Method for producing 1,5-benzothiazepine compound

Abstract

To provide a method for the production of 1,5-benzothiazepine compounds in high yields and high purity with a reduced amount of solvents without repeating purification of intermediate compounds.SOLUTION: A method for producing a 1,5-benzothiazepine compound is provided, comprising: a step of reacting a raw material compound with another raw material compound in the presence of a triazine compound to yield an intermediate compound; and a step of deprotecting the intermediate compound to synthesize a 1,5-benzothiazepine compound (1).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a process for producing 1,5-benzothiazepine compounds. [Background technology]

[0002] N-{(2R)-2-[({[3,3-Dibutyl-7-(methylthio)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl]oxy}acetyl)amino]-2-phenylethanolyl}glycine (elobixibat) is an ileal bile acid transporter (IBAT) inhibitor and can be used to treat or prevent diseases such as dyslipidemia, constipation, diabetes and liver disease.

[0003] A method for producing 1,5-benzothiazepine compounds including elobixibat is disclosed, for example, in WO 02 / 50051. Specifically, 1,5-benzothiazepine compounds can be produced by oxidizing benzothiazepine and then removing the protecting group, but the method disclosed in WO 02 / 50051 requires many steps and the use of various reagents.

[0004] However, such a method using many reagents is undesirable from the viewpoint of environmental protection and safety. For example, when a different solvent is used for each step, the solvent needs to be removed after each step, so that a large amount of multiple solvents needs to be used and the production cost for removing the solvent is high. In addition, the product obtained in each step needs to be purified, which is not suitable for large-scale industrial production.

[0005] In addition, WO 2014 / 174066 discloses a method for producing a crystalline monohydrate of elobixibat. However, the method disclosed in WO 2014 / 174066 is also not suitable for large-scale industrial production. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] WO 02 / 50051 [Patent Document 2] International Publication No. 2014 / 174066 Summary of the Invention [Problem to be solved by the invention]

[0007] Therefore, there has been a demand for a method for producing 1,5-benzothiazepine compounds suitable for large-scale industrial production, particularly a method for producing 1,5-benzothiazepine compounds with higher yields and higher purity than conventional methods, and with improved production costs.

[0008] The present invention has been made to solve the above-mentioned problems of the conventional technology, and aims to provide a method for producing a 1,5-benzothiazepine compound with high purity in high yield, by reducing the amount of solvent used and without repeated purification of intermediates. [Means for solving the problem]

[0009] As a result of intensive research into the above-mentioned problems, the present inventors unexpectedly discovered a method for producing a high-purity 1,5-benzothiazepine compound in a sufficiently high yield by using a triazine compound.

[0010] The object of the present invention is to provide a compound of formula (I): [ka] (In the formula, R 1 and R 2 are each independently C 1~4 is alkyl, R 3 is C1~4 is alkyl, R 4 is hydrogen, hydroxy, halo, nitro, cyano and C 1~4 is selected from the group consisting of alkyl, R 5 is hydrogen, hydroxy, halo, nitro, cyano and C 1~4 alkyl) A method for producing Compounds of formula (II): [ka] (In the formula, R 1 From R 4 is defined above) in the presence of a triazine compound to produce a compound of formula (III): [ka] (In the formula, R 5 is as defined above, R 6 is a protecting group) to produce a compound of formula (IV): [ka] (In the formula, R 1 From R 6 is as defined above) and Deprotecting the compound of formula (IV) to obtain a compound of formula (I). This is achieved by a method comprising:

[0011] The triazine compound is preferably selected from the group consisting of 2,4,6-trichloro-1,3,5-triazine (TCT), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 2,4-dichloro-6-methoxy-1,3,5-triazine (DCMT), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), and mixtures thereof. More preferably, the triazine compound is 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM).

[0012] In the above formulas (I), (II) and (IV), R 1 and R 2 is preferably each n-butyl.

[0013] In the above formulas (I), (II) and (IV), R 3 It is preferred that is methyl.

[0014] In the above formulas (I), (II), (III) and (IV), R 4 and R 5 is preferably hydrogen.

[0015] In the above formulas (III) and (IV), R 6 is C 1~4 Preferably it is selected from the group consisting of alkyl and trisubstituted silyl, more preferably tert-butyl.

[0016] The compound of formula (IV) is preferably deprotected by reaction with trifluoroacetic acid.

[0017] The deprotection of the compound of the formula (IV) is preferably carried out in the presence of toluene and water, and the amount of water used is preferably 0.2 to 2.0% by mass relative to the amount of toluene.

[0018] The compound of formula (I) is preferably precipitated from the solution by adding heptane.

