Crystallization of heterocyclic derivatives

Abstract

Disclosed are a crystalline form 1, a crystalline form 3 and a crystalline form 4 of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonic acid salt represented by formula (A-I).

Description

Technical Field

[0001] This disclosure relates to the crystallization of heterocyclic derivatives. Background Technology

[0002] Prostaglandins (PGs) are produced locally at the site of inflammation and are associated with the development of inflammation. Among PGs, prostaglandin E2 (PGE2), in particular, acts as an inflammatory inducer in both acute and chronic inflammation, triggering symptoms such as fever and hyperalgesia. PGE2 is known to be synthesized via PGE2 synthase (PGES), which serves as the final stage in the PGE2 synthesis pathway, acting as an inflammatory mediator. Three subtypes of PGES have been identified. Among them, membrane-bound prostaglandin E synthase-1 (mPGES-1), similar to cyclooxygenase 2 (COX2), is primarily induced during inflammation and is closely related to PGE2 production in inflammatory lesions. Based on this mechanism, mPGES-1 inhibitors can be considered as effective therapeutic agents for inflammatory diseases. Because mPGES-1 inhibitors only inhibit COX-2-dependent PGE2 production, they can reduce various side effects compared to NSAIDs and COX-2 inhibitors.

[0003] As an mPGES-1 inhibitor, Patent Document 1 describes 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).

[0004] [Chemical Formula 1]

[0005]

[0006] Existing technical documents

[0007] Patent documents

[0008] Patent Document 1: International Publication No. 2013 / 024898 Summary of the Invention

[0009] The problem that the invention aims to solve

[0010] It is known that compounds used as pharmaceuticals may have different physical properties, such as storage stability and solubility, which directly affect the effective utilization of the active ingredients in pharmaceuticals, due to their different forms (e.g., salts or solvates or their crystals).

[0011] The purpose of this disclosure is to provide crystallization of heterocyclic derivatives. Specifically, the purpose of this disclosure is to provide crystallization of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate (hereinafter also referred to as "p-toluenesulfonate of compound A") represented by the following formula (AI).

[0012] [Chemical Formula 2]

[0013]

[0014] Problem Solving Methods

[0015] The inventors have discovered a novel crystallization of p-toluenesulfonate of compound A. Furthermore, the inventors have found that the discovered crystallization of p-toluenesulfonate of compound A possesses excellent physical properties, such as storage stability and solubility, which directly and significantly impact its effective utilization as a pharmaceutical ingredient.

[0016] This disclosure relates, for example, to the following: <1> ~ <22> .

[0017] <1> The type I crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by the following formula (AI),

[0018] [Chemical Formula 3]

[0019]

[0020] The crystal exhibits diffraction peaks at diffraction angles (2θ±0.2°) of 7.1°, 14.3°, 15.8°, and 18.3° in powder X-ray diffraction.

[0021] <2> The type I crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by the following formula (AI),

[0022] [Chemical Formula 4]

[0023]

[0024] The crystals exhibited an endothermic peak at 265.8 ± 3.0 °C in differential scanning calorimetry.

[0025] <3> The type 3 crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by the following formula (AI),

[0026] [Chemical Formula 5]

[0027]

[0028] The crystal exhibits diffraction peaks at diffraction angles (2θ±0.2°) of 6.3°, 15.0°, 16.4°, 17.9°, and 22.7° in powder X-ray diffraction.

[0029] <4> The type 3 crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by the following formula (AI),

[0030] [Chemical Formula 6]

[0031]

[0032] The crystals exhibit an endothermic peak at 247.4 ± 3.0 °C in differential thermal analysis.

[0033] <5> The type IV crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by the following formula (AI),

[0034] [Chemical Formula 7]

[0035]

[0036] The crystal exhibits diffraction peaks at diffraction angles (2θ±0.2°) of 7.4°, 8.0°, 14.5°, 16.1°, and 20.6° in powder X-ray diffraction.

[0037] <6> The type IV crystal of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by the following formula (AI),

[0038] [Chemical Formula 8]

[0039]

[0040] The crystals exhibit an endothermic peak at 212.5 ± 3.0 °C in differential thermal analysis.

[0041] <7> A composition comprising <1> or <2> The crystals mentioned above, <1> or <2> The content of the crystals is 95% or more of the total mass of the composition, and the content of the compound represented by the following formula (VII) is 100 × 10⁻⁶ in free volume. -4 Less than 50% by mass, preferably 50×10 -4 Quality below %

[0042] [Chemical Formula 9]

[0043] .

[0044] <8> A composition comprising <1> or <2> The crystals and the compounds represented by the following formula (VII),

[0045] [Chemical Formula 10]

[0046]

[0047] <1> or <2> The content of the crystals is 95% or more of the total mass of the composition, and the content of the compound represented by the above formula (VII) is 100 × 10⁻⁶ in free volume. -6 Less than 50% by mass, preferably 50×10 -6 Quality percentage below:

[0048] <9> according to <7> or <8> The composition, wherein the content of the compound represented by the following formula (XI) is 100 × 10⁻⁶ in free volume. -4 It is preferably free of compounds represented by the above formula (XI) and contains less than % by mass.

[0049] [Chemical Formula 11]

[0050] .

[0051] <10> <1> or <2> The method for producing the crystals.

[0052] <11> <3> or <4> The method for producing the crystals.

[0053] <12> according to <11> The manufacturing method includes a step of exposing N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by formula (AI), to a temperature condition above 130°C.

[0054] <13> <5> or <6> The method for producing the crystals.

[0055] <14> according to <13> The manufacturing method includes a step of contacting N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide-4-methylbenzenesulfonate, represented by formula (AI), with acetonitrile and then exposing it to a temperature condition above 90°C.

[0056] <15> <7> , <8> or <9> A method for manufacturing the composition.

[0057] <16> according to <10> ~ <15> The manufacturing method described in any one of the following methods includes:

[0058] A process for obtaining N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate (i.e., p-toluenesulfonate of the compound represented by formula (I)) according to any one of [1] to

[28] ,

[0059] [Chemical Formula 12]

[0060]

[0061] [Chemical Formula 13]

[0062] .

[0063] <17> according to <1> or <2> The crystallization, which is achieved through <10> or <16> Manufactured using the aforementioned manufacturing method.

[0064] <18> according to <3> or <4> The crystallization, which is achieved through <11> , <12> or <16> Manufactured using the aforementioned manufacturing method.

[0065] <19> according to <5> or <6> The crystallization, which is achieved through <13> , <14> or <16> Manufactured using the aforementioned manufacturing method.

[0066] <20> according to <7> , <8> or <9> The composition, which is obtained by <15> or <16> Manufactured using the aforementioned manufacturing method.

[0067] <21> A pharmaceutical composition containing <1> ~ <6> and <17> ~ <19> Crystallization or as described in any of the above <7> ~ <9> and <20> The composition described in any one of the above statements is the active ingredient.

[0068] <22> A membrane-bound prostaglandin E synthase-1 inhibitor, which contains <1> ~ <6> and <17> ~ <19> Crystallization or as described in any of the above <7> ~ <9> and <20> The composition described in any one of the above statements is the active ingredient.

[0069] <16> [1] to

[28] are described below.

[0070] [1] A method for manufacturing a p-toluenesulfonate salt of a compound (compound A) represented by the following formula (I),

[0071] [Chemical Formula 14]

[0072]

[0073] The method includes a step of converting the N,N-dimethylacetamide compound of the compound (compound A) represented by formula (I) above into the p-toluenesulfonate salt of the compound (compound A) represented by formula (I) above.

[0074] [2] The manufacturing method according to [1] further includes a step of converting the compound represented by formula (II) into an N,N-dimethylacetamide compound represented by formula (I).

[0075] [Chemical Formula 15]

[0076]

[0077] (where R is in the formula) 1 Protecting groups representing carboxyl groups or H,R 2 This refers to a group that integrates with -OC (=O)- to form a protecting group of aniline amino groups.

[0078] [Chemical Formula 16]

[0079] .

[0080] [3] According to the manufacturing method described in [2], wherein,

[0081] The process of converting the compound represented by formula (II) above into the compound represented by formula (I) includes hydrolyzing the compound represented by formula (II) above in the presence of a base to obtain the compound represented by formula (III) below.

[0082] [Chemical Formula 17]

[0083] .

[0084] [4] According to the manufacturing method described in [2] or [3], wherein,

[0085] The process of converting a compound represented by formula (II) above into a compound represented by formula (I) includes converting a compound represented by formula (III) below into a compound represented by formula (VIII) below.

[0086] [Chemical Formula 18]

[0087]

[0088] [Chemical Formula 19]

[0089] .

[0090] [5] The manufacturing method according to any one of [2] to [4], wherein,

[0091] The process of converting the compound represented by formula (II) above into the compound represented by formula (I) includes converting the compound represented by formula (VIII) below into an N,N-dimethylacetamide compound of the compound represented by formula (I) below.

[0092] [Chemical Formula 20]

[0093]

[0094] [Chemical Formula 21]

[0095] .

[0096] [6] The manufacturing method according to any one of [2] to [5], wherein,

[0097] R in equation (II) above 1 and R 2 Each can be used independently to represent a C1 to C6 alkyl group.

[0098] [7] The manufacturing method according to any one of [2] to [6], wherein,

[0099] R in equation (II) above 1 and R 2 It is a methyl group.

[0100] [8] The manufacturing method according to any one of [1] to [7] further includes a step of obtaining a compound represented by the above formula (II), the step comprising:

[0101] By contacting a compound represented by formula (IV) below with a compound represented by formula (V) below, a compound represented by formula (II) above is obtained.

[0102] [Chemical Formula 22]

[0103]

[0104] (where R is in the formula) 1 R in equation (II) above 1 (Similarly, X represents Cl, Br, I, or OTf.)

[0105] [Chemical Formula 23]

[0106]

[0107] (where R is in the formula) 2 R in equation (II) above 2 same.).

[0108] [9] According to the manufacturing method described in [8], wherein,

[0109] In the above formula (IV), X is Cl, Br, or I.

[0110]

[10] According to the manufacturing method described in [8] or [9], wherein,

[0111] In the above formula (IV), X is Br.

[0112]

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

[10] , wherein,

[0113] In the process of obtaining the compound represented by formula (II) above, the compound represented by formula (IV) above or its protector is contacted with the compound represented by formula (V) above in the presence of a palladium catalyst.

[0114]

[12] According to the manufacturing method described in

[11] , wherein,

[0115] The palladium catalyst described above contains 0-valent palladium.

[0116]

[13] According to the manufacturing method described in

[11] or

[12] , wherein,

[0117] The palladium catalyst mentioned above is tris(dibenzylacetone)dipalladium(0).

[0118]

[14] The manufacturing method according to any one of

[11] to

[13] , wherein,

[0119] In the process of obtaining the compound represented by formula (II) above, the compound represented by formula (IV) above or its protector is contacted with the compound represented by formula (V) above in the presence of a ligand.

[0120]

[15] According to the manufacturing method described in

[14] , wherein,

[0121] The aforementioned ligand is 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl.

[0122]

[16] The manufacturing method according to any one of [8] to

[15] , wherein,

[0123] The compound represented by formula (IV) above, or its protecting agent, is a compound represented by formula (IX) below.

[0124] [Chemical Formula 24]

[0125]

[0126] (where R is in the formula) 1 R in equation (II) above 1 Similarly, X is the same as X in equation (IV) above.

[0127]

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

[16] , wherein,

[0128] The steps of obtaining the compound represented by formula (II) by contacting the compound represented by formula (IV) above with the compound represented by formula (V) above sequentially include:

[0129] The compound represented by formula (IV) above is converted into the compound represented by formula (IX) above;

[0130] By contacting the compound represented by formula (IX) above with the compound represented by formula (V) above, a compound represented by formula (X) is obtained.

[0131] [Chemical Formula 25]

[0132]

[0133] (where R is in the formula) 1 R in equation (II) above 1 Same, R 2 R in the above formula (V) 2 Same. ); and

[0134] The compound represented by formula (X) above is hydrolyzed in the presence of an acid to obtain the compound represented by formula (II) above.

[0135]

[18] The manufacturing method according to any one of [1] to

[17] further comprises:

[0136] The process of contacting a compound represented by formula (VI) below with methoxyacetic acid to obtain a compound represented by formula (IV) above,

[0137] [Chemical Formula 26]

[0138]

[0139] (where R is in the formula) 1 R in equation (II) above 1 Similarly, X is the same as X in equation (IV) above.

[0140]

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

[18] further comprises:

[0141] The process of purifying the N,N-dimethylacetamide compound of the compound represented by formula (I) above by recrystallization.

[0142]

[20] According to the manufacturing method described in

[19] , wherein,

[0143] The recrystallization of the N,N-dimethylacetamide compound represented by the above formula (I) was carried out using a mixed solvent of N,N-dimethylacetamide and water.

[0144]

[21] According to the manufacturing method described in

[19] or

[20] , wherein,

[0145] The recrystallization of the N,N-dimethylacetamide compound represented by the above formula (I) is carried out using a mixed solvent of N,N-dimethylacetamide and water, wherein the content of N,N-dimethylacetamide in the mixed solvent is 75% by volume or more.

[0146]

[22] The manufacturing method according to [1] to

[21] further includes, after the step of converting the N,N-dimethylacetamide compound of the compound represented by formula (I) above into the p-toluenesulfonate salt of the compound represented by formula (I) above:

[0147] The process includes a step of purifying the p-toluenesulfonate of the compound represented by formula (I) by contacting it with activated carbon; and a step of recrystallizing the p-toluenesulfonate of the compound represented by formula (I) after contact with activated carbon to obtain a type I crystal of the p-toluenesulfonate of the compound represented by formula (I).

[0148]

[23] According to the manufacturing method described in

[22] , wherein,

[0149] The mass of activated carbon in contact with the p-toluenesulfonate of the compound represented by formula (I) above is more than 0.04 times the mass of the p-toluenesulfonate of the compound represented by formula (I) above.

[0150]

[24] A method for manufacturing a p-toluenesulfonate salt of a compound (compound A) represented by the following formula (I),

[0151] [Chemical Formula 27]

[0152]

[0153] The method includes, in sequence:

[0154] A process for obtaining a compound represented by formula (II), the process comprising:

[0155] By contacting a compound represented by formula (IV) below with a compound represented by formula (V) below, a compound represented by formula (II) below is obtained.

[0156] [Chemical Formula 28]

[0157]

[0158] (where R is in the formula) 1 (The protecting group or H represents the carboxyl group, and X represents Cl, Br, I, or OTf.)

[0159] [Chemical Formula 29]

[0160]

[0161] (where R is in the formula) 2 This refers to a group that integrates with -OC (=O)- to form a protecting group of aniline amino groups.

[0162] [Chemical Formula 30]

[0163]

[0164] (where R is in the formula) 1 R in equation (IV) above 1 Same, R 2 R in the above formula (V) 2 same.);

[0165] A process for converting the compound represented by formula (II) above into an N,N-dimethylacetamide compound of the compound represented by formula (I) above (compound A), the process comprising:

[0166] Hydrolyzing the compound represented by formula (II) in the presence of a base yields the compound represented by formula (III) below.

[0167] [Chemical Formula 31]

[0168] ;

[0169] The compound represented by formula (III) above is converted into a compound represented by formula (VIII) below.

[0170] [Chemical Formula 32]

[0171] ;as well as

[0172] The compound represented by formula (VIII) above is converted into an N,N-dimethylacetamide compound of the compound represented by formula (I) above (compound A); and

[0173] The process of converting the N,N-dimethylacetamide compound (compound A) represented by the above formula (I) into the p-toluenesulfonate salt of the compound (compound A) represented by the above formula (I).

[0174]

[25] A method for manufacturing a p-toluenesulfonate salt of a compound (compound A) represented by the following formula (I),

[0175] [Chemical Formula 33]

[0176]

[0177] The method includes, in sequence:

[0178] The process of contacting a compound represented by formula (VI) with methoxyacetic acid to obtain a compound represented by formula (IV) is described below.

[0179] [Chemical Formula 34]

[0180]

[0181] (where R is in the formula) 1 (The protecting group or H represents the carboxyl group, and X represents Cl, Br, I, or OTf.)

[0182] [Chemical Formula 35]

[0183]

[0184] (where R is in the formula) 1 And X respectively with R in the above formula (VI) 1 (and X are the same.)

[0185] The process of converting the compound represented by formula (IV) above into the compound represented by formula (II) below,

[0186] [Chemical Formula 36]

[0187]

[0188] (where R is in the formula) 1 R in equation (VI) above 1 Same, R 2 This refers to a group that integrates with -OC (=O)- to form a protecting group of aniline amino groups.

