DESC:FIELD OF THE INVENTION:
The present invention relates to an efficient and industrially advantageous process for the preparation of Elobixibat of Formula-I or solvate thereof.
The present invention also relates to provides 2-butanol solvate of Elobixibat of Formula-V.
The present invention also relates to provides process for preparation of Elobixibat intermediates of Formula-III, IV, and their use for the preparation of Elobixibat of Formula-I or solvate thereof.
BACKGROUND OF THE INVENTION:
Elobixibat is chemically known 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, having the structure of Formula-I,

Formula-I
Elobixibat has been initially developed by AstraZeneca later in the partnership with EA Pharma Co., Ltd. launched in Japan. Elobixibat was approved by pharmaceutical and medical devices agency (PMDA) of Japan on January 19th 2018 as a Elobixibat hydrate under the proprietary name Goofice®. Elobixibat is an ileal bile acid transporter (IBAT) inhibitor, which can be used in the treatment or prevention of diseases such as dyslipidemia, constipation, diabetes and liver diseases.
The US patent number US 7192945 (hereinafter US ‘945) first discloses Elobixibat. The process for preparation of Elobixibat has been also disclosed by 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 presence of N,N-diisopropylethylamine, O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate and dichloromethane to obtain crude 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 was further purified by column 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. Resulting product was hydrolysed using sodium hydroxide in 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. Resulting product was further reacted with glycine tert-butyl ester in presence of N,N-diisopropylethylamine, O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate and dichloromethane, followed by purification using column to obtain 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. Resulting product was then hydrolysed using trifluoroacetic acid and dichloromethane to obtain crude Elobixibat, which was purified by preparative HPLC (High-performance liquid chromatography) to obtain Elobixibat having 85% yield.
Major drawback of US ‘945 process is, it required preparative HPLC for the purification of Elobixibat. Also, the process required column chromatography for the purification of several intermediates of Elobixibat, which is not suitable for large scale industrial production of Elobixibat. Further, US ‘945 is also silent about the purity of the final Elobixibat.
The US patent number US 9745276 (hereinafter US ‘276) discloses crystal modification I, crystal modification IV polymorphic form of Elobixibat. US ‘276 also discloses methanol, ethanol, 1-propanol and 2- propanol solvated form of Elobixibat. The crystal modification IV of Elobixibat is a monohydrate and is thermodynamically most stable form over other forms.
Various crystal modifications and solvated forms of Elobixibat may have disadvantages including residual solvents, a variable degree of crystallinity and difficulties in handling and formulating. Thus, there is a need to develop novel solvated form of Elobixibat having improved properties with respect to stability, bulk handling and solubility.
As prior art process requires preparative HPLC during purification of Elobixibat and requires column chromatography for the purification of several intermediates of Elobixibat, it results into lower yield. Thus, there is a need to develop a novel process for the preparation of Elobixibat or solvate thereof which overcomes the drawback of the prior art.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide a process for the preparation of Elobixibat of Formula-I or solvate thereof.
Another object of the present invention is to provide a 2-butanol solvate of Elobixibat of Formula-V.
Another one object of the present invention is to provides process for preparation of Elobixibat intermediates of Formula-III, IV, and their use for the preparation of Elobixibat of Formula-I or solvate thereof.
SUMMARY OF INVENTION:
First aspect of the present invention is to provide a process for preparation of Elobixibat of Formula-I or salt or hydrate thereof,

[Formula-I]
comprising the steps of:
a) reacting compound of Formula-II,

[Formula-II]
with base in presence of acetonitrile and water solvent to obtain compound of Formula-III;

[Formula-III]
b) converting compound of Formula-III to compound of Formula-IV;

[Formula-IV]
“wherein compound of Formula-IV is isolated by treating compound of Formula-IV with ketone and aliphatic hydrocarbon solvent”;
c) converting compound of Formula-IV to 2-butanol solvate of compound Formula-V; and

[Formula-V]
d) converting 2-butanol solvate of compound Formula-V to Elobixibat of Formula-I or salt or hydrate thereof.
Second aspect of the present invention is to provide a process for preparation of compound of Formula-III,

[Formula-III]
comprising reacting compound of Formula-II,

[Formula-II]
with base in presence of acetonitrile and water to obtain compound of Formula-III.
Third aspect of present invention is to provide a process for purification of compound of Formula-III,

[Formula-III]
comprising treating compound of Formula-III with alcohol and water solvent.
Fourth aspect of the present invention is to provide process for purification of compound of Formula-IV,

[Formula-IV]
comprising treating compound of Formula-IV with ketone and aliphatic hydrocarbon solvent.
Fifth aspect of the present invention is to provide a process for preparation of 2-butanol solvate of compound Formula-V,

[Formula-V]
comprising converting Elobixibat of Formula-I,

[Formula-I]
to 2-butanol solvate of compound Formula-V.
Sixth aspect of the present invention is to provide 2-butanol solvate of compound Formula-V,

[Formula-V].
Seventh aspect of the present invention is to provide process for preparation of Elobixibat of Formula-I or salt or hydrate thereof,

