Process for producing 1,5-benzothiazepine compounds

Abstract

Provided is a method for producing a 1,5-benzothiazepin compound, the method being suitable for large, industrial scale production in which less solvent is used, intermediates are not repeatedly purified, and a high-yield of high-purity product is achieved. This method for producing a compound of formula (I) includes: a step for 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); and a step for deprotecting the compound of formula (IV) to obtain the compound of formula (I).

Description

Technical Field

[0001] The present invention relates to a method for producing a 1,5-benzothiazepine compound.

Background Art

[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 for the treatment or prevention of diseases such as dyslipidemia, constipation, diabetes, and liver diseases.

[0003] A method for producing a 1,5-benzothiazepine compound containing elobixibat is disclosed in, for example, International Publication No. 02 / 50051. Specifically, it can be produced by oxidizing benzothiazepine and then removing the protecting group. However, the method disclosed in International Publication No. 02 / 50051 requires many steps and also requires the use of various reagents.

[0004] However, such a method using many reagents is not preferable from the viewpoints of environmental protection and safety. For example, when different solvents are used for each step, it is necessary to remove the solvent after each step, so a large amount of a plurality of solvents needs to be used, and the production cost for removing the solvent also becomes high. In addition, it is also necessary to purify the product obtained in each step, and it is not suitable for large-scale production on an industrial scale.

[0005] Also, International Publication No. 2014 / 174066 discloses a method for producing a crystalline monohydrate of elobixibat. However, the method disclosed in International Publication No. 2014 / 174066 is also not suitable for large-scale production on an industrial scale.

Prior Art Documents

Patent Document

[0006]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0007] Therefore, there has been a demand for a method for producing a 1,5-benzothiazepine compound suitable for large-scale production on an industrial scale. In particular, compared with the conventional production methods, there has been a demand for a method with improved production costs that can produce a 1,5-benzothiazepine compound with a high yield and high purity.

[0008] The present invention has been made to solve the above problems of the prior art, and an object thereof is to provide a method for producing a 1,5-benzothiazepine compound with a high yield and high purity by reducing the amount of solvent used and without repeating the purification of intermediates.

Means for Solving the Problems

[0009] As a result of intensive studies on the above problems, the present inventors unexpectedly found that by using a triazine compound, the solvents in a plurality of steps can be made the same, and a method capable of obtaining a 1,5-benzothiazepine compound with a sufficiently high yield and high purity has been found, leading to the present invention.

[0010] An object of the present invention is a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[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 formulas (I), (II) and (IV), R 1 and R 2 are each preferably n-butyl.

[0013] In the formulas (I), (II) and (IV), R 3 is preferably methyl.

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

[0015] In the formulas (III) and (IV), R 6 is preferably selected from the group consisting of C 1~4 alkyl and trisubstituted silyl, and 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 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 based on the amount of the toluene.

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

[0019] The compound of formula (II) is a compound of formula (V):

Chemical formula

Chemical formula

Chemical formula

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

[0021] In the above 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] When reacting the compound of the formula (V) with the compound of the formula (VI), the amount of water used is preferably 0.01 to 0.5% by mass based on the amount of the compound of the formula (V).

[0024] The intermediate compound of the formula (VII) is preferably not isolated and used as it 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 the formula (III) is preferably produced by deprotecting the compound of the formula (VIII):

Chemical formula

[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 method of the present invention can further include a step of converting the compound of the formula (I) into a stable crystalline hydrate of the formula (I).

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

[0030] n-Heptane is preferably added to the solution of the compound of the formula (I) in ethyl acetate.

[0031] The stable crystalline hydrate is preferably a crystalline monohydrate.

Advantages of the Invention

[0032] According to the present invention, a 1,5-benzothiazepine compound with high purity can be produced in a 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, a 1,5-benzothiazepine compound can be produced in a method with a small environmental load without using a large amount of solvent. Further, since it is not necessary to repeatedly purify the intermediate, the production cost is low and it is suitable for large-scale production on an industrial scale.

