Method for preparing elobiksibat or solvate thereof

Abstract

To provide a method for preparing elobixibat or a solvate thereof in an efficient and industrially favorable manner.SOLUTION: A method for preparing elobixibat or a solvate thereof represented by formula I is provided, and a 2-butanol solvate of elobixibat represented by formula V is also provided. Further, a method for preparing elobixibat intermediates represented by formulas III and IV is provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an efficient and industrially advantageous process for the preparation of elobixibat of formula I or a solvate thereof.

[0002] The present invention also relates to a 2-butanol solvate of elobixibat of formula V:

[0003] The present invention also relates to processes for the preparation of elobixibat intermediates of formula III, IV and their use for the preparation of elobixibat of formula I or a solvate thereof. [Background technology]

[0004] Elobixibat has the structure of Formula I

[0005] [ka]

[0006] is known chemically as [(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,

[0007] Elobixibat was originally developed in Japan by the later AstraZeneca in collaboration with EA Pharma, a company established in the country. Elobixibat was approved by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on January 19, 2018, as elobixibat hydrate under the trade name Goofice®. Elobixibat is an ileal bile acid transporter (IBAT) inhibitor that can be used in the treatment or prevention of diseases such as dyslipidemia, constipation, diabetes, and liver disease.

[0008] U.S. Patent No. 7,192,945 (hereinafter US'945) first disclosed elobixibat. A process for the preparation of elobixibat was described, which comprises reacting 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine with (R)-2-phenylglycine methyl ester hydrochloride in the presence of N,N-diisopropylethylamine, O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate and dichloromethane to give 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine. A method is disclosed by obtaining a crude product of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-1'-phenyl-1'-methoxycarbonylmethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine, which is further purified by column chromatography to obtain pure 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-1'-phenyl-1'-methoxycarbonylmethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine. The obtained product is hydrolyzed using sodium hydroxide in the presence of methanol to obtain 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-1'-phenyl-1'-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine. The resulting product was further reacted with glycine tert-butyl ester in the presence of N,N-diisopropylethylamine, O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate, and dichloromethane, followed by purification using a column to give 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(tert-butoxycarbonylmethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine.The resulting product was then hydrolyzed using trifluoroacetic acid and dichloromethane to give crude elobixibat, which was purified by preparative HPLC (high performance liquid chromatography) to give elobixibat with a yield of 85%.

[0009] The main drawback of the method in US '945 is that it required preparative HPLC for the purification of elobixibat. Also, this method requires column chromatography for the purification of several intermediates of elobixibat, which is not suitable for large-scale industrial production of elobixibat. Furthermore, US '945 is also silent regarding the purity of the final elobixibat.

[0010] U.S. Patent No. 9,745,276 (hereinafter US'276) discloses crystalline modification I and crystalline modification IV polymorphic forms of elobixibat. US'276 also discloses methanol, ethanol, 1-propanol, and 2-propanol solvated forms of elobixibat. Crystalline modification IV of elobixibat is a monohydrate and is the thermodynamically most stable form among the other forms.

[0011] The various crystalline modifications and solvated forms of elobixibat can have drawbacks, including residual solvent, variable crystallinity, and difficulties in handling and formulation. Therefore, there is a need to develop new solvated forms of elobixibat with improved properties in terms of stability, bulk handling, and solubility.

[0012] The prior art methods require preparative HPLC during the purification of elobixibat and column chromatography for the purification of several intermediates of elobixibat, resulting in relatively low yields. Therefore, there is a need to develop a new method for the preparation of elobixibat or a solvate thereof that overcomes the shortcomings of the prior art. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] U.S. Patent No. 7,192,945 [Patent Document 2] U.S. Patent No. 9,745,276 Summary of the Invention [Problem to be solved by the invention]

[0014] The main object of the present invention is to provide a process for the preparation of elobixibat of formula I or a solvate thereof.

[0015] Another object of the present invention is to provide a 2-butanol solvate of elobixibat of formula V.

[0016] Another object of the present invention is to provide a process for the preparation of elobixibat intermediates of formula III, IV and their use for the preparation of elobixibat of formula I or a solvate thereof. [Means for solving the problem]

[0017] A first aspect of the present invention is a compound of formula I

[0018] [ka]

[0019] 1. A process for the preparation of elobixibat or a salt or hydrate thereof according to claim 1 a) In the presence of acetonitrile and water solvent, a compound of formula II

[0020] [ka]

[0021] with a base to form a compound of formula III

[0022] [ka]

[0023] obtaining a compound of formula (I); b) reacting a compound of formula III with a compound of formula IV

[0024] [ka]

[0025] a process for converting the compound "The compound of formula IV is isolated by treating the compound of formula IV with a ketone and an aliphatic hydrocarbon solvent." The process and c) reacting a compound of formula IV with a compound of formula V

[0026] [ka]

[0027] to a 2-butanol solvate of the compound of formula (I), d) converting the 2-butanol solvate of the compound of formula V into elobixibat of formula I or a salt or hydrate thereof; The object of the present invention is to provide a method comprising:

[0028] A second aspect of the present invention is a compound of formula III

[0029] [ka]

[0030] 2. A process for the preparation of a compound of formula II in the presence of acetonitrile and water.