[Formula-I]
comprising the steps of:
a) converting compound of Formula-IV,

[Formula-IV]
to 2-butanol solvate of compound Formula-V; and

[Formula-V]
b) converting 2-butanol solvate of compound Formula-V to Elobixibat of Formula-I or salt or hydrate thereof.
Eighth aspect of the present invention is to provide a process for preparation of amorphous form of Elobixibat of Formula-I,

[Formula-I]
comprising treating Elobixibat of Formula-I or its 2-butanol solvate with ketone and aliphatic hydrocarbon solvent.
Ninth aspect of the present invention is to provide a process for purification of compound of Formula-II,

[Formula-II]
comprising the treating compound of Formula-II with ketone and water solvent.
Tenth aspect of the present invention is to provide a process for preparation of amorphous Elobixibat of Formula-I comprising treating 2-butanol solvate of Elobixibat with solvent selected from ketone selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone; n-heptane, n-hexane, methylene chloride, ethylene dichloride, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, water or mixture thereof.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 1: Illustrates the X-ray powder diffractogram (XRPD) of 2-butanol solvate of Elobixibat of Formula-V according to Example-04.
Figure 2: Illustrates the X-ray powder diffractogram (XRPD) of amorphous Form of Elobixibat of Formula-I according to Example-05.
Figure 3: Illustrates the differential scanning calorimetry (DSC) of 2-butanol solvate of Elobixibat of Formula-V according to Example-04.
Figure 4: Illustrates the thermogravimetric analysis (TGA) of 2-butanol solvate of Elobixibat of Formula-V according to Example-04.
DETAILED DESCRIPTION OF INVENTION:
In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as understood by the person skilled in the art.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may not only mean “one”, but also encompasses the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” may mean at least a second or more.
As used in this specification, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “consisting” (and any form of consisting, such as “consists”), “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.
The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be fully understood and appreciated.
According to first embodiment, present invention is to provides process for preparation of Elobixibat of Formula-I or salt or hydrate thereof,

[Formula-I]
comprising the steps of:
a) reacting compound of Formula-II,

[Formula-II]
with base in presence of acetonitrile and water solvent to obtain compound of Formula-III,

[Formula-III]
b) converting compound of Formula-III to compound of Formula-IV,

[Formula-IV]
“wherein compound of Formula-IV is isolated by treating compound of Formula-IV with ketone and aliphatic hydrocarbon solvent”
c) converting compound of Formula-IV to 2-butanol solvate of compound Formula-V; and

