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Recrystallization purification method for high-purity obeticholic acid

A technology of obeticholic acid and purification method, which is applied in the field of biomedicine and can solve the problems of incomplete removal of single impurities and limited industrial application of column chromatography

Inactive Publication Date: 2016-05-04
四川新功生物科技集团有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The document JMC2014,57,937-954 also adopted the report of column chromatography method purification; the industrial application of column chromatography is relatively limited; at the same time, the method of directly adopting butyl acetate crystallization is not thorough to the removal of simple impurities, so the prior art Defects need to be overcome for better production process

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Take 100g of crude obeticholic acid with a purity of 89.6% (single impurities greater than 2%), add acetone according to 3 times its weight and add triethylamine according to 20% of its weight, heat to reflux for 2 hours, then start to slowly cool down to 10°C , crystals were precipitated, and obeticholic acid organic amine salt crystals were obtained by filtration.

[0020] The obeticholic acid organic amine salt crystals were dissolved in purified water, acidified with 10 wt% dilute hydrochloric acid to a pH value of 2.0, filtered and dried to obtain refined obeticholic acid.

[0021] The refined obeticholic acid was heated and dissolved with ethyl acetate, then cooled to 20°C, crystals were precipitated, filtered and dried to obtain recrystallized obeticholic acid with a purity of 98.7% (single impurities less than 0.1%), and the recovery rate was 84.5%. %.

Embodiment 2

[0023] Take 100g of obeticholic acid crude product with a purity of 89.6% (single impurities greater than 2%), add ethyl acetate by 4 times its weight and add ethylenediamine by 5% by its weight, heat and reflux for 3 hours, and start to slowly cool down to At 15°C, crystals were precipitated, and the organic amine salt of obeticholic acid was obtained by filtration.

[0024] The crystals of the organic amine salt of obeticholic acid were dissolved in purified water, acidified with dilute sulfuric acid with a mass percentage of 10% of the organic amine salt of obeticholic acid to a pH value of 2.5, filtered and dried to obtain refined obeticholic acid.

[0025] The refined obeticholic acid was heated and dissolved with butyl acetate, then cooled to 20°C, crystals were precipitated, filtered and dried to obtain recrystallized obeticholic acid with a purity of 98.9% (single impurities less than 0.1%), and the recovery rate was 85.3% %.

Embodiment 3

[0027] Take 100 g of obeticholic acid crude product with a purity of 89.6% (monopoly is greater than 2%), add sec-butanol by 5 times its weight and add phenethylamine by 10% by its weight, heat and reflux for 4 hours, then start to slowly cool down to 20 ℃, crystals were precipitated, and obeticholic acid organic amine salt crystals were obtained by filtration.

[0028] The crystals of the organic amine salt of obeticholic acid were dissolved in purified water, acidified with dilute sulfuric acid with a mass percentage of 60% of the organic amine salt of obeticholic acid to a pH value of 3.0, filtered and dried to obtain refined obeticholic acid.

[0029] The refined obeticholic acid was heated and dissolved with propyl acetate, then cooled to 20°C, crystals were precipitated, filtered and dried to obtain recrystallized obeticholic acid with a purity of 99.1% (single impurities less than 0.1%), and the recovery rate was 82.3 %.

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Abstract

The invention discloses a recrystallization purification method for high-purity obeticholic acid. Obeticholic acid and organic amine are salified and then re-crystallized in an organic solvent to obtain high-purity obeticholic acid. The method includes the specific steps that crude obeticholic acid reacts with organic amine in the organic solvent to obtain obeticholic acid organic amine salt; the obeticholic acid organic amine salt is subjected to acid adjustment to be re-crystallized in an obeticholic acid mode. According to the purification method, high-purity (purity is larger than 98.5% and the individual impurity rate is smaller than 0.1%) obeticholic acid can be obtained, the steps of column chromatography and the like which cannot produce a large amount of high-purity obeticholic acid are not needed for the method, and therefore the purification method can better adapt to industrial production.

Description

technical field [0001] Embodiments of the present invention relate to the field of biomedicine, and more specifically, embodiments of the present invention relate to a method for recrystallization and purification of high-purity obeticholic acid. Background technique [0002] Obeticholic acid is a new drug for the treatment of cholestatic liver cirrhosis. It requires high purity of raw materials used in clinical practice. In the process of synthesis and preparation, other impurities with similar structures are often introduced, which affects the quality of the product. purity. The prior art patent US2008 / 0214515A1 discloses a method of recrystallization using ethyl acetate for purification. The document JMC2014,57,937-954 also adopted the report of column chromatography method purification; the industrial application of column chromatography is relatively limited; at the same time, the method of directly adopting butyl acetate crystallization is not thorough to the removal ...

Claims

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Application Information

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IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 秦岭许庆李虹霖占伟谢建
Owner 四川新功生物科技集团有限公司
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