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Preparation method of obeticholic acid and intermediate thereof

A volume and compound technology, applied in the production of steroids, organic chemistry, bulk chemicals, etc., can solve the problems of large pollution, complicated operation and high cost

Active Publication Date: 2018-07-10
SHANGHAI SHYNDEC PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0025] The problem to be solved by the present invention is that the existing obeticholic acid preparation method has defects such as cumbersome operation, high cost, harsh reaction conditions, large pollution, etc., thus provides a kind of preparation method and Its intermediate, the preparation method of the present invention is easy and simple to operate, with low cost, mild condition, environment friendly, suitable for industrialization

Method used

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  • Preparation method of obeticholic acid and intermediate thereof
  • Preparation method of obeticholic acid and intermediate thereof
  • Preparation method of obeticholic acid and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0231] The preparation of embodiment 1 compound 1

[0232]

Embodiment 2

[0234] The preparation of embodiment 2 compound 1

[0235] N 2 Put ethyltriphenylphosphine bromide (242.4g, 653mmol), tetrahydrofuran (300ml), potassium tert-butoxide (111g, 990mmol) into a four-necked flask under protection, stir at 65°C for 30min, and add compound 19 (80g, 198mmol) in tetrahydrofuran solution (100ml), stirred for 1-2h, the reaction solution was acidified with 6mol / L hydrochloric acid, the solution was evaporated to dryness, ethyl acetate (500ml) and water (600ml) were added to extract and separate the liquid, and the organic layer was washed with saturated It was washed twice with 400 ml of saline, dried and evaporated to dryness, and a solid (58.8 g, 72.2%) was obtained by column chromatography. Identification data is the same as in Example 1.

Embodiment 3

[0236] The preparation of embodiment 3 compound 1

[0237] N 2 Put ethyltriphenylphosphine bromide (2.4g, 6.5mmol), tetrahydrofuran (10ml), potassium tert-butoxide (1.1g, 9.9mmol) into a four-necked flask under protection, stir at -10°C for 30min, and add the compound dropwise 19 (0.8g, 1.9mmol) in tetrahydrofuran (5ml), stirred for 1-2h, the reaction solution was acidified with 6mol / L hydrochloric acid, the solution was evaporated to dryness, and ethyl acetate (20ml) and water (20ml) were added to extract liquid, the organic layer was washed twice with 20 ml of saturated brine, dried and evaporated to dryness, and a solid (0.56 g, 68.4%) was obtained by column chromatography. Identification data is the same as in Example 1.

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Abstract

The invention discloses a preparation method of obeticholic acid and an intermediate thereof. The invention provides a preparation method of a compound V. The preparation method of the compound V comprises the following steps: carrying out hydroxyl protective reaction on a compound VI and a hydroxyl protective reagent to obtain the compound V. The preparation method is simple and convenient to operate, low in cost, gentle in condition, environmentally friendly and suitable for industrialization.

Description

technical field [0001] The invention relates to a preparation method of obeticholic acid and an intermediate thereof. Background technique [0002] Obeticholic acid, chemical name 3α,7α-dihydroxy-6α-ethyl-5β-cholanic acid, is a new drug developed by Intercept Pharmaceuticals, also known as INT747 or 6α-ethylchenodeoxycholic acid, It is a semi-synthetic derivative of chenodeoxycholic acid (CDCA), which can activate farnesoid X receptor (FXR), and has anti-cholestasis and anti-fibrosis effects. Its indications under research include primary biliary Liver cirrhosis (PBC), nonalcoholic fatty liver disease (NASH), primary sclerosing cholangitis (PSC), portal hypertension and diarrhea. Among them, primary biliary cirrhosis (PBC) was approved by the FDA on May 29, 2016, and non-alcoholic fatty liver disease (NASH) is also undergoing phase III clinical trials. [0003] The published synthesis processes of obeticholic acid are summarized in chronological order as follows: [0004]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00C07J31/00C07J17/00
CPCC07J9/005C07J17/00C07J31/006Y02P20/55
Inventor 张杰王国平李春刚傅民黄文武刘超陆庆龄邹强
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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