[Formula-V]
d) converting 2-butanol solvate of compound Formula-V to Elobixibat of Formula-I or salt or hydrate thereof.
In the first embodiment of step a), compound of Formula-II can be prepared process known in the prior art.
In the first embodiment of step a), the base can be selected from the group consisting of inorganic bases such as “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tertbutoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide; organic bases such as triethylamine, methylamine, ethylamine, 1,8-diazabicycle[5.4.0]undec7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethyl amino pyridine (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).
In the first embodiment of step a), reaction of compound of Formula-II with base can be carried out at temperature of 10°C to 40°C for 1 hours to 15 hours.
In the first embodiment of step a), reaction of compound of Formula-II with base can be carried in presence of acetonitrile and water as a solvent to obtain compound of Formula-III.
In the first embodiment of step a), acetonitrile solvent can be used in the ratio of 02 volumes to 10 volumes with respect to compound of Formula-II.
After completion of reaction, mixture can be cooled, and ethyl acetate can be added to the resulting mixture followed by addition of aqueous hydrochloric acid to adjust the pH of the mixture below 2.0. Resulting mixture can be allowed to separate organic and aqueous layers. Resulting organic layer-1 can be kept aside and ethyl aetate can be added to the aqueous layer-1 followed by Stirring for 20 minutes at 0°C to 5°C. Resulting mixture can be allowed to separate organic and aqueous layers. All the organic layers can be combined and purified water can be added and stirred for 20 minutes at 0°C to 5°C. Resulting mixture can be allowed to separate organic and aqueous layers. Resulting organic layer can be extracted with purified water at 0°C to 5°C and can be further extracted with aqueous sodium chloride at 0°C to 5°C. The obtained organic layer can be distilled under vacuum at 35°C to 40°C. Resulting mass can be treated with isopropanol and water to obtain compound of Formula-III.
Resulting compound of Formula-III may have purity greater than 98 % by HPLC (High-performance liquid chromatography).
In the first embodiment of step b), compound of Formula-III can be converted to compound of Formula-IV by reacting compound of Formula-III with glycine tert-butyl ester hydrochloride in presence of coupling agent, base and solvent.
The coupling agent can be selected from the group consisting of N,N'-carbonyl diimidazole, O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyl-uronium hexafluorophosphate (HBTU).
The base can be selected from the group consisting of triethylamine, methylamine, ethylamine, 1,8-diazabicycle[5.4.0]undec7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine (DIPA), N,N-diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethyl amino pyridine (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).
The solvent can be selected from the group consisting of dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform or mixture(s) thereof.
In the first embodiment of step b), compound of Formula-III can be converted to compound of Formula-IV by reacting compound of Formula-III with glycine tert-butyl ester hydrochloride of in presence of coupling agent, base and solvent at temperatures of -5°C to 35°C for 1 hour to 5 hours.
In the first embodiment of step b), compound of Formula-IV can be isolated by treating compound of Formula-IV with ketone and aliphatic hydrocarbon solvent.
The ketone solvent can be selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone or mixture(s) thereof.
The aliphatic hydrocarbon solvent can be selected from the group consisting of cyclohexane, n-heptane, n-hexane, n-pentane or mixture(s) thereof.
The treatment of compound of Formula-IV can be carried out by slurry wash using ketone and aliphatic hydrocarbon or by solvent- anti solvent method using ketone and aliphatic hydrocarbon. Particularly, ketone can be added to compound of Formula-IV, Resulting mixture can be stirred at 20°C to 40°C. Aliphatic hydrocarbon solvent can be added to resulting mixture at 25°C to 35°C and resulting mixture can be stirred for 1 hour to 5 hours at same temperature. Resulting solid can be filtered, washed with aliphatic hydrocarbon solvent to obtain compound of Formula-IV.
Resulting compound of Formula-IV may have purity greater than 99 % by HPLC (High-performance liquid chromatography).
In the first embodiment of step c), compound of Formula-IV can be converted to 2-butanol solvate of compound Formula-V by reacting compound of Formula-IV with acid in presence of solvent to obtain in-situ Elobixibat of Formula-I, which can be further converted to 2-butanol solvate of compound Formula-V using 2-butanol.
The acid can be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, methane sulfonic acid, p-toluenesulfonic acid, acetic acid, and trifluoroacetic acid.
The solvent can be selected from the group consisting of toluene, xylene, cyclohexane, n-hexane, n-heptane, n-pentane, water or mixture(s) thereof.
2-butanol solvent can used in the ratio of 01 volume to 15 volume with respect to compound of Formula-IV.
Generally, 2-butanol solvate of compound Formula-V can be prepared by adding 2-butanol to in-situ formed Elobixibat of Formula-I. Resulting mixture can be heated at 40°C to 45°C and can be stirred for 1 hours at same temperature. Resulting mixture can be cooled at 25°C to 35°C and stirred for 2 hours to 4 hours at 25°C to 35°C. Resulting mixture can be filtered, washed with 2-butanol and dried under vacuum at 40°C to 45°C to obtain 2-butanol solvate of compound Formula-V.
Resulting 2-butanol solvate of compound Formula-V may have purity greater than 99.9 % by HPLC (High-performance liquid chromatography).
In the first embodiment of step d), 2-butanol solvate of compound Formula-V can be converted to Elobixibat of Formula-I or salt or hydrate thereof.
In the first embodiment of step d), obtained Elobixibat of Formula-I or salt or hydrate thereof may purity greater than 99.50 % by HPLC (High-performance liquid chromatography).
According to second embodiment, present invention is to provides process for preparation of compound of Formula-III,

[Formula-III]
comprising reacting compound of Formula-II,

[Formula-II]
with base in presence of acetonitrile and water to obtain compound of Formula-III.
In the second embodiment, the compound of Formula-II can be prepared process known in the prior art.
In the second embodiment, the base can be selected from the group consisting of inorganic bases such as “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tertbutoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide; organic bases such as triethylamine, methylamine, ethylamine, 1,8-diazabicycle[5.4.0]undec7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethyl amino pyridine (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).
In the second embodiment, the reaction of compound of Formula-II with base can be carried out at temperature of 10°C to 40°C for1 hour to 15 hours.
In the second embodiment, acetonitrile solvent can be used in the ratio of 02 volumes to 10 volumes with respect to compound of Formula-II.
In the second embodiment, the reaction of compound of Formula-II with base can be carried in presence of acetonitrile and water as a solvent to obtain compound of Formula-III.
After completion of reaction, mixture can be cooled, and ethyl acetate can be added to the resulting mixture followed by addition of aqueous hydrochloric acid to adjust the pH of the mixture below 2.0. Resulting mixture can be allowed to separate organic and aqueous layers. Resulting organic layer-1 can be kept aside and ethyl aetate can be added to the aqueous layer-1 followed by Stirring for 20 minutes at 0°C to 5°C. Resulting mixture can be allowed to separate organic and aqueous layers. All the organic layers can be combined and purified water can be added and stirred for 20 minutes at 0°C to 5°C. Resulting mixture can be allowed to separate organic and aqueous layers. Resulting organic layer can be extracted with purified water at 0°C to 5°C and can be further extracted with aqueous sodium chloride at 0°C to 5°C. The obtained organic layer can be distilled under vacuum at 35°C to 40°C. Resulting mass can be treated with isopropanol and water to obtain compound of Formula-III.
Resulting compound of Formula-III may have purity greater than 98 % by HPLC (High-performance liquid chromatography).
According to third embodiment, present invention provides process for purification of compound of Formula-III,