[0019] The compound of formula (II) may be a compound of formula (V): [ka] (In the formula, R 1 From R 4 is defined above) in the presence of water to obtain a compound of formula (VI): [ka] (In the formula, R 7 is a protecting group, X is a leaving group. to produce an intermediate compound of formula (VII): [ka] (In the formula, R 1 From R 4 and R 7 is defined above) and an alkylation reaction comprising the steps of: Ester R to obtain the compound of formula (II) 7 Hydrolysis of OC(O)- It is preferably produced by

[0020] In the above formulas (VI) and (VII), R 7 is C 1~4 Alkyl and C 1~4 Preferably, it is selected from the group consisting of haloalkyl.

[0021] In said formula (VI), X is preferably selected from the group consisting of halo, trifluoromethanesulfonate, methanesulfonyl and p-toluenesulfonyl.

[0022] The synthesis of the intermediate compound of formula (VII) is preferably carried out in toluene.

[0023] The amount of water used when reacting the compound of formula (V) with the compound of formula (VI) is preferably 0.01 to 0.5% by mass relative to the amount of the compound of formula (V).

[0024] It is preferred that the intermediate compound of formula (VII) is not isolated but is used as is in the next step.

[0025] The alkylation reaction and the subsequent hydrolysis reaction are preferably carried out in the same solvent.

[0026] The compound of formula (III) may be a compound of formula (VIII): [ka] (In the formula, R 5 and R 6 is defined above) is preferably produced by deprotecting the compound in the presence of an alcohol having 3 or more carbon atoms.

[0027] The alcohol having 3 or more carbon atoms is preferably selected from the group consisting of 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, and mixtures thereof.

[0028] The process of the present invention may further comprise the step of converting said compound of formula (I) into a stable crystalline hydrate of formula (I).

[0029] The compound of formula (I) is preferably dissolved in ethyl acetate.

[0030] Preferably, n-heptane is added to a solution of a compound of formula (I) in ethyl acetate.

[0031] Preferably, the stable crystalline hydrate is a crystalline monohydrate. Effect of the Invention

[0032] According to the present invention, a 1,5-benzothiazepine compound with high purity can be produced in high yield by reacting a compound of formula (II) with a compound of formula (III) in the presence of a triazine compound.

[0033] In the present invention, 1,5-benzothiazepine compounds can be produced by a method that does not use a large amount of solvent and has a low environmental impact. In addition, since there is no need to repeatedly purify intermediates, the production cost is low and the method is suitable for large-scale industrial production. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] The method of the present invention comprises reacting a compound of formula (I): [ka] (In the formula, R 1 and R 2 are each independently C 1~4 is alkyl, R 3 is C 1~4 is alkyl, R 4 is hydrogen, hydroxy, halo, nitro, cyano and C 1~4 is selected from the group consisting of alkyl, R 5 is hydrogen, hydroxy, halo, nitro, cyano and C 1~4 alkyl) A method for producing Compounds of formula (II): [ka] (In the formula, R 1 From R 4 is defined above) in the presence of a triazine compound to produce a compound of formula (III): [ka] (In the formula, R 5 is as defined above, R 6 is a protecting group) to produce a compound of formula (IV): [ka] (In the formula, R 1 From R 6 is as defined above) and Deprotecting the compound of formula (IV) to obtain a compound of formula (I). The present invention relates to a method comprising the steps of:

[0035] As used herein, the term "alkyl" includes both straight and branched chain alkyl groups, and the term "halo" includes fluorine, chlorine, bromine and iodine.

[0036] As used herein, the term “C 1~4 "Alkyl" refers to a straight or branched chain alkyl group having from 1 to 4 carbon atoms. 1~4 Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0037] As used herein, the term “C 1~4 "Haloalkyl" means a C alkyl group in which at least one hydrogen atom is replaced by a halogen. 1~4 Represents alkyl. 1~4 Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl.

[0038] In the present specification, the term "protecting group" refers to a temporary substituent for protecting a reactive functional group that may be chemically modified. Such protecting groups are known to those skilled in the art and are described, for example, in TW Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1999, etc. Specific examples include esters of carboxylic acids such as alkyl esters and silyl esters of carboxylic acids.

[0039] Also, the protecting groups can be removed and deprotected using known techniques at an appropriate stage in the process for preparing the compounds of formula (I).

[0040] The compounds of formula (I) may have chiral and / or geometric isomeric centers, and the compounds of formula (I) of the present invention include all optical and geometric isomers that possess IBAT inhibitory activity.

