A) as described in Example 239 of Patent Document 1. With regard to a method for producing a p-toluenesulfonate salt of the compound represented by formula (I) (compound A) from a compound represented by formula (VIII), the method described in Example 239 of Patent Document 1 requires a purification step by chromatography (for example, a purification step using a silica gel column) in order to purify the compound represented by formula (I) (compound A) shown in the present application. However, according to a method that involves an N,N-dimethylacetamide solvate of compound A, for example, a high-purity p-toluenesulfonate salt of the compound represented by formula (I) (compound A) can be obtained without purification by chromatography by undergoing a recrystallization step of the N,N-dimethylacetamide solvate of the compound represented by formula (I) (compound A).

[0067] Furthermore, the step of obtaining the compound represented by formula (VIII) is not limited to the method described above, and for example, the method described in Patent Document 1 can also be used. That is, as the step of obtaining the compound represented by formula (VIII), for example, the method described above can be used, or the method described in Patent Document 1 can also be used. And, regardless of which method the compound represented by formula (VIII) is obtained by, by obtaining the p-toluenesulfonate of the compound represented by formula (I) (Compound A) via the N,N-dimethylacetamide solvate of the compound represented by formula (I) (Compound A), it is possible to obtain the p-toluenesulfonate of the compound represented by formula (I) (Compound A) with a low impurity content without purification by chromatography. As described above, by obtaining the p-toluenesulfonate of the compound represented by formula (I) (Compound A) via the N,N-dimethylacetamide solvate of the compound represented by formula (I) (Compound A), it is possible to reduce the effort and cost of purification by chromatography, and therefore it is possible to efficiently remove impurities contained in the compound represented by formula (I) (Compound A) produced by any method. Furthermore, in the step of producing a p-toluenesulfonate salt of the compound represented by the above formula (I) (compound A), by going through an N,N-dimethylacetamide solvate of the compound represented by the above formula (I) (compound A), it is possible to obtain a p-toluenesulfonate salt of the compound represented by the above formula (I) (compound A) having a low impurity content.

[0068] The content of compound B in the composition according to one embodiment of the second aspect of the present disclosure 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 a preferred embodiment, 200×10 －４Furthermore, the content of the N,N-dimethylacetamide solvate of compound A in the composition according to one embodiment of the second 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.

[0069] The salt or composition according to one embodiment of the second aspect of the present disclosure may be produced by a production method including step 6 of the first aspect of the present disclosure, or may be produced by a production method including steps 5 and 6 of the first aspect of the present disclosure in this order, or may be produced by a production method including steps 4, 5, and 6 of the first aspect of the present disclosure in this order, or may be produced by a production method including steps 2 / 3, 4, 5, and 6 of the first aspect of the present disclosure in this order, or may be produced by a production method including steps 1, 2 / 3, 4, 5, and 6 of the first aspect of the present disclosure in this order. The salt or composition according to one embodiment of the second aspect of the present disclosure may be recrystallized using a mixed solvent of N,N-dimethylacetamide and water, and in a preferred embodiment, may be recrystallized using a mixed solvent of N,N-dimethylacetamide and water, wherein the N,N-dimethylacetamide content is 75% by volume or more.

[0070] <Third Aspect: Composition Comprising p-Toluenesulfonate of Compound A> One embodiment of the third aspect of the present disclosure is a composition comprising p-toluenesulfonate of compound A, wherein the content of the p-toluenesulfonate of compound A in the entire composition is 95% by mass or more, and the content of compound B is a predetermined upper limit or less. One embodiment of the third aspect of the present disclosure is a composition comprising p-toluenesulfonate of compound A and compound B, wherein the content of the p-toluenesulfonate of compound A in the entire composition is 95% by mass or more, and the content of compound B is a predetermined upper limit or less. The composition in the third aspect of the present disclosure refers to a composition comprising one or more components contained in any materials used in the process of preparing the p-toluenesulfonate of compound A, and products of one-step or multi-step reactions between those components.

