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Preparation method of high-purity obeticholic acid

A high-purity obeticholic acid technology, applied in the field of preparation of obeticholic acid, can solve the problems of increased impurity chenodeoxycholic acid, low configuration selectivity and the like

Active Publication Date: 2017-05-31
NANJING GRITPHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In this route, the cis-trans configuration of the ethylidene reaction product in step 4 is E / Z=4:1, and the selectivity of configuration is low. Also, this route fails to solve step 4 basic ester hydrolysis and step 5 alkali During the catalytic hydrogenation of ethylene as a solvent, the ethylene group is thermally degraded into the compound KLCA under alkaline conditions, which eventually leads to the increase of the impurity chenodeoxycholic acid in obeticholic acid

Method used

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Examples

Experimental program
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Effect test

Embodiment 1a

[0051] Example 1a Preparation of 3α-hydroxyl-7-keto-5β-cholanic acid (III)

[0052]

[0053] Add chenodeoxycholic acid (II) (113g, 0.288mol), sodium bromide (1.78g, 0.0173mol), acetic acid (30mL) and methanol (600mL) successively to the reaction flask, stir at room temperature until all dissolve, and cool to -10°C±2°C, slowly add 13% sodium hypochlorite solution (225mL, 0.39mol) dropwise to the reaction system, control the internal temperature at -10~0°C and stir the reaction until the content of chenodeoxycholic acid (II) is detected by HPLC less than 1%. After the reaction was completed, the ice bath was removed, and the reaction solution naturally rose to room temperature, and 5% sodium bisulfite solution (25 mL) was added dropwise to the reaction system, stirred for 30 minutes, suction filtered, and dried to obtain 3α-hydroxy-7-keto - Crude 5β-cholanic acid (III) (115.83 g). Add the crude product and methanol (1L) into the reaction flask, heat to 65°C, reflux for half...

Embodiment 1b

[0054] Example 1b Preparation of 3α-hydroxyl-7-keto-5β-cholanic acid (III)

[0055]

[0056] Add chenodeoxycholic acid (II) (100g, 0.255mol), anhydrous magnesium sulfate (200g), chloroform (300mL) to the reaction flask in turn, stir at room temperature, and add pyridinium chlorochromate dichloride dropwise to the reaction system Methane solution (61 g of pyridinium chlorochromate dissolved in 2.5 L of dichloromethane), and the reaction solution was stirred at room temperature for 30 min. The solid insoluble matter was filtered, the filtrate was washed with water and saturated brine successively, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3α-hydroxy-7-keto-5β-cholanic acid (III) (73g, yield 73.3 %, HPLC detection: 97.7%).

Embodiment 2a

[0057] Example 2a Preparation of 3α-hydroxyl-7-keto-5β-cholanoic acid methyl ester (IVa)

[0058]

[0059] 3α-Hydroxy-7-keto-5β-cholanic acid (III) (50 g) and methanol (360 mL) were sequentially added into the three-neck flask and stirred to dissolve. Cool to below 10°C, add thionyl chloride (14mL) dropwise, then heat to 65°C, and reflux for 3h. After the reaction is completed, cool to 5°C, and add H 2 O (360ml), natural cooling and crystallization, adding seed crystals, accelerated stirring. A large amount of solid precipitated out, stirred for 3 hours, filtered the product, and dried to obtain IVa (47.3 g, yield 91.3%) with a purity of 98.95%.

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Abstract

The invention relates to a preparation method of high-purity obeticholic acid. A compound chenodeoxycholic acid (CDCA) shown as a formula II is used as a starting raw material and subjected to oxidation, esterification, hydroxy protection, ethylidene formation, catalytic hydrogenation, carbonyl reduction and esterolysis reaction to obtain the high-purity obeticholic acid. The preparation method of the high-purity obeticholic acid, provided by the invention, has the advantages of low toxicity, low pollution, high purity, good stereoselectivity, low content of impurities, mild reaction conditions, high safety, simplicity and convenience in production operation and the like, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of obeticholic acid. Background technique [0002] Obeticholic Acid (Obeticholic Acid), also known as INT-747, was developed by Intercept Pharmaceutical Company of the United States, and its indications are primary biliary cirrhosis (PBC) and non-alcoholic fatty liver disease (NASH). Clinical phase III. Obeticholic acid is a semi-synthetic chenodeoxycholic acid and a specific agonist of the farnesoid derivative X receptor. Animal experiments have proved that it can improve insulin resistance and reduce liver fat content. It is the first drug developed for the treatment of cholestatic liver disease in 2009, and the market potential is huge. [0003] Obeticholic acid, whose chemical name is 6α-ethyl-3α,7α-dihydroxy-5β-cholanic acid, has the following structural formula: [0004] [0005] Patent WO02072598A1 discloses a method for preparing obetic...

Claims

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Application Information

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IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 杨建楠李营余秋阳赵卿李战周静陆滢炎
Owner NANJING GRITPHARMA CO LTD
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