[0041] The compound of formula (I) may also be in the form of a pharma- ceutically acceptable salt, and when the compound of the present invention is basic, it may be an inorganic or organic acid salt thereof, such as an acid addition salt with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid, acetic acid or maleic acid. When the compound of the present invention is acidic, it may be an alkali metal salt thereof, such as a sodium salt or a potassium salt, an alkaline earth metal salt thereof, such as a calcium salt or a magnesium salt, an ammonium salt, or a salt with an organic base which provides a physiologically acceptable cation, such as a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0042] Furthermore, the compounds of formula (I) may be in the form of pro-drugs which are broken down in the human or animal body to give compounds of formula (I). Examples of pro-drugs include in vivo hydrolysable esters and in vivo hydrolysable amides of compounds of formula (I).

[0043] The compound of formula (I) may be a solvate such as a hydrate, and the compound of formula (I) of the present invention includes all solvates having IBAT inhibitory activity. In particular, a crystalline hydrate is preferable, and a crystalline monohydrate is more preferable.

[0044] In one embodiment, the compound of formula (I) is R 1 and R 2 It is preferred that at least one of R is n-butyl. More preferably, R 1 and R 2 are n-butyl.

[0045] In one embodiment, the compound of formula (I) is R 3 is preferably methyl or ethyl, more preferably methyl.

[0046] In one embodiment, the compound of formula (I) is R 4 and R 5 It is preferred that at least one of R is hydrogen. More preferably, 4 and R 5 are hydrogen.

[0047] The process of the present invention comprises the step of reacting a compound of formula (II) with a compound of formula (III) in the presence of a triazine compound to obtain a compound of formula (IV).

[0048] The compound of formula (III) is preferably used in an excess amount in a stoichiometric ratio relative to the compound of formula (II). The compound of formula (III) is preferably used in an amount of 1.0 to 1.3 equivalents relative to the compound of formula (II), and more preferably used in an amount of 1.2 equivalents.

[0049] R of the compound of formula (III) 6 is a protecting group, preferably a protecting group that can be removed under acidic conditions. 6 is C 1~4It is preferably selected from the group consisting of alkyl and trisubstituted silyl, more preferably tert-butyl or trimethylsilyl, and most preferably tert-butyl.

[0050] The triazine compound is preferably selected from the group consisting of 2,4,6-trichloro-1,3,5-triazine (TCT), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 2,4-dichloro-6-methoxy-1,3,5-triazine (DCMT), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), and mixtures thereof. A particularly preferred triazine compound is 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM). By using these triazine compounds, the above step can be carried out using the same solvent as that used in the step of producing the compound of formula (III), which is preferable since it is possible to greatly reduce the amount of solvent used.

[0051] The triazine compound is preferably used in an excess amount based on the stoichiometric ratio relative to the compound of formula (II), and the triazine compound is preferably used in an amount of 1.0 to 1.5 equivalents relative to the compound of formula (II).

[0052] The solvent used is not particularly limited, but it is preferable to use the same solvent as that used in the step of producing the compound of formula (III) from the viewpoint of the amount of solvent used.

[0053] The step of reacting the compound of formula (II) with the compound of formula (III) in the presence of a triazine compound is carried out at a temperature higher than 0° C. and lower than the boiling point of the solvent used, preferably at 5 to 80° C., and more preferably at 10 to 40° C.

[0054] After the reaction is completed, the insoluble matter can be removed by filtration and washed with the same solvent as used. The filtrate can then be concentrated, ethyl acetate can be added, and the mixture can be washed successively with water, an acidic aqueous solution (e.g., 3% hydrochloric acid), a basic aqueous solution (e.g., 5% sodium bicarbonate aqueous solution), and saline. The compound of formula (IV) can then be obtained by crystallization and filtration, followed by drying under reduced pressure.

[0055] The process of the present invention includes the step of deprotecting a compound of formula (IV) to obtain a compound of formula (I). 6 This is accomplished by partial hydrolysis, preferably acid hydrolysis, which can be carried out in the presence of a suitable acid to give the carboxylic acid compound of formula (I).

[0056] Examples of suitable acids include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid, formic acid, acetic acid, and trifluoroacetic acid. Preferably, the acid is trifluoroacetic acid.

[0057] The solvent used in the hydrolysis is preferably an ether such as tetrahydrofuran, dioxane, cyclopentyl methyl ether, or 1,2-dimethoxyethane; an ester such as ethyl acetate or isopropyl acetate; an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; an aliphatic halogenated hydrocarbon such as dichloromethane or chloroform; an aromatic halogenated hydrocarbon such as chlorobenzene; a nitrile such as acetonitrile or propionitrile; an amide such as N,N-dimethylformamide or N-methylpyrrolidone; or a mixture of these solvents. In particular, the solvent used in the hydrolysis is preferably an aromatic hydrocarbon, more preferably toluene or xylene. Most preferably, toluene is used.

