Method for preparing elobixibat

Abstract

To provide a process for the preparation of certain 1,5-benzothiazepine compounds, specifically a process for the preparation of elobixibat. and in particular a process for the preparation of a crystalline monohydrate of elobixibat.SOLUTION: Provided is a process for the preparation of a crystal modification IV of elobixibat. The process comprises the steps of: (i) dissolving crude elobixibat in a mixture of ethanol and ethyl acetate; (ii) crystallizing a crystalline ethanolate of elobixibat from the solution of crude elobixibat in the mixture of ethanol and ethyl acetate obtained in step (i); (iii) drying the crystalline ethanolate of elobixibat to obtain a crystalline anhydrate of elobixibat; and (iv) hydrating the crystalline anhydrate of elobixibat to obtain crystal modification IV of elobixibat.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a process for the preparation of certain 1,5-benzothiazepine compounds, in particular to a process for the preparation of elobixibat. The process can be carried out under mild and safe conditions and can be used to prepare elobixibat on an industrial scale. The present invention also relates to a process for the preparation of the crystalline monohydrate of elobixibat. [Background technology]

[0002] Elobixibat (1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine) is an ileal bile acid transporter (IBAT) inhibitor that can be used for the prevention or treatment of dyslipidemia (WO 02 / 50051), constipation (WO 2004 / 089350) and liver diseases such as cholestatic liver disease and non-alcoholic steatohepatitis (WO 2012 / 064266).

[0003] Ileal bile acid transporter (IBAT) is located in the small intestine, specifically the ileum, and is responsible for mediating the uptake of bile acids from the small intestine to the liver as part of a process known as enterohepatic circulation. Typically, approximately 95 percent of bile acids are recirculated to the liver via IBAT, with the remaining 5 percent being secreted into the colon. By inhibiting the reabsorption of bile acids from the small intestine to the liver, increased amounts of bile acids are secreted into the colon. Higher concentrations of bile acids in the colon, in turn, lead to increased electrolyte and water secretion, resulting in softer feces and higher motility in the large intestine. Thus, as an inhibitor of ileal bile acid transporter, elobixibat can be used to treat constipation.

[0004] The preparation of elobixibat and several related 1,5-benzothiazepine compounds is disclosed in WO 02 / 50051. The preparation of elobixibat consisted of many successive steps and involved several reagents that were undesirable from an environmental or safety standpoint. Purification of the final product (elobixibat) and several intermediate products required preparative chromatography, which works well for small-scale synthesis but is not suitable for industrial-scale production.

[0005] Several stable crystalline modifications of elobixibat, including crystalline modification IV of elobixibat, are disclosed in WO 2014 / 174066 and WO 2016 / 062848. However, the methods for obtaining the hydrated and anhydrous forms described in these documents are not optimized for industrial-scale production. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] WO 02 / 50051 [Patent Document 2] WO 2004 / 089350 [Patent Document 3] WO 2012 / 064266 [Patent Document 4] WO 2014 / 174066 [Patent Document 5] WO 2016 / 062848 [Patent Document 6] US 2017 / 0143738 [Patent Document 7] US 2017 / 0143783 [Non-patent literature]

[0007] [Non-Patent Document 1] Wuts, P.G.M. and Greene, T.W., Greene's Protective Groups in Organic Synthesis, 4th ed.; John Wiley & Sons, Hoboken, 2006. Summary of the Invention

[0008] Therefore, there is a need for improved methods for the preparation of elobixibat or its crystalline monohydrate, such as crystalline modification IV, which would allow for the production of elobixibat on an industrial scale in higher yield and purity than previously described methods.

[0009] The present invention provides an improved process for the preparation of elobixibat and closely related 1,5-benzothiazepine compounds. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In a first aspect, the present invention provides a method for producing a composition comprising the steps of: Formula (I):

[0011] [ka]

[0012] [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] or a pharma- ceutically acceptable salt thereof, comprising the steps of: Formula (II):

[0013] [ka]

[0014] [In the formula, R 1 ~R 4 is as defined above] and a compound of formula (III):

[0015] [ka]

[0016] [In the formula, R 5 is as defined above, R 6 is a suitable protecting group. with a compound of formula (IV):

[0017] [ka]

[0018] obtaining a compound of formula (I); deprotecting the compound of formula (IV) to obtain a compound of formula (I); The present invention relates to a method comprising the steps of:

[0019] As used herein, the term "halo" refers to fluoro, chloro, bromo, and iodo.

[0020] As used herein, the term "C 1~4 "Alkyl" refers to a straight or branched alkyl group having 1 to 4 carbon atoms. 1~4 Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0021] As used herein, the term "C 1~4"Haloalkyl" is defined as C 1~4 It refers to an alkyl group in which at least one hydrogen atom has been replaced by a halogen. 1~4 Examples of haloalkyl include fluoromethyl, difluoromethyl and trifluoromethyl.

