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Method for preparing intermediates of obeticholic acid and obeticholic acid

A technology for obeticholic acid and intermediates is applied in the field of synthesis technology for preparing obeticholic acid intermediates and obeticholic acid and pharmaceutical intermediates, and can solve the problems of increasing the difficulty of feeding materials and post-processing, increasing production costs and the like , to achieve the effect of reducing synthesis cost, easy realization and production cost

Inactive Publication Date: 2018-06-22
LIVZON NEW NORTH RIVER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this route, BnBr strong stimulus material is used, which increases the difficulty of feeding and post-treatment; For expensive cerium trichloride, increased production cost

Method used

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  • Method for preparing intermediates of obeticholic acid and obeticholic acid
  • Method for preparing intermediates of obeticholic acid and obeticholic acid
  • Method for preparing intermediates of obeticholic acid and obeticholic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] carbonyl reduction reaction

[0070] Synthesis of Obeticholic Acid Intermediate 2

[0071]

[0072] 1) In a 1000ml round bottom flask, add 150ml of methanol and 14.0g (9.3mmol) of the starting material in sequence. After the solution is stirred and dissolved and the temperature drops to 0-5°C, add NaBH in batches 4 (1.06g, 27.9mmol); the reaction solution naturally rose to room temperature and continued to react for 8 to 10 hours;

[0073] 2) Reduce the temperature of the reaction solution to 0-5°C, slowly add 150ml of water and 50ml of methanol successively dropwise and continue to stir for 0.5-1 hour;

[0074] 3) The methanol was evaporated under reduced pressure, and then 50 ml of ethyl acetate was added successively to extract the aqueous phase three times;

[0075] 4) After merging the ethyl acetate phases, use anhydrous sodium sulfate to dry the organic phase;

[0076] 5) Ethyl acetate was distilled off under reduced pressure at 45-50°C to obtain 3.94 g of i...

Embodiment 2

[0095] carbonyl reduction reaction

[0096] Synthesis of Obeticholic Acid Intermediate 2

[0097]

[0098] 1) In a 1000ml round bottom flask, add 250ml of ethanol and 10.1g (19.7mmol) of compound 1 in sequence. After the solution is stirred and dissolved and the temperature drops to -5~0℃, add NaBH in batches 4 (2.10g, 55.5mmol), then the reaction solution naturally rose to room temperature and continued to react for 8 to 10 hours;

[0099] 2) Lower the temperature of the reaction solution to -5-0°C, slowly add 300ml of water and 50ml of ethanol dropwise in sequence and continue stirring for 0.5-1 hour;

[0100] 3) Ethanol was evaporated under reduced pressure, and then 100ml of ethyl acetate was added successively to extract the aqueous phase for 3 times;

[0101] 4) After merging the ethyl acetate phases, dry the organic phase using anhydrous sodium sulfate;

[0102] 5) Ethyl acetate was distilled off under reduced pressure at 45-50°C to obtain 9.86 g of intermediate 2...

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Abstract

The invention discloses a method for preparing intermediates of obeticholic acid and the obeticholic acid. A synthetic route of the intermediates is shown as follows. The intermediates of the obeticholic acid have good stereoselectivity in the reaction process, so that difficulty of synthesis of the obeticholic acid is simplified greatly, and the synthesis cost of the obeticholic acid is reduced;the method has mild reaction conditions, and is industrially easy to implement, and the obeticholic acid intermediates and obeticholic acid which have low content of impurities can be obtained; the adopted raw materials are safe, and the cost is low, so that the production cost is reduced effectively.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a synthesis process of a pharmaceutical intermediate, in particular to a method for preparing an obeticholic acid intermediate and obeticholic acid. Background technique [0002] Obeticholic Acid (Obeticholic Acid, CAS: 459789-99-2), trade name Ocalive, chemical name 3α, 7α-dihydroxy-6α-ethyl-5β-cholanic acid, has a specific three-dimensional structure, and its structural formula is as follows The formula shows: [0003] [0004] Obeticholic acid is a new type of drug for the treatment of primary biliary cirrhosis (PBC) developed by the American company Intercept. It was approved on May 27, 2016 and December 12, 2016. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the marketing. Primary biliary cirrhosis (PBC) is a chronic, progressive autoimmune disease, 90% of which occur in women (mostly women aged 40-60). The final conclusion is cirrho...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00
CPCY02P20/55C07J9/005
Inventor 姜桥李冰冰唐阳刚李敬辉邓意
Owner LIVZON NEW NORTH RIVER PHARMA
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