[0031] [ka]

[0032] with a base to obtain a compound of formula III.

[0033] A third aspect of the present invention is a compound of formula III

[0034] [ka]

[0035] The present invention provides a method for the purification of a compound of formula III, comprising treating the compound of formula III with an alcohol and an aqueous solvent.

[0036] A fourth aspect of the present invention is a compound of formula IV

[0037] [ka]

[0038] The present invention provides a method for the purification of a compound of formula IV, comprising treating the compound of formula IV with a ketone and an aliphatic hydrocarbon solvent.

[0039] A fifth aspect of the present invention is a compound of formula V

[0040] [ka]

[0041] 1. A process for the preparation of a 2-butanol solvate of a compound of formula I

[0042] [ka]

[0043] to the 2-butanol solvate of the compound of formula V.

[0044] A sixth aspect of the present invention is a compound of formula V

[0045] [ka]

[0046] The object of the present invention is to provide a 2-butanol solvate of the compound of formula (I).

[0047] A seventh aspect of the present invention is a compound of formula I

[0048] [ka]

[0049] 1. A process for the preparation of elobixibat or a salt or hydrate thereof comprising: a) Formula IV

[0050] [ka]

[0051] to a compound of formula V

[0052] [ka]

[0053] to a 2-butanol solvate of the compound of formula (I); b) converting the 2-butanol solvate of the compound of formula V into elobixibat of formula I or a salt or hydrate thereof; The object is to provide the following:

[0054] An eighth aspect of the present invention is a compound of formula I

[0055] [ka]

[0056] The present invention provides a method for the preparation of amorphous elobixibat of formula I, comprising treating elobixibat of formula I or its 2-butanol solvate with a ketone and an aliphatic hydrocarbon solvent.

[0057] A ninth aspect of the present invention relates to a compound of formula II

[0058] [ka]

[0059] The present invention provides a method for the purification of a compound of formula II, comprising treating a compound of formula II with a ketone and an aqueous solvent.

[0060] A tenth aspect of the present invention is to provide a process for the preparation of amorphous elobixibat of formula I, comprising the step of treating a 2-butanol solvate of elobixibat with a solvent selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone; n-heptane, n-hexane, methylene chloride, ethylene dichloride, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, water, or a mixture thereof. [Brief explanation of the drawings]

[0061] [Figure 1] FIG. 1 illustrates the X-ray powder diffractogram (XRPD) of the 2-butanol solvate of elobixibat of formula V according to Example 04. [Figure 2] FIG. 1 illustrates the X-ray powder diffractogram (XRPD) of amorphous form of elobixibat of formula I according to Example 05. [Figure 3] FIG. 1 illustrates the differential scanning calorimetry (DSC) of 2-butanol solvate of elobixibat of formula V according to Example 04. [Figure 4] FIG. 1 illustrates the thermogravimetric analysis (TGA) of 2-butanol solvate of elobixibat of formula V according to Example 04. DETAILED DESCRIPTION OF THE INVENTION

[0062] In order to provide a clear and consistent understanding of the terms used herein, a number of definitions are provided below. Furthermore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art.

[0063] When used in connection with the term "comprising" in the claims and / or herein, the use of the words "a" or "an" not only means "one," but can also encompass the meanings "one or more," "at least one," and "one or more than one." Similarly, the word "another" can mean at least a second or more.

[0064] As used herein, the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "consisting" (and any form of consisting, such as "consisting"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "include" and "includes"), or "containing" (and any form of containing, such as "contain" and "contains") are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0065] The present invention will now be described in detail with reference to specific preferred embodiments so that its various aspects may be fully understood and appreciated.

[0066] According to a first embodiment, the present invention provides a compound of formula I

[0067] [ka]

[0068] 1. A process for the preparation of elobixibat or a salt or hydrate thereof comprising: a) In the presence of acetonitrile and water solvent, a compound of formula II

[0069] [ka]

[0070] with a base to form a compound of formula III

[0071] [ka]

[0072] obtaining a compound of formula (I); b) reacting a compound of formula III with a compound of formula IV

[0073] [ka]

[0074] a process for converting the compound "the compound of formula IV is isolated by treating the compound of formula IV with a ketone and an aliphatic hydrocarbon solvent"; c) reacting a compound of formula IV with a compound of formula V

[0075] [ka]

[0076] to a 2-butanol solvate of the compound of formula (I); d) converting the 2-butanol solvate of the compound of formula V to elobixibat of formula I or a salt or hydrate thereof; The object of the present invention is to provide a method comprising:

[0077] In a first embodiment of step a), the compound of formula II can be prepared by methods known in the prior art.

[0078] In a first embodiment of step a), the base is an inorganic base such as an "alkali metal hydroxide" such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; an "alkali metal carbonate" such as sodium carbonate, potassium carbonate, lithium carbonate, etc.; an "alkali metal bicarbonate" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, etc.; an "alkali metal hydride" such as sodium hydride, potassium hydride, lithium hydride, etc.; an "alkali metal alkoxide" such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, etc.; triethylamine, methylamine, ethylamine, 1,8-diazabicyclo[5.