[0189] This process includes, in sequence:

[0190] The compound represented by formula (IV) above is converted into the compound represented by formula (IX) below.

[0191] [Chemical Formula 37]

[0192]

[0193] (where R is in the formula) 1 And X respectively with R in the above formula (VI) 1 (and X are the same.)

[0194] By contacting the compound represented by formula (IX) above with the compound represented by formula (V) below, a compound represented by formula (X) below is obtained.

[0195] [Chemical Formula 38]

[0196]

[0197] (where R is in the formula) 2 R in equation (II) above 2 same.)

[0198] [Chemical Formula 39]

[0199]

[0200] (where R is in the formula) 1 R in equation (VI) above 1 Same, R 2 R in equation (II) above 2 Same. ; and

[0201] The compound represented by formula (X) above is hydrolyzed in the presence of acid to obtain the compound represented by formula (II) above;

[0202] A process for converting the compound represented by formula (II) above into an N,N-dimethylacetamide compound of the compound represented by formula (I) above (compound A), the process comprising:

[0203] The compound represented by formula (II) above is hydrolyzed in the presence of a base to give the compound represented by formula (III) below.

[0204] [Chemical Formula 40]

[0205] ;

[0206] The compound represented by formula (III) above is converted into a compound represented by formula (VIII) below.

[0207] [Chemical Formula 41]

[0208] ;and

[0209] The compound represented by formula (VIII) above is converted into an N,N-dimethylacetamide compound of the compound represented by formula (I) above (compound A);

[0210] The process of converting the N,N-dimethylacetamide compound (compound A) represented by the above formula (I) into the p-toluenesulfonate of the compound (compound A) represented by the above formula (I);

[0211] The process of purifying the N,N-dimethylacetamide of the compound (compound A) represented by the above formula (I) by recrystallization;

[0212] The process of purifying p-toluenesulfonate of the compound (compound A) represented by formula (I) above by contacting it with activated carbon; and

[0213] The process of recrystallizing the p-toluenesulfonate of the compound (compound A) represented by formula (I) above after contact with activated carbon to obtain type I crystals of the p-toluenesulfonate of the compound (compound A) represented by formula (I) above.

[0214]

[26] According to the manufacturing method described in

[24] or

[25] , wherein,

[0215] The above R 1 and the above R 2 It is a C1~C6 alkyl group, preferably methyl, and X is Cl, Br or I, preferably Br.

[0216]

[27] According to the manufacturing method described in

[25] , wherein,

[0217] The above R 1 and the above R 2 It is a C1-C6 alkyl group, preferably methyl.

[0218] X is Cl, Br, or I, preferably Br.

[0219] The contact between the compound represented by formula (IV) above or its protecting agent and the compound represented by formula (V) above is carried out in the presence of a palladium catalyst.

[0220] The recrystallization of the N,N-dimethylacetamide compound represented by formula (I) above is carried out using a mixed solvent of N,N-dimethylacetamide and water, preferably using a mixed solvent of N,N-dimethylacetamide and water with an N,N-dimethylacetamide content of 75% by volume or more.

[0221] The mass of activated carbon in contact with the p-toluenesulfonate of the compound represented by formula (I) above is 0.04 times or more, preferably 0.08 times or more, of the mass of the p-toluenesulfonate of the compound represented by formula (I) above.

[0222]

[28] The manufacturing method according to any one of

[24] to

[27] , wherein,

[0223] The contact between the compound represented by formula (IV) above or its protector and the compound represented by formula (V) above is carried out in the presence of a palladium catalyst containing 0-valent palladium and a ligand, preferably in the presence of tris(dibenzylacetone)dipalladium(0) and 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl.

[0224] The effects of the invention

[0225] According to this disclosure, novel crystals of p-toluenesulfonate of compound A, pharmaceutical compositions containing the same, and membrane-bound prostaglandin E synthase-1 inhibitors can be provided. Additionally, according to this disclosure, a method for manufacturing crystals of p-toluenesulfonate of compound A can be provided.

[0226] According to one embodiment of this disclosure, type I crystals of p-toluenesulfonate of compound A can be provided. The type I crystals of p-toluenesulfonate of compound A are highly stable crystals. According to one embodiment of this disclosure, type I crystals of p-toluenesulfonate of compound A with excellent preservation stability, as well as pharmaceutical compositions containing the same and membrane-bound prostaglandin E synthase-1 inhibitors, can be provided.

[0227] According to one embodiment of this disclosure, type 3 crystals of p-toluenesulfonate of compound A can be provided. The type 3 crystals of p-toluenesulfonate of compound A have high solubility and are crystals of p-toluenesulfonate of compound A. According to one embodiment of this disclosure, type 3 crystals of p-toluenesulfonate of compound A with excellent in vivo solubility and absorption (e.g., bioavailability), as well as pharmaceutical compositions containing the crystals and membrane-bound prostaglandin E synthase-1 inhibitors, can be provided.

[0228] According to one embodiment of the present disclosure, type 4 crystals of p-toluenesulfonate of compound A, as well as pharmaceutical compositions containing the same and membrane-bound prostaglandin E synthase-1 inhibitors, can be provided.

[0229] According to one embodiment of this disclosure, crystals of p-toluenesulfonate of compound A with excellent stability can be provided. According to one embodiment of this disclosure, crystals of p-toluenesulfonate of compound A with excellent solubility can be provided. Such crystals of p-toluenesulfonate of compound A with excellent physical properties are suitable for use as active ingredients in pharmaceutical compositions and membrane-bound prostaglandin E synthase-1 inhibitors. Attached Figure Description

[0230] Figure 1 This is a graph showing the results of powder X-ray diffraction of type I crystals of p-toluenesulfonate of compound A in Example 1.

[0231] Figure 2 This is a graph showing the results of thermophysical property measurements of type I crystals of p-toluenesulfonate of compound A in Example 1, based on differential scanning calorimetry (DSC).

[0232] Figure 3 This is a graph showing the results of thermophysical property determination based on differential thermal analysis (DTA) and thermogravimetric analysis (TGA) of type I crystals of p-toluenesulfonate of compound A in Example 1.

[0233] Figure 4 This is a diagram showing the results of powder X-ray diffraction of the amorphous p-toluenesulfonate of compound A in Preparation Example 1.

[0234] Figure 5 This is an enlarged view showing the results of powder X-ray diffraction of the amorphous p-toluenesulfonate of compound A in Preparation Example 1.

[0235] Figure 6 This is a graph showing the results of powder X-ray diffraction of type 3 crystals of p-toluenesulfonate of compound A in Example 2.

[0236] Figure 7 This is a graph showing the results of thermophysical property determination based on differential thermal analysis (DTA) and thermogravimetric analysis (TGA) for the type 3 crystals of p-toluenesulfonate of compound A in Example 2.

[0237] Figure 8 This is a graph showing the results of powder X-ray diffraction of the intermediate product in the manufacture of type 4 crystals of p-toluenesulfonate of compound A in Example 3.

[0238] Figure 9 This is a graph showing the results of thermophysical property determination based on differential thermal analysis (DTA) and thermogravimetric analysis (TGA) of the intermediate product in the manufacture of type 4 crystals of p-toluenesulfonate of compound A in Example 3.

[0239] Figure 10This is a graph showing the results of powder X-ray diffraction of type 4 crystals of p-toluenesulfonate of compound A in Example 3.

[0240] Figure 11 This is a graph showing the results of thermophysical property determination based on differential thermal analysis (DTA) and thermogravimetric analysis (TGA) for the type 4 crystals of p-toluenesulfonate of compound A in Example 3.

[0241] Figure 12 This is a graph showing the results of powder X-ray diffraction of the intermediate product in the manufacture of type 5 crystals of p-toluenesulfonate of compound A in Comparative Example 1.

[0242] Figure 13 This is a graph showing the results of thermophysical property determination based on differential thermal analysis (DTA) and thermogravimetric analysis (TGA) of the intermediate product in the manufacture of type 5 crystals of p-toluenesulfonate of compound A in Comparative Example 1.

[0243] Figure 14 This is a graph showing the results of powder X-ray diffraction of type 5 crystals of p-toluenesulfonate of compound A in Comparative Example 1.

[0244] Figure 15 This is a graph showing the results of the thermophysical property determination of type 5 crystals of p-toluenesulfonate of compound A in Comparative Example 1, based on differential thermal analysis (DTA) and thermogravimetric analysis (TGA).

[0245] Figure 16 This is a graph showing the results of powder X-ray diffraction of the intermediate product in the manufacture of type 6 crystals of p-toluenesulfonate of compound A in Comparative Example 2.

[0246] Figure 17 This is a graph showing the results of powder X-ray diffraction of type 6 crystals of p-toluenesulfonate of compound A in Comparative Example 2.

[0247] Figure 18 This is a graph showing the results of the thermophysical property determination of type 6 crystals of p-toluenesulfonate of compound A in Comparative Example 2, based on differential thermal analysis (DTA) and thermogravimetric analysis (TGA).

[0248] Figure 19 This is a graph showing the results of powder X-ray diffraction of the intermediate product in the manufacture of type 7 crystals of p-toluenesulfonate of compound A in Comparative Example 3.

[0249] Figure 20 This is a graph showing the results of powder X-ray diffraction of type 7 crystals of p-toluenesulfonate of compound A in Comparative Example 3.

[0250] Figure 21This is a graph showing the results of the thermophysical property determination of type 7 crystals of p-toluenesulfonate of compound A in Comparative Example 3, based on differential thermal analysis (DTA) and thermogravimetric analysis (TGA).

[0251] Figure 22 This is a graph showing the results of powder X-ray diffraction after stirring at 20°C for 3, 4, 7 and 8 days in Example 9.

[0252] Figure 23 This is a graph showing the results of powder X-ray diffraction after stirring at 55°C for 3 days and 4 days in Example 9.

[0253] Figure 24 This is a graph showing the results of powder X-ray diffraction of type I crystals of p-toluenesulfonate of compound A after various treatments in Example 12.

[0254] Figure 25 This is a graph showing the results of powder X-ray diffraction of type II crystals of p-toluenesulfonate of compound A in Comparative Example 4.

[0255] Figure 26 This is a graph showing the results of the thermophysical properties of type II crystals of p-toluenesulfonate of compound A in Comparative Example 4, based on differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA).

[0256] Figure 27 This is a graph showing the results of powder X-ray diffraction during heating and cooling of type 2 crystals of p-toluenesulfonate of compound A in Example 14.

[0257] Figure 28 This is a graph showing the results of powder X-ray diffraction in various solvents used to evaluate the stability of type 1 crystals of p-toluenesulfonate of compound A in Example 16.

[0258] Figure 29 This is a graph showing the results of powder X-ray diffraction of type I crystals of p-toluenesulfonate of compound A in Reference Example 1.

[0259] Figure 30 This is a graph showing the results of the thermophysical properties of type I crystals of p-toluenesulfonate of compound A in Reference Example 1, based on differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Detailed Implementation

[0260] The following describes the methods for implementing this disclosure, but this disclosure is not limited to the following embodiments.

[0261] In this disclosure, unless otherwise specified, the term "compound" includes the free form of the compound, its salts, and their solvates, including any form of the compound. On the other hand, the terms "hydrochloride salt of the compound," "N,N-dimethylacetamide compound of the compound," and "p-toluenesulfonate salt of the compound" refer to the specifically stated salt or solvate of the compound, excluding other forms of the compound. In a more specific description, for example, "converting a compound represented by structural formula (1) into a compound represented by structural formula (2)" means converting a compound represented by structural formula (1) in any form into a compound represented by structural formula (2) in any form. For another example, the statement "hydrolyzing a compound represented by structural formula (1) to obtain an N,N-dimethylacetamide compound represented by structural formula (2)" means hydrolyzing a compound represented by structural formula (1) in any form to obtain a compound represented by structural formula (2) in the form of an N,N-dimethylacetamide compound. For example, the description of "contacting the hydrochloride salt of a compound represented by structural formula (1) with a compound represented by structural formula (3) to obtain a p-toluenesulfonate salt of a compound represented by structural formula (2)" refers to contacting the hydrochloride salt of a compound represented by structural formula (1) with any form of a compound represented by structural formula (3) to obtain a p-toluenesulfonate salt of a compound represented by structural formula (2). In this disclosure, "N,N-dimethylacetamide complex of the compound" refers to a solvate formed by the mediated reaction of N,N-dimethylacetamide with the compound. The p-toluenesulfonate salt of the compound of this disclosure can be, for example, a salt of the compound and p-toluenesulfonic acid in a 1:1 ratio. The N,N-dimethylacetamide complex of the compound of this disclosure can be, for example, a solvate of the compound and N,N-dimethylacetamide complex in a 1:1 ratio.

[0262] The chemical reactions in this disclosure can be appropriately quenched using methods commonly used by those skilled in the art, and the products can be recovered using methods commonly used by those skilled in the art, such as vacuum distillation, filtration, or extraction. Furthermore, the products of the chemical reactions in this disclosure can be purified using methods commonly used by those skilled in the art, such as recrystallization or column chromatography. From the viewpoint of large-scale production, purification can be carried out by recrystallization in a preferred embodiment. Additionally, the reactions in each step of this disclosure can be tracked using methods commonly used by those skilled in the art, including chromatography such as reversed-phase liquid chromatography (HPLC), and the products can be analyzed using methods commonly used by those skilled in the art, such as HPLC, nuclear magnetic resonance (NMR), mass analysis, X-ray crystal structure determination, and DSC.

[0263] In this disclosure, 4-methylbenzenesulfonic acid is sometimes referred to as p-toluenesulfonic acid, para-toluenesulfonic acid, toluenesulfonic acid (tosyl acid) or p-TsOH.

[0264] In this disclosure, "having a diffraction peak at a diffraction angle (2θ±X°) of Y°" means that a diffraction peak exists at a diffraction angle (2θ) of Y±X°. For example, "having a diffraction peak at a diffraction angle (2θ±0.2°) of 14.5°" means that a diffraction peak exists in the range of diffraction angle (2θ) above 14.3° and below 14.7°. It should be noted that in this disclosure, the diffraction angles and diffraction patterns of powder X-ray diffraction refer to the diffraction angles and diffraction patterns obtained by irradiation with copper Kα rays (CuKα).

[0265] <Type I crystallization of p-toluenesulfonate of compound A>

[0266] The first aspect of this disclosure relates to type I crystallization of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by the following formula (AI).

[0267] [Chemical Formula 42]

[0268]

[0269] That is, the first aspect of this disclosure relates to type I crystallization of p-toluenesulfonate of compound A. The first aspect of this disclosure may, in one embodiment, be the type I crystallization of p-toluenesulfonate of compound A manufactured by the manufacturing method of the fifth aspect of this disclosure, described later.

[0270] In one embodiment of the first aspect of this disclosure, type I crystals of the p-toluenesulfonate of compound A exhibit diffraction peaks at diffraction angles of 7.1°, 14.3°, 15.8°, and 18.3° in powder X-ray diffraction at diffraction angles of (2θ), (2θ±0.1°), (2θ±0.2°), (2θ±0.3°), (2θ±0.4°), or (2θ±0.5°). In a preferred embodiment of the first aspect of this disclosure, type I crystals of the p-toluenesulfonate of compound A exhibit diffraction peaks at diffraction angles of 7.1°, 14.3°, 15.8°, and 18.3° in powder X-ray diffraction. In one embodiment of this disclosure, the type I crystals of p-toluenesulfonate of compound A exhibit diffraction peaks at diffraction angles (2θ±0.2°) of 7.1°, 14.3°, 15.8°, 18.3°, and 22.0° in powder X-ray diffraction. In another embodiment of this disclosure, the type I crystals of p-toluenesulfonate of compound A exhibit diffraction peaks at diffraction angles (2θ±0.2°) of 7.1°, 8.5°, 14.3°, 15.8°, 18.3°, 18.8°, 19.6°, 20.1°, 22.0°, and 25.8° in powder X-ray diffraction. In one embodiment of this disclosure, the type 1 crystals of p-toluenesulfonate of compound A can exhibit diffraction peaks in powder X-ray diffraction at diffraction angles (2θ ± 0.2°) of 7.1°, 8.5°, 11.8°, 14.3°, 14.7°, 15.8°, 16.4°, 17.4°, 18.3°, 18.8°, 19.6°, 20.1°, 22.0°, 23.5°, 24.4°, 25.3°, 25.8°, 27.3°, 28.8°, and 29.0°.