[0022] As used herein, the term "protecting group" refers to a temporary substituent that protects a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, such as alkyl and silyl esters of carboxylic acids. The field of protecting group chemistry has been extensively reviewed, see, for example, Wuts, PGM and Greene, TW, Greene's Protective Groups in Organic Synthesis, 4th Edition; John Wiley & Sons, Hoboken, 2006.

[0023] As used herein, the term "about" refers to a value or parameter herein, including (and describing) an embodiment relating to the value or parameter itself. For example, a statement expressed as "about 20" includes the statement "20." Numerical ranges are inclusive of the numbers that define the range. Generally speaking, the term "about" refers to the stated value of the variable, and all values ​​of the variable that are within experimental error of the stated value (e.g., within a 95% confidence interval of the mean) or within 10 percent of the stated value, whichever is greater.

[0024] In a preferred embodiment, the present invention provides a compound of formula (I), 1 and R 2 In another preferred embodiment, the present invention relates to a method for preparing a compound of formula (I), 3 In another preferred embodiment, the present invention relates to a method for preparing a compound of formula (I), 4 In yet another preferred embodiment, the present invention relates to a method for the preparation of a compound of formula (I), 5In a most preferred embodiment, the present invention relates to a method for the preparation of a compound of formula (I), 1 and R 2 are n-butyl, and R 3 is methyl, R 4 and R 5 and each are hydrogen (i.e., elobixibat).

[0025] In the first step of the claimed process, a carboxylic acid of formula (II) is subjected to a condensation reaction with an O-protected peptide of formula (III), preferably in the presence of a coupling reagent and a suitable base.

[0026] The compound of formula (III) is preferably used in slight excess over the compound of formula (II), more preferably in an amount of about 1.0 to about 1.3 equivalents relative to the compound of formula (II), and most preferably in an amount of about 1.2 equivalents relative to the compound of formula (II).

[0027] R in formula (III) 6 is a suitable protecting group, more preferably a protecting group that can be removed under acidic conditions. In a preferred embodiment, R 6 is C 1~4 More preferably, R is selected from the group consisting of alkyl and trisubstituted silyl. 6 is tert-butyl or trimethylsilyl, most preferably tert-butyl.

[0028] Examples of suitable coupling reagents include carbodiimides, such as dicyclohexylcarbodiimide and diisopropylcarbodiimide; N,N'-carbonyldiimidazole; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU); and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU). In a preferred embodiment, the coupling reagent is a carbodiimide or O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, most preferably O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate.

[0029] The coupling reagent may be used in slight excess over the compound of formula (II), most preferably in an amount of about 1.0 to about 1.3 equivalents relative to the compound of formula (II).

[0030] Examples of suitable bases include tertiary alkylamines, such as triethylamine; and aromatic amines, such as pyridine and 2,6-lutidine. In a preferred embodiment, the base is 2,6-lutidine.

[0031] The base is preferably used in excess of the compound of formula (II), preferably in an amount of about 1.5 to about 4.0 equivalents, more preferably about 2.5 to about 3.5 equivalents, relative to the compound of formula (II).

[0032] Suitable solvents for the condensation reaction include ethers such as tetrahydrofuran, dioxane, cyclopentyl methyl ether and 1,2-dimethoxyethane; esters such as ethyl acetate and isopropyl acetate; hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene and xylene; ketones such as acetone and 2-butanone; such as dichloromethane and chloroform; halogenated aromatic hydrocarbons such as chlorobenzene; nitriles such as acetonitrile and propionitrile; amides such as N,N-dimethylformamide and N-methylpyrrolidone; and mixtures of any of these solvents. In a preferred embodiment, the solvent is a halogenated hydrocarbon or nitrile, more preferably a halogenated hydrocarbon such as dichloromethane or chloroform, most preferably dichloromethane.

[0033] The reaction may be carried out at a temperature between about 0° C. and the boiling point of the reaction solvent. The reaction is preferably carried out at a temperature of about 10° C. or higher, and most preferably at a temperature of about 15° C. to about 35° C.

[0034] Once the reaction is complete, the mixture can be washed successively with an aqueous solution of an acid (e.g., an aqueous solution of hydrochloric acid), water, an aqueous solution of a base (e.g., an aqueous solution of sodium bicarbonate) and water, and the solvent can be evaporated. The product can then be further purified, such as by crystallization. The compound of formula (IV) is preferably crystallized from acetonitrile or heptane, most preferably from acetonitrile. In the most preferred embodiment, the compound of formula (IV) is recrystallized twice from acetonitrile.