[Formula-III]
comprising treating compound of Formula-III with alcohol and water solvent.
In the third embodiment, the alcohol solvent can be selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, butanol or mixture(s) thereof.
In the third embodiment, the alcohol solvent can be used in the proportion of 01 volumes to 10 volumes with respect to the compound of Formula-III.
In the third embodiment, treatment of compound of Formula-III using alcohol and water can be carried out by slurry wash or solvent-anti solvent method. Particularly, compound of Formula-III can be stirred in presence of alcohol. Resulting mixture can be distilled below 45°C to obtained distilled mass, which can be further cooled at 25°C to 35°C. Purified water can be added to resulting mass and obtained mixture can be stirred for 3 hours to 7 hours at 25°C to 35°C. Resulting mixture can be filtered, washed with purified water and dried under vacuum at 50°C to 55°C to obtain a compound Formula-III.
In the third embodiment, the obtained compound of Formula-III may have purity greater than 98 % by HPLC (High-performance liquid chromatography).
According to fourth embodiment, present invention provides process for purification of compound of Formula-IV,

[Formula-IV]
comprising treating compound of Formula-IV with ketone and aliphatic hydrocarbon solvent.
In the fourth embodiment, ketone solvent can be selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone or mixture(s) thereof.
In the fourth embodiment, ketone solvent can be used 01 volumes to 10 volumes with respect to compound of Formula-IV.
In the fourth embodiment, aliphatic hydrocarbon solvent can be selected from the group consisting of cyclohexane, n-heptane, n-hexane, n-pentane or mixture(s) thereof.
In the fourth embodiment, aliphatic hydrocarbon solvent can be used 01 volumes to 20 volumes with respect to compound of Formula-IV.
The treatment of compound of Formula-IV can be carried out by slurry wash using ketone and aliphatic hydrocarbon or by solvent- anti solvent method using ketone and aliphatic hydrocarbon. Particularly, ketone can be added to compound of Formula-IV, resulting mixture can be stirred at 20°C to 40°C. Aliphatic hydrocarbon solvent can be added to resulting mixture at 25°C to 35°C and resulting mixture can be stirred for 1 hour to 5 hours at same temperature. Resulting solid can be filtered, washed with aliphatic hydrocarbon solvent to obtain compound of Formula-IV.
In the fourth embodiment, the obtained compound of Formula-IV may have purity greater than 99 % by HPLC (High-performance liquid chromatography).
According to fifth embodiment, present invention provides process for preparation of 2-butanol solvate of compound Formula-V,

[Formula-V]
comprising converting Elobixibat of Formula-I,

[Formula-I]
to 2-butanol solvate of compound Formula-V.
In the fifth embodiment, Elobixibat of Formula-I can be converted to 2-butanol solvate of compound Formula-V by interacting Elobixibat of Formula-I with 2-butanol to obtain 2-butanol solvate of compound Formula-V.
Generally, 2-butanol solvate of compound Formula-V can be prepared by stirring mixture of 2-butanol and Elobixibat of Formula-I at 20°C to 45°C for 1 hour to 6 hours. Resulting mixture can be filtered, washed with 2-butanol and dried under vacuum at 40°C to 45°C to obtain 2-butanol solvate of compound Formula-V.
In the fifth embodiment, 2-butanol can used in the ratio of 01 volume to 15 volume with respect to the Elobixibat of Formula-I.
In the fifth embodiment, the Elobixibat of Formula-I can be hydrated form or any other crystalline form or amorphous form of Elobixibat of Formula-I.
In the fifth embodiment, the obtained 2-butanol solvate of compound Formula-V may have purity greater than 99.9 % by HPLC (High-performance liquid chromatography).
According to sixth embodiment, present invention provides 2-butanol solvate of compound Formula-V,

[Formula-V]
In the sixth embodiment, 2-butanol solvate of compound of Formula-V can be characterized by X-ray powder diffraction (XRPD) having peaks at 6.0, 18.7 and 22.0 ± 0.2° 2?.
In the sixth embodiment, 2-butanol solvate of compound of Formula-V can be further characterized by X-ray powder diffraction (XRPD) having peaks at 9.9, 12.8, 18.1, 18.9, 20.3, 21.5 and 23.5 ± 0.2° 2?.
In the sixth embodiment, 2-butanol solvate of compound of Formula-V can be further characterized by differential scanning calorimetry (DSC) having endotherms at about 113.38°C.
In the sixth embodiment, 2-butanol solvate of compound of Formula-V can be further characterized by thermogravimetric analysis (TGA) as given in Figure 04.
According to seventh embodiment, present invention provides process for preparation of Elobixibat of Formula-I or salt or hydrate thereof,

