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Preparation method of OCA (obeticholic acid)

A technology for obeticholic acid and a preparation process, which is applied in the field of preparation of obeticholic acid, can solve the problems of high boiling point of butyl acetate, difficult to remove, incomplete configuration transformation, and reduced product purity, and achieves safe, non-toxic solvent, Short production cycle and good stereoselectivity

Inactive Publication Date: 2018-02-06
NANJING CHANGAO PHARMA SCI & TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When introducing 6α-ethyl, patent CN101203526A and patent CN104781272A mentioned configuration conversion under high temperature conditions, but due to factors such as complex reaction process and incomplete configuration conversion, the potential introduction of chiral impurities, such as 6β-ethyl Base chenodeoxycholic acid, 6α-ethyl ursodeoxycholic acid and 6β-ethyl ursodeoxycholic acid, etc. In addition, if the reaction temperature is too high, new impurity chenodeoxycholic acid (CDCA) may be introduced, resulting in Reduced product purity
In order to improve product purity, the patent CN104781272A mentions recrystallization with butyl acetate, and the purity of obeticholic acid product recrystallized through butyl acetate can reach no less than 98.5%, but this method has complex post-processing and the boiling point of butyl acetate Higher disadvantages that are difficult to remove
And the patent CN101203526A and the patent CN104781272A both mentioned the treatment method of alkali dissolution and acid crystallization. Experiments have proved that this refining method has no obvious effect on the removal of isomer impurities

Method used

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  • Preparation method of OCA (obeticholic acid)
  • Preparation method of OCA (obeticholic acid)
  • Preparation method of OCA (obeticholic acid)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Preparation of (E)-3α,7α-dihydroxy-6-ethylene-5β-cholan-24-acid

[0031] Add (E)-3α-hydroxy-6-ethylene-7-keto-5β-cholan-24-acid (100.0g, 0.26mol) and methanol (1.0L) to the reaction flask, cool to 0°C, Sodium borohydride (22.7 g, 0.60 mol) was added, the addition was completed, and the reaction was carried out at 30° C. for 3 hours. Cool to 0°C, dropwise add 1.0 mol / L hydrochloric acid to adjust pH to 4, add ethyl acetate (1.0L) and water (1.0L), separate liquids, and evaporate the organic phase to dryness under reduced pressure at 40°C. Dichloromethane (1.5L) was added, heated at 40°C and stirred for 30 minutes, cooled to 10°C, stirred for 2 hours, filtered, and the filter cake was dried at 40°C to obtain a white solid, namely (E)-3α,7α-dihydroxy-6- Ethylene-5β-cholan-24-acid (98.8 g, purity: 99.7%, yield: 90.8%).

Embodiment 2

[0033] Preparation of (E)-3α,7α-dihydroxy-6-ethylene-5β-cholan-24-acid ethyl ester

[0034] Add (E)-3α-hydroxy-6-ethylene-7-one-5β-cholan-24-acid ethyl ester (50.0g, 0.11mol), tetrahydrofuran (400.0ml) and absolute ethanol to the reaction flask (100.0ml), cooled to 0°C, sodium borohydride (12.5g, 0.33mol) was added, the addition was completed, and the reaction was carried out at 0°C for 3 hours. Cool to 0°C, add 1.0mol / L hydrochloric acid dropwise to adjust pH to 7, add ethyl acetate (500.0ml) and water (500.0ml), separate the liquids, and evaporate the organic phase to dryness under reduced pressure at 40°C. Ethyl acetate (500.0ml) was added, heated at 50°C and stirred for 30 minutes, cooled to 10°C, stirred for 2 hours, filtered, and the filter cake was dried at 60°C to obtain an off-white solid, namely (E)-3α,7α-dihydroxy-6 - Ethylene-5β-cholan-24-acid ethyl ester (46.5 g, purity: 99.3%, yield: 92.5%).

Embodiment 3

[0036] Preparation of obeticholic acid

[0037] Add (E)-3α,7α-dihydroxy-6-ethylene-5β-cholane-24-acid (95.0g, 0.23mol), sodium hydroxide (18.4g, 0.16mol), water to the reaction flask (750 mL) and 5% palladium on carbon (9.5 g), the reaction mixture was heated to 30° C. under the pressure of 1 to 3 atmospheres, and the hydrogen was no longer absorbed after 5 hours of hydrogenation reaction. The reaction solution was filtered, water (675 mL) was added to the filtrate, and the temperature was raised to 50°C. Add 1.0mol / L hydrochloric acid solution dropwise to adjust pH to 3.0, continue to keep stirring for 30min, cool to 10°C and stir for crystallization for 2 hours, filter, and vacuum dry the filter cake at 50°C for 3 hours to obtain a white solid, namely obeticholic acid ( 80.9 g, purity: 99.89%, yield: 84.8%).

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Abstract

The invention discloses a preparation method of OCA (obeticholic acid). (E)-3 alpha-hydroxy-6-ethylidene-7-one-5 beta-cholane-24-acid or (E)-3 alpha-hydroxy-6-ethylidene-7-one-5 beta-cholane-24-acid ester, a solvent and a reducing agent are placed in a reactor to react to produce (E)-3 alpha, 7 alpha-dihydroxy-6-ethylidene-5 beta-cholane-24-acid or (E)-3 alpha, 7 alpha-dihydroxy-6-ethylidene-5 beta-cholane-24-acid ester. (E)-3 alpha, 7 alpha-dihydroxy-6-ethylidene-5 beta-cholane-24-acid or (E)-3 alpha, 7 alpha-dihydroxy-6-ethylidene-5 beta-cholane-24-acid ester, alkali, a solvent and a catalyst are placed in the reactor for hydrogenation to produce OCA. OCA with the purity of 99.5% or above can be obtained with the preparation method, the process is simple and good in reproducibility, thesolvent is safe, non-toxic, conventional and easy to obtain, post-treatment is simple, and the production cycle is short.

Description

technical field [0001] The invention relates to the field of chemical medicine, in particular to a preparation method of obeticholic acid. Background technique [0002] On May 27, 2016, the U.S. FDA approved the farnesoid X receptor (FXR) agonist Obeticholic Acid (OCA) developed by Intercept Pharmaceuticals, Inc. to be marketed. Oxycholic acid (UDCA) is used for primary biliary cholangitis with an inadequate response to UDCA, or as monotherapy in adults with primary biliary cholangitis who are intolerant to UDCA. [0003] Obeticholic acid (Compound I) is a chenodeoxycholic acid derivative, which is a human bile acid mimetic and is currently used in other indications for the treatment of nonalcoholic steatohepatitis and other liver and intestinal diseases Clinical trials are underway. [0004] [0005] Molecular formula: C 26 H 44 O 4 Molecular weight: 420.63 [0006] Primary biliary cholangitis is a rare liver disease caused primarily by autoimmune destruction of th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00C07B53/00
CPCC07B53/00C07B2200/07C07J9/005
Inventor 李纬王正泽赵磊林辉谢少斐
Owner NANJING CHANGAO PHARMA SCI & TECH CO LTD
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