Embodiments for Carrying Out the Invention

[0034] The method of the present invention is for producing a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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

[0036] As used herein, the term "C 1~4 alkyl" represents a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms. Examples of C 1~4 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" represents a C 1~4 alkyl in which at least one hydrogen atom is substituted with a halogen. Examples of C 1~4 haloalkyl include fluoromethyl, difluoromethyl, and trifluoromethyl.

[0038] As used herein, 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 T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1999. Specifically, esters of carboxylic acids such as alkyl esters and silyl esters of carboxylic acids are exemplified.

[0039] Also, the protecting group can be removed and deprotected using known techniques at an appropriate stage in the method for producing the compound of formula (I).

[0040] The compound of formula (I) can have chiral centers and / or geometric isomer centers, and all optical isomers and geometric isomers having IBAT inhibitory activity are included in the compound of formula (I) of the present invention.

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

[0042] Furthermore, the compound of formula (I) may be in the form of a prodrug that decomposes in the human or animal body to give the compound of formula (I). Examples of prodrugs include in vivo hydrolyzable esters and in vivo hydrolyzable amides of the compound of formula (I).

[0043] In addition, 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. It is particularly preferably a crystalline hydrate, and more preferably a crystalline monohydrate.

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

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

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

[0047] The method of the present invention includes a 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 with respect to the compound of formula (II). The compound of formula (III) is preferably used in an amount of 1.0 to 1.3 equivalents, more preferably 1.2 equivalents, with respect to the compound of formula (II).

[0049] R 6 of the compound of formula (III) is a protecting group, and preferably a protecting group that can be removed under acidic conditions. In one embodiment, R 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 process can be carried out using the same solvent as in the process for producing the compound of formula (III), so it is possible to greatly reduce the amount of solvent used, which is preferable.

[0051] The triazine compound is preferably used in an excess amount in a stoichiometric ratio with respect to the compound of formula (II). The triazine compound is preferably used in an amount of 1.0 to 1.5 equivalents with respect to the compound of formula (II).

[0052] The solvent to be used is not particularly limited, but it is preferable to use the same solvent as in the process for 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. It is preferably carried out at 5 to 80°C, 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 the solvent used. Then, the filtrate is concentrated, ethyl acetate is added, and it may be washed successively with water, an acidic aqueous solution (for example, 3% hydrochloric acid), a basic aqueous solution (for example, 5% sodium hydrogen carbonate aqueous solution), and brine. Next, after crystallization and filtration, drying under reduced pressure can give the compound of formula (IV).

[0055] The method of the present invention includes a step of deprotecting the compound of formula (IV) to obtain the compound of formula (I). The deprotection is carried out by hydrolysis of the C(O)OR 6 moiety, preferably by acid hydrolysis. The hydrolysis is carried out in the presence of a suitable acid and can 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] Solvents used for hydrolysis include ethers such as tetrahydrofuran, dioxane, cyclopentyl methyl ether, and 1,2-dimethoxyethane; esters such as ethyl acetate and isopropyl acetate; aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene and xylene; aliphatic halogenated hydrocarbons such as dichloromethane and chloroform; aromatic halogenated hydrocarbons such as chlorobenzene; nitriles such as acetonitrile and propionitrile; amides such as N,N-dimethylformamide and N-methylpyrrolidone; and mixtures of these solvents are preferred. In particular, the solvent used for 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. It is preferably carried out at 10 to 110 °C, more preferably at 15 to 40 °C.

[0059] When deprotecting the compound of formula (IV), the amount of water used 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, an 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 brine until the pH of the aqueous layer becomes 3 or more. The obtained organic layer is 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 a compound of formula (V):

Chemical formula

Chemical formula

Chemical formula

[0062] The compound of formula (VI) is an alkylating agent, and R 7 is preferably selected from the group consisting of C 1~4 alkyl and C 1~4 haloalkyl. R 7 is more preferably C 1~4 alkyl such as methyl, ethyl and tert-butyl, and most preferably ethyl. X is preferably selected from the group consisting of halo, trifluoromethanesulfonate, methanesulfonyl and p-toluenesulfonyl. X is more preferably 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 an excess amount in a stoichiometric ratio with respect to the compound of formula (V). The compound of formula (VI) is preferably used in an amount of 1.0 to 1.4 equivalents with respect 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 the phase transfer catalyst include tetra-n-butylammonium bromide (TBAB), benzyltrimethylammonium chloride, benzyltriethylammonium chloride, methyltricaprylylammonium chloride, methyltributylammonium chloride and methyltrioctylammonium chloride. Tetra-n-butylammonium bromide is most preferred.