[Formula-I]
comprising the steps of:
a) converting compound of Formula-IV,

[Formula-IV]
to 2-butanol solvate of compound Formula-V; and

[Formula-V]
b) converting 2-butanol solvate of compound Formula-V to Elobixibat of Formula-I or salt or hydrate thereof.
In the seventh embodiment of step a), compound of Formula-IV can be converted to 2-butanol solvate of compound Formula-V by interacting compound of Formula-IV with acid in presence of solvent to obtain in-situ Elobixibat of Formula-I, which can be further converted to 2-butanol solvate of compound Formula-V.
The acid can be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, methane sulfonic acid, p-toluenesulfonic acid, acetic acid, and trifluoroacetic acid.
The solvent can be selected from the group consisting of toluene, xylene, cyclohexane, n-hexane, n-heptane, n-pentane, water or mixture(s) thereof.
In the seventh embodiment of step a), compound of Formula-IV can be converted to 2-butanol solvate of compound Formula-V by reacting compound of Formula-IV with acid in presence of solvent at 20°C to 40°C to obtain in-situ Elobixibat of Formula-I.
The in-situ formed Elobixibat of Formula-I can be interacted with 2-butanol to obtain 2-butanol solvate of compound Formula-V.
Generally, 2-butanol solvate of compound Formula-V can be prepared by stirring mixture of 2-butanol and Elobixibat of Formula-I at 20°C to 45°C for 1 hour to 6 hours. Resulting mixture can be filtered, washed with 2-butanol and dried under vacuum at 40°C to 45°C to obtain 2-butanol solvate of compound Formula-V.
2-butanol can be used in the proportion of 01 volume to 15 volume with respect to the in-situ Elobixibat of Formula-I.
In the seventh embodiment of step b), 2-butanol solvate of compound Formula-V can be converted to Elobixibat of Formula-I or salt or hydrate thereof.
In the seventh embodiment of step b), Elobixibat of Formula-I or salt or hydrate thereof may purity greater than 99.50 % by HPLC (High-performance liquid chromatography).
According eighth embodiment, present invention provides process for preparation of amorphous form of Elobixibat of Formula-I,

[Formula-I]
comprising treating Elobixibat of Formula-I or its 2-butanol solvate with ketone and aliphatic hydrocarbon solvent.
In the eighth embodiment, ketone solvent can be selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone or mixture(s) thereof.
In the eighth embodiment, ketone solvent can be used in the proportion of 01 volumes to 15 volumes with respect to compound of Formula-IV.
In the eighth embodiment, aliphatic hydrocarbon solvent can be selected from the group consisting of cyclohexane, n-heptane, n-hexane, n-pentane or mixture(s) thereof.
In the eighth embodiment, aliphatic hydrocarbon solvent can be used in the ratio of 01 volume to 10 volumes with respect to compound of Formula-IV.
In the eighth embodiment, the starting material Elobixibat of Formula-I used for the preparation of amorphous form of Elobixibat can be crystalline form or solvated form.
In the eighth embodiment, the treatment of Elobixibat of Formula-I can be carried out by slurry wash using ketone and aliphatic hydrocarbon or by solvent- anti solvent method using ketone and aliphatic hydrocarbon. Alternatively, ketone can be added to Elobixibat of Formula-I, Resulting mixture can be stirred at 30°C to 50°C and can be distilled under vacuum to remove ketone solvent. Resulting mass can be stirred for 15 minutes to 20 minutes at 40°C to 45°C. Aliphatic hydrocarbon solvent can be added to resulting mixture at 25°C to 35°C and resulting mixture can be stirred for 3 hours to 5 hours at same temperature. Resulting solid can be filtered, washed with aliphatic hydrocarbon solvent to obtain Amorphous Elobixibat of Formula-I.
Resulting amorphous Elobixibat of Formula-I may have purity greater than 99 % by HPLC (High-performance liquid chromatography).
Resulting amorphous form of Elobixibat of Formula-I can be characterized by XRPD as given in Figure 02.
According to ninth embodiment, present invention provides process for purification of compound of Formula-II,

[Formula-II]
comprising the treating compound of Formula-II with ketone and water solvent.
In the ninth embodiment, the crude compound of Formula-II can be prepared process known the prior-arts.
In the ninth embodiment, the ketone solvent can be selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone or mixture(s) thereof.
In the ninth embodiment, ketone solvent can be used in the proportion of 1 volume to 10 volumes with respect to the compound of Formula-II.
In the ninth embodiment, the treatment of compound of Formula-II can be carried out by slurry wash using ketone and water or by solvent- anti solvent method using ketone and water. Particularly, ketone can be added to compound of Formula-II, resulting mixture can be stirred at 30°C to 50°C. Water can be added to resulting mixture at 25°C to 35°C and resulting mixture can be stirred for 3 hours to 10 hours at same temperature. Resulting solid can be filtered, washed with water and dried under vacuum to obtain compound of Formula-II.
In the ninth embodiment, the obtained compound of Formula-II may have purity greater than 98 % by HPLC (High-performance liquid chromatography).
According to tenth embodiment, present invention provides a process for preparation of amorphous Elobixibat of Formula-I comprising treating 2-butanol solvate of Elobixibat with solvent selected from ketone selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone; n-heptane, n-hexane, methylene chloride, ethylene dichloride, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, water or mixture thereof.
EXAMPLES:
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.
Example-01: Preparation of compound of Formula-II