[0049] The base may be selected from the group consisting of organic bases such as [4.0]undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium diisopropylamine (LDA), n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine (DIPA), diisopropylethylamine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethylaminopyridine (DMAP), morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triazole, and 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0079] In a first embodiment of step a), the reaction of the compound of formula II with the base can be carried out at a temperature between 10°C and 40°C for a period between 1 hour and 15 hours.

[0080] In a first embodiment of step a), the reaction of the compound of formula II with a base can be carried out in the presence of acetonitrile and water as solvent to give the compound of formula III.

[0081] In the first embodiment of step a), the acetonitrile solvent can be used in a ratio of 0.2 to 10 volumes relative to the compound of formula II.

[0082] After completion of the reaction, the mixture can be cooled, and ethyl acetate can be added to the resulting mixture, followed by the addition of aqueous hydrochloric acid to adjust the pH of the mixture to less than 2.0. The resulting mixture can be separated into an organic layer and an aqueous layer. The resulting organic layer-1 can be separated, and ethyl acetate can be added to the aqueous layer-1, followed by stirring at 0°C to 5°C for 20 minutes. The resulting mixture can be separated into an organic layer and an aqueous layer. All organic layers can be combined, and purified water can be added and stirred at 0°C to 5°C for 20 minutes. The resulting mixture can be separated into an organic layer and an aqueous layer. The resulting organic layer can be extracted with purified water at 0°C to 5°C and further extracted with aqueous sodium chloride at 0°C to 5°C. The resulting organic layer can be distilled under vacuum at 35°C to 40°C. The resulting mass can be treated with isopropanol and water to obtain a compound of Formula III.

[0083] The resulting compound of formula III can have a purity of more than 98% by HPLC (High Performance Liquid Chromatography).

[0084] In a first embodiment of step b), the compound of formula III can be converted to the compound of formula IV by reacting the compound of formula III with glycine tert-butyl ester hydrochloride in the presence of a coupling agent, a base and a solvent.

[0085] The coupling agent may be selected from the group consisting of N,N'-carbonyldiimidazole, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU).

[0086] The base may be selected from the group consisting of triethylamine, methylamine, ethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium diisopropylamine (LDA), n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine (DIPA), N,N-diisopropylethylamine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethylaminopyridine (DMAP), morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triazole, 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0087] The solvent may be selected from the group consisting of dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform or mixtures thereof.

[0088] In a first embodiment of step b), the compound of formula III can be converted to the compound of formula IV by reacting the compound of formula III with glycine tert-butyl ester hydrochloride in the presence of a coupling agent, a base and a solvent at a temperature between −5° C. and 35° C. for 1 hour to 5 hours.

[0089] In a first embodiment of step b), the compound of formula IV can be isolated by treating the compound of formula IV with a ketone and an aliphatic hydrocarbon solvent.

[0090] The ketone solvent may be selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone, or mixtures thereof.

[0091] The aliphatic hydrocarbon solvent may be selected from the group consisting of cyclohexane, n-heptane, n-hexane, n-pentane or mixtures thereof.

[0092] The compound of Formula IV can be treated by slurry washing using a ketone and an aliphatic hydrocarbon, or by a solvent-antisolvent method using a ketone and an aliphatic hydrocarbon. Specifically, a ketone can be added to the compound of Formula IV, and the resulting mixture can be stirred at 20°C to 40°C. An aliphatic hydrocarbon solvent can be added to the resulting mixture at 25°C to 35°C, and the resulting mixture can be stirred at the same temperature for 1 hour to 5 hours. The resulting solid can be filtered and washed with an aliphatic hydrocarbon solvent to obtain the compound of Formula IV.

[0093] The resulting compound of formula IV can have a purity of more than 99% by HPLC (High Performance Liquid Chromatography).

[0094] In a first embodiment of step c), the compound of formula IV can be converted into the 2-butanol solvate of the compound of formula V by reacting the compound of formula IV with an acid in the presence of a solvent to obtain in situ elobixibat of formula I, which can be further converted into the 2-butanol solvate of the compound of formula V with 2-butanol.

[0095] The acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, and trifluoroacetic acid.

[0096] The solvent may be selected from the group consisting of toluene, xylene, cyclohexane, n-hexane, n-heptane, n-pentane, water or mixtures thereof.

[0097] The 2-butanol solvent can be used in a ratio of 0.1 to 1.5 volumes relative to the compound of formula IV.

[0098] Generally, the 2-butanol solvate of the compound of formula V can be prepared by adding 2-butanol to the in-situ formed elobixibat of formula I. The resulting mixture can be heated to 40-45°C and stirred at the same temperature for 1 hour. The resulting mixture can be cooled to 25-35°C and stirred at 25-35°C for 2-4 hours. The resulting mixture can be filtered, washed with 2-butanol, and dried under vacuum at 40-45°C to obtain the 2-butanol solvate of the compound of formula V.

[0099] The resulting 2-butanol solvate of the compound of formula V can have a purity of greater than 99.9% by HPLC (high performance liquid chromatography).

[0100] In a first embodiment of step d), the 2-butanol solvate of the compound of formula V can be converted to elobixibat of formula I or a salt or hydrate thereof.