[0066] Examples of the base 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 hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, and lithium hydrogen carbonate. Metal carbonates are preferred, and sodium carbonate is more preferred.

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

[0068] Solvents used in the alkylation reaction include ethers such as tetrahydrofuran, dioxane, cyclopentyl methyl ether, and 1,2-dimethoxyethane; esters such as ethyl acetate and isopropyl acetate; aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene and xylene; ketones such as acetone and 2-butanone; aliphatic halogenated hydrocarbons such as dichloromethane and chloroform; aromatic halogenated hydrocarbons such as chlorobenzene; nitriles such as acetonitrile and propionitrile; amides such as N,N-dimethylformamide and N-methylpyrrolidone; and mixtures of these solvents are preferred. 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. It is preferably carried out 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, it is washed with water, and the phase transfer catalyst and the base are extracted and removed into the aqueous layer. The obtained compound of formula (VII) can be used in the next step without further purification or isolation.

[0071] In the next step, the compound of formula (VII) is preferably hydrolyzed under basic conditions to obtain the compound of formula (II). The hydrolysis may be carried out in an organic solvent to which a basic aqueous solution is added.

[0072] Examples of the base 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 hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate. Metal hydroxides are preferred, and sodium hydroxide is more preferred.

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

[0074] Solvents used for hydrolysis include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol; ethers such as tetrahydrofuran, dioxane, cyclopentyl methyl ether and 1,2-dimethoxyethane; aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene and xylene; ketones such as acetone and 2-butanone; aliphatic halogenated hydrocarbons such as dichloromethane and chloroform; aromatic halogenated hydrocarbons such as chlorobenzene; and mixtures of these solvents are preferred. In particular, the solvent used for 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 viewpoints of the amount of the solvent used and the simplification of the process.

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

[0077] After adding water and a solvent as necessary, an acid such as formic acid is added, 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 preferably produced by deprotecting the compound of formula (VIII):

Chemical formula

[0079] Deprotection is

Chemical formula

[0080] As the 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] Deprotection is carried out at a temperature higher than 0 °C and lower than the boiling point of the alcohol used. It is preferably carried out at 0 to 80 °C, more preferably at 5 to 40 °C.

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

[0083] The method of the present invention can further include a step of converting the compound of formula (I) into a stable crystalline hydrate of formula (I). This can be achieved by recrystallizing the compound of formula (I) from a solvent containing ethanol. In a preferred embodiment, the compound of formula (I) is eriboxibat, and the stable crystalline hydrate is a crystalline monohydrate. Most preferably, it is the crystalline monohydrate of the crystalline modification IV (also referred to as crystalline form IV) of eriboxibat.

[0084] A method for obtaining the crystalline modification IV of eriboxibat by crystallizing eriboxibat from ethanol or a mixture of ethanol and water is known. First, the crystalline ethanolate of eriboxibat, which is a solvate, is formed, and this can be isolated and dried under reduced pressure and at a high temperature to obtain the non-solvate of eriboxibat. The non-solvate of eriboxibat absorbs moisture in the air and is converted into 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 includes a step of dissolving the compound of formula (I) in ethyl acetate. Also, the step of converting the compound of formula (I) into a stable crystalline hydrate of formula (I) preferably includes a step of crystallizing the crystalline ethanolate of the compound of formula (I) from a solution of the compound of formula (I) in ethyl acetate.

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

[0087] The crystal modification IV of erotobixibat has an X-ray powder diffraction (XRPD) pattern obtained by CuKα1 radiation, which has at least specific peaks at °2θ positions of 6.3 ± 0.2 and / or 19.4 ± 0.2.

[0088] In one embodiment, the crystal modification IV of erotobixibat has specific peaks at °2θ positions of 6.3 ± 0.2 and 19.4 ± 0.2, and characteristic peaks at one or more °2θ positions of 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, and has an X-ray powder diffraction (XRPD) pattern obtained by CuKα1 radiation.

