Preparation method for obeticholic acid and intermediate thereof

A technology of obeticholic acid and intermediates, applied in the field of drug synthesis, which can solve problems such as difficult catalytic hydrogenation and incomplete ester hydrolysis

Active Publication Date: 2016-04-13
NANJING GRITPHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In order to solve the problems of incomplete ester hydrolysis and difficult catalytic hydrogenation in the existing obeticholic acid synthesis process, and further improve the yield and quality of obeticholic acid, the present invention provides an obeticholic acid intermediate 3α-hydroxyl-6 - The preparation method of ethyl-7-keto-5β-cholanic acid formula (I), the preparation method avoids the influence of hydroxyl in the catalytic hydrogenation reaction, and there is no ester hydrolysis step

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1a3

[0037] Embodiment 1a Preparation of 3α-hydroxyl-7-keto-5β-cholanic acid (III)

[0038]

[0039] 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 h...

Embodiment 1b3

[0040] The preparation of embodiment 1b3α-hydroxyl-7-keto-5β-cholanic acid (III)

[0041]

[0042] 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 2a3

[0043]Example 2a Synthesis of 3α-hydroxyl-7-keto-5β-cholane-24 acid benzyl ester (IVa)

[0044] In the reaction flask, add compound III (20g, 51mmol), anhydrous tetrahydrofuran (450ml), stir, add potassium carbonate (10.5g, 76mmol), heat up to reflux, add benzyl bromide (30ml), reflux reaction, 12h monitoring Reaction (TLC conditions: acetone: dichloromethane: acetic acid = 1:15:1). Reaction finishes, adds triethylamine (30ml), continues reaction to form quaternary ammonium salt and removes excess benzyl bromide, is cooled to room temperature, diatomaceous earth assists and filters solid insoluble matter, filtrate is concentrated under reduced pressure, adds water (200ml), with acetic acid Ethyl ester (200ml*3) was extracted, the organic phases were combined, washed with purified water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 20.3g of compound (IVa), with a yield of 82.8%.

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Abstract

The invention relates to a preparation method for obeticholic acid and an intermediate thereof. The intermediate 3alpha-hydroxy-6alpha-ethyl-7-keto-5beta-cholanic acid is obtained by subjecting 3alpha-hydroxy-6-ethylidene-7-keto-5beta-cholanic acid benzyl ester compounds to a reaction under the action of a catalyst and a hydrogen donor. The catalyst is selected from Pd/C or PtO2 or Raney Ni. The hydrogen donor is selected from cyclohexene or cyclohexadiene or tetrahydronaphthalene. According to the method, the yield is high, the stereoselectivity is high, safety is good, the reaction condition is mild, and the method is applicable to 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 and an intermediate thereof. Background technique [0002] Obeticholic Acid (Obeticholic Acid), also known as INT-747, was developed by Intercept Pharmaceutical Company of the United States. Its indications are primary biliary cirrhosis (PBC) and non-alcoholic fatty liver disease (NASH), and it is currently in clinical trials. 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] CN10...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 杨建楠李营赵卿霍立茹李战周静
Owner NANJING GRITPHARMA CO LTD
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