[0101] In a first embodiment of step d), the obtained elobixibat of formula I or a salt or hydrate thereof can have a purity of more than 99.50% by HPLC (High Performance Liquid Chromatography).

[0102] According to a second embodiment, the present invention provides a compound of formula III

[0103] [ka]

[0104] 2. A process for the preparation of a compound of formula II in the presence of acetonitrile and water.

[0105] [ka]

[0106] with a base to obtain a compound of formula III.

[0107] In a second embodiment, compounds of formula II can be prepared by methods known in the prior art.

[0108] In a second embodiment, the base is an inorganic base such as an "alkali metal hydroxide" such as lithium hydroxide, sodium hydroxide, or potassium hydroxide; an "alkali metal carbonate" such as sodium carbonate, potassium carbonate, or lithium carbonate; an "alkali metal bicarbonate" such as sodium bicarbonate, potassium bicarbonate, or lithium bicarbonate; an "alkali metal hydride" such as sodium hydride, potassium hydride, or lithium hydride; an "alkali metal alkoxide" such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, or potassium tert-butoxide; triethylamine, methylamine, ethylamine, 1,8-diazabicyclo[5.4.0]diamine, methylamine, ...1,8-diazabicyclo[5.4.0]diamine, methylamine, ethylamine, 1,8-diazabicyclo[5. ]undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium diisopropylamine (LDA), n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine (DIPA), diisopropylethylamine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethylaminopyridine (DMAP), morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triazole, 1,4-diazabicyclo[2.2.2]octane (DABCO), and other organic bases.

[0109] In a second embodiment, the reaction of the compound of formula II with the base can be carried out at a temperature between 10°C and 40°C for a period of 1 hour to 15 hours.

[0110] In the second embodiment, the acetonitrile solvent can be used in a ratio of 0.2 to 10 volumes relative to the compound of formula II.

[0111] In a second embodiment, the reaction of a compound of formula II with a base can be carried out in the presence of acetonitrile and water as solvent to give a compound of formula III.

[0112] After completion of the reaction, the mixture can be cooled, and ethyl acetate can be added to the resulting mixture, followed by the addition of aqueous hydrochloric acid to adjust the pH of the mixture to less than 2.0. The resulting mixture can be separated into an organic layer and an aqueous layer. The resulting organic layer-1 can be separated, and ethyl acetate can be added to the aqueous layer-1, followed by stirring at 0°C to 5°C for 20 minutes. The resulting mixture can be separated into an organic layer and an aqueous layer. All organic layers can be combined, and purified water can be added and stirred at 0°C to 5°C for 20 minutes. The resulting mixture can be separated into an organic layer and an aqueous layer. The resulting organic layer can be extracted with purified water at 0°C to 5°C and further extracted with aqueous sodium chloride at 0°C to 5°C. The resulting organic layer can be distilled under vacuum at 35°C to 40°C. The resulting mass can be treated with isopropanol and water to obtain a compound of Formula III.

[0113] The resulting compound of formula III can have a purity of more than 98% by HPLC (High Performance Liquid Chromatography).

[0114] According to a third embodiment, the present invention provides a compound of formula III

[0115] [ka]

[0116] The present invention provides a method for the purification of a compound of formula III, comprising treating the compound of formula III with an alcohol and an aqueous solvent.

[0117] In a third embodiment, the alcohol solvent may be selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, butanol, or mixtures thereof.

[0118] In the third embodiment, the alcohol solvent can be used in a ratio of 0.1 to 10 volumes relative to the compound of formula III.

[0119] In a third embodiment, the treatment of the compound of formula III with alcohol and water can be carried out by slurry washing or solvent-antisolvent methods. In particular, the compound of formula III can be stirred in the presence of alcohol. The resulting mixture can be distilled at less than 45°C to obtain a distilled mass, which can be further cooled to 25°C to 35°C. Purified water can be added to the resulting mass, and the resulting mixture can be stirred at 25°C to 35°C for 3 to 7 hours. The resulting mixture can be filtered, washed with purified water, and dried under vacuum at 50°C to 55°C to obtain the compound of formula III.

[0120] In a third embodiment, the compound of formula III obtained may have a purity of greater than 98% by HPLC (High Performance Liquid Chromatography).

[0121] According to a fourth embodiment, the present invention provides a compound of formula IV

[0122] [ka]

[0123] The present invention provides a method for the purification of a compound of formula IV, comprising treating the compound of formula IV with a ketone and an aliphatic hydrocarbon solvent.

[0124] In a fourth embodiment, the ketone solvent may be selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone, or mixtures thereof.

[0125] In a fourth embodiment, the ketone solvent can be used in an amount of 0.1 to 10 volumes relative to the compound of formula IV.

[0126] In a fourth embodiment, the aliphatic hydrocarbon solvent may be selected from the group consisting of cyclohexane, n-heptane, n-hexane, n-pentane, or mixtures thereof.

[0127] In a fourth embodiment, the aliphatic hydrocarbon solvent can be used in an amount of 0.1 to 20 volumes relative to the compound of formula IV.