[0071] The content of compound B in the composition according to one embodiment of the third 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 －４ Furthermore, the content of the p-toluenesulfonate salt of compound A in the composition according to one embodiment of the third 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.

[0072] A composition according to one embodiment of the third aspect of the present disclosure may be produced by a production method including step 8 of the first aspect of the present disclosure, or may be produced by a production method including steps 7 and 8 of the first aspect of the present disclosure in this order, or may be produced by a production method including steps 6, 7 and 8 of the first aspect of the present disclosure in this order, or may be produced by a production method including steps 5, 6, 7 and 8 of the first aspect of the present disclosure in this order, or may be produced by a production method including steps 4, 5, 6, 7 and 8 of the first aspect of the present disclosure in this order, or may be produced by a production method including steps 2 / 3, 4, 5, 6, 7 and 8 of the first aspect of the present disclosure in this order, or may be produced by a production method including steps 1, 2 / 3, 4, 5, 6, 7 and 8 of the first aspect of the present disclosure. The composition according to one embodiment of the third aspect of the present disclosure may be purified by contact with activated carbon and then purified by recrystallization. For example, the composition may be purified by contact with activated carbon in an amount of at least 0.04 times the mass of p-toluenesulfonate of the compound represented by formula (I) above (compound A), and then purified by recrystallization. In a preferred embodiment, the composition may be purified by contact with activated carbon in an amount of at least 0.08 times the mass of p-toluenesulfonate of the compound represented by formula (I) above (compound A), and then purified by recrystallization.

[0073] The present disclosure will be described in more detail below using examples, but the present disclosure is not limited to the following examples.

[0074] 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-H２ O = p-toluenesulfonic acid monohydrate MeCN = acetonitrile HPLC = high performance liquid chromatography

[0075] 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).

[0076] Powder X-ray diffraction spectra in the examples were measured using 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).

[0077] Example 1: Preparation of Compound 9 (p-toluenesulfonate of Compound A) Compound 9 was prepared by the preparation method outlined below.

[0078] Step 1: Synthesis of methyl 6-bromo-2-(methoxymethyl)-1H-benzimidazole-4-carboxylate (Compound 1) 80.0 kg of methyl 2,3-diamino-5-bromobenzoate and 294 kg of methoxyacetic acid were added to a nitrogen-purged stirring vessel. 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 reaction mixture was further 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%).

[0079] 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%).

[0080] 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)

[0081] 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).

[0082] 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)

[0083] 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).

[0084] 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)

[0085] 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%)).

[0086] 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%).

[0087] 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)

[0088] 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) 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%).

[0089] Step 8: Purification of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonic acid (Compound 9) 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. Seed 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. The mixture was stirred for 5 hours or more while maintaining the temperature at 20-30°C. After adding seed crystals of Compound 9 (240 g), the solution was heated to 50-60°C and stirred at 50-60°C for at least 5 hours. The solution was cooled to 20-30°C and then stirred at 20-30°C for an additional 12 hours. The slurry was filtered to recover the insoluble matter, and the recovered insoluble matter (cake) was washed with toluene (125 kg) and then 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, yielding 44.9 kg of powder (yield: 94%) of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonic acid (Compound 9). The results of powder X-ray crystallography of the resulting powder are shown in Figure 1. According to Figure 1, peaks were observed at 2θ = 7.1°, 14.3°, 15.8°, and 18.3°. Furthermore, the results of measuring the thermal properties of the obtained powder by DSC are shown in Figure 2, and the results of measuring the thermal properties by TG-DTA are shown in Figure 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 toluene, which is the residual solvent in the obtained Compound 9, was 460 ppm, N,N-dimethylformamide was 514 ppm, and no acetonitrile was detected.