[0058] The hydrolysis is carried out at a temperature higher than 0°C and lower than the boiling point of the solvent used, preferably at 10 to 110°C, and more preferably at 15 to 40°C.

[0059] The amount of water used in deprotecting the compound of formula (IV) is 0.2 to 2.0% by mass, preferably 0.5 to 1.0% by mass, based on the amount of the solvent. For example, when toluene is used as the solvent, water is used in an amount of 0.2 to 2.0% by mass, preferably 0.5 to 1.0% by mass, based on the amount of toluene. By adding a small amount of water during the reaction, the increase in optical isomers can be suppressed, and the selectivity of the compound of formula (I) can be improved.

[0060] After the hydrolysis is completed, the acid is washed with water, and then washed with saturated saline until the pH of the aqueous layer is at least 3. The resulting organic layer can be further purified by crystallization and centrifugation, washed with heptane, particularly n-heptane, and then dried under reduced pressure to obtain the compound of formula (I).

[0061] In the method of the present invention, the compound of formula (II) is reacted with a compound of formula (V): [ka] (In the formula, R 1 From R 4 is defined above) in the presence of water to obtain a compound of formula (VI): [ka] (In the formula, R 7 is a protecting group, X is a leaving group. to produce an intermediate compound of formula (VII): [ka] (In the formula, R 1 From R 4 and R 7 is defined above) and an alkylation reaction comprising the steps of: Ester R to obtain the compound of formula (II) 7 Hydrolysis of OC(O)- It is preferably produced by

[0062] The compound of formula (VI) is an alkylating agent, R 7 is C 1~4 Alkyl and C 1~4 Preferably, R is selected from the group consisting of haloalkyl. 7 C such as methyl, ethyl and tert-butyl 1~4 More preferably, X is alkyl, and most preferably, ethyl. Preferably, X is selected from the group consisting of halo, trifluoromethanesulfonate, methanesulfonyl, and p-toluenesulfonyl. More preferably, X is halo, and most preferably, a halogen selected from chlorine, bromine, and iodine. In a most preferred embodiment, the compound of formula (VI) is ethyl bromoacetate.

[0063] The compound of formula (VI) is preferably used in a stoichiometric excess amount relative to the compound of formula (V), and the compound of formula (VI) is preferably used in an amount of 1.0 to 1.4 equivalents relative to the compound of formula (V).

[0064] The step of reacting the compound of formula (V) with the compound of formula (VI) is carried out in the presence of water. By using water as a reactant, the reaction rate between the compound of formula (V) and the compound of formula (VI) can be significantly increased. The amount of water used is 0.01 to 0.5% by mass, preferably 0.02 to 0.2% by mass, based on the amount of the compound of formula (V).

[0065] The step of reacting the compound of formula (V) with the compound of formula (VI) is preferably carried out in the presence of a phase transfer catalyst and a base.Examples of phase transfer catalysts include tetra-n-butylammonium bromide (TBAB), benzyltrimethylammonium chloride, benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride and methyltrioctylammonium chloride.Tetra-n-butylammonium bromide is the most preferred.

[0066] Examples of bases include metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; metal carbonates such as sodium carbonate, potassium carbonate, and lithium carbonate; and metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, and lithium bicarbonate. Metal carbonates are preferred, and sodium carbonate is more preferred.

[0067] The base is preferably used in a stoichiometric excess amount relative to the compound of formula (VI), more preferably 3.0 to 6.0 equivalents, more preferably 3.5 to 5.0 equivalents relative to the compound of formula (VI).

[0068] The solvent used in the alkylation reaction is preferably an ether such as tetrahydrofuran, dioxane, cyclopentyl methyl ether, or 1,2-dimethoxyethane; an ester such as ethyl acetate or isopropyl acetate; an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; a ketone such as acetone or 2-butanone; an aliphatic halogenated hydrocarbon such as dichloromethane or chloroform; an aromatic halogenated hydrocarbon such as chlorobenzene; a nitrile such as acetonitrile or propionitrile; an amide such as N,N-dimethylformamide or N-methylpyrrolidone; or a mixture of these solvents. In particular, the solvent used in the alkylation reaction is preferably an aromatic hydrocarbon or an aliphatic halogenated hydrocarbon, more preferably toluene or xylene. Most preferably, toluene is used.