[0035] In a second step, the compound of formula (IV) is reacted with C(O)OR 6 The deprotection is effected by hydrolysis, preferably by acid hydrolysis, of said group, which can be carried out in the presence of a suitable acid to give the corresponding carboxylic acid of formula (I).

[0036] 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. In a preferred embodiment, the acid is trifluoroacetic acid.

[0037] Suitable solvents for the hydrolysis reaction include ethers such as tetrahydrofuran, dioxane, cyclopentyl methyl ether and 1,2-dimethoxyethane; esters such as ethyl acetate and isopropyl acetate; hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; halogenated aromatic hydrocarbons such as chlorobenzene; nitriles such as acetonitrile and propionitrile; amides such as N,N-dimethylformamide and N-methylpyrrolidone; and mixtures of any of these solvents. In a preferred embodiment, the solvent is an aromatic hydrocarbon, more preferably an aromatic hydrocarbon such as toluene or xylene, most preferably toluene.

[0038] The reaction can be carried out at a temperature between about 0° C. and the boiling point of the reaction solvent. The reaction is preferably carried out at a temperature of about 15° C. to about 35° C.

[0039] Once the hydrolysis is complete, the acid can be removed by washing with water and the organic solvent can be evaporated. The product can then be further purified by crystallization or precipitation, etc. The compound of formula (I) is preferably crystallized from ethanol or precipitated from the solution by addition of heptane, particularly n-heptane.

[0040] In a further embodiment of the invention, the compound of formula (II) Formula (V):

[0041] [ka]

[0042] [In the formula, R 1 ~R 4 is as defined above] and a compound of formula (VI):

[0043] [ka]

[0044] [In the formula, R 7 is a suitable protecting group, X is a suitable leaving group. with a compound of formula (VII):

[0045] [ka]

[0046] and obtaining an intermediate compound of formula (I) Next, Ester R 7 hydrolysis of OC(O)- to obtain a compound of formula (II); It is prepared by an alkylation reaction comprising:

[0047] In the alkylating agent of formula (VI), R 7 is preferably C 1~4 Alkyl and C 1~4 More preferably, R is selected from the group consisting of haloalkyl. 7 is methyl, ethyl or tert-butyl, etc. 1~4 alkyl, most preferably R 7 is ethyl. X is preferably selected from the group consisting of halo, trifluoromethanesulfonate, methanesulfonyl and p-toluenesulfonyl. More preferably, X is a halogen, more preferably a halogen selected from chloride, bromide and iodide. In a most preferred embodiment, the compound of formula (VI) is ethyl bromoacetate.

[0048] The compound of formula (VI) may be used in slight excess relative to the compound of formula (V). The best yields are obtained when the compound of formula (VI) is used in an amount of about 1.1 to about 1.4 equivalents relative to the compound of formula (V).

[0049] The alkylation reaction between the compound of formula (V) and the compound of formula (VI) is preferably carried out in the presence of a phase transfer catalyst and a base. Examples of suitable 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 most preferred. Examples of suitable 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. In a preferred embodiment, the base is a metal carbonate, most preferably sodium carbonate. The base may be used in excess of the compound of formula (VI), preferably in an amount of about 3.0 to about 6.0 equivalents relative to the compound of formula (VI), more preferably in an amount of about 3.5 to about 4.0 equivalents.

[0050] Suitable solvents for the alkylation reaction include ethers such as tetrahydrofuran, dioxane, cyclopentyl methyl ether and 1,2-dimethoxyethane; esters such as ethyl acetate and isopropyl acetate; hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene and xylene; ketones such as acetone and 2-butanone; halogenated hydrocarbons such as dichloromethane and chloroform; halogenated aromatic hydrocarbons such as chlorobenzene; nitriles such as acetonitrile and propionitrile; N,N-dimethylformamide and N-methylpyrrolidone; and mixtures of any of these solvents. In a preferred embodiment, the solvent is an aromatic or halogenated hydrocarbon, more preferably toluene or xylene, most preferably toluene.

[0051] The reaction may be carried out at a temperature between about 0° C. and the boiling point of the reaction solvent. The reaction is preferably carried out at a temperature of about 20° C. or higher, most preferably at a temperature of about 75° C. to about 85° C., especially when an aromatic hydrocarbon is used as the solvent.

[0052] Once the alkylation reaction is complete, water can be added to extract the phase transfer catalyst and base into the aqueous layer. The intermediate compound of formula (VII) can then be isolated and further purified. It has been found that at least when an aromatic hydrocarbon is used as the solvent, the compound of formula (VII) can be obtained in high yield and high purity. In such a case, the intermediate compound of formula (VII) can be used immediately in the next step without further isolation and purification. Thus, in a preferred embodiment, the intermediate compound of formula (VII) is not isolated and is used immediately in the next step.