[0089] In another embodiment, the crystal modification IV of erotobixibat 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, and at one or more °2θ positions of 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, 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, and has an X-ray powder diffraction (XRPD) pattern obtained by CuKα1 radiation.

[0090] In another embodiment, the crystalline modification IV of eriboxibat has an X-ray powder diffraction (XRPD) pattern obtained with CuKα1 radiation, having characteristic peaks at one or more °2θ positions of 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, 20.5±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, 23.3±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.

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

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

Examples

[0093] Hereinafter, the present invention will be described more specifically with reference to 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 purchased as commercially available reagents or 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 the reaction was carried out with stirring at 80 °C. After the reaction, it was cooled, and then the reaction solution was 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 total 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 a 10% aqueous sodium hydroxide solution was added, and the reaction was carried out 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] Next, the organic layer was cooled to 5 °C, 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 dry 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 [(2R)-2-amino-2-phenylacetamido]acetic acid 1,1-dimethylethyl 11.40 kg of 2-[(2R)-2-benzyloxycarbamido-2-phenylacetamido]acetic acid 1,1-dimethylethyl, 91.6 kg of 2-propanol, and 1.37 kg of 10% palladium-carbon (50% water content) were added to the reaction vessel. The reaction was carried out at 10 °C under a hydrogen pressure of 0.03 MPa.

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

[0099] Example 4: 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 1,1-dimethylethyl To the reaction vessel, the entire amount of the 2-propanol solution of [(2R)-2-amino-2-phenylacetamide]acetic acid 1,1-dimethylethyl 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 the reaction was carried out with stirring at 20 °C. Insoluble matters were filtered from the obtained reaction solution, and the residue was washed with 26.4 kg of 2-propanol. The filtrate was concentrated until the liquid volume reached 60.6 kg, 119.0 kg of ethyl acetate was added to the concentrate, and it was washed successively with dilute hydrochloric acid, an aqueous sodium hydrogen carbonate solution, and brine. After washing, 251.1 kg of n-heptane was added to remove the aqueous layer, and 66.00 g 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-phenylacetamide]acetic acid 1,1-dimethylethyl seed crystals were added to the obtained organic layer and stirred. After cooling to 0 °C, the precipitated crystals were centrifuged and washed with 79.2 kg of n-heptane to obtain [(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-phenylacetamide]acetic acid 1,1-dimethylethyl as wet crystals.

[0100] Subsequently, the obtained wet crystals were dried under reduced pressure at 50 °C or lower to obtain 16.87 kg of dry 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-phenylacetamide]acetic acid 1,1-dimethylethyl.

[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 ethanolate To a flask, 25.00 g 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 obtained in Example 4, 319.65 g of toluene, and 1.61 g of water were added, 132.73 g of trifluoroacetic acid was added dropwise, and the reaction was carried out with stirring at 30 °C. The reaction solution was washed successively with 200.07 g of water and 200.06 g of 10% brine, the organic layer was concentrated to 124.8 g, and then 200.23 g of ethyl acetate was added. It was washed 4 times with 200 g of 10% brine, the solvent was replaced with toluene by concentration substitution, and it 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 eribixibat ([(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 seed crystals were added and stirred at 25 °C, then 124.91 g of n-heptane was added and cooled to 0 °C, and further stirred. The precipitated crystals were filtered and dried under reduced pressure at 35 °C or lower to obtain 21.82 g of eribixibat crude crystals as an ethanolate.

[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 To the reaction vessel, 13.98 kg of the eriboxibat crude crystal ethanol adduct obtained in Example 5 and 28.0 kg of ethyl acetate were added and dissolved while 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 the seed crystal of eriboxibat monohydrate and 140.2 kg of n-heptane were added at 25 °C, followed by stirring and cooling 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 lower to obtain 13.26 kg of the eriboxibat ethanol adduct.

[0103] To the reaction vessel, 124.6 kg of purified water, 1.10 kg of absolute ethanol, and 12.60 kg of the above eriboxibat ethanol adduct were added, and the mixture was stirred at 25 °C. The crystals were filtered with a centrifuge, washed with 41.2 kg of purified water, and then dried under reduced pressure at 45 °C. By flowing conditioned nitrogen gas and adjusting the moisture content to 2.7%, 11.68 kg of eriboxibat monohydrate was obtained.

