Preparation method for obeticholic acid

A technology of obeticholic acid and ketocholic acid, which is applied in the fields of synthetic chemistry and biomedicine, can solve problems such as complicated steps and long synthetic routes, and achieve the effects of easy scale-up production, low toxicity and hazards, and simple operation methods

Active Publication Date: 2020-05-01
ZHONGSHAN BAILING BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthetic route is long and the steps are relatively complicated

Method used

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  • Preparation method for obeticholic acid
  • Preparation method for obeticholic acid
  • Preparation method for obeticholic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] (1) In a 1L reaction flask, put 40.2g (0.1mol) of 6-methylene-7-ketocholelithic acid, 400ml of dimethyl sulfoxide, and 40ml of nitromethane, and add anhydrous potassium hydroxide powder while stirring 18g (0.32mol), heat up, react at 80°C, TLC tracking, stop the reaction when the raw materials disappear, cool down to 20°C, add 500ml of water, continue to cool down to 0°C-5°C, and then add sodium dihydrogen phosphate until The pH value of the solution was below 6, and continued to stir overnight, and a white powdery solid was precipitated, filtered, fully washed with purified water, and dried to obtain 6-α-(2-nitroethyl)-7-ketocholelithic acid (compound 3 ), which was purified by recrystallization from 95% ethanol.

[0055] (2) Add compound 3 after purification to a 1L three-necked flask, add 400ml of methanol, 100 microliters of acetyl chloride, heat up and reflux for 1 hour, follow the completion of the reaction by TLC, distill off methanol and by-product water, and th...

Embodiment 2

[0058] (1) In a 1L reaction flask, put 40.2g (0.1mol) of 6-methylene-7-ketocholelithic acid and 400ml of nitromethane into it, add 18g (0.32mol) of anhydrous potassium hydroxide powder under stirring, and heat up , react at 100°C, TLC tracking, stop the reaction when the raw materials disappear, evaporate most of the nitromethane, then cool down to 20°C, add 500ml of water, continue to cool down to 0-5°C, and then add sodium dihydrogen phosphate , adjust the pH value of the solution to below 6, continue to stir overnight, white powdery solids are precipitated, filtered, fully washed with purified water, and dried to obtain 6-α-(2-nitroethyl)-7-ketocholelithic acid ( Compound 3), which was purified by recrystallization from 95% ethanol.

[0059] (2) Add 3 after purification to a 1L three-necked flask, add 200ml of dimethylformamide, 40ml of water, 42g of sodium bicarbonate, 39g of sodium sulfide, 70g of sodium hydrosulfite (sodium dithionite), and then heat up to 80-100°C The ...

Embodiment 3

[0062] (1) In a 1L reaction flask, put 40.2g (0.1mol) of 6-methylene-7-ketocholelithic acid and 400ml of nitromethane into it, add 18g (0.32mol) of anhydrous potassium hydroxide powder under stirring, and heat up , react at 90°C, TLC tracking, stop the reaction when the raw materials disappear, evaporate most of the nitromethane, then cool down to 20°C, add 500ml of water, continue to cool down to 0-5°C, and then add sodium dihydrogen phosphate , adjust the pH value of the solution to below 6, continue to stir overnight, white powdery solids are precipitated, filtered, fully washed with purified water, dried to obtain 6-α-(2-nitroethyl)-7-ketocholelithic acid ( Compound 3), which was purified by recrystallization from 95% ethanol.

[0063] (2) Compound 3 after purification was added to a 1L stainless steel autoclave, 400ml of methanol, 100ml of water, 15g of potassium dihydrogen phosphate, 4g of 5% silica-loaded platinum dioxide catalyst were added, vacuum pumped, hydrogen rep...

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Abstract

The invention discloses a preparation method for obeticholic acid, belonging to the technical fields of synthetic chemistry application and biological medicines. The preparation method comprises the following steps: with 6-methylene-7-ketolithocholic acid as a reactant, dissolving the 6-methylene-7-ketolithocholicacid and nitromethane into a polar aprotic solvent together, and carrying out treating with inorganic base so as to obtain 6-alpha-(2-nitroethyl)-7-ketolithocholicacid; and performing two-step reduction treatment on the 6-alpha-(2-nitroethyl)-7-ketolithocholicacid to remove nitryl soas to finally obtain a target product, namely the obeticholic acid. The method provided by the invention is simple in synthetic route, simple and convenient to operate, simple and easily available inraw materials, low in cost, less in side reaction, high in product purity, good in yield, convenient to purify and applicable to large-scale production.

Description

technical field [0001] The invention belongs to the technical field of synthetic chemistry application and biomedicine, and specifically relates to a preparation method of obeticholic acid. Background technique [0002] Obeticholic acid (6-α-ethyl-chenodeoxycholic acid) is a promising bile acid drug that can promote bile acid synthesis for the treatment of primary biliary cirrhosis and non-alcoholic Fatty liver disease, but it has not yet been put into large-scale production and application. [0003] The common synthesis method of obeticholic acid is to use 7-ketocholelithic acid as the key raw material, first protect the carboxyl group and hydroxyl group on the raw material molecule and then enolize it to obtain enol silyl ether, and then react with acetaldehyde under the promotion of Lewis acid condensation reaction. This method is feasible and the purity of the product is high, but it requires complex and harsh chemical reaction conditions, the reaction result is extrem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 欧松张和平郭然梁待亮吕巧莉单宇哲阮宇峰杨琳
Owner ZHONGSHAN BAILING BIOTECHNOLOGY CO LTD
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