[0053] In the next step, the compound of formula (VII) is hydrolyzed, preferably under basic conditions, to give the compound of formula (II). The hydrolysis can be carried out in an organic solvent, to which an aqueous solution of a base is added.

[0054] Examples of suitable 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. In a preferred embodiment, the base is a metal hydroxide, most preferably sodium hydroxide. The base is preferably used in excess of the compound of formula (VII), preferably in an amount of about 2.0 to about 6.0 equivalents relative to the compound of formula (VII), more preferably in an amount of about 3.0 to about 5.0 equivalents, more preferably in an amount of about 3.5 to about 4.5 equivalents.

[0055] Suitable solvents for the hydrolysis reaction 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; hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene and xylene; ketones such as acetone and 2-butanone; halogenated hydrocarbons such as dichloromethane and chloroform; halogenated aromatic hydrocarbons such as chlorobenzene; and mixtures of any of these solvents. In a preferred embodiment, the solvent is an alcohol or an aromatic hydrocarbon, more preferably an aromatic hydrocarbon such as toluene or xylene, most preferably toluene.

[0056] It is particularly advantageous if the same solvent is used during the alkylation and subsequent hydrolysis reactions.

[0057] The reaction may be carried out at a temperature between about 0° C. and the boiling point of the reaction solvent. The reaction is preferably carried out at a temperature of about 20° C. or higher when an aromatic hydrocarbon is used as the solvent, and most preferably at a temperature of about 45° C. to about 55° C., or at a temperature of about 20° C. to about 30° C. when an alcohol is used as the solvent.

[0058] Once the hydrolysis reaction is complete, the reaction mixture can be acidified by the addition of an acid such as formic acid, and the organic layer can be washed and concentrated. The reaction product can then be further purified. Both the compound of formula (II) and the corresponding sodium salt can be precipitated or crystallized from an organic solvent. Thus, in a preferred embodiment of the present invention, the compound of formula (II) is first crystallized as the corresponding sodium salt, which is then protonated and crystallized as the parent compound. In some embodiments, crystallizing the compound of formula (II) as the corresponding sodium salt removes any non-salt organic impurities. The sodium salt of the compound of formula (II) is preferably crystallized from a mixture of ethyl acetate and aqueous sodium hydroxide, and the compound of formula (II) is preferably crystallized from a mixture of ethyl acetate and n-heptane.

[0059] In a further embodiment of the invention, the process also comprises the step of converting the compound of formula (I) to a stable crystalline hydrate of formula (I). This can be achieved by recrystallizing the compound of formula (I) from ethanol or from a solvent mixture comprising ethanol and one or more other suitable solvents. In a preferred embodiment, the compound of formula (I) is elobixibat and the stable crystalline hydrate of formula (I) is the crystalline monohydrate of elobixibat, most preferably the crystalline modification IV of elobixibat (also designated crystalline form IV of elobixibat).

[0060] It has been previously disclosed that the crystalline modification IV can be obtained by crystallizing crude elobixibat from ethanol or from a mixture of ethanol and water. Under such conditions, a crystalline ethanolate of elobixibat is formed first, which can be isolated and dried. Drying of the crystalline ethanolate gives an anhydrous product, which quickly absorbs moisture from the air, thereby resulting in the crystalline modification IV of elobixibat. It has now been found that improved results are obtained when crude elobixibat is dissolved in a mixture of ethanol and ethyl acetate. Since elobixibat is sufficiently soluble in this solvent mixture, an additional filtration step of the resulting solution can be carried out to remove any foreign particles or microorganisms. Improved results can also be obtained when n-heptane is added to a solution of the compound of formula (I) in a mixture of ethanol and ethyl acetate.

[0061] In a second aspect, the present invention provides a process for the preparation of crystalline modification IV of elobixibat, comprising the steps of: (i) dissolving crude elobixibat in a mixture of ethanol and ethyl acetate; (ii) crystallizing the crystalline ethanolate of elobixibat from the solution of crude elobixibat in a mixture of ethanol and ethyl acetate obtained from step (i); (iii) drying the crystalline ethanolate of elobixibat to obtain a crystalline anhydrate of elobixibat; (iv) hydrating the crystalline anhydrate of elobixibat to obtain the crystalline modification IV of elobixibat. The present invention relates to a method comprising the steps of:

[0062] The crystalline modification IV of elobixibat may have an X-ray powder diffraction (XRPD) pattern, obtained using CuKα1-radiation, with at least specific peaks at the positions 6.3±0.2 and / or 19.4±0.2 °2θ.

[0063] In one embodiment, the crystalline modification IV of elobixibat may have an X-ray powder diffraction (XRPD) pattern obtained using CuKα1-radiation having specific peaks at °2θ positions of 6.3±0.2 and 19.4±0.2 and one or more characteristic peaks selected from 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.