[0090] [Step 9: Pulverization of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonic acid (Compound 9) Powder] The powder of Compound 9 (44.7 kg) obtained in Step 8 was finely pulverized using a pulverizer (jet mill) to obtain 43.9 kg (98% yield) of fine powder of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonic acid (Compound 9).

[0091] [Obtaining 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 this 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 above can be used as seed crystals for compound 9. The results of powder X-ray diffraction of the resulting crystals of compound 9 are shown in Figure 9. The results of measurement of the thermal properties of the resulting crystals of compound 9 by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are shown in Figure 10. 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).

[0092] Example 2: 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. ２After 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.

[0093] 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 yield was higher in 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.

[0094]

[0095] Example 3 Purification Efficiency and Impurity Removal Efficiency in Step 8 The contents of Compound B, which is an impurity, were measured for Compound 8 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 8 as in Step 8.

[0096] The results are shown in Table 2 below. Unexpectedly, recrystallization of compound 8 alone was unable to effectively remove compound B. On the other hand, contacting compound 8 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 8.

[0097]

[0098] Example 4: Retest of Steps 5 to 7 Steps 5 to 7 were retested in the same manner as in Example 1. Compound 7, the starting material for Step 5, was prepared according to Steps 1 to 4 of Example 1.

[0099] [Step 5] Compound 7 (58.8 kg) and DMF (167 kg) were added to a stirring vessel purged with nitrogen gas. While stirring the mixture at 30°C or below, 1,1'-carbonyldiimidazole (26.3 kg) was added, and the reaction was allowed to proceed for at least 1 hour at a temperature of 20°C to 30°C. The reaction mixture was analyzed by HPLC, and the completion of the reaction was confirmed when the peak area of ​​the starting compound 7 was 1.0% or less of the total area of ​​all detected peaks. Then, 3-chloro-2-methylaniline (52.8 kg) and benzoic acid (0.91 kg) were added to the reaction mixture at a temperature of 20°C to 30°C. The reaction mixture was then heated to 50-60°C and allowed to react for at least 20 hours. The reaction solution was analyzed by HPLC, and the completion of the reaction was confirmed based on the peak area of ​​the reaction intermediate having a carbonylimidazole structure being 2.0% or less of the total area of ​​all detected peaks. DMAc (331 kg) was then added while the reaction solution was kept at 50-60°C. Water (235 kg) was added dropwise while maintaining the temperature of the reaction solution at 50-60°C, followed by stirring at a temperature of 50-60°C for at least 1 hour. The reaction solution was then cooled to 25°C or less and stirred at 20-25°C for an additional 2 hours or more. The slurry was filtered to recover the insoluble matter, and the recovered insoluble matter (cake) was washed sequentially with a mixture of DMAc (133 kg) and water (142 kg), and then with water (212 kg). The recovered insoluble matter was then dried under reduced pressure while maintaining the temperature outside the vessel at 60°C or less, yielding 79.8 kg of compound 8 as a powder (yield 89%). The results of powder X-ray crystallography of the obtained powder are shown in FIG.

[0100] [Step 6] The crude product of compound 8 (39.5 kg) obtained in Step 5 and DMAc (122 kg) were added to a stirring vessel. The temperature of the resulting solution was raised to 70-80°C, and water (34.0 kg) was added at 70-80°C. The solution was cooled to below 25°C over 90 minutes and then stirred at 20-30°C for at least 30 minutes. The slurry was filtered to recover the insoluble matter, and the resulting insoluble matter (cake) was washed with a mixture of DMAc (37.0 kg) and water (39.5 kg), followed by water (79.0 kg). The recovered insoluble matter was then dried under reduced pressure while maintaining the temperature outside the vessel below 60°C, yielding 37.2 kg of purified compound 8 as a powder (94% yield). The results of powder X-ray crystallography of the resulting powder are shown in Figure 5. The results of thermal property measurements of the resulting powder using a differential scanning calorimeter (DSC) are shown in Figure 6. The DSC shown in FIG. 6 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).