[0271] The type I crystals of p-toluenesulfonate of compound A, according to one embodiment of the first aspect of this disclosure, exhibit an endothermic peak at 265.8 ± 3.0 °C in differential scanning calorimetry (DSC). The type I crystals of p-toluenesulfonate of compound A, according to one embodiment of the first aspect of this disclosure, also exhibit diffraction peaks at diffraction angles (2θ ± 0.2°) of 7.1°, 14.3°, 15.8°, and 18.4° in powder X-ray diffraction, and an endothermic peak at 265.8 ± 3.0 °C in DSC. Furthermore, the type I crystals of p-toluenesulfonate of compound A, according to one embodiment of the first aspect of this disclosure, exhibit an endothermic peak at 263.0 ± 3.0 °C in differential thermal analysis. Additionally, the type I crystals of p-toluenesulfonate of compound A, according to one embodiment of the first aspect of this disclosure, remain stable for more than 7 days at a temperature of 40 °C and a relative humidity of 75%.

[0272] The p-toluenesulfonate crystal of compound A, according to one embodiment of the first aspect of this disclosure, is a type I crystal with excellent stability. In this disclosure, excellent stability of the crystal means, for example, excellent storage stability, or, for example, stability to processing during formulation, or, for example, the most stable crystal form among multiple crystal forms of the same compound.

[0273] Excellent storage stability of p-toluenesulfonate crystals of compound A means that, during static crystallization or when the crystals are exposed to stimuli such as heating, light, or humidity, the p-toluenesulfonate of compound A contained in the crystals does not significantly decompose and its crystal form does not change significantly. Examples of no significant change observed include crystals of p-toluenesulfonate of compound A with the same crystal form as before exposure to the stimulus, accounting for 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, or 99.65% or more of the p-toluenesulfonate source material contained in the crystals after exposure to the stimulus. Furthermore, as other examples where no significant changes were observed, the reduction rate of the proportion of p-toluenesulfonate crystals of compound A with the same crystal form as the observed crystals to the total proportion of p-toluenesulfonate crystals of compound A before and after exposure to the irritant is less than 10%, less than 5%, less than 3%, less than 1%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.01%, or less than 0.005%. In these cases, the proportion (%) can be, for example, the proportion (%) of the peak area in HPLC (e.g., the peak area of ​​absorbance at a wavelength of 230 nm), or it can be a mass percentage; in a preferred embodiment, it can be the proportion of the peak area in HPLC.

[0274] The stability of the p-toluenesulfonate crystals of compound A to formulation treatment means that, when subjected to treatments during formulation such as mixing the crystals with excipients, pulverizing the crystals, exposing the crystals to water, or pressing the crystals into tablets, the p-toluenesulfonate of compound A contained in the crystals does not significantly decompose and its crystal form does not significantly change. Examples of no significant change observed include: the proportion of p-toluenesulfonate crystals of compound A with the same crystal form as before treatment to the proportion of the p-toluenesulfonate source of compound A contained in the treated crystals being 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 99% or more, 99.5% or more, 99.6% or more, or 99.65% or more. Furthermore, as other examples where no significant changes were observed, the reduction rate of the proportion of p-toluenesulfonate crystals of compound A with the same crystal form as the observed crystals to the total proportion of p-toluenesulfonate crystals of compound A before and after the treatment is less than 10%, less than 5%, less than 3%, less than 1%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.01%, or less than 0.005%. In these cases, the proportion can be, for example, the percentage of peak area in HPLC (e.g., the peak area of ​​absorbance at a wavelength of 230 nm), or it can be a percentage by mass; in a preferred embodiment, it can be the percentage of peak area in HPLC.

[0275] The most stable crystal form of p-toluenesulfonate of compound A among multiple crystal forms of the same compound can refer to, for example, the crystal form exhibiting the best stability among the tested p-toluenesulfonate crystals of compound A when multiple p-toluenesulfonate crystals of compound A are subjected to tests for the aforementioned storage stability or formulation stability. The most stable crystal form of p-toluenesulfonate of compound A among multiple crystal forms of the same compound can also refer to, for example, the crystal form that is most abundant in the mixture when multiple p-toluenesulfonate crystals of compound A are present in equal proportions in the same mixture and incubated.

[0276] <Type 3 crystallization of p-toluenesulfonate of compound A>

[0277] The second aspect of this disclosure relates to type 3 crystallization of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by the following formula (AI).

[0278] [Chemical Formula 43]

[0279]

[0280] That is, the second aspect of this disclosure relates to the type 3 crystallization of p-toluenesulfonate of compound A. The second aspect of this disclosure can be, in one embodiment, the type 3 crystallization of p-toluenesulfonate of compound A produced by the manufacturing method of the sixth aspect of this disclosure, described later.

[0281] In one embodiment of the second aspect of this disclosure, the type 3 crystals of p-toluenesulfonate of compound A exhibit diffraction peaks at diffraction angles (2θ ± 0.1°), (2θ ± 0.2°), (2θ ± 0.3°), (2θ ± 0.4°), or (2θ ± 0.5°) of 6.3°, 15.0°, 16.4°, 17.9°, and 22.7°. In a preferred embodiment of the second aspect of this disclosure, the type 3 crystals of p-toluenesulfonate of compound A exhibit diffraction peaks at diffraction angles (2θ ± 0.2°) of 6.3°, 15.0°, 16.4°, 17.9°, and 22.7°.

[0282] The type 3 crystals of p-toluenesulfonate of compound A, according to one embodiment of the second aspect of this disclosure, exhibit an endothermic peak at 247.4 ± 3.0 °C in differential thermal analysis. The type 3 crystals of p-toluenesulfonate of compound A, according to one embodiment of the second aspect of this disclosure, also exhibit diffraction peaks at diffraction angles (2θ ± 0.2°) of 6.3°, 15.0°, 16.4°, 17.9°, and 22.7° in powder X-ray diffraction, and an endothermic peak at 247.4 ± 3.0 °C in differential thermal analysis. Furthermore, the type 3 crystals of p-toluenesulfonate of compound A, according to one embodiment of the second aspect of this disclosure, remain stable for more than 7 days at a temperature of 40 °C and a relative humidity of 75%.

[0283] The p-toluenesulfonate of compound A, according to one embodiment of the second aspect of this disclosure, exhibits excellent solubility in its type 3 crystal form. It is not intended to be limited by any particular theory, but it can be considered that the type 3 crystal form of p-toluenesulfonate of compound A has relatively low stability compared to the type 1 crystal form, which is the most stable crystal form, and therefore requires less energy to dissolve, resulting in high solubility.

[0284] <Type IV crystallization of p-toluenesulfonate of compound A>

[0285] The third aspect of this disclosure relates to type 4 crystals of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by the following formula (AI).

[0286] [Chemical Formula 44]

[0287]

[0288] That is, the third aspect of this disclosure relates to the type IV crystallization of p-toluenesulfonate of compound A. The third aspect of this disclosure may be, in one embodiment, the type IV crystallization of p-toluenesulfonate of compound A manufactured by the manufacturing method of the seventh aspect of this disclosure, described later.

[0289] In one embodiment of the third aspect of this disclosure, the type 4 crystals of the p-toluenesulfonate of compound A exhibit diffraction peaks at diffraction angles (2θ ± 0.1°), (2θ ± 0.2°), (2θ ± 0.3°), (2θ ± 0.4°), or (2θ ± 0.5°) of 7.4°, 8.0°, 14.5°, 16.1°, and 20.6° in powder X-ray diffraction. In a preferred embodiment of the third aspect of this disclosure, the type 4 crystals of the p-toluenesulfonate of compound A exhibit diffraction peaks at diffraction angles (2θ ± 0.2°) of 7.4°, 8.0°, 14.5°, 16.1°, and 20.6° in powder X-ray diffraction.

[0290] The type 4 crystals of p-toluenesulfonate of compound A according to one embodiment of the third aspect of this disclosure have an endothermic peak at 212.5 ± 3.0 °C in differential thermal analysis. The type 4 crystals of p-toluenesulfonate of compound A according to one embodiment of the third aspect of this disclosure also have diffraction peaks at diffraction angles (2θ ± 0.2°) of 7.4°, 8.0°, 14.5°, 16.1°, and 20.6° in powder X-ray diffraction, and an endothermic peak at 212.5 ± 3.0 °C in differential thermal analysis.

[0291] <Composition>

[0292] The fourth aspect of this disclosure is a composition comprising type I crystals of p-toluenesulfonate of compound A of the first aspect of this disclosure, wherein the content of type I crystals of p-toluenesulfonate of compound A is 95% by mass or more of the total composition, and the content of the compound represented by formula (VII) below (hereinafter also referred to as "compound B") is below a given upper limit.

[0293] [Chemical Formula 45]

[0294]

[0295] Another embodiment of the fourth aspect of this disclosure is a composition comprising type I crystals of p-toluenesulfonate of compound A of the first aspect of this disclosure and compound B, wherein the content of type I crystals of p-toluenesulfonate of compound A is 95% by mass or more of the total composition, and the content of compound B is below a given upper limit. The composition in the fourth aspect of this disclosure refers to a composition comprising one or more components contained in any materials used in the preparation of type I crystals of p-toluenesulfonate of compound A, and reaction products of one or more stages thereof.

[0296] Compound B poses a potential mutagenic risk and may occur during the production of type I crystals of p-toluenesulfonate of compound A. In the composition of one embodiment of this disclosure, the amount of compound B is reduced, thereby reducing the risk of mutagenicity when the composition is used in the manufacture of a pharmaceutical product, and also alleviating the burden of controlling the amount of compound B, which is required to be controlled at the ppm level, during the production of type I crystals of p-toluenesulfonate of compound A.

[0297] In one embodiment of the fourth aspect of this disclosure, the content of compound B in the composition, expressed in free form, can be, for example, 1000 × 10⁻⁶ of the total composition. -4 less than % of mass, 600×10 -4 less than % of mass, 300×10 -4 less than 100% of mass, 100×10 -4 less than 50% of mass, 50×10 -4 less than % of mass or 20×10 -4 For example, the content of compound B, expressed as a free fraction, is less than 100 × 10⁻⁶ by mass. -4 Less than 95% by mass. Furthermore, in one embodiment of the fourth aspect of this disclosure, the content of p-toluenesulfonate of compound A in the composition can be 95% or more by mass, 96% or more by mass, 97% or more by mass, 98% or more by mass, or 99% or more by mass of the total composition.

[0298] In a composition according to an embodiment of the fourth aspect of this disclosure, the content of the compound represented by the following formula (XI) (hereinafter also referred to as "compound C") is below a given upper limit in free volume conversion, such given upper limit is, for example, 1000 × 10⁻⁶. -4 mass%, 600×10 -4 mass%, 300×10 -4 mass%, 100×10 -4 mass%, 50×10 -4 mass% or 20×10⁻⁶ 4As a specific example, the content of compound C, expressed as a free fraction, is 50 × 10⁻⁶. -4 Less than % by mass. The composition of a preferred embodiment of the fourth aspect of this disclosure does not contain compound C.

[0299] [Chemical Formula 46]

[0300]

[0301] Compound C is a synthetic intermediate used in the manufacture of compound A by the manufacturing method described in Patent Document 1. However, it has been clearly established that, based on evaluations using multiple In Silico assay software capable of predicting mutagenicity (genotoxicity), compound C is highly likely to be mutagenic (genotoxic). Therefore, in the composition of one embodiment of the fourth aspect of this disclosure, if the content of compound C is below the aforementioned upper limit or does not contain compound C, the risk of mutagenicity in the pharmaceuticals used in the manufacture of the composition of one embodiment of the fourth aspect of this disclosure can be reduced, and the burden of controlling the amount of compound C, which is required to be controlled at the ppm level, can be alleviated in the manufacture of type I crystals of the p-toluenesulfonate of compound A.

[0302] <Method for manufacturing type I crystals of p-toluenesulfonate of compound A or compositions comprising it>

[0303] The fifth aspect of this disclosure is a method for manufacturing type I crystals of p-toluenesulfonate of compound A or a composition comprising the same. This fifth aspect may be, in one embodiment, a method for manufacturing type I crystals of p-toluenesulfonate of compound A according to an embodiment of the first aspect of this disclosure, or a method for manufacturing a composition according to an embodiment of the fourth aspect of this disclosure.

[0304] The manufacturing method of the fifth aspect of this disclosure includes a step of obtaining N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate (i.e., p-toluenesulfonate of the compound represented by the following formula (I)) as represented by formula (AI).

[0305] [Chemical Formula 47]

[0306]

[0307] [Chemical Formula 48]

[0308]

[0309] The following describes one embodiment of such a manufacturing method.

[0310] <Step 1>

[0311] The first step is to obtain a compound represented by the following formula (IV).

[0312] [Chemical Formula 49]

[0313]

[0314] (where R is in the formula) 1 (The protecting group or H represents the carboxyl group, and X represents Cl, Br, I, or OTf.)

[0315] R in equation (IV) above 1 The protecting group is a carboxyl group or H, preferably a carboxyl group. In this disclosure, the carboxyl group is used as long as it is not removed in the second / third step described later, and can be removed in the fourth step described later as at least the bonds other than the carbamate bonds in the compound represented by formula (II) below are broken to obtain R of formula (II). 1 Any group of the compound that is H can be used, without particular limitation. For example, it can be an alkyl, cycloalkyl, alkenyl, alkoxymethyl, or benzyl protecting group. In one embodiment, it can be a C1-C6 alkyl, C4-C6 cycloalkyl, C1-C6 alkenyl, C1-C6 alkoxymethyl (C1-C6 alkoxylated methyl), benzyl, phenethyl, or p-methoxybenzyl. In a preferred embodiment, it can be a C1-C6 alkyl. In another preferred embodiment, it can be methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, vinyl, allyl, methoxymethyl, benzyl, or p-methoxybenzyl. In a more preferred embodiment, it can be methyl or ethyl. In the most preferred embodiment, it can be methyl.

[0316] [Chemical Formula 50]

[0317]

[0318] (where R is in the formula) 1 R in equation (VI) above 1 Same, R 2 This refers to a group that integrates with -OC (=O)- to form a protecting group of aniline amino groups.

[0319] Regarding R in equation (IV) above 1 In this context, X can be Cl, Br, I, or OTf (O-SO2-CF3). In a preferred embodiment, it can be Cl, Br, or I; in a more preferred embodiment, it can be Cl or Br; and in the most preferred embodiment, it can be Br.

[0320] In a most preferred embodiment, the compound represented by formula (IV) above may be methyl 6-bromo-2-(methoxymethyl)-1H-benzimidazole-4-carboxylate represented by formula (IV').

[0321] [Chemical Formula 51]

[0322]

[0323] The form of the above formula (IV') obtained in the first step is not particularly limited, and in one embodiment it can be obtained in the form of a free body.

[0324] In one embodiment, the first step may be a step that includes contacting a compound represented by formula (VI) below with methoxyacetic acid to obtain a compound represented by formula (IV) above.

[0325] [Chemical Formula 52]

[0326]

[0327] (where R is in the formula) 1 and X and R in equation (IV) 1 (And X is the same.)

[0328] The contact temperature between the compound represented by formula (VI) and methoxyacetic acid is not particularly limited, as long as the temperature at which the imidazole ring of the compound represented by formula (IV) forms is present. For example, it can be 50°C to 150°C, 60°C to 120°C, 70°C to 105°C, or 80°C to 95°C. Furthermore, when contacting the compound represented by formula (VI) with methoxyacetic acid, the contact can be carried out in a solvent, or it can be carried out without a solvent by dissolving the compound represented by formula (VI) in methoxyacetic acid. From the viewpoint of maximizing reaction efficiency, in a preferred embodiment, the contact can be carried out without a solvent by dissolving the compound represented by formula (VI) in methoxyacetic acid. Alternatively, when using a solvent, an organic solvent that dissolves the compound represented by formula (VI) and methoxyacetic acid and has a boiling point below the aforementioned temperature range can be suitably used, for example, N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMA).

[0329] The reaction time of the compound represented by formula (VI) above with methoxyacetic acid is not particularly limited, as long as it is sufficient to obtain the compound represented by formula (IV) above. For example, it can be 5 to 20 hours. In addition, during this period, the reaction vessel can be purged with an inert gas such as nitrogen or argon.

[0330] When the compound represented by formula (VI) above is contacted with methoxyacetic acid, the equivalent relationship between the two is not particularly limited as long as the compound represented by formula (VI) above can be obtained in a high yield (e.g., yield of 75% or more) relative to the starting material. In one embodiment, the equivalent of methoxyacetic acid relative to 1 equivalent of the compound represented by formula (VI) above can be, for example, 1 to 100 equivalents, 2 to 50 equivalents, or 4 to 25 equivalents, and as a specific example, it can be 10 equivalents.

[0331] <Step 2 / 3>

[0332] Step 2 / 3 is the process of obtaining a compound represented by the following formula (II).

[0333] [Chemical Formula 53]

[0334]

[0335] (where R is in the formula) 1 R in equation (VI) above 1 Same, R 2 This refers to a group that integrates with -OC (=O)- to form a protecting group of aniline amino groups.

