Type-1 obeticholic acid preparation method

Abstract

The invention discloses a type-1 obeticholic acid preparation method. The type-1 obeticholic acid preparation method comprises the following steps that firstly, the mixture of 3 alpha-hydroxyl-6 alpha-ethyl-7-ketone-5 beta-cholane-24-acid ester, alkali and a solvent is heated to reach the temperature of 75-105 DEG C, a reducing agent is added for reaction, TLC tracking is performed till raw materials react completely, the reaction solution is cooled to reach the temperature of 30-50 DEG C, an organic solvent and water are added, a pH value of the solution is regulated to be 3-5 by using hydrochloric acid, solution separation is performed, and organic phase reduced-pressure drying by distillation is performed to obtain a colorless light yellow oily residue; secondly, water and alkali are added into the obtained residue, heating is performed for dissolution, and a solution is obtained; finally, a dilute hydrochloric acid is slowly and dropwise added into the obtained solution to regulate the pH value to be 3-4, and cooling, stirring for crystallization, filtering and vacuum drying are performed to obtain a type-1 obeticholic acid.

Description

technical field

[0001] The invention relates to the field of chemistry and medicine, in particular to a preparation method of obeticholic acid type 1. Background technique

[0002] Obeticholic acid (compound Ⅰ) is a farnesoid X receptor (FXR) agonist developed by Intercept Pharmaceuticals of the United States for the treatment of primary biliary cirrhosis and nonalcoholic fatty liver disease. liver disease. The structural formula is as follows:

[0003]

[0004] Molecular formula: C 26 h 44 o 4 Molecular weight: 420.63

[0005] Polymorphism exists widely in pharmaceuticals. Different crystal forms of the same drug have significant differences in solubility, melting point, density, and stability, which affect the stability, uniformity, bioavailability, efficacy, and safety of the drug to varying degrees. Therefore, comprehensive and systematic polymorph screening in drug development and selection of the most suitable crystal form for development is one of the import...

Examples

Embodiment 1

[0051] Add 3α-hydroxyl-6α-ethyl-7-keto-5β-cholan-24-acid (50g, 0.12mol), sodium hydroxide (24g, 0.60mol) and water (400mL) in the reaction flask, stir The temperature was raised to 95° C., sodium borohydride (9.1 g, 0.24 mol) was added, and the mixture was reacted for 5 hours. TLC traced that the reaction of the raw materials was complete. After the reaction, cool to 40°C, add ethyl acetate (400mL) and water (200mL), adjust the pH to 3 with 37% hydrochloric acid, separate the layers, dry the organic phase over anhydrous sodium sulfate for 2 hours, filter, and reduce the filtrate at 40°C Evaporated to dryness under pressure to obtain a colorless oily residue. Add water (750mL) and NaOH (9.6g, 0.24mol) to the residue and heat up to 40°C, stir until dissolved, slowly add 0.4mol / L dilute hydrochloric acid solution dropwise to adjust the pH to 3.0, continue to keep stirring for 30min, and cool to 10°C Stir and crystallize for 2 hours, filter, and vacuum-dry the filter cake at 50° ...

Embodiment 2

[0057]Add 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid (50g, 0.12mol), sodium methoxide (38.9g, 0.72mol), methanol (100mL) and water ( 300 mL), heated to 80°C with stirring, added sodium borohydride (9.1 g, 0.24 mol), and reacted for 7 hours. TLC traced that the reaction of the raw materials was complete. After the reaction, cool to 40°C, add dichloromethane (400mL) and water (200mL), adjust the pH to 4 with 85% phosphoric acid, separate the layers, dry the organic phase over anhydrous sodium sulfate for 2 hours, filter, and reduce the filtrate at 40°C Evaporated to dryness under pressure to obtain a pale yellow oily residue. Add water (750mL) and sodium methoxide (19.4g, 0.36mol) to the residue and heat up to 30°C, stir until dissolved, slowly add 0.2mol / L dilute hydrochloric acid solution dropwise to adjust the pH to 4.0, continue to keep stirring for 30min, and cool to 15 Stir and crystallize at ℃ for 3 hours, filter, and vacuum-dry the filter cake at 40℃ for 5 hours t...