[0128] The compound of Formula IV can be treated by slurry washing using a ketone and an aliphatic hydrocarbon, or by a solvent-antisolvent method using a ketone and an aliphatic hydrocarbon. Specifically, a ketone can be added to the compound of Formula IV, and the resulting mixture can be stirred at 20°C to 40°C. An aliphatic hydrocarbon solvent can be added to the resulting mixture at 25°C to 35°C, and the resulting mixture can be stirred at the same temperature for 1 hour to 5 hours. The resulting solid can be filtered and washed with an aliphatic hydrocarbon solvent to obtain the compound of Formula IV.

[0129] In a fourth embodiment, the compound of formula IV obtained may have a purity of greater than 99% by HPLC (High Performance Liquid Chromatography).

[0130] According to a fifth embodiment, the present invention provides a compound of formula V

[0131] [ka]

[0132] 1. A process for the preparation of a 2-butanol solvate of a compound of formula I

[0133] [ka]

[0134] to a 2-butanol solvate of a compound of formula V.

[0135] In a fifth embodiment, elobixibat of formula I can be converted to the 2-butanol solvate of the compound of formula V by interacting elobixibat of formula I with 2-butanol to obtain the 2-butanol solvate of the compound of formula V.

[0136] Generally, the 2-butanol solvate of the compound of formula V can be prepared by stirring a mixture of 2-butanol and elobixibat of formula I for 1 to 6 hours at 20° C. to 45° C. The resulting mixture is filtered, washed with 2-butanol, and dried under vacuum at 40° C. to 45° C. to obtain the 2-butanol solvate of the compound of formula V.

[0137] In a fifth embodiment, 2-butanol can be used in a ratio of 0.1 to 1.5 volumes relative to elobixibat of formula I.

[0138] In a fifth embodiment, elobixibat of Formula I can be a hydrated form or any other crystalline or amorphous form of elobixibat of Formula I.

[0139] In a fifth embodiment, the resulting 2-butanol solvate of the compound of formula V may have a purity of greater than 99.9% by HPLC (High Performance Liquid Chromatography).

[0140] According to a sixth embodiment, the present invention provides a compound of formula V

[0141] [ka]

[0142] The present invention provides a 2-butanol solvate of the compound of formula (I).

[0143] In a sixth embodiment, the 2-butanol solvate of the compound of formula V can be characterized by X-ray powder diffraction (XRPD) with peaks at 6.0, 18.7, and 22.0±0.2 degrees 2θ.

[0144] In a sixth embodiment, the 2-butanol solvate of the compound of formula V can be further characterized by X-ray powder diffraction (XRPD) with peaks at 9.9, 12.8, 18.1, 18.9, 20.3, 21.5, and 23.5±0.2 degrees 2θ.

[0145] In a sixth embodiment, the 2-butanol solvate of the compound of formula V can be further characterized by differential scanning calorimetry (DSC) having an endotherm at about 113.38°C.

[0146] In a sixth embodiment, the 2-butanol solvate of the compound of formula V can be further characterized by thermogravimetric analysis (TGA) as provided in FIG.

[0147] According to a seventh embodiment, the present invention provides a compound of formula I

[0148] [ka]

[0149] 1. A process for the preparation of elobixibat or a salt or hydrate thereof comprising: a) Formula IV

[0150] [ka]

[0151] Compound of formula V

[0152] [ka]

[0153] to a 2-butanol solvate of the compound of formula (I); b) converting the 2-butanol solvate of the compound of formula V into elobixibat of formula I or a salt or hydrate thereof; The present invention provides a method comprising:

[0154] In a seventh embodiment of step a), the compound of formula IV can be converted into the 2-butanol solvate of the compound of formula V by interacting the compound of formula IV with an acid in the presence of a solvent to obtain in situ elobixibat of formula I, which can be further converted into the 2-butanol solvate of the compound of formula V.

[0155] The acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, and trifluoroacetic acid.

[0156] The solvent may be selected from the group consisting of toluene, xylene, cyclohexane, n-hexane, n-heptane, n-pentane, water or mixtures thereof.

[0157] In a seventh embodiment of step a), the compound of formula IV can be converted to the 2-butanol solvate of the compound of formula V by reacting the compound of formula IV with an acid in the presence of a solvent at 20°C to 40°C to obtain elobixibat of formula I in situ.

[0158] The in-situ formed elobixibat of formula I can be interacted with 2-butanol to give the 2-butanol solvate of the compound of formula V.

[0159] Generally, the 2-butanol solvate of the compound of formula V can be prepared by stirring a mixture of 2-butanol and elobixibat of formula I for 1 to 6 hours at 20° C. to 45° C. The resulting mixture is filtered, washed with 2-butanol, and dried under vacuum at 40° C. to 45° C. to obtain the 2-butanol solvate of the compound of formula V.

[0160] 2-butanol can be used in a ratio of 0.1 to 1.5 volumes relative to the in-situ elobixibat of Formula I.

[0161] In a seventh embodiment of step b), the 2-butanol solvate of the compound of formula V can be converted to elobixibat of formula I or a salt or hydrate thereof.

[0162] In a seventh embodiment of step b), elobixibat of formula I or a salt or hydrate thereof can have a purity of more than 99.50% by HPLC (High Performance Liquid Chromatography).