[0336] Step 2 / 3 involves contacting the compound or its protector represented by formula (IV) above with the compound represented by formula (V) below to obtain the compound or its protector represented by formula (II) above.

[0337] [Chemical Formula 54]

[0338]

[0339] (where R is in the formula) 2 R in equation (II) above 2 same.)

[0340] R in equation (II) above 2 This refers to a group that integrates with -OC (=O)- to form a protecting group of the aniline amino group. In this case, the protecting group of the aniline amino group is simply formed by removing R from formula (II) above in step 4 described later. 1 Come on R 1 Any protecting group that was not removed during the conversion to H can be used; there are no particular limitations. R serves as the protecting group for forming such an aniline amino group. 2For example, it can be a hydrocarbon group having one or more alkyl, cycloalkyl, alkenyl or aromatic rings. In one embodiment, it can be C1-C6 alkyl, C4-C6 cycloalkyl, C1-C6 alkenyl, benzyl, phenethyl, p-methoxybenzyl or 9-fluorenemethyl. In a preferred embodiment, it can be C1-C6 alkyl. In another preferred embodiment, it can be methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, vinyl, allyl, benzyl, phenethyl or 9-fluorenemethyl. In a more preferred embodiment, it can be methyl or ethyl. In the most preferred embodiment, it can be methyl.

[0341] In a most preferred embodiment, the compound represented by formula (II) above may be methyl 6-[(methoxycarbonyl)amino]-2-(methoxymethyl)-1H-benzimidazole-4-carboxylate represented by formula (II') below.

[0342] [Chemical Formula 55]

[0343]

[0344] The form of the compound represented by formula (II') obtained in step 2 / 3 is not particularly limited. In one embodiment, it can be a salt of the acid used in the deprotection of the secondary amino group at position 1, for example, a hydrochloride salt. Furthermore, in the most preferred embodiment described above, the compound represented by formula (V) is a methyl carbamate represented by formula (V').

[0345] [Chemical Formula 56]

[0346]

[0347] The protective body of the compound represented by formula (II) above refers to the compound represented by formula (II'') below.

[0348] [Chemical Formula 57]

[0349]

[0350] (where R is in the formula) 1 and X and R in the above equation (VI) 1 And X is the same, R 3 Protecting groups for amino groups, such as tert-butyloxycarbonyl (Boc), allyloxycarbonyl (Alloc), 9-fluorenylmethoxycarbonyl (Fmoc), trimethylsilyl (TMS), or benzyl.

[0351] Step 2 / 3 involves contacting the compound or its protecting agent represented by formula (IV) above with the compound represented by formula (V) above to obtain the compound or its protecting agent represented by formula (II) above. It is not expected to be limited to any particular theory, but in this reaction, the functional group represented by X in the compound or its protecting agent represented by formula (IV) above can be replaced by the nitrogen atom in the terminal amide of the compound represented by formula (V) above by utilizing the Buchwald-Hartwig cross-coupling reaction, thereby obtaining the compound or its protecting agent represented by formula (II) above.

[0352] The temperature at which the compound represented by formula (IV) or its protected form is brought into contact with the compound represented by formula (V) is not particularly limited, as long as it allows the compound represented by formula (II) or its protected form to be obtained. For example, it can be 60°C to 120°C, 70°C to 110°C, 80°C to 105°C, or 88°C to 97°C. At this time, the solvent used for bringing the compound represented by formula (IV) or its protected form into contact with the compound represented by formula (V) is not particularly limited, as long as its boiling point is above the above temperature range or can be refluxed within the above temperature range, and it is a solvent that is non-reactive to both the compound represented by formula (IV) and its protected form, as well as the compound represented by formula (V) in the reaction system. For example, toluene or 1,4-dioxane can be suitably used. In a preferred embodiment, the alkane may be toluene. Furthermore, the contact time between the compound represented by formula (IV) or its protecting agent and the compound represented by formula (V) is not particularly limited, and may range from 10 minutes to 168 hours. During this period, the reaction vessel may be purged with an inert gas such as nitrogen or argon.

[0353] The equivalent relationship when the compound represented by formula (IV) above is brought into contact with the compound represented by formula (V) above is not particularly limited as long as the compound represented by formula (IV) above or its protected body can be obtained in a high yield (e.g., yield of 85% or more) relative to the compound represented by formula (IV) above or its protected body used as a starting material. For example, the compound represented by formula (V) above can be 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) above or its protected body. As a specific example, it can be 2 equivalents.

[0354] In one embodiment, the contact between the compound represented by formula (IV) or its protector and 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 enables the contact between the compound represented by formula (IV) or its protector and the compound represented by formula (V) to obtain the compound represented by formula (II) or its protector. For example, it can be a palladium catalyst containing 0-valent palladium (Pd(0)) or a palladium catalyst containing divalent palladium (Pd(2)). In one embodiment, it can be a palladium catalyst containing 0-valent palladium (Pd(0)). Specific examples of palladium catalysts include tris(dibenzylacetone)dipalladium(0) (Pd2(dba)3), bis(dibenzylacetone)palladium(0) (Pd(dba)2), palladium acetate (2), and palladium chloride (2), etc. In a preferred embodiment, it can be tris(dibenzylacetone)dipalladium(0). The equivalent of the palladium catalyst used to contact the compound represented by formula (IV) or its protector with the compound represented by formula (V) can be, for example, 0.0005 equivalent to 0.2 equivalent, 0.001 to 0.1 equivalent, or 0.003 to 0.05 equivalent, relative to 1 equivalent of the compound represented by formula (IV) or its protector.

[0355] In one embodiment, the contact between the compound represented by formula (IV) above or its protector and the compound represented by formula (V) above is carried out in the presence of a ligand in addition to a palladium catalyst. As a ligand, any compound represented by formula (IV) or its protector can be brought into contact with the compound represented by formula (V) to obtain the compound represented by formula (II) or its protector, and there is no particular limitation. Examples include 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (XPhos), 1,1'-bis(diphenylphosphine)ferrocene (DPPF), 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (BINAP), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (Xantphos), and 2-dicyclohexylphosphine-2',6'-diisopropoxybiphenyl (RuPhos). In a preferred embodiment, it can be 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (XPhos). The equivalent of the ligand that contacts the compound represented by formula (IV) or its protector with the compound represented by formula (V) can be, for example, 0.005 equivalent to 0.08 equivalent, 0.008 equivalent to 0.05 equivalent, or 0.01 equivalent to 0.04 equivalent, relative to 1 equivalent of the compound represented by formula (IV) or its protector.

[0356] In one embodiment, the compound represented by formula (IV) or its protected form is contacted with the compound represented by formula (V) 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 allows contact between the compound represented by formula (IV) or its protected form and the compound represented by formula (V) to obtain the compound represented by formula (II) or its protected form; for example, it can be potassium carbonate, cesium carbonate, potassium hydroxide, sodium tert-butoxide, or sodium methoxide. The equivalent amount of the base when contacting the compound represented by formula (IV) or its protected form with the compound represented by formula (V) relative to 1 equivalent of the compound represented by formula (IV) or its protected form can be, for example, 1.5 to 20 equivalents, 2.0 to 10 equivalents, or 3.0 to 7.0 equivalents.

[0357] The second / third step sequentially includes: in one embodiment, converting the compound represented by formula (IV) above into the compound represented by formula (IX) below, contacting the compound represented by formula (IX) above with the compound represented by formula (V) above to obtain the compound represented by formula (X) below; and hydrolyzing the compound represented by formula (X) above in the presence of an acid to obtain the compound represented by formula (II) above.

[0358] [Chemical Formula 58]

[0359]

[0360] (where R is in the formula) 1 R in equation (II) above 1 (Similarly, X is the same as X in equation (IV) above.)

[0361] [Chemical Formula 59]

[0362]

[0363] (where R is in the formula) 1 R in equation (II) above 1 Same, R 2 R in the above formula (V) 2 same.)

[0364] In this case, the conversion of the compound represented by formula (IV) above into the compound represented by formula (IX) above can be carried out by methods commonly performed by those skilled in the art, for example by contacting, for example, about 1.1 to 3 equivalents of ditert-butyl dicarbonate ((Boc)₂O) with 1 equivalent of the compound represented by formula (IV) above in an organic solvent such as toluene at a temperature of about room temperature to 60°C, wherein about 1.2 to 5 equivalents of base (e.g., potassium carbonate) may be further present in the system.

[0365] In one embodiment, the following operations in step 2 / 3 can be carried out in the same reaction vessel (one-pot method): converting the compound represented by formula (IV) above into the compound represented by formula (IX) above, and contacting the compound represented by formula (IX) above with the compound represented by formula (V) above to obtain the compound represented by formula (X) above. As a specific example, the following situation can be given: after contacting the compound represented by formula (IV) above with di-tert-butyl dicarbonate in an organic solvent such as toluene, which optionally contains a base, the compound represented by formula (V) above, 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) above.

[0366] 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 methods commonly used by those skilled in the art, such as contacting an excess of concentrated hydrochloric acid or trifluoroacetic acid with isopropanol (2-propanol), methanol or acetonitrile. In this case, the reaction solution can be heated to about 50-60°C as needed.

[0367] In one embodiment, the compound represented by formula (X) above is hydrolyzed in the presence of acid to obtain the compound represented by formula (II) above. This process can be carried out directly without purification after the compound represented by formula (IX) above is contacted with the compound represented by formula (V) above to obtain the compound represented by formula (X). In this case, the reaction solution obtained by contacting the compound represented by formula (IX) above with the compound represented by formula (V) above to obtain the compound represented by formula (X) above is filtered to remove insoluble substances such as potassium carbonate and alkali. If necessary, the solvent is reduced by vacuum distillation or the solution is dried and solidified. Then, the solvent and acid used for hydrolysis in the presence of acid are added, and the mixture is incubated.

[0368] <Step 4>

[0369] The fourth step is the process of converting a compound represented by formula (II) into a compound represented by formula (VIII).

[0370] [Chemical Formula 60]

[0371]

[0372] (where R is in the formula) 1 Protecting groups representing carboxyl groups or H,R 2 This refers to a group that integrates with -OC (=O)- to form a protecting group of aniline amino groups.

[0373] [Chemical Formula 61]

[0374]

[0375] In one embodiment, the process of converting a compound represented by formula (II) above into a compound represented by formula (VIII) above includes converting a compound represented by formula (II) above into a compound represented by formula (III) below.

[0376] [Chemical Formula 62]

[0377]

[0378] In a preferred embodiment, the process of converting the compound represented by formula (II) above into the compound represented by formula (VIII) above includes: hydrolyzing the compound represented by formula (II) above in the presence of a base to obtain the compound represented by formula (III) above.

[0379] The conversion of the compound represented by formula (II) above into the compound represented by formula (III) above can be performed by methods commonly used by those skilled in the art. According to the method including such a step, the compound represented by formula (XI) below (compound C), which has concerns about mutagenicity, can be separated in powder form. Therefore, the risk of mutagenicity caused by the scattering of compound C separated in powder form can be avoided, and the time and economic costs for operators to use for protection and environmental countermeasures (lockdown) can be reduced.

[0380] [Chemical Formula 63]

[0381]

[0382] In one embodiment, the step of converting the compound represented by formula (II) to the compound represented by formula (VIII) includes converting the compound represented by formula (II) to the compound represented by formula (III), wherein the compound represented by formula (III) can be obtained in its solution form. In one embodiment, the step of converting the compound represented by formula (II) to the compound represented by formula (VIII) includes hydrolyzing the compound represented by formula (II) in the presence of a base to obtain the compound represented by formula (III) in its solution form. In one embodiment, the step of converting the compound represented by formula (II) to the compound represented by formula (VIII) does not include separating 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 treating the compound represented by formula (III) in a state other than its solution form.

[0383] The alkaline hydrolysis of the compound represented by formula (II) above can be carried out under conditions commonly performed by those skilled in the art, for example, by adding the compound represented by formula (II) above or its salt (e.g., hydrochloride) to an aqueous solution of sodium hydroxide with a concentration of about 5-30% by mass or 10-25% by mass, with stirring at a temperature of about 40-70°C or 50-60°C. The reaction time is not particularly limited, and can be, for example, 10 minutes to 72 hours, 1 hour to 24 hours, or 2 hours to 12 hours; as an example, it can be 6 hours.

[0384] In one embodiment of this disclosure, the step of converting the compound represented by formula (II) to the compound represented by formula (VIII) includes, after converting the compound represented by formula (II) to the compound represented by formula (III), converting the compound represented by formula (III) to the compound represented by formula (VIII). The conversion of the compound represented by formula (III) to the compound represented by formula (VIII) can be performed by methods commonly practiced by those skilled in the art, for example, by contacting an acyl halide such as an acyl chloride or acyl bromide of 2-(trifluoromethyl)benzoic acid with the compound represented by formula (VIII) to amidate the aniline amino group in the compound represented by formula (VIII); it can also be performed by reacting 2-(trifluoromethyl)benzoic acid with the compound represented by formula (VIII) in HATU(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine) The process involves contacting the compound represented by formula (VIII) with a condensing agent such as 3-oxide hexafluorophosphate, and then performing an amidation of the aniline amino group in the compound represented by formula (VIII). From the viewpoint of avoiding the generation of byproducts due to the participation of the carboxyl group of the compound represented by formula (VIII) in amide formation, which would result in a decrease in yield, the conversion of the compound represented by formula (III) to the compound represented by formula (VIII) is preferably performed by contacting an acyl halide such as an acyl chloride or acyl bromide of 2-(trifluoromethyl)benzoic acid with the compound represented by formula (VIII), thereby performing an amidation of the aniline amino group in the compound represented by formula (VIII). For example, this can be performed by contacting the compound represented by formula (VIII) with 2-(trifluoromethyl)benzoyl chloride.

[0385] In the above-described case, the solvent used to contact the acyl halide of 2-(trifluoromethyl)benzoic acid with the compound represented by formula (VIII) can be a solvent commonly chosen by those skilled in the art, such as acetonitrile or a mixture of acetonitrile and water. Furthermore, the reaction temperature is not particularly limited as long as it is the temperature at which the compound represented by formula (VIII) is formed; for example, it can be -10°C to 20°C, -10°C to 10°C, or -5°C to 5°C. Similarly, the reaction time is not particularly limited as long as it is the time required to form the compound represented by formula (VIII); for example, it can be 1 minute to 3 hours, 5 minutes to 1 hour, or 10 minutes to 30 minutes. Additionally, from the viewpoint of decomposing the compound formed by multiple reactions of the acyl halide of 2-(trifluoromethyl)benzoic acid as a byproduct, thereby increasing the yield, the reaction solution can be further incubated at a temperature of, for example, 50 to 80°C or 60 to 70°C for, for example, 5 minutes to 12 hours, 15 minutes to 6 hours, or 30 minutes to 4 hours after the reaction under the above conditions. Furthermore, regarding the stoichiometric relationship between the acyl halide of 2-(trifluoromethyl)benzoic acid and the compound represented by formula (VIII) above, there are no particular limitations as long as the compound represented by formula (VIII) can be obtained in a high yield (e.g., yield of 80% or more) relative to the compound represented by formula (VIII). For example, one equivalent relative to the compound represented by formula (VIII) above can be 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. In addition, in the reaction system, relative to the compound represented by formula (VIII) above, a compound having a carboxyl group, such as acetic acid, may be present in approximately one equivalent (e.g., 0.7 to 1.5 equivalents or 0.9 to 1.1 equivalents).

[0386] 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) can be carried out in the same reaction vessel (one-pot reaction). 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 acyl halide of 2-(trifluoromethyl)benzoic acid can be further added to the reaction solution.

[0387] <Step 5>

[0388] Step 5 is the process of converting the compound represented by formula (VIII) into an N,N-dimethylacetamide compound of the compound represented by formula (I) (compound A).

[0389] [Chemical Formula 64]

[0390]

[0391] [Chemical Formula 65]

[0392]

[0393] In one embodiment, the fifth step includes: converting the compound represented by formula (VIII) above into the compound represented by formula (I) above, and contacting the compound represented by formula (I) above with N,N-dimethylacetamide to obtain an N,N-dimethylacetamide compound of the compound represented by formula (I).

[0394] The conversion of the compound represented by formula (VIII) above into the compound represented by formula (I) above can be carried out by methods commonly performed by those skilled in the art. For example, the compound represented by formula (VIII) above can be contacted with 1,1'-carbonyldiimidazole (CDI) to obtain the compound represented by formula (XII) below, or the compound represented by formula (VIII) below can be contacted with thionyl chloride to obtain the compound represented by formula (XIII) below. Alternatively, the conversion can 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-methylmorpholine hydrochloride).