[0069] The alkylation reaction is carried out at a temperature higher than 0° C. and lower than the boiling point of the solvent used, preferably at 20 to 110° C., more preferably at 50 to 100° C., and particularly preferably at 70 to 90° C.

[0070] After the alkylation reaction is completed, the phase transfer catalyst and base are removed by washing with water and extraction into the aqueous layer. The resulting compound of formula (VII) can be used in the next step without further purification or isolation.

[0071] In a next step, the compound of formula (VII) can be hydrolyzed, preferably under basic conditions, to give the compound of formula (II). The hydrolysis may be carried out in an organic solvent with the addition of an aqueous base solution.

[0072] Examples of bases include metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; metal carbonates such as sodium carbonate, potassium carbonate, and lithium carbonate; and metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, and lithium bicarbonate. Metal hydroxides are preferred, and sodium hydroxide is more preferred.

[0073] The base is preferably used in an excess amount in a stoichiometric ratio relative to the compound of formula (VII), more preferably 2.0 to 6.0 equivalents, more preferably 3.0 to 5.0 equivalents, particularly preferably 3.5 to 4.5 equivalents relative to the compound of formula (VII).

[0074] The solvent used in the hydrolysis is preferably an alcohol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, or t-butanol; an ether such as tetrahydrofuran, dioxane, cyclopentyl methyl ether, or 1,2-dimethoxyethane; an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as toluene or xylene; a ketone such as acetone or 2-butanone; an aliphatic halogenated hydrocarbon such as dichloromethane or chloroform; an aromatic halogenated hydrocarbon such as chlorobenzene; or a mixture of these solvents. In particular, the solvent used in the hydrolysis is preferably an alcohol or an aromatic hydrocarbon, more preferably toluene or xylene. Most preferably, toluene is used.

[0075] It is preferable to use the same solvent in the alkylation reaction and the subsequent hydrolysis from the viewpoint of the amount of solvent used and simplification of the process.

[0076] The hydrolysis is carried out at a temperature higher than 0°C and lower than the boiling point of the solvent used, preferably at 10 to 110°C, more preferably at 20 to 90°C, and particularly preferably at 30 to 70°C.

[0077] If necessary, water and a solvent are added, followed by the addition of an acid such as formic acid, and the organic layer is cooled and further purified by crystallization and centrifugation, washed with toluene, and then dried under reduced pressure to obtain the compound of formula (II).

[0078] In the method of the present invention, the compound of formula (III) is reacted with a compound of formula (VIII): [ka] (In the formula, R 5 and R 6 is defined above) is preferably produced by deprotecting the compound in the presence of an alcohol having 3 or more carbon atoms.

[0079] Deprotection is [ka] Deprotection can be carried out in the presence of a suitable alcohol to give compounds of formula (III).

[0080] As a suitable alcohol, an alcohol having 3 or more carbon atoms is used. It is preferably selected from the group consisting of 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, and mixtures thereof. Most preferably, 2-propanol is used.

[0081] The deprotection is carried out at a temperature higher than 0°C and lower than the boiling point of the alcohol used, preferably at 0 to 80°C, and more preferably at 5 to 40°C.

[0082] After the deprotection is completed, the insoluble matter is removed by filtration, and the filtrate is washed with a solvent to obtain the compound of formula (III).

[0083] The process of the present invention may further comprise a step of converting the compound of formula (I) into a stable crystalline hydrate of formula (I). This can be done by recrystallizing the compound of formula (I) from a solvent comprising ethanol. In a preferred embodiment, the compound of formula (I) is elobixibat and the stable crystalline hydrate is a crystalline monohydrate. Most preferably, it is a crystalline monohydrate of the crystalline modification IV (also designated crystalline form IV) of elobixibat.

[0084] It is known how to obtain the crystalline modification IV of elobixibat by crystallizing elobixibat from ethanol or a mixture of ethanol and water. A solvate, the crystalline ethanolate of elobixibat, is first formed, which can be isolated and dried under reduced pressure and elevated temperature to obtain the nonsolvate of elobixibat. The nonsolvate of elobixibat absorbs atmospheric moisture and is converted to the crystalline modification IV.

[0085] In the present invention, the step of converting the compound of formula (I) into a stable crystalline hydrate of formula (I) preferably comprises dissolving the compound of formula (I) in ethyl acetate, and preferably comprises crystallizing the crystalline ethanolate of the compound of formula (I) from a solution of the compound of formula (I) in ethyl acetate.

[0086] The crystallized crystalline ethanolate of the compound of formula (I) is dried to obtain a crystalline non-solvate of the compound of formula (I), which can be converted to a stable crystalline hydrate of the compound of formula (I) by absorbing moisture.