[Formula-II]
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. Resulting mixture was cooled at 0°C to 10°C and N,N-diisopropylethylamine (102.2 g), o-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (69.82 g) was added under nitrogen at 0°C to 10°C. Resulting reaction mixture was heated at 25°C to 35°C for 3 hours. After completion of reaction, resulting mixture was cooled at 20°C to 30° and washed with purified water (3 x 500 mL). Resulting organic layer was distilled under vacuum below 45°C followed by stripping using acetone. Acetone (200 mL) was added to resulting mass below 45°C and resulting mixture was cooled at 25°C to 35°C followed by addition of purified water (600 mL). Resulting mixture was stirred for 8 hours. Resulting mixture was filtered, washed with purified water, dried under vacuum at 45°C to 50°C to obtain title compound (120.5 g).
HPLC Purity: 99.28 %
Example-02: Preparation of compound of Formula-III

[Formula-III]
To a stirred solution of purified water (400 mL) and sodium hydroxide (3.06 g), acetonitrile (200 mL) and compound of Formula-II (25 g) was added at 10°C to 15°C. Resulting mixture was stirred for 08 hours at 10°C to 15°C. After completion of reaction, resulting mixture was cooled at 0°C to 5°C and ethyl acetate (375 mL) was added and stirred for 15 minutes at 0°C to 5°C. To the resulting mixture, 3% aqueous hydrochloric acid solution (103 mL) was added to adjust the pH of the mixture below 2.0. Resulting mixture was stirred for 30 minutes at 0°C to 5°C and mixture was allowed to separate organic and aqueous layers. Resulting organic layer was washed with water (2 x 100 mL), 20% aqueous sodium chloride wash (2 x 100 mL). Resulting organic layer was distilled under vacuum below 45°C obtain a mass. Isopropyl alcohol (125 mL) was added to resulting mass below 40°C and further cooled to 25°C to 30°C followed by addition of purified water (260 mL). Resulting mixture was stirred for 6 hours at 25°C to 35°C. Resulting mixture was filtered, washed with purified water (2 x 25 mL) and dried under vacuum at 50°C to 55°C to obtain title compound (23.5 g).
HPLC Purity: 98.19 %
Example-03: Preparation of compound of Formula-IV

[Formula-IV]
To a stirred solution of dichloromethane (400 mL) and 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) was added 0°C to 5°C. Resulting mixture was maintained for 1 hour at -5°C to 5°C. After completion of reaction, Aqueous hydrochloric acid solution was slowly added at 0°C to 5°C to adjust pH below 2.0. Resulting mixture was stirred for 30 minutes at 0°C to 5°C. Further, temperature of the mixture was raised to 25°C to 35°C and mixture was stirred for 20 minutes at same temperature. Resulting mixture was allowed to separate organic and aqueous layers. Resulting aqueous layer-1 was kept aside and 3% aqueous hydrochloride acid solution was added to the resulting organic layer-1 to adjust pH below 2.0. Resulting mixture was stirred for 20 minutes at 25°C to 35°C and mixture was allowed to separate organic and aqueous layers. Resulting aqueous layer-2 was kept aside and purified water (100 mL) was added to the resulting organic layer-2 and mixture was stirred for 20 minutes to 30 minutes at 25°C to 35°C and mixture was allowed to separate organic and aqueous layers. Resulting aqueous layer-3 was kept aside and 7% aqueous sodium bicarbonate solution (100 mL) was added to the resulting organic layer-3 and mixture was stirred for 30 minutes at 25°C to 35°C and mixture was allowed to separate organic and aqueous layers. Resulting aqueous layer-4 was kept aside and purified water (100 mL) was added to the resulting organic layer-4 and mixture was stirred for 20 minutes at 25°C to 35°C and mixture was allowed to separate organic and aqueous layers. Resulting organic layer-5 was distilled under vacuum below 45°C to obtain oil, which was further stripped using acetone (20 mL). Acetone (20 mL) was added to resulting mass, and stirred for 15 minutes at 25°C to 35°C and n-heptane (200 mL) was added slowly to the mixture at 25°C to 35°C. Resulting mixture was filtered, washed with n-heptane (2 x 20 mL) to obtain a solid. Acetonitrile (80 mL) was added to resulting solid and heated mixture at 40°C to 45°C for 2 hours. Resulting mixture was cooled slowly at 25°C to 35°C and stirred for 5 hours. Resulting mixture was filtered, washed with acetonitrile (20 mL) and dried under vacuum at 55°C to 60°C to obtain title compound (14.0 g). HPLC Purity: 99.26%
Example-04: Preparation of 2-Butanol solvate of Elobixibat of Formula-V