[0395] [Chemical Formula 66]

[0396]

[0397] [Chemical Formula 67]

[0398]

[0399] In a preferred embodiment, the compound represented by formula (XII) above is contacted with 3-chloro-2-methylaniline, wherein the compound represented by formula (XII) above is obtained by contacting the compound represented by formula (VIII) above with CDI.

[0400] The solvent used to contact the compound represented by formula (VIII) above with CDI can be a solvent that is not reactive with both the compound represented by formula (VIII) above and CDI, such as N,N-dimethylformamide and N,N-dimethylacetamide. Furthermore, the temperature and time for contacting the compound represented by formula (VIII) above with CDI are not particularly limited as long as the compound represented by formula (XII) above is obtained. For example, the reaction can be carried out at temperatures of approximately 5~50°C, 10~40°C, or 20~30°C for 10 minutes to 24 hours, 20 minutes to 6 hours, or 30 minutes to 2 hours, respectively. Furthermore, the stoichiometric relationship of contacting the compound represented by formula (VIII) with CDI is not particularly limited as long as the compound represented by formula (VIII) can be obtained from the compound represented by formula (VIII) in a high yield (e.g., yield of 90% or more). The CDI can be, for example, 1.00 to 2.00 equivalents, 1.05 to 1.40 equivalents, or 1.10 to 1.20 equivalents relative to 1 equivalent of the compound represented by formula (VIII).

[0401] The solvent used to contact the compound represented by formula (XII) with 3-chloro-2-methylaniline can be a solvent that is not reactive with both the compound represented by formula (XII) and 3-chloro-2-methylaniline, such as N,N-dimethylformamide and N,N-dimethylacetamide. Furthermore, the temperature and time for contacting the compound represented by formula (XII) with 3-chloro-2-methylaniline are not particularly limited as long as the compound represented by formula (I) can be obtained. For example, the reaction can be carried out at a temperature of approximately 40–70°C or 50–60°C for 10 minutes to 168 hours, 1 hour to 72 hours, or 6 hours to 30 hours. Furthermore, the stoichiometric relationship of contacting the compound represented by formula (XII) with 3-chloro-2-methylaniline is not particularly limited, as long as the compound represented by formula (XII) can be obtained in a high yield (e.g., yield of 90% or more) relative to the compound represented by formula (XII). For example, the amount of 3-chloro-2-methylaniline can be 1.1 to 10 equivalents, 1.5 to 5.0 equivalents, or 2.0 to 3.0 equivalents relative to 1 equivalent of the compound represented by formula (XII). Additionally, contacting the compound represented by formula (XII) with 3-chloro-2-methylaniline can be carried out in the presence of a compound having a carboxyl group, such as benzoic acid.

[0402] Contacting the compound represented by formula (VIII) above with CDI and contacting the compound represented by formula (XII) above with 3-chloro-2-methylaniline can be carried out in the same reaction vessel (one-pot reaction). In this case, for example, it can be carried out by contacting the compound represented by formula (VIII) above with CDI in N,N-dimethylformamide, followed by adding 3-chloro-2-methylaniline and benzoic acid to the reaction solution.

[0403] The N,N-dimethylacetamide compound of the compound represented by formula (I) can be obtained by contacting the compound represented by formula (I) with N,N-dimethylacetamide using methods commonly performed by those skilled in the art. For example, it can be performed by adding DMA or a mixture containing DMA (e.g., a mixture of DMA and water) to a solvent in which the compound represented by formula (I) in any form (e.g., the free form of the compound represented by formula (I)) is dissolved, and then incubating. In one embodiment, this can be performed by adding a mixture of DMA and water to the solution after contacting the compound represented by formula (XII) with 3-chloro-2-methylaniline. The temperature conditions at this time can be, for example, 40-70°C or 50-60°C, and the incubation time can be, for example, 10 minutes to 24 hours.

[0404] By using the compound represented by formula (II) as a starting material, the N,N-dimethylacetamide compound of the compound represented by formula (I) can be obtained through steps 4 and 5 described above. That is, in one embodiment, steps 4 and 5 can also be combined to perform the process of converting the compound represented by formula (II) into the N,N-dimethylacetamide compound of the compound represented by formula (I).

[0405] <Step 6>

[0406] Step 6 is a step of purifying the crude product of the N,N-dimethylacetamide compound (compound A) represented by formula (I) by recrystallization. In one embodiment, it is a step of purifying the N,N-dimethylacetamide compound of the compound represented by formula (I) obtained in step 5 by recrystallization. The recrystallization of the crude product of the N,N-dimethylacetamide compound of the compound represented by formula (I) can be carried out in N,N-dimethylacetamide or a mixed solvent containing the same. In one embodiment, it can 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 compound represented by formula (I) can be carried out in a mixed solvent of N,N-dimethylformamide and water, wherein the N,N-dimethylacetamide content is 50% or more, 60% or more, 70% or more, 75% or more, or 78% or more and 99% or less, 95% or less, 90% or less, or 80% or less; or in a mixed solvent of N,N-dimethylacetamide and water, wherein the N,N-dimethylacetamide content is 75% or more, or 75% or more and 99% or less. If recrystallization is carried out in such a solvent, the N,N-dimethylacetamide compound represented by formula (I) can be obtained in high yield and with high purity. Furthermore, if recrystallization is carried out in such a solvent, the content of the compound represented by formula (VII) below (hereinafter also referred to as "compound B"), which is generated during the manufacturing process and poses a risk of mutagenicity, decreases, and a purified N,N-dimethylacetamide compound of the compound represented by formula (I) above can be obtained. In particular, if a mixed solvent of N,N-dimethylacetamide with a content of 70% or more, 75% or more, or 78% or more of N,N-dimethylacetamide and water is used, the content of compound B decreases further, and a purified N,N-dimethylacetamide compound of the compound represented by formula (I) above can be obtained.

[0407] [Chemical Formula 68]

[0408]

[0409] In these cases, a decrease in the content of compound B means that the content of compound B in the purified product (crystal) obtained by recrystallization can be, for example, 1800 × 10⁻⁶. -4 less than 1000×10 -4 less than 500×10 -4 less than % of mass, 400×10 -4 less than % of mass, 300×10 -4 less than % of mass, 200×10 -4 less than 1% of mass or 170×10 -4 When the mass percentage is less than 10%, especially when using a mixed solvent of N,N-dimethylacetamide and water containing 70% or more, 75% or more, or 78% or more of N,N-dimethylacetamide, it is possible to obtain a compound B content of, for example, 1000 × 10⁻⁶. -4 Below 500% by mass, 500×10 -4 Below % of mass, 400×10 -4 Below % of mass, 300×10 -4 Below % of mass, 200×10 -4 less than 1% of mass or 170×10 -4 Purified product (crystallized) of less than % by mass.

[0410] <Step 7>

[0411] Step 7 is the process of converting the N,N-dimethylacetamide compound (compound A) represented by formula (I) above into the p-toluenesulfonate salt of compound (compound A) represented by formula (I) above. In one embodiment, step 7 is the process of converting the purified (crystalled) N,N-dimethylacetamide compound (compound A) represented by formula (I) obtained in step 6 into the p-toluenesulfonate salt of compound (I) above. Step 7 is typically carried out by contacting the N,N-dimethylacetamide compound (compound A) represented by formula (I) above with p-toluenesulfonic acid (Tosyl acid, 4-methylbenzenesulfonic acid). The contact conditions between the N,N-dimethylacetamide compound represented by formula (I) and p-toluenesulfonic acid are as simple as converting the N,N-dimethylacetamide compound represented by formula (I) into the p-toluenesulfonate salt of the compound represented by formula (I), without particular limitation. The solvent can be, for example, N,N-dimethylformamide, acetonitrile, or a mixture thereof. Specifically, a mixture of N,N-dimethylformamide and acetonitrile (e.g., a 1:6 mass ratio) can be used. The contact temperature can be, for example, 30–70°C or 45–60°C. The contact time can be, for example, 10 minutes to 24 hours or 1 hour to 12 hours. Furthermore, the form of the added p-toluenesulfonic acid is not particularly limited; it can be added in hydrate form, for example, as a solvent. In addition, regarding the equivalence relationship in the reaction system, relative to 1 equivalent of the N,N-dimethylacetamide compound represented by the above formula (I), p-toluenesulfonic acid or its hydrate may be, for example, 1.01 equivalent to 2.00 equivalent, 1.03 equivalent to 1.50 equivalent, or 1.05 equivalent to 1.20 equivalent.

[0412] <Step 8>

[0413] Step 8 is a step of obtaining type I crystals of p-toluenesulfonate of compound A from the crude product of p-toluenesulfonate of compound A (represented by formula (I) above). In one embodiment, step 8 is a step of obtaining type I crystals of p-toluenesulfonate of compound A from the crude product of p-toluenesulfonate of compound A (represented by formula (I) above) obtained in step 7. In one embodiment, step 8 sequentially includes: purifying the p-toluenesulfonate of compound A by contacting it with activated carbon; and recrystallizing the p-toluenesulfonate of compound A (represented by formula (I) above) after contact with activated carbon to obtain type I crystals of p-toluenesulfonate of compound A.

[0414] Purification of the p-toluenesulfonate salt of the compound represented by formula (I) above by contacting it with activated carbon is carried out by the following method: Activated carbon is added to a solution of the p-toluenesulfonate salt of the compound represented by formula (I) above, incubated, and then the activated carbon is removed 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) above and maintains the salt form; for example, N,N-dimethylformamide can be suitably used. Furthermore, the contact can be carried out at a temperature of approximately 30~60°C or 40~50°C for approximately 5 minutes to 24 hours or 10 minutes to 6 hours, with 1 hour being a specific example. Furthermore, the amount of activated carbon contacted with the p-toluenesulfonate of the compound represented by formula (I) above can be, for example, 0.04 times or more, 0.05 times or more, 0.08 times or more, 0.09 times or more, 0.10 times or more, 0.14 times or more, or 0.15 times or more of the mass of the p-toluenesulfonate of the compound, or less than 1.00 times, less than 0.50 times, or less than 0.20 times the mass, and in a preferred embodiment, more than 0.08 times the mass. If the amount of activated carbon contacted with the p-toluenesulfonate of the compound represented by formula (I) above is above the aforementioned lower limit, compound B, which contains impurities with a risk of mutagenicity, can be removed efficiently.

[0415] The recrystallization of the p-toluenesulfonate of the compound represented by formula (I) after contact with activated carbon to obtain type 1 crystals of p-toluenesulfonate of compound A can be carried out by methods commonly used by those skilled in the art. In one embodiment, it can be carried out by the following method: after purifying the p-toluenesulfonate of the compound represented by formula (I) by contacting activated carbon, seed crystals of the p-toluenesulfonate of the compound represented by formula (I) are added to the filtrate obtained by removing activated carbon by filtration as needed, and the filtrate is heated and cooled.

[0416] If step 8 sequentially includes: purifying the p-toluenesulfonate of the compound represented by formula (I) by contacting activated carbon; and recrystallizing the p-toluenesulfonate of the compound represented by formula (I) after contact with activated carbon to obtain type I crystals of p-toluenesulfonate of compound A, then compared with recrystallization alone, the content of compound B, which contains impurities with a risk of mutagenicity, in the purified product (type I crystals of p-toluenesulfonate of compound A) obtained by recrystallization can be significantly reduced. More specifically, the content of compound B in the purified product (type I crystals of p-toluenesulfonate of compound A) obtained by recrystallization can be reduced to 100 × 10⁻⁶. -4 less than % of mass, 70×10 -4 less than 50% of mass, 50×10 -4less than % of mass, 40×10 -4 less than % of mass, 30×10 -4 less than % of mass, 20×10 -4 less than 1% of mass, 15×10 -4 less than 1% of mass, 12×10 -4 less than 1% of mass or 10×10 -4 Quality percentage below %.

[0417] <Implementation Method of the Manufacturing Method in the Fifth Aspect>

[0418] One embodiment of the fifth aspect of this disclosure may be a method for manufacturing type I crystallization of p-toluenesulfonate of compound A or a composition containing thereof, comprising at least one of the steps described above. Specifically, one embodiment of the fifth aspect of this disclosure may be a method for manufacturing type I crystallization of p-toluenesulfonate of compound A or a composition containing thereof, including step 7. One embodiment of the fifth aspect of this disclosure may be a method for manufacturing type I crystallization of p-toluenesulfonate of compound A or a composition containing thereof, sequentially including steps 4 and 7. One embodiment of the fifth aspect of this disclosure may be a method for manufacturing type I crystallization of p-toluenesulfonate of compound A or a composition containing thereof, sequentially including steps 2 / 3, 4, and 7. One embodiment of the fifth aspect of this disclosure may be a method for manufacturing type I crystallization of p-toluenesulfonate of compound A or a composition containing thereof, sequentially including steps 4, 5, and 7. One embodiment of the fifth aspect of this disclosure may be a method for manufacturing type I crystallization of p-toluenesulfonate of compound A or a composition containing thereof, sequentially including steps 2 / 3, 4, 5, and 7. One embodiment of the fifth aspect of this disclosure may be a method for manufacturing type I crystallization of p-toluenesulfonate of compound A or a composition comprising thereof, sequentially including steps 1, 2 / 3, 4, 5, and 7. Another embodiment of the fifth aspect of this disclosure may be a method for manufacturing type I crystallization of p-toluenesulfonate of compound A or a composition comprising thereof, further including step 6 immediately preceding step 7 in these embodiments. A third embodiment of the fifth aspect of this disclosure may be a method for manufacturing type I crystallization of p-toluenesulfonate of compound A or a composition comprising thereof, further including step 8 immediately following step 7 in these embodiments.

[0419] <Preparation method of type 3 crystallization of p-toluenesulfonate of compound A>

[0420] The sixth aspect of this disclosure is a method for manufacturing type 3 crystals of p-toluenesulfonate of compound A. In one embodiment, the sixth aspect of this disclosure may be a method for manufacturing type 3 crystals of p-toluenesulfonate of compound A according to an embodiment of the second aspect of this disclosure. In one embodiment, the sixth aspect of this disclosure may be a method for manufacturing type 3 crystals of p-toluenesulfonate of compound A, the method comprising a step of manufacturing type 1 crystals of p-toluenesulfonate of compound A by a manufacturing method according to an embodiment of the fifth aspect of this disclosure.

[0421] In one embodiment, the sixth aspect of this disclosure may include a step of exposing the p-toluenesulfonate of compound A to a temperature condition above a given lower limit. In a preferred embodiment, it may include a step of exposing type I crystals of the p-toluenesulfonate of compound A to a temperature condition above a given lower limit. In a more preferred embodiment, it may include a step of exposing type I crystals of the p-toluenesulfonate of compound A in a solid state to a temperature condition above a given lower limit. The given lower limit in these cases may be, for example, 130°C, 140°C, 150°C, or 160°C. In a preferred embodiment, the type I crystals of the p-toluenesulfonate of compound A exposed to a temperature condition above a given lower limit can be manufactured by a manufacturing method according to an embodiment of the fifth aspect of this disclosure. That is, a preferred embodiment of the manufacturing method of the sixth aspect of this disclosure may be a method for manufacturing type 3 crystals of p-toluenesulfonate of compound A, the method comprising: a step of manufacturing type 1 crystals of p-toluenesulfonate of compound A by a manufacturing method according to an embodiment of the fifth aspect of this disclosure; and a step of exposing the obtained type 1 crystals of p-toluenesulfonate of compound A to a temperature condition above a given lower limit. Alternatively, in another embodiment, the p-toluenesulfonate of compound A exposed to a temperature condition above a given lower limit may be an amorphous substance obtained from the p-toluenesulfonate of compound A manufactured by a manufacturing method that includes at least a seventh step in the manufacturing process of an embodiment of the fifth aspect of this disclosure. That is, the manufacturing method of one embodiment of the seventh aspect of this disclosure can be a method for manufacturing type 3 crystals of p-toluenesulfonate of compound A, the method comprising: a step of manufacturing an amorphous body, said amorphous body being obtained from p-toluenesulfonate of compound A manufactured by a manufacturing method comprising at least a seventh step in the manufacturing process of one embodiment of the fifth aspect of this disclosure; and a step of exposing the obtained amorphous body of p-toluenesulfonate of compound A to a temperature condition above a given lower limit.