[0087] Furthermore, the crystalline modification IV of elobixibat has an X-ray powder diffraction (XRPD) pattern, obtained with CuKα1 radiation, with specific peaks at least at the positions 6.3±0.2 and / or 19.4±0.2 °2θ.

[0088] In one embodiment, the crystalline modification IV of elobixibat has an X-ray powder diffraction (XRPD) pattern, obtained with CuKα1 radiation, having characteristic peaks at 6.3±0.2 and 19.4±0.2 °2θ positions, and characteristic peaks at one or more of the following positions: 10.2±0.2, 10.5±0.2, 9.4±0.2, 9.5±0.2, 12.5±0.2, 14.6±0.2, 15.6±0.2, and 23.3±0.2 °2θ positions.

[0089] In another embodiment, the crystalline modification IV of elobixibat has characteristic peaks at °2θ positions of 6.3±0.2, 19.4±0.2, 10.2±0.2, 10.5±0.2, 9.4±0.2, 9.5±0.2, 12.5±0.2, 14.6±0.2, 15.6±0.2 and 23.3±0.2, as well as at 8.3±0.2, 11.3±0.2, 13.4±0.2, 13.9±0.2, 16.3±0.2, 16.6±0.2, 18.2±0.2, 18.8±0.2, 19.1±0.2, 19.3±0.2, 19.7±0.2, 19.8±0.2, 19.9 ... 0.2, 19.8±0.2, 20.5±0.2, 21.0±0.2, 21.3±0.2, 21.4±0.2, 22.6±0.2, 22.9±0.2, 23.1±0.2, 23.9±0.2, 24.5±0.2, 24.7±0.2, 25.0±0.2, 25.2±0.2, 25.4±0.2, 25.7±0.2, 26.7±0.2, 26.9±0.2, 28.3±0.2 and 28.9±0.2 in °2θ positions.

[0090] In another embodiment, the crystalline modification IV of elobixibat exhibits characteristic peaks at 6.3±0.2, 8.3±0.2, 9.4±0.2, 9.5±0.2, 10.2±0.2, 10.5±0.2, 11.3±0.2, 12.5±0.2, 13.4±0.2, 13.9±0.2, 14.6±0.2, 15.6±0.2, 16.3±0.2, 16.6±0.2, 18.2±0.2, 18.8±0.2, 19.1±0.2, 19.3±0.2, 19.4±0.2, 19.7±0.2, 19.8±0.2, 20. 25.7±0.2, 26.7±0.2, 26.9±0.2, 28.3±0.2 and 28.9±0.2.

[0091] In a preferred embodiment, the process of crystallizing the crystalline ethanolate of the compound of formula (I) can be initiated by adding seed crystals of the crystalline modification IV of elobixibat.

[0092] In another preferred embodiment, n-heptane is added to a solution of a compound of formula (I) in ethyl acetate. EXAMPLES

[0093] The present invention will be described in more detail below using examples and comparative examples, but the scope of the present invention is not limited to the examples. Unless otherwise specified, the reagents used in the examples were commercially available reagents that were purchased and used, or were prepared by methods known to those skilled in the art and used.

[0094] Example 1: Preparation of ethyl 2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetate Into a reaction vessel, 13.00 kg of 3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-ol, 12.90 kg of sodium carbonate, 0.84 kg of tetrabutylammonium bromide, 113.18 kg of toluene, 0.52 kg of water and 5.58 kg of ethyl bromoacetate were added and reacted with stirring at 80° C. After the reaction, the reaction solution was cooled and then washed with water to obtain a toluene solution of ethyl 2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetate.

[0095] Example 2: Preparation of 2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetic acid To the entire amount of the toluene solution of ethyl 2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetate obtained in Example 1, 46.49 kg of 10% aqueous sodium hydroxide solution was added and reacted with stirring at 47° C. After the reaction, 77.5 kg of water and 124.1 kg of toluene were added, and then 11.07 kg of formic acid was added.

[0096] The organic layer was then cooled to 5° C., and the precipitated crystals were centrifuged and washed with toluene. The crystals were dried under reduced pressure at 55° C. or lower to obtain 13.45 kg of dried crystals of 2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetic acid.

[0097] Example 3: Preparation of 1,1-dimethylethyl [(2R)-2-amino-2-phenylacetamido]acetate Into a reaction vessel, 11.40 kg of 1,1-dimethylethyl 2-[(2R)-2-benzyloxycarbamido-2-phenylacetamido]acetate, 91.6 kg of 2-propanol, and 1.37 kg of 10% palladium-carbon (50% water content) were added. The reaction was carried out under a hydrogen pressure of 0.03 MPa at 10°C.

