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Method of preparing obeticholic acid

A technology of obeticholic acid and intermediates, which is applied in the field of preparation of obeticholic acid intermediates and obeticholic acid, pharmaceutical intermediates, and can solve the problems of increasing the difficulty of feeding and post-processing, increasing production costs, etc. , to achieve the effect of reducing synthesis cost, easy to realize, and good stereoselectivity

Inactive Publication Date: 2018-07-06
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 of preparing obeticholic acid
  • Method of preparing obeticholic acid
  • Method of preparing obeticholic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] carbonyl reduction reaction

[0072] Synthesis of Obeticholic Acid Intermediate 2

[0073]

[0074] 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;

[0075] 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;

[0076] 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;

[0077] 4) After merging the ethyl acetate phases, use anhydrous sodium sulfate to dry the organic phase;

[0078] 5) Ethyl acetate was distilled off under reduced pressure at 45-50°C to obtain 3.94 g of i...

Embodiment 2

[0098] carbonyl reduction reaction

[0099] Synthesis of Obeticholic Acid Intermediate 2

[0100]

[0101] 1) In a 1000ml round bottom flask, add 280ml of ethanol and 12.4g (29.8mmol) of compound 1 in sequence. After the solution is stirred and dissolved and the temperature drops to -5~0℃, add NaBH in batches 4 (3.2g, 83.3mmol), then the reaction solution naturally rose to room temperature and continued to react for 8 to 10 hours;

[0102] 2) Lower the temperature of the reaction solution to -5-0°C, slowly add 20ml of water and 80ml of ethanol dropwise in sequence and continue stirring for 0.5-1 hour;

[0103] 3) ethanol and water are evaporated under reduced pressure;

[0104] 4) Then, 30ml of ethyl acetate was added in turn for beating; after filtration, 12.2g of intermediate 2 was obtained (no need for further treatment, it can be directly put into the follow-up reaction), with a yield of 98.6%.

[0105] Intermediate 2 can be directly put into subsequent reactions wit...

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Abstract

The invention discloses a method of preparing an obeticholic acid intermediate and obeticholic acid. A synthesis route of the intermediate is shown below as shown in the specification. The preparationmethod has good stereoselectivity in a reaction process, so that the synthesis difficulty of obeticholic acid is greatly reduced, and the synthesis cost of obeticholic acid is lowered. The method ismild in reaction conditions and easy to realize industrially, and the low-impurity obeticholic acid intermediate and obeticholic acid can be obtained. Raw materials used by the method are safe and lowin cost, and the production cost is effectively lowered.

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 Intercept company of the United States. It was approved on May 27, 2016 and December 12, 2016. It has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Primary biliary cirrhosis (PBC) is a chronic, progressive autoimmune disease, 90% of which occur in women (mostly women aged 40-60). The final conclus...

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 李冰冰唐阳刚李敬辉李坚胜邓意
Owner LIVZON NEW NORTH RIVER PHARMA
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