[0422] <Preparation method of type IV crystallization of p-toluenesulfonate of compound A>

[0423] The seventh aspect of this disclosure is a method for manufacturing type IV crystals of p-toluenesulfonate of compound A. In one embodiment, the seventh aspect of this disclosure may be a method for manufacturing type IV crystals of p-toluenesulfonate of compound A according to an embodiment of the third aspect of this disclosure. In one embodiment, the seventh aspect of this disclosure may be a method for manufacturing type IV crystals of p-toluenesulfonate of compound A, the method including a step of manufacturing type I crystals of p-toluenesulfonate of compound A by a manufacturing method according to an embodiment of the fifth aspect of this disclosure. In one embodiment, the seventh aspect of this disclosure may be a method for manufacturing type IV crystals of p-toluenesulfonate of compound A, the method including a step of manufacturing an amorphous substance of p-toluenesulfonate of compound A by a manufacturing method including at least a seventh step according to an embodiment of the fifth aspect of this disclosure.

[0424] In one embodiment, the seventh aspect of this disclosure may include a step of contacting p-toluenesulfonate of compound A with acetonitrile and then exposing it to a temperature condition above a given lower limit; it may also include a step of contacting type I crystals of p-toluenesulfonate of compound A with acetonitrile and then exposing them to a temperature condition above a given lower limit. The given lower limit in these cases may be, for example, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, or 160°C. In one embodiment, the type I crystals of p-toluenesulfonate of compound A exposed to a temperature condition above a given lower limit can be manufactured by a manufacturing method according to an embodiment of the fifth aspect of this disclosure. That is, a manufacturing method according to an embodiment of the seventh aspect of this disclosure may be a method for manufacturing type IV crystals of p-toluenesulfonate of compound A, the method comprising: a step of manufacturing type I crystals of p-toluenesulfonate of compound A by a manufacturing method according to an embodiment of the fifth aspect of this disclosure; and a step of contacting the obtained type I crystals of p-toluenesulfonate of compound A with acetonitrile and then exposing them to a temperature condition above a given lower limit. In another embodiment, the p-toluenesulfonate of compound A exposed to a temperature condition above a given lower limit can be an amorphous substance obtained from a p-toluenesulfonate of compound A manufactured by a manufacturing method comprising at least a seventh step in the manufacturing process of an embodiment of the fifth aspect of this disclosure. That is, the manufacturing method of an embodiment of the seventh aspect of this disclosure can be a method for manufacturing type 4 crystals of p-toluenesulfonate of compound A, comprising: a step of manufacturing an amorphous substance obtained from a p-toluenesulfonate of compound A manufactured by a manufacturing method comprising at least a seventh step in the manufacturing process of an embodiment of the fifth aspect of this disclosure; and a step of contacting the obtained amorphous p-toluenesulfonate of compound A with acetonitrile and then exposing it to a temperature condition above a given lower limit.

[0425] <Pharmaceutical Compositions / Inhibitors>

[0426] The eighth aspect of this disclosure is a pharmaceutical composition comprising, as an active ingredient, a crystal of an embodiment of the first aspect of this disclosure, a crystal of an embodiment of the second aspect of this disclosure, a crystal of an embodiment of the third aspect of this disclosure, or a composition of an embodiment of the fourth aspect of this disclosure. In this disclosure, a pharmaceutical composition refers to a composition administered for the purpose of treatment and / or prevention of a subject. The ninth aspect of this disclosure is a membrane-bound prostaglandin E synthase-1 inhibitor (mPGES-1 inhibitor) comprising, as an active ingredient, a crystal of an embodiment of the first aspect of this disclosure, a crystal of an embodiment of the second aspect of this disclosure, a crystal of an embodiment of the third aspect of this disclosure, or a composition of an embodiment of the fourth aspect of this disclosure.

[0427] The pharmaceutical composition of one embodiment of the eighth aspect of this disclosure and the inhibitor of one embodiment of the ninth aspect of this disclosure can be formulated as a treatment and / or prevention preparation, and their dosage forms are not particularly limited, such as tablets, capsules, powders, granules, or fine granules. Furthermore, the pharmaceutical composition of one embodiment of the eighth aspect of this disclosure, the inhibitor of one embodiment of the ninth aspect of this disclosure, and the preparations containing them can be administered orally or non-orally. The dosage of the pharmaceutical composition of one embodiment of the eighth aspect of this disclosure, the inhibitor of one embodiment of the ninth aspect of this disclosure, and the preparations containing them is expected to be adjusted considering the patient's condition, such as age, weight, type and severity of disease, and route of administration. Generally, for adults, the effective amount of p-toluenesulfonate of compound A, when administered orally, is in the range of 0.01 mg to 5 g / ad per adult per day, preferably in the range of 1 mg to 500 mg / adult per day. Depending on the circumstances, sometimes a dosage below this range is sufficient, or conversely, sometimes a dosage above this range is required. Generally, rapid administration or continuous administration within 24 hours is possible when administered once daily or divided into multiple doses, or intravenously.

[0428] The pharmaceutical composition of one embodiment of the eighth aspect of this disclosure and the inhibitor of one embodiment of the ninth aspect of this disclosure, in addition to the crystals of one embodiment of the first aspect of this disclosure, the crystals of one embodiment of the second aspect of this disclosure, the crystals of one embodiment of the third aspect of this disclosure, or the composition of one embodiment of the fourth aspect of this disclosure as active ingredients, may contain pharmaceutically permissible additives, such as excipients, buffers, stabilizers, antioxidants, binders, disintegrants, fillers, emulsifiers, or flow modifiers, or at least one additive selected therefrom.

[0429] The pharmaceutical composition of one embodiment of the eighth aspect of this disclosure and the inhibitor of one embodiment of the ninth aspect, as well as the preparation comprising them, can be used as a preventive or therapeutic agent for, for example, the following conditions, based on the mPGES-1 inhibitory activity of the p-toluenesulfonate of compound A: inflammatory bowel disease, irritable bowel syndrome, migraine, headache, low back pain, lumbar spinal stenosis, lumbar disc herniation, temporomandibular joint disorder, cervicobrachial syndrome, cervical spondylosis, endometriosis, adenomyosis, premature birth, threatened premature birth, dysmenorrhea, overactive bladder, nocturia, interstitial cystitis, neurodegenerative diseases (e.g., Alzheimer's disease, multiple sclerosis), psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, neuralgia, complex regional pain syndrome, fasciopathy, viral infections (e.g., influenza, cold, herpes zoster, AIDS), bacterial infections, fungal infections, burns, postoperative, post-traumatic, and post-extraction inflammation / pain, malignant tumors (e.g., leukemia, malignant lymphoma, multiple follicles). Multiple myeloma, myeloproliferative syndrome, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, duodenal cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer, gallbladder / choleduct cancer, bile duct cancer, pancreatic cancer, thyroid cancer, breast cancer, lung cancer, ovarian cancer, cervical cancer, uterine endometrial cancer, vaginal cancer, vulvar cancer, kidney cancer, renal pelvis and ureter cancer, urothelial carcinoma, penile cancer, prostate cancer, testicular tumors, bone / soft tissue sarcoma, malignant bone tumors, skin cancer, thymoma, mesothelioma, and cancers of unknown primary origin, etc. Atherosclerosis, stroke, gout, arthritis, degenerative joint disease, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ossification of ligaments, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, chronic prostatitis, chronic pelvic pain syndrome, conjunctivitis, iritis, scleritis, uveitis, wound repair, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, and cancer pain from uterine fibroids.

[0430] Example

[0431] The present disclosure will be described in more detail below using examples, but the present disclosure is not limited to the following examples.

[0432] The following embodiments use the following abbreviations.

[0433] IPC = In-Process Control (In-Process Testing)

[0434] dba = Dibenzylideneacetone

[0435] XPhos=2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0436] IPA = 2-Propanol

[0437] CDI = 1,1'-Carbonyldiimidazole

[0438] DMF = N,N-dimethylformamide

[0439] DMAc, DMA = N,N-dimethylacetamide

[0440] pTsOH-H2O = p-Toluenesulfonic acid monohydrate

[0441] MeCN = Acetonitrile

[0442] HPLC = High Performance Liquid Chromatography

[0443] In the embodiments 1 H-NMR spectra were measured using a JNM-ECS400 nuclear magnetic resonance instrument (manufactured by JEOLRESONANCE Co., Ltd.). The 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).

[0444] Unless otherwise stated, the powder X-ray diffraction patterns in Examples 1-11 were determined using a MiniFlex600 (manufactured by RIGAKU Corporation) (voltage: 40 kV, current: 15 mA, wavelength: CuKα, Soler slit: 5.0 degrees, scanning range: 4-40 degrees, scanning rate / counting time: 20.0).

[0445] Unless otherwise stated, the DSC measurements in Examples 1-11 were performed using a DSC-60A (manufactured by Shimadzu Corporation) (crucible: alumina (open), gas: nitrogen (20.0 mL / min), heating rate: 10.0 °C / min, holding temperature: 300 °C, holding time: 0 min).

[0446] Unless otherwise stated, the TG / DTA in Examples 1-11 was measured using TG-8120 (manufactured by RIGAKU Corporation) (crucible: alumina (open), gas: nitrogen, heating rate: 10.0°C / min, holding temperature: 300°C, holding time: 0 min).

[0447] [Example 1: Preparation of Type I crystals of p-toluenesulfonate of compound A]

[0448] Type I crystals of p-toluenesulfonate of compound A were produced by a manufacturing method outlined below.

[0449] [Chemical Formula 69]

[0450]

[0451] [Step 1: Synthesis of methyl 6-bromo-2-(methoxymethyl)-1H-benzimidazole-4-carboxylate (Compound 1)]

[0452] [Chemical Formula 70]

[0453]

[0454] 80.0 kg of methyl 2,3-diamino-5-bromobenzoate and 294 kg of methoxyacetic acid were added to a nitrogen-purged stirred tank. The temperature of the stirred tank was heated to above 85°C, and the reaction was carried out for 10 hours while maintaining the internal temperature at 80°C to 95°C. The reaction was confirmed to be complete by HPLC when the peak area of ​​methyl 2,3-diamino-5-bromobenzoate as the starting material reached less than 1% of the total area of ​​all detected peaks. The temperature of the reaction solution was then cooled to 20-30°C. Acetone (506 kg) was added and stirred, followed by diatomaceous earth (8.0 kg), activated carbon (16.0 kg), and acetone (129 kg). The temperature of the reaction solution was further maintained at 20-30°C and stirred for more than 1 hour. After filtering out the insoluble matter, the retained insoluble matter was washed with acetone (378 kg). The recovered filtrate was then concentrated to 390 L by vacuum distillation while maintaining the external temperature of the container below 50°C. Water (800 L) was added while maintaining the temperature of the reaction solution at 20–50°C. The temperature of the reaction solution was then cooled to below 15°C. Approximately 1100 kg of a 10% sodium hydroxide aqueous solution was added while maintaining the temperature below 20°C to adjust the pH of the solution to 5.5–7.5. The temperature of the reaction solution was maintained at 20-30°C, and the solution was stirred for more than 30 minutes. The slurry was then filtered to recover the insoluble matter. The recovered insoluble matter was washed with water (602 kg), and then the recovered insoluble matter was dried under reduced pressure while the external temperature of the container was maintained below 60°C. The crude product of methyl 6-bromo-2-(methoxymethyl)-1H-benzimidazole-4-carboxylate (compound 1), the target compound, was obtained in the form of 91.6 kg of powder (yield 94%).

[0455] [Chemical Formula 71]

[0456]

[0457] The crude product of compound 1 (91.5 kg) and acetone (1011 kg) were added to a nitrogen-replaced stirred tank. The temperature of the stirred tank was raised to 35-45°C to dissolve compound 1 in acetone. Activated carbon (9.2 kg) and acetone (73.2 kg) were added, and the temperature of the reaction solution was maintained at 35-45°C and stirred for more than 1 hour. Insoluble matter containing activated carbon was removed by filtration. The retained insoluble matter was washed with acetone (434 kg), and then the solvent was distilled off by heating. The filtrate was concentrated to 640 L. The resulting solution was cooled to 20-30°C and stirred for more than 12 hours while maintaining the temperature at 20-30°C. Then, the solution was cooled to below 10°C for more than 1 hour and stirred for more than 1 hour while maintaining the temperature at 0-10°C. The slurry was filtered and the insoluble matter was recovered. The recovered insoluble matter (filter cake) was washed with cooled acetone (73.1 kg). Then, by vacuum drying the recovered insoluble matter while keeping the temperature outside the container below 60°C, methyl 6-bromo-2-(methoxymethyl)-1H-benzimidazole-4-carboxylate (compound 1) was obtained in the form of 79.3 kg of powder (yield 87%).

[0458] The spectral data of compound 1 are shown below.

[0459] ESI-MS (-): Calculated value 297.0, Measured value 297.0 (MH)

[0460] 1 H 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)

[0461] [Steps 2 / 3: Synthesis of 6-[(methoxycarbonyl)amino]-2-(methoxymethyl)-1H-benzimidazole-4-carboxylic acid methyl ester hydrochloride (compound 4)]

[0462] [Chemical Formula 72]

[0463]

[0464] Compound 1 (79.2 kg), potassium carbonate (54.9 kg), and toluene (688 kg) obtained in step 1 were added to a stirred tank that had been purged with nitrogen. Di-tert-butyl dicarbonate (86.8 kg) was added at a temperature of 15–30 °C, and the reaction solution was heated to 40–50 °C and allowed to react for more than 20 hours. The reaction was confirmed to be complete by HPLC when the peak area of ​​compound 1 (as a starting material) fell below 0.6% of the total area of ​​all detected peaks. The reaction solution was then cooled to below 30 °C to obtain a solution containing compound 2 (compound 2 solution).

[0465] In another stirred tank purged with nitrogen, methyl carbamate (39.8 kg), potassium carbonate (73.3 kg), and toluene (138 kg) were added, and degassing was performed under reduced pressure. A solution of compound 2 and toluene (550 kg) were then added, followed by degassing under reduced pressure. 64.7%-Pd2(dba)3 (1.88 kg) and XPhos (2.54 kg) were added, and degassing was performed under reduced pressure. The reaction solution was heated to 88–97 °C and reacted at 88–97 °C for 4 hours. The reaction was confirmed to be complete by HPLC when the peak area of ​​compound 2 (as a starting material) reached less than 1.0% of the total area of ​​all detected peaks. The reaction solution was then cooled to 20–30 °C. The insoluble matter was filtered and removed. After washing the retained insoluble matter with acetonitrile (437 kg), 2-propanol (310 kg) was added to the filtrate containing the recovered compound 3. The temperature of the solution was maintained below 30°C, and concentrated hydrochloric acid (81.6 kg) was further added. The temperature of the reaction solution was raised to 50–60°C and maintained at 50–60°C for at least 1 hour. The reaction was confirmed to be complete by HPLC when the peak area of ​​compound 3 as the starting material was less than 0.1% of the total area of ​​all detected peaks. The temperature of the reaction solution was then cooled to below 25°C and incubated at 15–25°C for 1 hour. The slurry was filtered and the insoluble matter was recovered. The recovered insoluble matter (filter cake) was washed with acetonitrile (683 kg). Then, by vacuum drying the recovered insoluble matter while keeping the external temperature of the container below 60°C, methyl 6-[(methoxycarbonyl)amino]-2-(methoxymethyl)-1H-benzimidazole-4-carboxylate hydrochloride (compound 4) was obtained in the form of 76.0 kg of powder (yield 87%).

[0466] The spectral data of compound 4 are shown below.

[0467] ESI-MS (+): Calculated value 294.1, Measured value 294.0 (M+H)

[0468] 1 H 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)

[0469] [Step 4: Synthesis of 2-(methoxymethyl)-6-(2-(trifluoromethyl)benzamide)-1H-benzimidazole-4-carboxylic acid (compound 7)]

[0470] [Chemical Formula 73]

[0471]

[0472] Water (76.2 kg) and a 30% sodium hydroxide aqueous solution (153 kg) were added to a stirred tank purged with nitrogen and mixed. Compound 4 (75.6 kg) obtained in step 2 / 3 was added, and degassing was performed using nitrogen. The reaction solution was heated to 50-60°C and maintained at 50-60°C for at least 6 hours. The reaction was confirmed by HPLC when the peak area of ​​compound 5, as a reaction intermediate, was less than 1.0% of the total area of ​​all detected peaks. The temperature of the reaction solution was then cooled to below 30°C, and water (756 L) and acetic acid (13.7 kg) were added. Acetonitrile (356 kg) was added, and the solution was cooled to below 0°C. 47.9 kg of 2-(trifluoromethyl)benzoyl chloride was added dropwise at -5 to 5°C, and the temperature was maintained at -5 to 5°C for at least 15 minutes. By HPLC, the reaction was determined to be complete when the peak area of ​​compound 6, as a reaction intermediate, was less than 1.0% of the total area of ​​all detected peaks. The reaction solution was then heated to above 60°C, maintained at 60-70°C, and allowed to react for at least 2 hours. By HPLC, the reaction was determined to be complete when the total peak area of ​​the compound obtained by the reaction of 2-(trifluoromethyl)benzoyl chloride, a byproduct of the previous reaction, with compound 6 (reacting as 2 or 3 molecules) was less than 0.1% of the total area of ​​all detected peaks. Acetonitrile (238 kg) was added at a temperature below 70°C, and the temperature was further maintained at 60-70°C while acetic acid (55.0 kg) was added over a period of at least 30 minutes. The reaction solution was maintained at 60-70°C and stirred for at least 1 hour, then cooled to below 30°C, maintained at 20-30°C, and stirred for at least 1 hour. The slurry was filtered and the insoluble matter was recovered. The recovered insoluble matter (filter cake) was washed sequentially with a mixture of MeCN (142 kg) and water (182 kg), water (183 kg), and 2-propanol (144 kg). Then, by maintaining the external temperature of the container below 60°C and drying the recovered insoluble matter under reduced pressure, 2-(methoxymethyl)-6-(2-(trifluoromethyl)benzamido)-1H-benzimidazole-4-carboxylic acid (compound 7) was obtained as 85.1 kg of powder (94% yield).