[0098] Insoluble matter was removed from the solution after the reaction by filtration, and the filtrate was washed with 11.4 kg of 2-propanol to obtain 1,1-dimethylethyl [(2R)-2-amino-2-phenylacetamido]acetate as a 2-propanol solution.

[0099] Example 4: Preparation of 1,1-dimethylethyl [(2R)-2-(2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetamido)-2-phenylacetamido]acetate In a reaction vessel, the entire amount of the 2-propanol solution of 1,1-dimethylethyl [(2R)-2-amino-2-phenylacetamido]acetate obtained in Example 3 and 13.20 kg of 2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetic acid obtained in Example 2 were added and stirred. 10.10 kg of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) was added and reacted with stirring at 20°C. Insoluble matter was filtered from the obtained reaction solution, and the residue was washed with 26.4 kg of 2-propanol. The filtrate was concentrated to a liquid volume of 60.6 kg, and 119.0 kg of ethyl acetate was added to the concentrate, which was then washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate solution, and saline solution in that order. After washing, 251.1 kg of n-heptane was added to remove the aqueous layer, and 66.00 g of seed crystals of [(2R)-2-(2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetamido)-2-phenylacetamido]acetic acid 1,1-dimethylethyl were added to the resulting organic layer at 25° C. and stirred. After cooling to 0°C, the precipitated crystals were centrifuged and washed with 79.2 kg of n-heptane to obtain 1,1-dimethylethyl [(2R)-2-(2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetamido)-2-phenylacetamido]acetate as wet crystals.

[0100] The obtained wet crystals were then dried under reduced pressure at 50°C or less to obtain 16.87 kg of dry crystals of 1,1-dimethylethyl [(2R)-2-(2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetamide)-2-phenylacetamide]acetate.

[0101] Example 5: Preparation of [(2R)-2-(2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetamido)-2-phenylacetamido]acetic acid ethanol solvate 25.00 g of 1,1-dimethylethyl [(2R)-2-(2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetamide)-2-phenylacetamide]acetate obtained in Example 4, 319.65 g of toluene, and 1.61 g of water were added to a flask, 132.73 g of trifluoroacetic acid was added dropwise, and the mixture was reacted at 30 ° C. with stirring. The reaction solution was washed with 200.07 g of water and 200.06 g of 10% saline solution in order, and the organic layer was concentrated to 124.8 g, and then 200.23 g of ethyl acetate was added. The mixture was washed four times with 200 g of 10% saline solution, the solvent was replaced with toluene by concentration replacement, and the mixture was further concentrated to 68.5 g. 37.50 g of ethyl acetate, 32.52 g of ethanol, 125.34 g of n-heptane, and 0.13 g of elobixibat ([(2R)-2-(2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetamide)-2-phenylacetamide]acetic acid) monohydrate seed crystals were added and stirred at 25 ° C., and then 124.91 g of n-heptane was added, cooled to 0 ° C., and further stirred. The precipitated crystals were filtered and dried under reduced pressure at 35 ° C. or less to obtain 21.82 g of elobixibat crude crystals as an ethanol solvate.

[0102] Example 6: Preparation of [(2R)-2-(2-{[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-yl]oxy}acetamido)-2-phenylacetamido]acetic acid monohydrate In a reaction vessel, 13.98 kg of the elobixibat crude crystal ethanol solvate obtained in Example 5 and 28.0 kg of ethyl acetate were added and dissolved under stirring at 40°C. The resulting solution was filtered, and the filtrate was washed with 7.0 kg of ethyl acetate. Then, 25.2 kg of ethanol was added, and 7.00 g of seed crystals of elobixibat monohydrate and 140.2 kg of n-heptane were added at 25°C, and the mixture was stirred and cooled to 0°C. The precipitated crystals were centrifuged and washed with 27.9 kg of n-heptane. The obtained crystals were dried under reduced pressure at 35°C or less to obtain 13.26 kg of elobixibat ethanol solvate.

[0103] Into a reaction vessel, 124.6 kg of purified water, 1.10 kg of absolute ethanol, and 12.60 kg of the above elobixibat ethanol solvate were added, and stirred at 25° C. The crystals were filtered using a centrifuge, washed with 41.2 kg of purified water, and then dried under reduced pressure at 45° C. Humidified nitrogen gas was introduced to adjust the moisture content to 2.7%, yielding 11.68 kg of elobixibat monohydrate. [Industrial Applicability]

[0104] INDUSTRIAL APPLICABILITY The method of the present invention is useful because it can produce a 1,5-benzothiazepine compound with high purity in high yield, has low production costs, and is suitable for large-scale industrial production.