[0101] [Step 7] The purified product of Compound 9 obtained in Step 6 (37.0 kg) and DMF (88.3 kg) were added to a stirring tank. The temperature of the mixture was raised to 50-60°C, and Compound 9 was dissolved in DMF. Acetonitrile (218 kg) was added to the solution at 45-60°C. p-Toluenesulfonic acid hydrate (pTsOH-H ２A solution of 12.8 kg of DMF in 116 kg of acetonitrile was added dropwise to the mixture. Furthermore, 175 kg of acetonitrile was added while the temperature was kept at 45-60°C. After stirring for at least 5 hours at 50-60°C, the slurry was filtered to recover the insoluble matter. The resulting insoluble matter (cake) was washed with a mixture of 8.7 kg of DMF and 50.9 kg of acetonitrile, followed by 87.2 kg of acetonitrile. The recovered insoluble matter was then dried under reduced pressure while maintaining the temperature outside the vessel at 60°C or below, yielding 39.0 kg of crude powder of Compound 9 (yield: 92%). The results of powder X-ray crystallography of the resulting powder are shown in Figure 7. Furthermore, the results of measuring the thermal properties of the resulting powder by TG-DTA are shown in Figure 8. The TG-DTA shown in Fig. 8 was measured using a TG-8120 (manufactured by Rigaku Corporation) (cell: alumina (open), gas: nitrogen, heating rate: 10.0°C / min, hold temperature: 400°C, hold time: 0 min). The residual solvent contents in the obtained powder were 22659 ppm for acetonitrile and 5824 ppm for DMF.

Claims

1. A compound represented by the following formula (I): The method for producing a p-toluenesulfonate salt of the compound represented by formula (I) comprises a step of converting an N,N-dimethylacetamide solvate of the compound represented by formula (I) into the p-toluenesulfonate salt of the compound represented by formula (I).

2. 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)—, The method according to claim 1, further comprising a step of converting the compound represented by the formula:

3. The step of converting the compound represented by formula (II) into the 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): The method of claim 2, comprising obtaining a compound represented by the formula:

4. R in the above formula (II) １ and R ２ Each of them is independently C １ ~C ６ The process according to claim 2, wherein R represents an alkyl group.

5. R in the above formula (II) １ and R ２ The process according to claim 2, wherein is methyl.

6. The following formula (IV): (In the formula, R １ is R in formula (II) １ and X represents Cl, Br, I or OTf. (In the formula, R ２ is R in formula (II) ２ (which is the same as (I)), to obtain the compound represented by formula (II) or a protected form thereof.

7. The method according to claim 6, wherein in the step of obtaining the compound represented by formula (II), the 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.

8. The method according to claim 6, wherein X in formula (IV) is Br.

9. The following formula (VI): (In the formula, R １ is R in formula (II) １ and X is the same as X in formula (IV). The method according to claim 6, further comprising contacting a compound represented by the following formula with methoxyacetic acid to obtain the compound represented by formula (IV).

10. The method according to claim 1, further comprising a step of purifying the N,N-dimethylacetamide solvate of the compound represented by formula (I) by recrystallization.

11. A compound represented by the following formula (I): N,N-dimethylacetamide solvate of the compound represented by the formula:

12. A compound represented by the following formula (I): The composition contains an N,N-dimethylacetamide solvate of a compound represented by formula (I) in an amount of 95% by mass or more based on the total mass of the composition, and has the following formula (VII): The content of the compound represented by the formula (I) is 1800×10 of the total composition in terms of the free form. －４ % by weight or less.

13. A compound represented by the following formula (I): and a p-toluenesulfonate salt of a compound represented by the following formula (VII): The content of the p-toluenesulfonate salt of the compound represented by formula (I) is 95% by mass or more of the entire composition, and the content of the compound represented by formula (VII) is 100×10 in terms of a free form. －４ % by weight or less.

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