[Formula-V]
To a stirred solution of toluene (154 mL) and compound of Formula-IV (22 g), trifluoracetic acid (116.6 g) in toluene (66 mL) solution was added at 0°C to 5°C. Resulting mixture was stirred for 3 hours at 25°C to 35°C. After completion reaction, resulting mixture was cooled at 0°C to 5°C and purified water (110 mL) was added and mixture was allowed to separate organic and aqueous layers. Resulting organic layer was washed with purified water (2 x 110 mL). Resulting organic was distilled below 45°C and 2-butanol (100 mL) was added at 25°C to 35°C and mixture was heated at 40°C to 45°C and stirred for 1 hours at same temperature. Resulting mixture was cooled at 25°C to 35°C and stirred for 2 hours to 4 hours at 25°C to 35°C. Further, resulting mixture was filtered, washed with 2-butanol (20 mL) and dried under vacuum at 40°C to 45°C to obtain title compound (17 g).HPLC Purity: 99.37 %/ Chiral Purity: 99.9 %
Example-05: Preparation of amorphous form of Elobixibat of Formula-I

Formula-I
2-butanol solvate of Elobixibat of Formula-V (52 gm) was dissolved in acetone (520 mL) at 40°C to 45°C. Resulting solution was distilled under vacuum at 40°C to 45°C and mixture was stirred for 15 minutes to 20 minutes at 40°C to 45°C, n-heptane (350 mL) was added to resulting mixture below 45°C and mixture was stirred for 5 hours at 25°C to 35°C. Resulting solid was filtered, washed with n-heptane (100 mL), and dried under vacuum at 45°C to 50°C to obtain title compound (50.5 g) HPLC Purity: 99.50 %/ Chiral Purity: 99.91 %
Example-06: Preparation of amorphous form of Elobixibat of Formula-I
Stir a mixture of 2-butanol solvate of Elobixibat of Formula-V (0.5 gm), acetone (0.5 mL) and water (10 mL) at 25°C to 35°C for 3 hours. The resulting solid was filtered, washed with water and dried at 65°C to 70°C for 12 hours to obtain title compound (0.41 g).
Example-07: Preparation of amorphous form of Elobixibat of Formula-I
Stir a mixture of 2-butanol solvate of Elobixibat of Formula-V (0.5 gm), dimethylformamide (0.5 mL) and water (10 mL) at 25°C to 35°C for 3 hours. The resulting solid was filtered, washed with water and dried at 65°C to 70°C for 12 hours to obtain title compound (0.40 g).
Example-08: Preparation of amorphous form of Elobixibat of Formula-I
Stir a mixture of 2-butanol solvate of Elobixibat (0.5 gm), methylene chloride (0.5 mL) and n-heptane (10 mL) at 25°C to 35°C for 3 hours. The resulting solid was filtered, washed with n-heptane and dried at 65°C to 70°C for 12 hours to obtain title compound (0.35 g).
Example-09: Preparation of amorphous form of Elobixibat of Formula-I
Stir a mixture of 2-butanol solvate of Elobixibat of Formula-V (0.5 gm), dimethyl sulfoxide (0.5 mL) and water (10 mL) at 25°C to 35°C for 3 hours. The resulting solid was filtered, washed with water and dried at 65°C to 70°C for 12 hours to obtain title compound (0.42 g).
Example-10: Preparation of amorphous form of Elobixibat of Formula-I
Stir a mixture of 2-butanol solvate of Elobixibat of Formula-V (0.5 gm), dimethyl acetamide (0.5 mL) and water (10 mL) at 25°C to 35°C for 3 hours. The resulting solid was filtered, washed with water and dried at 65°C to 70°C for 12 hours to obtain title compound (0.4 g).

I /We claim:
1. A process for preparation of Elobixibat of Formula-I or salt or hydrate thereof,

[Formula-I]
comprising the steps of:
a) reacting compound of Formula-II,

[Formula-II]
with base in presence of acetonitrile and water solvent to obtain compound of Formula-III;

[Formula-III]
b) converting compound of Formula-III to compound of Formula-IV;

[Formula-IV]
“wherein compound of Formula-IV is isolated by treating compound of Formula-IV with ketone and aliphatic hydrocarbon solvent”;
c) converting compound of Formula-IV to 2-butanol solvate of compound Formula-V; and

[Formula-V]
d) converting 2-butanol solvate of compound Formula-V to Elobixibat of Formula-I or salt or hydrate thereof.
2. The process as claimed in claim 1, wherein reaction of compound of Formula-II with base in presence of acetonitrile and water solvent is carried out at 10°C to 40°C, wherein base is selected from 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 tertbutoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine, methylamine, ethylamine, 1,8-diazabicycle[5.4.0]undec7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethyl amino pyridine (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. The process as claimed in claim 1, wherein ketone solvent is acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone or mixture(s) thereof and aliphatic hydrocarbon solvent is cyclohexane, n-heptane, n-hexane, n-pentane or mixture(s) thereof.
4. 2-butanol solvate of compound Formula-V,

[Formula-V].
5. 2-butanol solvate of compound Formula-V as claimed in claim 4, wherein 2-butanol solvate of compound of Formula-V is characterized by X-ray powder diffraction (XRPD) having peaks at 6.0, 18.7 and 22.0 ± 0.2° 2?.
6. 2-butanol solvate of compound Formula-V as claimed in claim 4, wherein 2-butanol solvate of compound of Formula-V is further characterized by differential scanning calorimetry (DSC) having endotherms at about 113.38°C.
7. A process for preparation of amorphous form of Elobixibat of Formula-I,