[0473] The spectral data of compound 7 are shown below.

[0474] ESI-MS (+): Calculated value 394.1, Measured value 394.0 (M+H)

[0475] 1 H 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)

[0476] [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)]

[0477] [Chemical Formula 74]

[0478]

[0479] Compound 7 (82.8 kg) obtained in step 4 and DMF (235 kg) were added to a stirred tank purged with nitrogen. 1,1'-carbonyldiimidazole (38.8 kg) was added while stirring the solution below 30°C, and the reaction mixture was kept at 20–30°C for at least 1 hour. The reaction was confirmed complete by HPLC when the peak area of ​​compound 7, as the starting material, was less than 1.0% of the total area of ​​all detected peaks. The reaction mixture was then cooled to 20–30°C, and 74.3 kg of 3-chloro-2-methylaniline and 1.28 kg of benzoic acid were added. The reaction mixture was heated to 50–60°C and reacted for at least 20 hours. The reaction was confirmed to be complete by HPLC when the peak area of ​​the reaction intermediate with the carbonyl imidazole structure was less than 2.0% of the total area of ​​all detected peaks. DMAc (465 kg) was added to the reaction solution at 50–60 °C. The reaction solution was maintained at 50–60 °C, and water (331 kg) was added dropwise, followed by stirring at 50–60 °C for more than 1 hour. The reaction solution was cooled to below 25 °C, maintained at 20–25 °C, and stirred for more than 2 hours. The slurry was filtered, and the insoluble matter was recovered. The recovered insoluble matter (filter cake) was washed sequentially with a mixture of DMAc (183 kg) and water (195 kg), and then with water (293 kg). Then, by maintaining the external temperature of the container below 60°C and subjecting the recovered insoluble matter to vacuum drying, the crude product of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide DMA solvate (compound 8) was obtained in the form of 115 kg of powder (yield 91%).

[0480] [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)]

[0481] [Chemical Formula 75]

[0482]

[0483] The crude product of compound 8 obtained in step 5 (105 kg) and DMAc (322 kg) were added to the stirred 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 below 25°C for more than 90 minutes, and then stirred at 20-30°C for more than 30 minutes. The slurry was filtered and the insoluble matter was recovered. The recovered insoluble matter (filter cake) was washed with a mixture of DMAc (98.4 kg) and water (105 kg), followed by washing with water (211 kg). Then, by maintaining the temperature outside the container below 60°C and subjecting the recovered insoluble matter to vacuum drying, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide DMA solvate (compound 8) was obtained in the form of 98.7 kg of powder (yield 94%).

[0484] The spectral data of compound 8 are shown below.

[0485] ESI-MS(+): Calculated value of free particles after solvent removal: 517.1; Measured value: 517.0 (M+H)

[0486] 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)

[0487] [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 (meaning the same as "p-toluenesulfonate of Compound A"))]

[0488] [Chemical Formula 76]

[0489]

[0490] Compound 8 (98.0 kg) and DMF (231 kg) obtained in step 6 were added to a stirred tank. The solution was heated to 50-60°C to dissolve compound 8 in DMF. Then, MeCN (576 kg) was added to the solution, which was set at 45-60°C. While maintaining the temperature at 45-60°C, a solution containing pTsOH-H2O (33.9 kg) dissolved in MeCN (307 kg) was added dropwise, and MeCN (461 kg) was further added while maintaining the temperature at 45-60°C. The reaction solution was then stirred for more than 5 hours while maintaining the temperature at 50-60°C. The slurry was filtered to recover insoluble matter, and the recovered insoluble matter (filter cake) was washed with a mixture of DMF (23.1 kg) and MeCN (134 kg), followed by washing with MeCN (230 kg). Then, by maintaining the temperature outside the container below 60°C and drying the recovered insoluble matter under reduced pressure, crude product N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate (compound 9) was obtained in the form of 96.5 kg of powder (yield 86%).

[0491] [Step 8: Preparation of type I crystals of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide-4-methylbenzenesulfonic acid (p-toluenesulfonate of compound A)]

[0492] [Chemical Formula 77]

[0493]

[0494] The crude product of compound 9 obtained in step 7 (48.0 kg) and DMF (113 kg) were added to a stirred tank, and the temperature inside the stirred tank was raised to 35-40°C to dissolve it. Activated carbon (4.8 kg) was added, and the reaction solution was heated to 40-50°C, maintained at 40-50°C, and stirred for 1 hour. The slurry was filtered to remove insoluble matter, and the retained insoluble matter was washed with a mixture of DMF (22.6 kg) and toluene (41.5 kg). Toluene (208 kg) was added to the resulting filtrate at 20-30°C. Type I crystals of compound 9 (48.0 g) were added, and toluene (872 kg) was added dropwise at 20-30°C, maintained at 20-30°C, and stirred for at least 5 hours. After adding 240 g of seed crystals of compound 9, the solution was heated to 50-60 °C and stirred at 50-60 °C for more than 5 hours. The solution was then cooled to 20-30 °C and stirred further at 20-30 °C for more than 12 hours. The slurry was filtered and the insoluble matter was recovered. The recovered insoluble matter (filter cake) was washed with toluene (125 kg) and then with MeCN (75.2 kg). Then, by maintaining the external temperature of the container below 60 °C and drying the recovered insoluble matter under reduced pressure, type I crystals of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide-4-methylbenzenesulfonic acid (compound 9), i.e., type I crystals of the p-toluenesulfonate of compound A, were obtained in 44.9 kg of powder (94% yield). The powder X-ray diffraction results of the obtained p-toluenesulfonate type 1 crystals of compound A are shown below. Figure 1 .according to Figure 1 Peaks were observed at 2θ = 7.1°, 14.3°, 15.8°, and 18.3°. Further, the obtained powder was analyzed by HPLC, and the purity of compound 9 based on the peak area at 230 nm was 99.95%. Furthermore, the residual amount of toluene as solvent in the type I crystals of p-toluenesulfonate of the obtained compound A was 460 ppm, N,N-dimethylformamide was 514 ppm, and acetonitrile was not detected.

[0495] In addition, the results of differential scanning calorimetry (DSC) for the type I crystallization of p-toluenesulfonate of compound A are shown in... Figure 2 The results of thermophysical property determination of type I crystals of p-toluenesulfonate of compound A, based on differential calorimetry (DTA) and thermogravimetric analysis (TGA), are presented below. Figure 3 .according to Figure 2 The type I crystals of p-toluenesulfonate of compound A exhibit an endothermic peak at 265.76 °C in DSC. Furthermore, according to... Figure 3 The type 1 crystals of p-toluenesulfonate of compound A have an endothermic peak at 263.0 °C in DTA, and no weight change or endothermic / exothermic reaction was observed above 200 °C until decomposition, indicating that it is stable.

[0496] <Experimental Example 1: Purification efficiency and impurity removal efficiency in step 6>

[0497] For the powders of compound 8 or its crude product after purification in step 6 using a solvent with a volume ratio of DMA to H2O of 79:21 before purification in step 6, and after purification in step 6 using a solvent with a volume ratio of DMA to H2O of 69:31, the content of compound B, which is an impurity that needs to be controlled at the ppm level, was determined by the following formula.

[0498] [Chemical Formula 78]

[0499]

[0500] The results are shown in Table 1 below. According to Table 1, the purified product of compound 8 can be obtained in high yield with recrystallization under any solvent conditions, and the content of compound B, which is an impurity, decreases. Furthermore, when comparing solvent conditions, the content of compound B decreases significantly when the volume ratio of DMA to H2O is 79:21. That is, the removal efficiency of compound B is higher when the volume ratio of DMA to H2O is 79:21. The above results indicate that N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, obtained in the form of DMA solvate (compound 8) as a synthetic intermediate of compound 9, can be efficiently removed by recrystallization to remove impurities that need to be controlled at the ppm level.

[0501]

[0502] <Experimental Example 2: Purification efficiency and impurity removal efficiency in step 8>

[0503] The content of compound B as an impurity was determined for compound 9 obtained before purification in step 8, after purification by recrystallization without contact with activated carbon in step 8, and after purification by recrystallization with 0.05 times, 0.10 times, or 0.15 times the mass of the crude product of compound 9 as in step 8.

[0504] The results are shown in Table 2 below. Surprisingly, recrystallization of compound 9 alone failed to effectively remove compound B. On the other hand, contact with activated carbon prior to recrystallization effectively removed compound B, particularly when the mass of activated carbon in contact was 0.10 times and 0.15 times the mass of the crude product of compound 9, resulting in more efficient removal of compound B.

[0505]

[0506] [Preparation Example 1: Preparation of the amorphous form of p-toluenesulfonate of compound A]

[0507] Type I crystals (10 g) of p-toluenesulfonate of compound A obtained in Example 1 were suspended in methanol (1 L) and concentrated, dried, and solidified under reduced pressure at an external temperature of 55°C to obtain an amorphous p-toluenesulfonate of compound A. The powder X-ray diffraction results of the obtained amorphous substance are shown below. Figure 4 The result after magnification along the vertical axis is shown in Figure 5 No peaks were observed in the analysis results, confirming that the obtained product was an amorphous form of p-toluenesulfonate of compound A.

[0508] [Example 2: Preparation of type 3 crystals of p-toluenesulfonate of compound A 1]

[0509] The amorphous solid (14 g) of p-toluenesulfonate of compound A obtained in Preparation Example 1 was placed in an electric furnace and heated at 210 °C for 1 hour, yielding type III crystals (13.5 g) of p-toluenesulfonate of compound A in 96% yield. The powder X-ray diffraction results of the obtained type III crystals of p-toluenesulfonate of compound A are shown below. Figure 6 The thermophysical properties of the type 3 crystals of p-toluenesulfonate of compound A, obtained by differential calorimetry (DTA) and thermogravimetric analysis (TGA), are shown below. Figure 7 .according to Figure 6 Peaks were observed at 2θ = 6.3°, 15.0°, 16.4°, 17.9°, and 22.7°. Additionally, according to... Figure 7 The type 3 crystals of p-toluenesulfonate of compound A have an endothermic peak at 247.4 °C in DTA.

[0510] [Example 3: Preparation of Type IV crystals of p-toluenesulfonate of compound A 1]

[0511] The amorphous p-toluenesulfonate of compound A obtained in Preparation Example 1 (14 g) was added to acetonitrile (1 L) and stirred, resulting in crystal precipitation. The mixture was stirred overnight, then filtered to obtain crystals. The crystals were dried overnight at room temperature and atmospheric pressure, thus yielding the powder X-ray diffraction results. Figure 8 Furthermore, the results of thermophysical property measurements based on differential thermal analysis (DTA) and thermogravimetric analysis (TGA) are as follows: Figure 9 The crystallization is used as an intermediate product. According to... 1 The H-NMR results confirmed that the crystals were acetonitrile compounds formed by the mediated combination of acetonitrile with 1 / 2 acetonitrile molecules relative to compound A1 (hereinafter, the crystals obtained here will be referred to as "crystals of the 1 / 2 acetonitrile compound of p-toluenesulfonate of compound A obtained in Example 3"). The obtained crystals were placed in an electric furnace and heated at 160°C for 1.5 hours, yielding type IV crystals (12.7 g) of p-toluenesulfonate of compound A in 91% yield. The powder X-ray diffraction results of the obtained type IV crystals of p-toluenesulfonate of compound A are shown below. Figure 10 The results of thermophysical property determination of the four-type crystals of p-toluenesulfonate of compound A, based on differential calorimetry (DTA) and thermogravimetric analysis (TGA), are shown below. Figure 11 .according to Figure 10 Peaks were observed at 2θ = 7.4°, 8.0°, 14.5°, 16.1°, and 20.6°. Additionally, according to... Figure 11 The type 4 crystals of p-toluenesulfonate of compound A have an endothermic peak at 212.5 °C in DTA.

[0512] [Comparative Example 1: Preparation of Type 5 crystals of p-toluenesulfonate of compound A]

[0513] The amorphous p-toluenesulfonate of compound A obtained in Preparation Example 1 (14 g) was added to chloroform (0.8 L) and stirred, resulting in crystal precipitation. The mixture was stirred overnight and then filtered to obtain the crystals. The powder X-ray diffraction results were then obtained. Figure 12 Furthermore, the results of thermophysical property measurements based on differential thermal analysis (DTA) and thermogravimetric analysis (TGA) are as follows: Figure 13 The crystallization is used as an intermediate product. According to... 1 H-NMR results confirmed that the crystals were chloroform compounds. The obtained crystals were placed in an electric furnace and heated at 170°C for 1.5 hours to obtain type 5 crystals (12.9 g) of p-toluenesulfonate of compound A in 92% yield. The powder X-ray diffraction results of the obtained type 5 crystals of p-toluenesulfonate of compound A are shown below. Figure 14 The results of the thermophysical properties of the type 5 crystals of p-toluenesulfonate of compound A obtained by differential calorimetry (DTA) and thermogravimetric analysis (TGA) are shown below. Figure 15 .

[0514] [Comparative Example 2: Preparation of Type 6 crystals of p-toluenesulfonate of compound A]

[0515] The amorphous p-toluenesulfonate of compound A obtained in Preparation Example 1 (15 g) was added to 2,2,2-trifluoroethanol (TFE, 60 mL) cooled to 5 °C and stirred, resulting in crystal precipitation. After stirring the mixture for 5 days, the crystals were filtered to obtain the final powder X-ray diffraction result. Figure 16 The crystallization is used as an intermediate product. According to... 1 H-NMR results confirmed that the crystals were trifluoroethanol compounds. The obtained crystals were placed in an electric furnace and heated at 150°C for 30 minutes to obtain type 6 crystals (12.5 g) of p-toluenesulfonate of compound A in 83% yield. The powder X-ray diffraction results of the obtained type 6 crystals of p-toluenesulfonate of compound A are shown below. Figure 17 The results of thermophysical property determination of the type 6 crystals of p-toluenesulfonate of compound A, based on differential calorimetry (DTA) and thermogravimetric analysis (TGA), are shown below. Figure 18 .

[0516] [Comparative Example 3: Preparation of Type 7 crystals of p-toluenesulfonate of compound A]

[0517] The amorphous p-toluenesulfonate of compound A obtained in Preparation Example 1 (15 g) was added to 2,2,2-trifluoroethanol (TFE, 60 mL) cooled to 5 °C and stirred, resulting in crystal precipitation. After stirring the mixture for 6 days, the crystals were filtered to obtain the final powder X-ray diffraction result. Figure 16 The crystals were used as an intermediate product. Furthermore, the filtered crystals were left to stand overnight in a funnel, and the powder X-ray diffraction results were obtained as follows: Figure 19 Crystallization. According to 1 H-NMR results confirmed that the crystals were trifluoroethanol compounds. The obtained crystals were placed in an electric furnace and heated at 150°C for 1 hour to obtain type 7 crystals (12.7 g) of p-toluenesulfonate of compound A in 85% yield. The powder X-ray diffraction results of the obtained type 7 crystals of p-toluenesulfonate of compound A are shown below. Figure 20 The thermophysical properties of the p-toluenesulfonate type 7 crystals of compound A, determined by differential calorimetry (DTA) and thermogravimetric analysis (TGA), are shown below. Figure 21 .

[0518] [Example 4: Preparation of Type III Crystals of p-Toluenesulfonate of Compound A 2]

[0519] The p-toluenesulfonate type 4 crystals of compound A obtained in Example 3 were heated at 205°C to obtain the p-toluenesulfonate type 3 crystals of compound A.

[0520] [Example 5: Preparation of type 3 crystals of p-toluenesulfonate of compound A 3]

[0521] The p-toluenesulfonate crystals of compound A obtained in Comparative Example 1 were heated at 205°C for 10 minutes to obtain p-toluenesulfonate crystals of compound A in type 3. Furthermore, based on this result, it was determined that the p-toluenesulfonate crystals of compound A in type 3 exhibit higher stability than the p-toluenesulfonate crystals in type 5.