Claims

1. Compounds of formula (I): 【Chemistry 1】 (In the formula, R １ and R ２ are each independently C １～４ is alkyl, R ３ is C １～４ is alkyl, R ４ is hydrogen, hydroxy, halo, nitro, cyano and C １～４ is selected from the group consisting of alkyl, R ５ is hydrogen, hydroxy, halo, nitro, cyano and C １～４ alkyl) A method for producing Compound of formula (II): 【Chemistry 2】 (In the formula, R １ From R ４ is defined above) in the presence of a triazine compound to produce a compound of formula (III): 【Chemistry 3】 (In the formula, R ５ is as defined above, R ６ is a protecting group) to produce a compound of formula (IV): 【Chemistry 4】 (In the formula, R １ From R ６ is as defined above) and Deprotecting the compound of formula (IV) to obtain a compound of formula (I). A method comprising:

2. 2. The method of claim 1, wherein the triazine compound is selected from the group consisting of 2,4,6-trichloro-1,3,5-triazine (TCT), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 2,4-dichloro-6-methoxy-1,3,5-triazine (DCMT), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), and mixtures thereof.

3. R １ and R ２ The method of claim 1 or 2, wherein each is n-butyl.

4. R ３ The method of any one of claims 1 to 3, wherein is methyl.

5. R ４ and R ５ The method of claim 1 , wherein each is hydrogen.

6. R ６ C １～４ 6. The method of claim 1, wherein the silyl group is selected from the group consisting of alkyl and trisubstituted silyl.

7. R ６ The method of any one of claims 1 to 6, wherein is tert-butyl.

8. 8. The method of any one of claims 1 to 7, wherein the compound of formula (IV) is deprotected by reaction with trifluoroacetic acid.

9. 9. The process according to any one of claims 1 to 8, wherein the deprotection of the compound of formula (IV) is carried out in the presence of toluene and water, and the amount of water used is 0.2 to 2.0% by weight relative to the amount of toluene.

10. 10. The process according to any one of claims 1 to 9, wherein the compound of formula (I) is precipitated from the solution by adding heptane.

11. The compound of formula (II) is a compound of formula (V): 【Chemistry 5】 (In the formula, R １ From R ４ is defined above) in the presence of water to obtain a compound of formula (VI): 【Chemistry 6】 (In the formula, R ７ is a protecting group, X is a leaving group. to produce an intermediate compound of formula (VII): 【Chemistry 7】 (In the formula, R １ From R ４ and R ７ is defined above) and an alkylation reaction comprising the steps of: The ester R to obtain the compound of formula (II) ７ Hydrolysis of O-C(O)- The method according to any one of claims 1 to 10, wherein the compound is produced by

12. R ７ C １～４ Alkyl and C １～４ 12. The method of claim 11 , wherein the alkyl group is selected from the group consisting of haloalkyl.

13. 13. The method of claim 11 or 12, wherein X is selected from the group consisting of halo, trifluoromethanesulfonate, methanesulfonyl, and p-toluenesulfonyl.

14. 14. The method according to any one of claims 11 to 13, wherein the synthesis of the intermediate compound of formula (VII) is carried out in toluene.

15. The method according to any one of claims 11 to 14, wherein the amount of water used in reacting the compound of formula (V) with the compound of formula (VI) is 0.01 to 0.5% by mass relative to the amount of the compound of formula (V).

16. 16. The process according to any one of claims 11 to 15, wherein the intermediate compound of formula (VII) is not isolated but is used as such in the next step.

17. 17. The method of any one of claims 11 to 16, wherein the alkylation reaction and the subsequent hydrolysis reaction are carried out in the same solvent.

18. The compound of formula (III) is a compound of formula (VIII): 【Chemistry 8】 (In the formula, R ５ and R ６ is defined above) The method according to any one of claims 1 to 17, wherein the compound is produced by deprotecting the compound in the presence of an alcohol having 3 or more carbon atoms.

19. 19. The method of claim 18, wherein the alcohol having 3 or more carbon atoms is selected from the group consisting of 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, and mixtures thereof.

20. 20. The method of any one of claims 1 to 19, further comprising converting the compound of formula (I) to a stable crystalline hydrate of formula (I).

21. 21. The method of claim 20, wherein the compound of formula (I) is dissolved in ethyl acetate.

22. 22. The process of claim 21, wherein n-heptane is added to a solution of the compound of formula (I) in ethyl acetate.

23. 23. The method of any one of claims 20 to 22, wherein the stable crystalline hydrate is a crystalline monohydrate.

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