Industrial Applicability

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

Claims

1. A compound of formula (I): 【Chemical 1】 (wherein, R １ and R ２ are each independently C １～４ alkyl, R ３ is C １～４ alkyl, and R ４ is selected from the group consisting of hydrogen, hydroxy, halo, nitro, cyano and C １～４ alkyl R ５ is selected from the group consisting of hydrogen, hydroxy, halo, nitro, cyano and C １～４ alkyl) A method for producing, A compound of formula (II): 【Chemical 2】 (wherein R １ to R ４ is as defined above) Is reacted in the presence of a triazine compound with a compound of formula (III): 【Chemical Formula 3】 (wherein, R ５ is as defined above, R ６ (wherein R is a protecting group) To obtain a compound of formula (IV): 【Chemical Formula 4】 (wherein, R １ to R ６ are as defined above) And the step of Deprotecting the compound of formula (IV) to obtain a compound of formula (I) Including, 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, The compound of formula (II) is a compound of formula (V): 【Chemical Formula 5】 (wherein R1 to R4 are as defined above) Is reacted in the presence of water with a compound of formula (VI): 【Chemical Formula 6】 (wherein, R7 is a protecting group, X is a leaving group) To obtain an intermediate compound of formula (VII): 【Chemical Formula 7】 (wherein R1 to R4 and R7 are as defined above) An alkylation reaction including the step of, and Hydrolysis of the ester R7O—C(O)— to obtain the compound of formula (II) Produced by, The compound of formula (III) is a compound of formula (VIII): 【Chemical 8】 (wherein R5 and R6 are as defined above) Produced by deprotecting in the presence of an alcohol having 3 or more carbon atoms, a method.

2. R １ and R ２ are each n-butyl, the method according to claim 1.

3. R ３ The method according to claim 1 or 2, wherein R is methyl.

4. R ４ and R ５ The method according to any one of claims 1 to 3, wherein each of them is hydrogen.

5. R ６ is C １～４ The method according to any one of claims 1 to 4, wherein R is selected from the group consisting of alkyl and trisubstituted silyl.

6. R ６ The method according to any one of claims 1 to 5, wherein R is tert-butyl.

7. The method according to any one of claims 1 to 6, wherein the compound of formula (IV) is deprotected by reaction with trifluoroacetic acid.

8. The method according to any one of claims 1 to 7, 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 mass based on the amount of the toluene.

9. The method according to any one of claims 1 to 8, wherein the compound of formula (I) is precipitated from the solution by adding heptane.

10. R ７ is C １～４ alkyl and C １～４ The method according to any one of claims 1 to 9, wherein the method is selected from the group consisting of haloalkyl.

11. The method according to any one of claims 1 to 10, wherein X is selected from the group consisting of halo, trifluoromethanesulfonate, methanesulfonyl and p-toluenesulfonyl.

12. The method according to any one of claims 1 to 11, wherein the synthesis of the intermediate compound of formula (VII) is carried out in toluene.

13. The method according to any one of claims 1 to 12, wherein the amount of water used when reacting the compound of formula (V) with the compound of formula (VI) is 0.01 to 0.5% by mass based on the amount of the compound of formula (V).

14. The method according to any one of claims 1 to 13, wherein the intermediate compound of formula (VII) is not isolated and is used as it is in the next step.

15. The method according to any one of claims 1 to 14, wherein the alkylation reaction and the subsequent hydrolysis reaction are carried out in the same solvent.

16. The method according to any one of claims 1 to 15, 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.

17. The method according to any one of claims 1 to 16, further comprising a step of converting the compound of formula (I) into a stable crystalline hydrate of formula (I).

18. The method according to claim 17, wherein the compound of formula (I) is dissolved in ethyl acetate.

19. The method according to claim 18, wherein n-heptane is added to a solution of the compound of formula (I) in ethyl acetate.

20. The method according to any one of claims 17 to 19, wherein the stable crystalline hydrate is a crystalline monohydrate.

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