[0522] [Example 6: Preparation of type 3 crystals of p-toluenesulfonate of compound A 4]

[0523] The p-toluenesulfonate crystals of compound A obtained in Comparative Example 2 were heated at 190°C for 10 minutes to obtain p-toluenesulfonate crystals of compound A in type 3. Furthermore, based on this result, it was determined that the p-toluenesulfonate crystals of compound A in type 3 are more stable than the p-toluenesulfonate crystals in type 6.

[0524] [Example 7: Preparation of type 3 crystals of p-toluenesulfonate of compound A 5]

[0525] Approximately 10 mg of the 1 / 2 acetonitrile compound of p-toluenesulfonate obtained in Example 3 was placed in an open crucible with a capacity of 100 μL. Using a TG / DTA apparatus, the crucible was heated to a temperature slightly above the desolventizing temperature until weight loss stabilized (10 minutes). This temperature was maintained, and desolventizing was performed. The sample was then cooled to ambient temperature and analyzed by XRPD, yielding type 3 crystals of p-toluenesulfonate of compound A.

[0526] [Example 8: Preparation of Type IV crystals of p-toluenesulfonate of compound A 2]

[0527] Approximately 10 mg of the 1 / 2 acetonitrile compound of p-toluenesulfonate obtained in Example 3 was allowed to stand for 7 days at 40°C and 75% relative humidity, yielding type IV crystals of p-toluenesulfonate of compound A. Furthermore, based on this result, it was determined that the type IV crystals of p-toluenesulfonate of compound A exhibit higher stability than the crystals of the 1 / 2 acetonitrile compound of p-toluenesulfonate obtained in Example 3.

[0528] [Example 9: Relative stability between crystals of p-toluenesulfonate of compound A]

[0529] 100 mg of p-toluenesulfonate crystals of compound A prepared in Examples 1-3 and Comparative Examples 1-3 were weighed separately, and a total of 600 mg was added to 30 mL of a mixed solvent of DMF and toluene at a volume ratio of 1:9. The mixture was stirred at 20°C or 55°C. The crystal form of p-toluenesulfonate of compound A in the mixture was determined by powder X-ray diffraction at 3, 4, 7, and 8 days after stirring began at 20°C, and at 3 and 4 days after stirring began at 55°C. The results at 20°C are shown below. Figure 22 The results at 55℃ are shown below. Figure 23 .according to Figure 22 and 23 The crystals in the mixture all became type I crystals of p-toluenesulfonate of compound A after 8 days at 20℃ and 3 days at 55℃, respectively. Therefore, it is clear that type I crystals are the most stable crystal form of p-toluenesulfonate of compound A.

[0530] [Example 10: Stability test of excipients for type I crystallization of compound A p-toluenesulfonate]

[0531] The type I crystals of p-toluenesulfonate of compound A were mixed with various excipients at a 1:1 mass ratio using a mortar and pestle. After standing in an open system at 40°C and 75% relative humidity for 2 weeks or 1 month, the presence of decomposition was evaluated using HPLC, and color changes were confirmed by visual observation. As a control, the stability of the type I crystals of p-toluenesulfonate of compound A alone was evaluated. The HPLC conditions are shown below.

[0532] Device: Shimadzu LC-2010 CHT

[0533] Column: COSMOSIL 3C18-MSII 4.6×100mm

[0534] Column temperature: 40℃

[0535] Flowability: Solution A; MeCN / H2O / MsOH = 600 / 400 / 1

[0536] Solution B; MeCN / H2O / MsOH = 900 / 100 / 1

[0537] Gradient: 0-8 min; A=100%

[0538] 8-10 min; A to B

[0539] 10-20 min; B=100%

[0540] 20-21 min; B to A

[0541] Flow rate: 0.5 mL / min

[0542] Wavelength: 230nm

[0543] Table 3 shows the results obtained by observing the percentage of the peak area occupied by the type I crystals of compound A's p-toluenesulfonate in HPLC and the color of the crystals. According to Table 3, even when mixed with any excipient, no decomposition of the type I crystals of compound A's p-toluenesulfonate was observed, and the color remained unchanged. Therefore, it is clear that the type I crystals of compound A's p-toluenesulfonate are highly stable crystals of the p-toluenesulfonate of compound A.

[0544]

[0545] [Example 11: Stability evaluation of type I crystals of compound A p-toluenesulfonate exposed to various stimuli]

[0546] The stability of type I crystals of p-toluenesulfonate of compound A, and crystals of the free form of compound A prepared according to the method described in Patent Document 1, was evaluated by exposing them to heating stimulation (standing at 60°C for 24 hours), light stimulation (D65 lamp, total illuminance 1.2 million lx·hr), or humidification stimulation (standing at 30°C and 90% relative humidity for 24 hours). The stability was assessed based on the percentage (%) of the peak area of ​​the free form of compound A or the type I crystals of p-toluenesulfonate of compound A observed in HPLC when exposed to stimulation. The results are shown in Table 4. According to Table 4, no decrease in purity or color change was observed in the type I crystals of p-toluenesulfonate of compound A after exposure to any stimulation. Therefore, it can be clearly concluded that the type I crystals of p-toluenesulfonate of compound A are stable crystals of p-toluenesulfonate of compound A.

[0547]

[0548] [Example 12: Stability of type I crystals of p-toluenesulfonate of compound A upon exposure to mechanical stimulation and water]

[0549] Powder X-ray diffraction (PXRD) measurements were performed on the following samples of type I crystals of compound A p-toluenesulfonate: pulverized (crushed), crystals after adding water and stirring (water treatment), samples stored under humidified conditions (30°C, 90% relative humidity), and samples prepared by pressing (2000 kgf × 30 min). The results of arranging type I crystals of compound A p-toluenesulfonate without any treatment are shown below. Figure 24 .according to Figure 24No change in crystal form was observed under any conditions. Therefore, it can be clearly determined that the type 1 crystals of p-toluenesulfonate of compound A are stable crystals of p-toluenesulfonate of compound A. The powder X-ray diffraction patterns in this example were measured using RINT-UltimaIII (manufactured by RIGAKU Corporation) (target: Cu, voltage .40 kV, current .40 mA, scan rate: 4 degrees / minute).

[0550] [Example 13: Stability test of type 3 crystals of p-toluenesulfonate of compound A]

[0551] Approximately 10 mg of type III crystals of p-toluenesulfonate of compound A obtained in Example 2 was left to stand for more than 7 days at 40°C and 75% relative humidity. The type III crystals of p-toluenesulfonate of compound A remained stable for more than 7 days. Therefore, it can be clearly demonstrated that the type III crystals of p-toluenesulfonate of compound A are stable crystals.

[0552] [Comparative Example 4: Preparation of Type II Crystals of p-Toluenesulfonate of Compound A]

[0553] The free form (50 mg) of compound A, obtained according to the method described in Patent Document 1, was added to ethyl acetate (1.0 mL). At 50°C, pTsOH-H2O in an amount equivalent to compound A was added and stirred. A gel-like substance precipitated on the bottom wall, followed by overall turbidity and crystallization. The crystals were recovered, and the powder X-ray diffraction results were as follows: Figure 25 The results of thermophysical property determination based on differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are as follows: Figure 26 Type II crystals of p-toluenesulfonate of compound A.

[0554] [Example 14: Study on the thermal stability of type II crystallization of p-toluenesulfonate of compound A]

[0555] according to Figure 26 As a result, although an endothermic peak was observed in the DSC of the type II crystals of p-toluenesulfonate of compound A at 177 °C, no mass change was observed in the TGA, therefore it can be considered that a crystal form transformation occurred near 177 °C. Therefore, the crystal form was studied by powder X-ray diffraction while the type II crystals of p-toluenesulfonate of compound A were heated to 30 °C, 150 °C, and 200 °C, and then further studied by powder X-ray diffraction while cooling to 150 °C and 30 °C. The results are shown in... Figure 27 .according to Figure 27The type II crystals of p-toluenesulfonate of compound A are thermally unstable. Furthermore, the type II crystals of p-toluenesulfonate of compound A transform into the type III crystals of p-toluenesulfonate of compound A at 200°C; therefore, it would be more accurate to say that the type III crystals of p-toluenesulfonate of compound A are thermally stable.

[0556] [Example 15: Study on the relative stability of type I-III crystals of p-toluenesulfonate of compound A]

[0557] Similar to Example 4, the most stable crystal form of compound A's p-toluenesulfonate was investigated based on the crystal forms of type I and type II crystals, type I and type III crystals, or type II and type III crystals of compound A's p-toluenesulfonate in the same solution when stirred. For acetone, type I and type II crystals, type I and type III crystals, or type II and type III crystals of compound A's p-toluenesulfonate were added at a mass ratio of 1:1, and the mixture was stirred at 30°C for 42 hours. Then, the crystal form of compound A's p-toluenesulfonate in the solution was studied by powder X-ray diffraction. Under any of the three conditions, the crystals of compound A's p-toluenesulfonate in the solution all transformed into type I crystals. This indicates that type I crystals are the most stable among the three crystal forms.

[0558] [Example 16: Confirmation of the stability of type I crystals of p-toluenesulfonate of compound A in various solvents]

[0559] To facilitate solvent-induced crystal transformation, type I crystals of p-toluenesulfonate of compound A were pulverized using a mortar and pestle. The pulverized material was stirred at 40°C for 115 hours after the addition of methanol, ethyl acetate, or methyl ethyl ketone. The crystal form of p-toluenesulfonate of compound A in solution was then investigated by powder X-ray diffraction, and the results are shown below. Figure 28 .according to Figure 28 No change in crystal form was observed under any conditions, confirming that the type I crystal of p-toluenesulfonate of compound A is a very stable crystal form.

[0560] [Example 17: Preparation of p-toluenesulfonate of compound A under various conditions 1]

[0561] For a solvent of 1.4 mL, 22 mg of the amorphous p-toluenesulfonate of compound A obtained in Preparation Example 1 was added at room temperature. Then, the following operation was repeated for two cycles: heating to a temperature between ±3 °C and 100 °C (the lower of the solvent's boiling point) while stirring at 600 rpm with a stir bar; and cooling to 20 °C at a rate of 0.2 °C per minute. The crystal form was evaluated after two cycles. As a result, the crystal form was stable when using acetone, acetonitrile, anisole, chloroform, cyclohexane, dichloromethane, and 1,4-dioxane. Under conditions where alkanes, ethanol, n-heptane, isopropyl acetate, methyl ethyl ketone, methyl tert-butyl ether (MTBE), 2-propanol, tetrahydrofuran, 2-methyltetrahydrofuran, or toluene are used as solvents, type I crystals of p-toluenesulfonate of compound A can be obtained.

[0562] [Example 18: Preparation of p-toluenesulfonate of compound A under various conditions 2]

[0563] To prepare the acetic acid in the vial, an amorphous form of p-toluenesulfonate of compound A obtained in Preparation Example 1 was added, and the acetic acid was allowed to evaporate by allowing the vial to stand at room temperature in a fume hood with the cap open. As a result, type I crystals of p-toluenesulfonate of compound A were obtained.

[0564] [Example 19: Preparation of p-toluenesulfonate of compound A under various conditions 3]

[0565] For the solvent, the amorphous p-toluenesulfonate of compound A obtained in Preparation Example 1 was added, and the slurry was stirred at 5°C. Under the conditions of using a mixed solution of DMF and toluene in a volume ratio of 1:9, acetone, ethanol or tetrahydrofuran as solvent, type I crystals of p-toluenesulfonate of compound A can be obtained.

[0566] [Example 20: Preparation of p-toluenesulfonate of compound A under various conditions 4]

[0567] With the solvent added, the amorphous p-toluenesulfonate of compound A obtained in Preparation Example 1 was added, and the slurry was stirred at 20°C. Under the condition that acetone, ethanol, methyl tert-butyl ether (MTBE) or tetrahydrofuran was used as the solvent, type I crystals of p-toluenesulfonate of compound A could be obtained.

[0568] [Example 21: Preparation of p-toluenesulfonate of compound A under various conditions 5]

[0569] For the solvent, the amorphous p-toluenesulfonate of compound A obtained in Preparation Example 1 was added, and the slurry was stirred at 50°C. Under the conditions of using a mixed solution of DMF and toluene with a volume ratio of 1:1, 1:2, 1:3, 1:4 or 1:9, a mixed solution of DMF and acetonitrile with a volume ratio of 1:1, 1:2, 1:3 or 1:4, a mixed solution of acetonitrile and toluene with a volume ratio of 1:1, acetone, chloroform, ethanol, methyl tert-butyl ether (MTBE), tetrahydrofuran or toluene as solvent, type I crystals of p-toluenesulfonate of compound A can be obtained.

[0570] [Example 22: Preparation of p-toluenesulfonate of compound A under various conditions 6]

[0571] The amorphous p-toluenesulfonate of compound A obtained in Preparation Example 1 was dissolved in DMF at a concentration of 350 mg / mL (for room temperature) or 500 mg / mL (for 50°C) and filtered through a 0.2 μm polytetrafluoroethylene filter. 275 μL (for room temperature) or 250 μL (for 50°C) of the filtrate was stirred at 300 rpm with a lean solvent added, and stirred for 2 hours. Then, using toluene as a lean solvent, the mixture was further stirred for 70 hours. Alternatively, using a solvent other than toluene as a lean solvent, seed crystals of p-toluenesulfonate of compound A were added, and the mixture was further stirred for 70 hours. As a result, type I crystals of p-toluenesulfonate of compound A could be obtained by stirring at 50°C with acetonitrile as a lean solvent, by stirring at 50°C with 2-propanol as a lean solvent, by stirring at room temperature or 50°C with methyl ethyl ketone as a lean solvent, or by stirring at room temperature or 50°C with toluene as a lean solvent. It should be noted that, in terms of the amount of lean solvent added, acetonitrile is 1.93 ml (room temperature) or 1.75 ml (50°C), 2-propanol is 2.20 ml (room temperature) or 2.00 ml (50°C), methyl ethyl ketone is 2.20 ml (room temperature) or 2.00 ml (50°C), and toluene is 2.48 ml (room temperature) or 2.25 ml (50°C).

[0572] [Reference Example 1: Obtaining Type I crystals of Compound 9 without using seed crystals]

[0573] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide was obtained by the method described in Example 11 of Patent Document 1. 480 ml of THF was added to 80 g of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, and the mixture was heated to 50°C to dissolve it. 32.4 g of p-toluenesulfonic acid hydrate was added, and the mixture was stirred at the same temperature for at least 1 hour. Then, 960 ml of acetone was added while the mixture was heated to 55°C. The mixture was further heated at 50°C and stirred for at least 2 hours, then cooled to room temperature and stirred at the same temperature for 30 minutes. The slurry was filtered and washed with 50 ml of cold acetone. The sample was heated to a temperature below 50°C and dried under reduced pressure to obtain 98.1 g of white crystals with a yield of 92%.

[0574] A portion of the white crystals obtained in the same manner as described above can be used as seed crystals for compound 9.

[0575] The powder X-ray diffraction results of the obtained type I crystals of compound 9 are shown below. Figure 29 The results of thermophysical property determination of the type I crystals of compound 9, based on differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), are shown below. Figure 30 The powder X-ray diffraction pattern in Reference Example 1 was measured using a RINT-UltimaIII (manufactured by RIGAKU Corporation) (target: Cu, voltage: 40 kV, current: 40 mA, scan rate: 4 degrees / min). The DSC in Reference Example 1 was measured using a DSC-50 (manufactured by Shimadzu Corporation) (crucible: alumina (open), gas: nitrogen (20.0 mL / min), heating rate: 10.0 °C / min, holding temperature: 400 °C, holding time: 0 min).

Claims

1. Type I crystals of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide-4-methylbenzenesulfonate, represented by the following formula (AI). ， The crystal exhibits diffraction peaks at diffraction angles (2θ±0.2°) of 7.1°, 14.3°, 15.8°, and 18.3° in powder X-ray diffraction.

2. Type I crystals of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide-4-methylbenzenesulfonate, represented by the following formula (AI). ， The crystals exhibited an endothermic peak at 265.8 ± 3.0 °C in differential scanning calorimetry.

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

4. Type III crystals of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide-4-methylbenzenesulfonate, represented by the following formula (AI). ， The crystals exhibit an endothermic peak at 247.4 ± 3.0 °C in differential thermal analysis.

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

6. Type IV crystals of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, represented by the following formula (AI). ， The crystals exhibit an endothermic peak at 212.5 ± 3.0 °C in differential thermal analysis.

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

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

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