[0163] According to an eighth embodiment, the present invention provides a compound of formula I

[0164] [ka]

[0165] The present invention provides a process for the preparation of an amorphous form of elobixibat of formula I, comprising treating elobixibat of formula I or a 2-butanol solvate thereof with a ketone and an aliphatic hydrocarbon solvent.

[0166] In an eighth embodiment, the ketone solvent may be selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone, or mixtures thereof.

[0167] In the eighth embodiment, the ketone solvent can be used in a ratio of 0.1 to 1.5 volumes relative to the compound of formula IV.

[0168] In an eighth embodiment, the aliphatic hydrocarbon solvent may be selected from the group consisting of cyclohexane, n-heptane, n-hexane, n-pentane, or mixtures thereof.

[0169] In the eighth embodiment, the aliphatic hydrocarbon solvent can be used in a ratio of 0.1 to 10 volumes relative to the compound of formula IV.

[0170] In an eighth embodiment, the starting material elobixibat of formula I used for the preparation of amorphous form of elobixibat can be in a crystalline or solvated form.

[0171] In an eighth embodiment, the processing of elobixibat of Formula I can be carried out by a slurry wash using a ketone and an aliphatic hydrocarbon, or by a solvent-antisolvent method using a ketone and an aliphatic hydrocarbon. Alternatively, a ketone can be added to elobixibat of Formula I, and the resulting mixture can be stirred at 30°C to 50°C and distilled under vacuum to remove the ketone solvent. The resulting mass can be stirred at 40°C to 45°C for 15 to 20 minutes. An aliphatic hydrocarbon solvent can be added to the resulting mixture at 25°C to 35°C, and the resulting mixture can be stirred at the same temperature for 3 to 5 hours. The resulting solid can be filtered and washed with an aliphatic hydrocarbon solvent to obtain amorphous elobixibat of Formula I.

[0172] The resulting amorphous elobixibat of Formula I can have a purity of greater than 99% by HPLC (High Performance Liquid Chromatography).

[0173] The obtained amorphous form of elobixibat of formula I can be characterized by XRPD as given in FIG.

[0174] According to a ninth embodiment, the present invention provides a compound of formula II

[0175] [ka]

[0176] The present invention provides a method for the purification of a compound of formula II, comprising treating a compound of formula II with a ketone and an aqueous solvent.

[0177] In a ninth embodiment, the crude compound of formula II can be prepared by methods known in the prior art.

[0178] In a ninth embodiment, the ketone solvent may be selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone, or mixtures thereof.

[0179] In the ninth embodiment, the ketone solvent can be used in a ratio of 1 volume to 10 volumes relative to the compound of formula II.

[0180] In a ninth embodiment, the compound of Formula II can be treated by a slurry wash using a ketone and water, or by a solvent-antisolvent method using a ketone and water. In particular, a ketone can be added to the compound of Formula II, and the resulting mixture can be stirred at 30°C to 50°C. Water can be added to the resulting mixture at 25°C to 35°C, and the resulting mixture can be stirred at the same temperature for 3 to 10 hours. The resulting solid can be filtered, washed with water, and dried under vacuum to obtain the compound of Formula II.

[0181] In a ninth embodiment, the compound of formula II obtained may have a purity of greater than 98% by HPLC (High Performance Liquid Chromatography).

[0182] According to a tenth embodiment, the present invention provides a process for the preparation of amorphous elobixibat of formula I, comprising treating a 2-butanol solvate of elobixibat with a solvent selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone; n-heptane, n-hexane, methylene chloride, ethylene dichloride, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, water, or a mixture thereof. [Example]

[0183] The following examples illustrate some of the embodiments of the invention described herein, and should not be construed as limiting the spirit or scope of the invention in any way.

[0184] Example 1 Preparation of Compounds of Formula II

[0185] [ka]

[0186] To a stirred solution of dichloromethane (1000 mL) and 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (100 g), (R)-2-phenylglycine methyl ester hydrochloride (41.87 g) was added at 25°C to 35°C. The resulting mixture was cooled to 0°C to 10°C, and N,N-diisopropylethylamine (102.2 g) and o-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (69.82 g) were added at 0°C to 10°C under nitrogen. The resulting reaction mixture was heated at 25°C to 35°C for 3 hours. After completion of the reaction, the resulting mixture was cooled to 20°C to 30°C and washed with purified water (3 x 500 mL). The resulting organic layer was distilled under vacuum at below 45°C, followed by stripping with acetone. To the resulting mass, acetone (200 mL) was added at below 45°C, and the resulting mixture was cooled to 25-35°C, followed by adding purified water (600 mL). The resulting mixture was stirred for 8 hours. The resulting mixture was filtered, washed with purified water, and dried under vacuum at 45-50°C to give the title compound (120.5 g). HPLC purity: 99.28%

[0187] Example 2 Preparation of Compounds of Formula III

[0188] [ka]