[0064] In another embodiment, the crystalline modification IV of elobixibat may have an X-ray powder diffraction (XRPD) pattern obtained using CuKα1-radiation with specific peaks at the following °2θ positions: 6.3±0.2, 19.4±0.2, 10.2±0.2, 10.5±0.2, 9.4±0.2 and 9.5±0.2.

[0065] 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 one or more 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, 20.0±0.2, 21.0±0.2, 22.0±0.2, 23.0±0.2, 24.0±0.2, 25.0±0.2, 26.0±0.2, 27.0±0.2, 28.0±0.2, 29.0±0.2, 30.0±0.2, 31.0±0.2, 32.0±0.2, 33.0±0.2, 34.0±0.2, 35.0±0.2, 36.0±0.2, 37.0±0.2, 38.0±0.2, 39.0±0.2, 40.0±0.2, 41.0±0.2, 42.0±0.2, 43.0±0.2, 44.0±0.2, 45.0±0.2, 46.0±0.2, 47.0±0.2, 48.0±0.2, 4 25.7±0.2, 26.7±0.2, 26.9±0.2, 28.3±0.2, and 28.9±0.2.

[0066] In another embodiment, the crystalline modification IV of elobixibat was obtained using CuKα1-radiation: 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, 1 The compound may have an X-ray powder diffraction (XRPD) pattern having characteristic peaks at °2θ positions of 9.8±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.

[0067] The mixture of ethanol and ethyl acetate in which crude elobixibat is dissolved can be a 10:1 to 0.5:1 mixture (w / w) of ethanol and ethyl acetate. In a preferred embodiment, crude elobixibat is dissolved in about a 1.85:1 (w / w) mixture of ethanol and ethyl acetate.

[0068] In one embodiment, the crystallization in step (ii) is initiated by adding seed crystals of crystalline modification IV of elobixibat to a solution of crude elobixibat in a mixture of ethanol and ethyl acetate.

[0069] In another embodiment, in step (ii), n-heptane is added to a solution of crude elobixibat in a mixture of ethanol and ethyl acetate.

[0070] The invention disclosed herein has several advantages. The claimed process for the preparation of elobixibat involves fewer steps than previously disclosed processes and is therefore more efficient and cost-effective. Elobixibat can also be isolated in higher yields and with lower impurity levels. The process includes improved purification steps and removes the need for several chromatography steps that are not suitable for use in large-scale synthesis. The process provides further improvements in the preparation of crystalline modification IV of elobixibat. Overall, the process allows for the preparation of elobixibat (or its stable crystalline monohydrate) on an industrial scale.

[0071] The compounds of formula (I) are ileal bile acid transporter (IBAT) inhibitors and are therefore useful in the treatment or prevention of conditions, disorders and diseases in which inhibition of bile acid circulation is desirable, such as disorders of fatty acid metabolism and glucose utilization, gastrointestinal diseases and disorders, and hepatic diseases and disorders.

[0072] Disorders of fatty acid metabolism and glucose utilization include, but are not limited to, hypercholesterolemia, dyslipidemia, metabolic syndrome, obesity, disorders of fatty acid metabolism, disorders of glucose utilization, disorders associated with insulin resistance, and type 1 and type 2 diabetes.

[0073] Gastrointestinal diseases and disorders include constipation (including chronic constipation, functional constipation, chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C)); Crohn's disease; primary bile acid malabsorption; irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); ileal inflammation; and reflux disease and their complications.

[0074] A liver disease, as defined herein, is any bile acid-dependent disease of the liver and organs connected to the liver, such as the pancreas, portal vein, liver parenchyma, intrahepatic biliary tree, extrahepatic biliary tree, and gallbladder. Liver diseases and disorders include inherited metabolic disorders of the liver; congenital anomalies of bile acid synthesis; congenital biliary malformations; biliary atresia; biliary atresia after Kasai operation; biliary atresia after liver transplantation; neonatal hepatitis; neonatal cholestasis; inherited forms of cholestasis; cerebrotendinous xanthomatosis; secondary disorders of BA synthesis; Zellweger syndrome; cystic fibrosis (hepatic manifestations); alpha 1-antitrypsin deficiency; Alagille syndrome (ALGS); Byler syndrome; primary disorders of bile acid (BA) synthesis; progressive familial intrahepatic cholestasis (PFIC), including PFIC-1, PFIC-2, PFIC-3 and non-specific PFIC, PFIC after bile diversion and PFIC after liver transplantation; benign recurrent intrahepatic cholestasis (BRIC), including BRIC1, BRIC2 and non-specific BRIC, BRIC after bile diversion and BRIC after liver transplantation; autoimmune hepatitis; Primary biliary cirrhosis (PBC);Liver fibrosis;Nonalcoholic fatty liver disease (NAFLD);Nonalcoholic steatohepatitis (NASH);Portal hypertension;Systemic cholestasis;Jaundice in pregnancy;Drug-induced jaundice;Intrahepatic cholestasis;Extrahepatic cholestasis;Primary sclerosing cholangitis (PSC);Gallstones and common bile duct stones;Biliary tree causing malignant obstruction;Pruritis due to cholestasis or jaundice;Pancreatitis;Progressive cholestasis These include, but are not limited to, problems associated with chronic autoimmune liver disease leading to cholestasis; fatty liver; alcoholic hepatitis; acute fatty liver; fatty liver of pregnancy; drug-induced hepatitis; iron overload disorders; hepatic fibrosis; cirrhosis; amyloidosis; viral hepatitis (including hepatitis A, B, C, D and E); hepatocellular carcinoma (hepatocellular carcinoma); and problems associated with cholestasis due to tumors and neoplasms of the liver, biliary tract and pancreas.