Embodiment 3

[0059] Add 3α-hydroxyl-6α-ethyl-7-ketone-5β-cholane-24-acid ethyl ester (54g, 0.12mol), NaOH (24g, 0.60mol), ethanol (230mL), water ( 200 mL), heated to 90°C with stirring, added potassium borohydride (12.9 g, 0.24 mol), and reacted for 6 hours, TLC traced the complete reaction of raw materials. After the reaction, cool to 40°C, add toluene (400mL) and water (200mL), adjust pH to 4 with 37% hydrochloric acid, separate liquids, dry the organic phase over anhydrous sodium sulfate for 2 hours, filter, and evaporate the filtrate at 60°C under reduced pressure Dry to a colorless oily residue. Add water (750mL) and NaOH (9.6g, 0.24mol) to the residue and heat up to 40°C, stir until dissolved, slowly add 0.2mol / L dilute hydrochloric acid solution dropwise to adjust the pH to 3.0, continue to keep stirring for 30min, and cool to 10°C Stir and crystallize for 2 hours, filter, and vacuum-dry the filter cake at 50° C. for 3 hours to obtain a white solid, obeticholic acid type 1 (41.9 g,...

technical field

[0001] The invention relates to the field of chemistry and medicine, in particular to a preparation method of obeticholic acid type 1. Background technique

[0002] Obeticholic acid (compound Ⅰ) is a farnesoid X receptor (FXR) agonist developed by Intercept Pharmaceuticals of the United States for the treatment of primary biliary cirrhosis and nonalcoholic fatty liver disease. liver disease. The structural formula is as follows:

[0003]

[0004] Molecular formula: C 26 h 44 o 4 Molecular weight: 420.63

[0005] Polymorphism exists widely in pharmaceuticals. Different crystal forms of the same drug have significant differences in solubility, melting point, density, and stability, which affect the stability, uniformity, bioavailability, efficacy, and safety of the drug to varying degrees. Therefore, comprehensive and systematic polymorph screening in drug development and selection of the most suitable crystal form for development is one of the import...

Examples

Embodiment 1

[0051] Add 3α-hydroxyl-6α-ethyl-7-keto-5β-cholan-24-acid (50g, 0.12mol), sodium hydroxide (24g, 0.60mol) and water (400mL) in the reaction flask, stir The temperature was raised to 95° C., sodium borohydride (9.1 g, 0.24 mol) was added, and the mixture was reacted for 5 hours. TLC traced that the reaction of the raw materials was complete. After the reaction, cool to 40°C, add ethyl acetate (400mL) and water (200mL), adjust the pH to 3 with 37% hydrochloric acid, separate the layers, dry the organic phase over anhydrous sodium sulfate for 2 hours, filter, and reduce the filtrate at 40°C Evaporated to dryness under pressure to obtain a colorless oily residue. Add water (750mL) and NaOH (9.6g, 0.24mol) to the residue and heat up to 40°C, stir until dissolved, slowly add 0.4mol / L dilute hydrochloric acid solution dropwise to adjust the pH to 3.0, continue to keep stirring for 30min, and cool to 10°C Stir and crystallize for 2 hours, filter, and vacuum-dry the filter cake at 50° ...

Embodiment 2

[0057]Add 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid (50g, 0.12mol), sodium methoxide (38.9g, 0.72mol), methanol (100mL) and water ( 300 mL), heated to 80°C with stirring, added sodium borohydride (9.1 g, 0.24 mol), and reacted for 7 hours. TLC traced that the reaction of the raw materials was complete. After the reaction, cool to 40°C, add dichloromethane (400mL) and water (200mL), adjust the pH to 4 with 85% phosphoric acid, separate the layers, dry the organic phase over anhydrous sodium sulfate for 2 hours, filter, and reduce the filtrate at 40°C Evaporated to dryness under pressure to obtain a pale yellow oily residue. Add water (750mL) and sodium methoxide (19.4g, 0.36mol) to the residue and heat up to 30°C, stir until dissolved, slowly add 0.2mol / L dilute hydrochloric acid solution dropwise to adjust the pH to 4.0, continue to keep stirring for 30min, and cool to 15 Stir and crystallize at ℃ for 3 hours, filter, and vacuum-dry the filter cake at 40℃ for 5 hours t...

Embodiment 3

[0059] Add 3α-hydroxyl-6α-ethyl-7-ketone-5β-cholane-24-acid ethyl ester (54g, 0.12mol), NaOH (24g, 0.60mol), ethanol (230mL), water ( 200 mL), heated to 90°C with stirring, added potassium borohydride (12.9 g, 0.24 mol), and reacted for 6 hours, TLC traced the complete reaction of raw materials. After the reaction, cool to 40°C, add toluene (400mL) and water (200mL), adjust pH to 4 with 37% hydrochloric acid, separate liquids, dry the organic phase over anhydrous sodium sulfate for 2 hours, filter, and evaporate the filtrate at 60°C under reduced pressure Dry to a colorless oily residue. Add water (750mL) and NaOH (9.6g, 0.24mol) to the residue and heat up to 40°C, stir until dissolved, slowly add 0.2mol / L dilute hydrochloric acid solution dropwise to adjust the pH to 3.0, continue to keep stirring for 30min, and cool to 10°C Stir and crystallize for 2 hours, filter, and vacuum-dry the filter cake at 50° C. for 3 hours to obtain a white solid, obeticholic acid type 1 (41.9 g,...

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