[0189] To a stirred solution of purified water (400 mL) and sodium hydroxide (3.06 g) was added acetonitrile (200 mL) and the compound of Formula II (25 g) at 10°C to 15°C. The resulting mixture was stirred at 10°C to 15°C for 8 hours. After completion of the reaction, the resulting mixture was cooled to 0°C to 5°C, and ethyl acetate (375 mL) was added and stirred at 0°C to 5°C for 15 minutes. 3% aqueous hydrochloric acid (103 mL) was added to the resulting mixture to adjust the pH of the mixture to less than 2.0. The resulting mixture was stirred at 0°C to 5°C for 30 minutes, and the mixture was allowed to separate into an organic layer and an aqueous layer. The resulting organic layer was washed with water (2 x 100 mL) and 20% aqueous sodium chloride washes (2 x 100 mL). The resulting organic layer was distilled under vacuum at less than 45°C to obtain a mass. To the resulting mass was added isopropyl alcohol (125 mL) at below 40°C, further cooled to 25-30°C, followed by the addition of purified water (260 mL). The resulting mixture was stirred at 25-35°C for 6 hours. The resulting mixture was filtered, washed with purified water (2 x 25 mL), and dried under vacuum at 50-55°C to give the title compound (23.5 g). HPLC purity: 98.19%

[0190] Example 3 Preparation of Compounds of Formula IV

[0191] [ka]

[0192] To a stirred solution of dichloromethane (400 mL) and the compound of Formula III (20 g), (R)-2-phenylglycine methyl ester hydrochloride (7.87 g), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (18.1 g), and N,N-diisopropylethylamine (12.2 g) were added at 0°C to 5°C. The resulting mixture was maintained at -5°C to 5°C for 1 hour. After completion of the reaction, aqueous hydrochloric acid was slowly added at 0°C to 5°C to adjust the pH to less than 2.0. The resulting mixture was stirred at 0°C to 5°C for 30 minutes. The temperature of the mixture was then raised to 25°C to 35°C, and the mixture was stirred at the same temperature for 20 minutes. The resulting mixture was separated into an organic layer and an aqueous layer. The resulting aqueous layer-1 was separated, and 3% aqueous hydrochloric acid was added to the resulting organic layer-1 to adjust the pH to less than 2.0. The resulting mixture was stirred at 25°C to 35°C for 20 minutes, allowing the mixture to separate into an organic layer and an aqueous layer. The resulting aqueous layer-2 was separated, and purified water (100 mL) was added to the resulting organic layer-2. The mixture was stirred at 25°C to 35°C for 20 to 30 minutes, allowing the mixture to separate into an organic layer and an aqueous layer. The resulting aqueous layer-3 was separated, and 7% aqueous sodium bicarbonate solution (100 mL) was added to the resulting organic layer-3. The mixture was stirred at 25°C to 35°C for 30 minutes, allowing the mixture to separate into an organic layer and an aqueous layer. The resulting aqueous layer-4 was separated, and purified water (100 mL) was added to the resulting organic layer-4. The mixture was stirred at 25°C to 35°C for 20 minutes, allowing the mixture to separate into an organic layer and an aqueous layer. The resulting organic layer-5 was distilled under vacuum at less than 45°C to obtain an oil, which was further stripped with acetone (20 mL). Acetone (20 mL) was added to the resulting mass and stirred at 25-35°C for 15 minutes, and n-heptane (200 mL) was slowly added to the mixture at 25-35°C. The resulting mixture was filtered and washed with n-heptane (2 x 20 mL) to obtain a solid. Acetonitrile (80 mL) was added to the resulting solid and the mixture was heated at 40-45°C for 2 hours. The resulting mixture was slowly cooled to 25-35°C and stirred for 5 hours. The resulting mixture was filtered, washed with acetonitrile (20 mL), and dried under vacuum at 55-60°C to obtain the title compound (14.0 g). HPLC purity: 99.26%

[0193] Example 4 Preparation of the 2-butanol solvate of elobixibat of formula V

[0194] [ka]

[0195] To a stirred solution of toluene (154 mL) and the compound of Formula IV (22 g), a solution of trifluoroacetic acid (116.6 g) in toluene (66 mL) was added at 0°C to 5°C. The resulting mixture was stirred at 25°C to 35°C for 3 hours. After completion of the reaction, the resulting mixture was cooled to 0°C to 5°C, purified water (110 mL) was added, and the mixture was separated into an organic layer and an aqueous layer. The resulting organic layer was washed with purified water (2 x 110 mL). The resulting organic layer was distilled below 45°C, and 2-butanol (100 mL) was added at 25°C to 35°C. The mixture was heated to 40°C to 45°C and stirred at the same temperature for 1 hour. The resulting mixture was cooled to 25°C to 35°C and stirred at 25°C to 35°C for 2 to 4 hours. The resulting mixture was filtered, washed with 2-butanol (20 mL), and dried under vacuum at 40°C to 45°C to obtain the title compound (17 g). HPLC purity: 99.37% / Chiral purity: 99.9%

[0196] Example 5 Preparation of the amorphous form of elobixibat of formula I

[0197] [ka]

[0198] The 2-butanol solvate of elobixibat of formula V (52 gm) was dissolved in acetone (520 mL) at 40-45°C. The resulting solution was distilled under vacuum at 40-45°C, and the mixture was stirred at 40-45°C for 15-20 minutes. To the resulting mixture was added n-heptane (350 mL) below 45°C, and the mixture was stirred at 25-35°C for 5 hours. The resulting solid was filtered, washed with n-heptane (100 mL), and dried under vacuum at 45-50°C to give the title compound (50.5 g). HPLC purity: 99.50% / Chiral purity: 99.91%

[0199] Example 6 Preparation of the amorphous form of elobixibat of formula I A mixture of 2-butanol solvate of elobixibat of formula V (0.5 gm), acetone (0.5 mL) and water (10 mL) is stirred for 3 hours at 25-35° C. The resulting solid is filtered, washed with water and dried at 65-70° C. for 12 hours to give the title compound (0.41 g).