[0075] In a further aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) prepared by the methods disclosed herein in association with one or more pharma- ceutically acceptable excipients. The excipients may include fillers, binders, disintegrants, glidants and lubricants. In a preferred embodiment, the compound of formula (I) prepared by the methods disclosed herein is elobixibat.

[0076] As used herein, the term "pharmaceutical acceptable" refers to those compounds and materials that are suitable for pharmaceutical use in humans and that are generally safe, non-toxic and not biologically or otherwise undesirable.

[0077] The pharmaceutical composition may be in a form suitable for oral administration, parenteral injection (including intravenous, subcutaneous, intramuscular and intravascular injection), topical administration or rectal administration. In a preferred embodiment, the pharmaceutical composition is in a form suitable for oral administration, for example a tablet or capsule.

[0078] Examples of suitable fillers include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose (such as lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, dry starch, hydrolyzed starch, and pregelatinized starch. In certain embodiments, the filler is mannitol and / or microcrystalline cellulose.

[0079] Examples of suitable binders include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (such as sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums (such as gum acacia and gum tragacanth), sodium alginate, cellulose derivatives (such as hydroxypropyl methylcellulose (or hypromellose), hydroxypropyl cellulose and ethyl cellulose) and synthetic polymers (such as acrylic and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers and polyvinylpyrrolidone (povidone)). In certain embodiments, the binder is hydroxypropyl methylcellulose (hypromellose).

[0080] Examples of suitable disintegrants include, but are not limited to, dry starch, modified starches (such as (partially) pregelatinized starch, sodium starch glycolate and sodium carboxymethyl starch), alginic acid, cellulose derivatives (such as sodium carboxymethylcellulose, hydroxypropylcellulose and low-substituted hydroxypropylcellulose (L-HPC)) and cross-linked polymers (such as carmellose, croscarmellose sodium, carmellose calcium and cross-linked PVP (crospovidone)). In a particular embodiment, the disintegrant is croscarmellose sodium.

[0081] Examples of suitable glidants and lubricants include, but are not limited to, talc, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, colloidal silica, aqueous silicon dioxide, synthetic magnesium silicate, finely divided silicon oxide, starch, sodium lauryl sulfate, boric acid, magnesium oxide, waxes (such as carnauba wax), hydrogenated oils, polyethylene glycol, sodium benzoate, polyethylene glycol, and mineral oil. In certain embodiments, the glidant or lubricant is magnesium stearate or colloidal silica.

[0082] The pharmaceutical composition may be conventionally coated with one or more coating layers. An enteric coating layer or a coating layer for delayed or targeted release of the compound of formula (I) is also contemplated. The coating layer may include one or more coating agents, and may optionally include a plasticizer and / or a pigment (or colorant).

[0083] Examples of suitable coating agents include, but are not limited to, cellulose-based polymers (such as ethyl cellulose, hydroxypropyl methylcellulose (or hypromellose), hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methylcellulose acetate succinate and hydroxypropyl methylcellulose phthalate), vinyl-based polymers (such as polyvinyl alcohol) and polymers based on acrylic acid and its derivatives (such as copolymers of acrylic acid and methacrylic acid, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid / polymethacrylic acid copolymers). In certain embodiments, the coating agent is hydroxypropyl methylcellulose. In other embodiments, the coating agent is polyvinyl alcohol.

[0084] Examples of suitable plasticizers include, but are not limited to, triethyl citrate, glyceryl triacetate, tributyl citrate, diethyl phthalate, acetyl tributyl citrate, dibutyl phthalate, dibutyl sebacate, and polyethylene glycol. In certain embodiments, the plasticizer is polyethylene glycol.

[0085] Examples of suitable pigments include, but are not limited to, titanium dioxide, iron oxide (such as yellow, brown, red, or black iron oxide), and barium sulfate.

