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Method for refining obeticholic acid

A technology of obeticholic acid and refining method, which is applied in the refining field of obeticholic acid and can solve problems such as difficulty in handling

Active Publication Date: 2016-05-04
NANJING GRITPHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chinese patent 201380043964.8 mentions the treatment method of butyl acetate recrystallization and "alkali-dissolved acid precipitation". The purity of the obeticholic acid product recrystallized by butyl acetate can reach no less than 98.5%, and the yield is about 77.9%. This method has the disadvantage that the solvent butyl acetate used has a high boiling point and is difficult to deal with afterward, and the traditional "alkali dissolution and acid precipitation" refining method has no obvious effect on the removal of isomer impurities

Method used

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  • Method for refining obeticholic acid
  • Method for refining obeticholic acid
  • Method for refining obeticholic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0032] Put 20g of crude obeticholic acid and 600ml of dichloromethane into the reaction flask, raise the temperature to 40°C, all the solids are dissolved, add 0.5g of activated carbon, reflux for 20min, keep warm at 40°C and filter, and collect the filtrate. Reheat the filtrate to reflux, stop heating and cool down to 0°C, stir and crystallize for 12 hours, filter, wash the filter cake with 50ml of n-hexane, and vacuum dry at 40°C for 12 hours to obtain 18.0g of obeticholic acid fine product.

Embodiment 2

[0034] Put 20g of crude obeticholic acid, 300ml of dichloromethane and 10ml of isopropanol into a reaction flask, raise the temperature to 42°C, and dissolve all the solids, add 0.5g of activated carbon, reflux for 30min, heat-preserve and filter, and collect the filtrate. Reheat the filtrate to reflux, stop heating and cool down to 0°C, stir and crystallize for 12 hours, filter, wash the filter cake with 50ml of n-hexane, and vacuum dry at 60°C for 12 hours to obtain 17.1g of obeticholic acid fine product.

Embodiment 3

[0036] Put 20g of crude obeticholic acid, 400ml of dichloromethane and 50ml of acetone into the reaction flask, raise the temperature to 40°C, all the solids are dissolved, add 0.5g of activated carbon, reflux for 1h, keep warm at 40°C and filter, and collect the filtrate. Reheat the filtrate to reflux, stop heating and cool down to 0°C, stir and crystallize for 12 hours, filter, wash the filter cake with 50ml of n-heptane, and vacuum dry at 40°C for 12 hours to obtain 17.3g of obeticholic acid fine product.

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Abstract

The invention belongs to the field of medicine synthesis, and relates to a method for refining high-purity obeticholic acid. The method for refining the obeticholic acid comprises the following steps that crude obeticholic acid is added to an organic solvent, heating and stirring are carried out till the crude obeticholic acid is completely dissolved, activated carbon decoloration is carried out, natural cooling and devitrification are carried out, and filtering and drying are carried out to obtain the high-purity obeticholic acid. According to the method, the content of isomer impurities in the obeticholic acid can be reduced to 0.15% or below, the content of chenodeoxycholic acid impurities can be reduced to 0.1% or below, the product purity is 99.55% or above, and the refining yield is not lower than 85%. In addition, the refining method is simple in technological process, convenient to operate, low in production cost, high in product purity, stable in technology and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for refining obeticholic acid. Background technique [0002] Obeticholic Acid, also known as INT-747, chemical name is 6α-ethyl-3α,7α-dihydroxy-5β-cholanic acid, molecular formula is C 26 h 44 o 4 , its structural formula is as follows: [0003] [0004] Obeticholic acid is a semi-synthetic analog of the primary bile acid chenodeoxycholic acid, and it is also a specific agonist of the farnesoid derivative X receptor. Preclinical and clinical studies suggest that obeticholic acid has a relatively Good anti-cholestasis, anti-inflammation and anti-fibrosis effects, proved that it has the effect of improving insulin resistance and reducing liver fat content, and can be used for the treatment of primary biliary cirrhosis (PBC) and non-alcoholic fatty liver disease ( NASH), the first drug developed for the treatment of cholestatic liver disease in two decades. ...

Claims

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Application Information

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IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 杨建楠李营霍立茹赵卿李战邓书兰陆滢炎
Owner NANJING GRITPHARMA CO LTD
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