[0200] Example 7 Preparation of the amorphous form of elobixibat of formula I A mixture of 2-butanol solvate of elobixibat of formula V (0.5 gm), dimethylformamide (0.5 mL) and water (10 mL) is stirred for 3 hours at 25-35° C. The resulting solid is filtered, washed with water and dried at 65-70° C. for 12 hours to give the title compound (0.40 g).

[0201] Example 8 Preparation of the amorphous form of elobixibat of formula I A mixture of 2-butanol solvate of elobixibat (0.5 gm), methylene chloride (0.5 mL) and n-heptane (10 mL) was stirred for 3 hours at 25-35° C. The resulting solid was filtered, washed with n-heptane and dried at 65-70° C. for 12 hours to give the title compound (0.35 g).

[0202] Example 9 Preparation of the amorphous form of elobixibat of formula I A mixture of 2-butanol solvate of elobixibat of formula V (0.5 gm), dimethyl sulfoxide (0.5 mL) and water (10 mL) is stirred for 3 hours at 25° C.-35° C. The resulting solid is filtered, washed with water and dried at 65° C.-70° C. for 12 hours to give the title compound (0.42 g).

[0203] Example 10 Preparation of the amorphous form of elobixibat of formula I A mixture of 2-butanol solvate of elobixibat of formula V (0.5 gm), dimethylacetamide (0.5 mL) and water (10 mL) is stirred for 3 hours at 25° C.-35° C. The resulting solid is filtered, washed with water and dried at 65° C.-70° C. for 12 hours to give the title compound (0.4 g).

Claims

1. Formula I 【Chemical 1】 1. A process for the preparation of elobixibat or a salt or hydrate thereof comprising: a) In the presence of acetonitrile and water solvent, a compound of formula II 【Chemistry 2】 with a base to form a compound of formula III 【Chemistry 3】 obtaining a compound of formula (I); b) reacting a compound of formula III with a compound of formula IV 【Chemistry 4】 a process for converting the compound "the compound of formula IV is isolated by treating the compound of formula IV with a ketone and an aliphatic hydrocarbon solvent"; c) reacting a compound of formula IV with a compound of formula V 【Chemistry 5】 to a 2-butanol solvate of the compound of formula (I), d) converting the 2-butanol solvate of the compound of formula V to elobixibat of formula I or a salt or hydrate thereof; A method comprising:

2. The reaction of the compound of formula II with a base in the presence of acetonitrile and water solvent is carried out at 10°C to 40°C, and the base is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, sodium hydride, potassium hydride, lithium hydride, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine, methylamine, ethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- 10. The method of claim 1, wherein the aryl group is selected from diazabicyclo(4.3.0)non-5-ene (DBN), lithium diisopropylamine (LDA), n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine (DIPA), diisopropylethylamine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethylaminopyridine (DMAP), morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methylimidazole, 1,2,4-triazole, or 1,4-diazabicyclo[2.2.2]octane (DABCO).

3. 2. The method of claim 1, wherein the ketone solvent is acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone, or a mixture thereof, and the aliphatic hydrocarbon solvent is cyclohexane, n-heptane, n-hexane, n-pentane, or a mixture thereof.

4. Formula V 【Chemistry 6】 2-butanol solvate of the compound.

5. 5. The 2-butanol solvate of the compound of formula V according to claim 4, characterized by X-ray powder diffraction (XRPD) peaks at 6.0, 18.7 and 22.0±0.2 degrees 2θ.

6. 5. The 2-butanol solvate of the compound of formula V of claim 4, further characterized by differential scanning calorimetry (DSC) with an endotherm at about 113.38°C.

7. Formula I 【Chemistry 7】 1. A process for the preparation of an amorphous form of elobixibat of formula I, comprising treating elobixibat of formula I or a solvate thereof with a ketone and an aliphatic hydrocarbon solvent, wherein the ketone solvent is selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone, or a mixture thereof, and the aliphatic hydrocarbon solvent is selected from cyclohexane, n-heptane, n-hexane, n-pentane, or a mixture thereof.

8. Formula II 【Chemistry 8】 10. A method for the purification of a compound of formula II, comprising treating a compound of formula II with a ketone and an aqueous solvent.

9. 9. The method of claim 8, wherein the ketone solvent is selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone, or mixtures thereof.

10. A process for the preparation of amorphous elobixibat of formula I, comprising treating a 2-butanol solvate of elobixibat with a solvent selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone; n-heptane, n-hexane, methylene chloride, ethylene dichloride, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, or mixtures thereof.

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