[0086] Examples of pharmaceutical compositions comprising compounds of formula (I), in particular elobixibat, are disclosed, for example, in WO 2014 / 174066, US 2017 / 0143738 and US 2017 / 0143783, which are incorporated herein by reference in their entireties.

[0087] The dosage required for the treatment or prevention of the conditions described herein will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors normally considered by the attending physician in determining the appropriate regimen and dosage level for a particular patient.

[0088] The amount of compound administered varies with respect to the patient to be treated and can vary from about 1 μg / kg body weight to about 50 mg / kg body weight per day. A unit dose form, such as a tablet or capsule, typically contains about 1 to about 250 mg of active ingredient, such as about 1 to about 100 mg, or about 1 to about 50 mg, or about 1 to about 20 mg, such as about 2.5 mg, or about 5 mg, or about 10 mg, or about 15 mg. The daily dose can be administered as a single dose or divided into one, two, three or more unit doses. The daily dose of an IBAT inhibitor administered orally is preferably within about 0.1 to about 250 mg, more preferably within about 1 to about 100 mg, such as within about 1 to about 5 mg, within about 1 to about 10 mg, within about 1 to about 15 mg, or within about 1 to about 20 mg.

[0089] In a further aspect, the present invention relates to a method of treating or preventing any of the diseases described herein in a subject, such as a human, comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) prepared by the methods disclosed herein. The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) prepared by the methods disclosed herein for use in the treatment or prevention of any of the diseases described herein. The present invention also relates to the use of a compound of formula (I) prepared by the methods disclosed herein in the manufacture of a medicament for the treatment or prevention of any of the diseases described herein. In a preferred embodiment of this aspect, the compound of formula (I) prepared by the methods disclosed herein is elobixibat. EXAMPLES

[0090] The present invention is further illustrated by the following examples, which are not intended to be limiting in any way.

[0091] Experimental Method General method The reagents and starting materials for the following examples are either commercially available or can be prepared by standard methods known in the art. The starting materials 3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-ol and 1,1-dimethylethyl 2-[(2R)-2-benzyloxycarbamido-2-phenylacetamide]acetate can be prepared as described in WO 02 / 50051 (see methods 26 and 85, respectively).

[0092] High resolution mass spectrometry (HRMS) was performed on a Waters Acquity H Class UPLC / Xevo G2-XS QTof.

[0093] Example 1 Preparation of {[3,3-dibutyl-7-(methylsulfanyl)-1,1-dioxide-5-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-8-yl]oxy}acetic acid

[0094] [ka]

[0095] 3,3-Dibutyl-7-(methylsulfanyl)-1,1-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-8-ol (70.00 kg), sodium carbonate (69.30 kg), tetrabutylammonium bromide (4.55 kg), toluene (606.20 kg), and ethyl bromoacetate (30.10 kg) were mixed in a reactor and stirred for 4 hours at 80° C. After cooling, the reaction mass was washed with water (1680 kg) and the aqueous layer was discarded. Sodium hydroxide solution (a mixture of 25.04 kg sodium hydroxide and 225.4 kg water) was added to the above toluene layer. The mixture was stirred at 47° C. for 3.5 hours. After cooling, ethyl acetate (374.74 kg) was added to the reaction solution, followed by formic acid with stirring until the pH was 3.6. The aqueous layer was discarded and the organic layer was washed with water (2×333.84 kg). The organic layer was concentrated under vacuum and ethyl acetate (599.24 kg) was added to the concentrated residue. After cooling, sodium hydroxide solution (a mixture of 125.19 kg sodium hydroxide and 709.41 kg water) was added slowly with stirring. Crystals of sodium salt were precipitated and then isolated by centrifugation. The sodium salt, ethyl acetate (599.24 kg) and water (333.8 kg) were mixed. Formic acid was added with stirring until the pH was 3.5. The organic layer was washed with water (2×333.8 kg) and concentrated under vacuum. n-Heptane (228.68 kg) was added to the concentrated residue and the mixture was stirred. The precipitated crystals were filtered and dried under vacuum to give dried crystals of the title compound as an off-white solid (65.38 kg). HRMS (ESI, m / z) C 26 H 34 NO5S2[MH] - Calculated value: 504.1880. Measured value: 504.1832.

[0096] Example 2 Preparation of tert-butyl-N-[(2R)-2-amino-2-phenylacetyl]glycinate

[0097] [ka]

[0098] In a reactor, absolute alcohol (266.30 kg), tert-butyl 2-[(2R)-2-benzyloxycarbamido-2-phenylacetamido]acetate (33.75 kg), 10% palladium on carbon (containing 50% water) (4.05 kg), and toluene (87.75 kg) were mixed. The mixture was heated at 18° C. under hydrogen at 3.5 kg / cm. 2 The mixture was stirred under pressure for 3 hours. The reaction was filtered and the filter bed was washed with absolute ethanol (106.65 kg). The filtrate was concentrated under vacuum to give the title compound as a colorless viscous liquid (21.70 kg). HRMS (ESI, m / z) C 14 H 21 N2O3[M+H] + Calculated value: 265.1553. Measured value: 265.1452.