[Formula-I]
comprising treating Elobixibat of Formula-I or its solvate with ketone and aliphatic hydrocarbon solvent, wherein ketone solvent is selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone or mixture(s) thereof; and aliphatic hydrocarbon solvent is selected from cyclohexane, n-heptane, n-hexane, n-pentane or mixture(s) thereof.
8. A process for purification of compound of Formula-II,

[Formula-II]
comprising the treating compound of Formula-II with ketone and water solvent.
9. The process as claimed in claim 8, wherein ketone solvent is selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone or mixture(s) thereof.
10. A process for preparation of amorphous Elobixibat of Formula-I comprising treating 2-butanol solvate of Elobixibat with solvent selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone; n-heptane, n-hexane, methylene chloride, ethylene dichloride, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide or mixture(s) thereof.

Dated this 25th day of March 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

ABSTRACT
“PROCESS FOR THE PREPARATION OF ELOBIXIBAT OR SOLVATE THEREOF”
The present invention relates to an efficient and industrially advantageous process for the preparation of Elobixibat of Formula-I or solvate thereof.

Formula-I
The present invention also relates to provides 2-butanol solvate of Elobixibat of Formula-V.

[Formula-V]
The present invention also relates to provides process for preparation of Elobixibat intermediates of Formula-III, IV, and their use for the preparation of Elobixibat of Formula-I or solvate thereof.

[Formula-III]
[Formula-IV]
Dated this 25th day of March 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.
Ami Lifesciences Pvt. Ltd. Sheet 01 of 04

Figure 01

Dated this 25th day of March 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd

Ami Lifesciences Pvt. Ltd. Sheet 02 of 04

Figure 02

Dated this 25th day of March 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd

Ami Lifesciences Pvt. Ltd. Sheet 03 of 04

Figure 03

Dated this 25th day of March 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd

Ami Lifesciences Pvt. Ltd. Sheet 04 of 04

Figure 04

Dated this 25th day of March 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd

,CLAIMS:I /We claim:
1. A process for preparation of Elobixibat of Formula-I or salt or hydrate thereof,

[Formula-I]
comprising the steps of:
a) reacting compound of Formula-II,

[Formula-II]
with base in presence of acetonitrile and water solvent to obtain compound of Formula-III;

[Formula-III]
b) converting compound of Formula-III to compound of Formula-IV;

[Formula-IV]
“wherein compound of Formula-IV is isolated by treating compound of Formula-IV with ketone and aliphatic hydrocarbon solvent”;
c) converting compound of Formula-IV to 2-butanol solvate of compound Formula-V; and

[Formula-V]
d) converting 2-butanol solvate of compound Formula-V to Elobixibat of Formula-I or salt or hydrate thereof.
2. The process as claimed in claim 1, wherein reaction of compound of Formula-II with base in presence of acetonitrile and water solvent is carried out at 10°C to 40°C, wherein base is selected from 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 tertbutoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, triethylamine, methylamine, ethylamine, 1,8-diazabicycle[5.4.0]undec7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethyl amino pyridine (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. The process as claimed in claim 1, wherein ketone solvent is acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone or mixture(s) thereof and aliphatic hydrocarbon solvent is cyclohexane, n-heptane, n-hexane, n-pentane or mixture(s) thereof.
4. 2-butanol solvate of compound Formula-V,

[Formula-V].
5. 2-butanol solvate of compound Formula-V as claimed in claim 4, wherein 2-butanol solvate of compound of Formula-V is characterized by X-ray powder diffraction (XRPD) having peaks at 6.0, 18.7 and 22.0 ± 0.2° 2?.
6. 2-butanol solvate of compound Formula-V as claimed in claim 4, wherein 2-butanol solvate of compound of Formula-V is further characterized by differential scanning calorimetry (DSC) having endotherms at about 113.38°C.
7. A process for preparation of amorphous form of Elobixibat of Formula-I,

[Formula-I]
comprising treating Elobixibat of Formula-I or its solvate with ketone and aliphatic hydrocarbon solvent, wherein ketone solvent is selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone or mixture(s) thereof; and aliphatic hydrocarbon solvent is selected from cyclohexane, n-heptane, n-hexane, n-pentane or mixture(s) thereof.
8. A process for purification of compound of Formula-II,

[Formula-II]
comprising the treating compound of Formula-II with ketone and water solvent.
9. The process as claimed in claim 8, wherein ketone solvent is selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone or mixture(s) thereof.
10. A process for preparation of amorphous Elobixibat of Formula-I comprising treating 2-butanol solvate of Elobixibat with solvent selected from acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl isopropyl ketone; n-heptane, n-hexane, methylene chloride, ethylene dichloride, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide or mixture(s) thereof.

Dated this 25th day of March 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.