[0099] Example 3 Preparation of tert-butyl-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-phenylethanoyl}glycinate

[0100] [ka]

[0101] In a reactor, the compound of Example 1 (65.00 kg), the compound of Example 2 (40.95 kg), and dichloromethane (864.50 kg) were mixed. 2,6-lutidine (37.05 kg) was added, followed by O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (46.15 kg) at 5° C. The mixture was stirred at 25° C. for 15 hours. Dichloromethane (1037.40 kg) was added, and the organic layer was washed successively with the following liquids: (1) dilute hydrochloric acid (a mixture of 74.10 kg hydrochloric acid and 667.55 kg water); (2) water (260.00 kg); (3) sodium bicarbonate solution (a mixture of 26.00 kg sodium bicarbonate and 260.00 kg water); and (4) water (260.00 kg). The organic layer was concentrated under vacuum. After adding acetonitrile (306.80 kg), the mixture was heated until dissolution and then cooled to 13° C. Crystals were allowed to precipitate, which were then centrifuged and washed with acetonitrile (51.35 kg). Acetonitrile (606.45 kg) was added to the total amount of crude crystals obtained. The mixture was heated until dissolved and then cooled to 0° C. The crystals were precipitated, centrifuged, and washed with acetonitrile (51.35 kg). The wet crystals were dried under vacuum to obtain the title compound as a white powder (81.20 kg). HRMS (ESI, m / z) C 40 H 52 N3O7S2[MH] - Calculated value: 750.3250. Measured value: 750.3164.

[0102] Example 4 Preparation of crude elobixibat

[0103] [ka]

[0104] Toluene (1331.10 kg) and the compound of Example 3 (76.50 kg) were mixed in a reactor. Trifluoroacetic acid (341.95 kg) was added at 3° C. and the mixture was stirred for 29 hours at 25° C. The reaction mixture was repeatedly washed with water (306.00 kg) until the pH of the aqueous layer was 3.4. After filtering the organic layer, the filtrate was concentrated under vacuum. n-Heptane (520.20 kg) was added to the concentrated residue and the mixture was stirred. The precipitated crystals were centrifuged and washed with n-heptane (104.04 kg). The crystals were dried under vacuum to give crude elobixibat as an off-white solid (64.34 kg). HRMS (ESI, m / z) C 36 H 44 N3O7S2[MH] - Calculated value: 694.2623. Measured value: 694.2553.

[0105] Example 5 Preparation of the crystalline modification IV of elobixibat

[0106] [ka]

[0107] Crude elobixibat (64.00 kg), ethyl acetate (154.88 kg), and absolute alcohol (288.00 kg) were mixed in a reactor and the mixture was stirred at 40° C. until dissolved. The solution was filtered and the filtrate was washed with a mixture of ethyl acetate (17.28 kg) and absolute alcohol (15.36 kg). After cooling the filtered solution, seed crystals of crystalline modification IV of elobixibat (0.032 kg) were added at 25° C. and the mixture was stirred for 2 hours. n-heptane (832.00 kg) was added and the mixture was kept stirring at 23° C. The crystals were precipitated, centrifuged and washed with n-heptane (43.52 kg). The wet crystals were dried under vacuum to obtain dry crystals. The dry crystals were then hydrated (humidified) by exposure to humid conditions (40 ± 25% RH) at 25 °C until a moisture content of 2.4% - 3.4% (determined by Karl Fischer titration) was achieved. The crystalline modification IV of elobixibat was obtained as a white powder (50.64 kg).

Claims

1. 1. A process for the preparation of crystalline modification IV of elobixibat having an X-ray powder diffraction (XRPD) pattern obtained using CuKα1-radiation with specific peaks at °2θ positions of 6.3±0.2 and 19.4±0.2 and one or more characteristic peaks selected from 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, (i) dissolving crude elobixibat in a mixture of ethanol and ethyl acetate; (ii) obtaining a crystalline ethanolate of elobixibat from a mixed solution of ethanol and ethyl acetate in which the crude elobixibat obtained in step (i) is dissolved; (iii) drying the crystalline ethanolate of elobixibat obtained from step (ii) to obtain a crystalline anhydrate of elobixibat; (iv) hydrating the crystalline anhydrate of elobixibat to obtain the crystalline modification IV of elobixibat. A method comprising:

2. 2. The process of claim 1, wherein n-heptane is added to the mixture of ethanol and ethyl acetate in step (ii) in which the crude elobixibat is dissolved.

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