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Tauroursodeoxycholic acid synthesis method

A technology for tauroursodeoxycholic acid and tauroursodeoxycholic acid is applied in the field of tauroursodeoxycholic acid synthesis, which can solve the problems of unstable amplification process, complex related substances and high production cost, and achieves chemical The effect of short synthesis route, high purity and few impurities

Inactive Publication Date: 2017-09-26
GUANGZHOU YINGYU PHARMA TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the synthetic methods of tauroursodeoxycholic acid mainly contain three types: (1) take ursodeoxycholic acid as raw material, first form mixed anhydride or active ester with ethyl chloroacetate, then react with taurine to synthesize tauroursodeoxycholic acid Deoxycholic acid; (2) ursodeoxycholic acid and taurine under alkaline conditions, using a condensation agent to obtain tauroursodeoxycholic acid; (3) ursodeoxycholic acid and 2,2'-disulfide Dibenzothiazole is condensed under the action of triethylamine and triphenylphosphine, and then reacted with taurine to obtain tauroursodeoxycholic acid; however, these three methods all have high production costs, long synthetic routes and related substances. At the same time, each method also has certain limitations to varying degrees: such as the use of toxic reagents and unstable reagents in the (1) method; the (2) method involves the use of expensive condensing agents ; (3) method amplification process is unstable

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] (1) Take chicken gall paste 100g, add 500mL water, stir to dissolve, centrifuge, filter, wash the filtrate three times with ethyl acetate (200mL*3), collect the lower layer solution; add 2 to 3 times the amount of ethanol to the filtrate, centrifuge, filter , the filtrate is concentrated to dryness, then 200ml of ethanol is added, centrifuged, filtered, the filtrate is adjusted to pH 2-5 with hydrochloric acid, the filtrate is evaporated to dryness, the concentrate is added to pure water to dissolve completely, super acidic ion exchange resin, the collection purity is greater than 95% The taurochenodeoxycholic acid component is concentrated to obtain about 10.3 g of taurochenodeoxycholic acid.

[0039] (2) Dissolve taurochenodeoxycholic acid (10.0 g, 20.0 mmol) in 50 mL of acetone aqueous solution (acetone (V) / water (V) = 4 / 1), and slowly add N in batches after the dissolution is complete. -Bromosuccinimide (5.6g, 30mmol), stirred at room temperature for 4h; sampled on ...

Embodiment 2

[0043](1) Take 100g of chicken gall paste, add 500mL of 0.1M sodium hydroxide aqueous solution, stir to dissolve, centrifuge, filter, wash the filtrate three times with ethyl acetate (200mL*3), collect the lower layer solution; the amount of solution added to the filtrate is 2-3 Double the amount of ethanol, centrifuge, filter, concentrate the filtrate to dryness, then add 200ml of ethanol, centrifuge, filter, adjust the pH value of the filtrate to 2-5 with hydrochloric acid, evaporate the filtrate, add pure water to dissolve the concentrate completely, super strong acid ion The resin was exchanged to collect taurochenodeoxycholic acid components with a purity greater than 95%, and concentrated to obtain about 10.2 g of taurochenodeoxycholic acid.

[0044] (2) step is the same as (2) step of embodiment 1.

[0045] (3) step is the same as (3) step of embodiment 1.

Embodiment 3

[0047] (1) Take 100g of chicken gall paste, add 500mL of water, stir to dissolve, centrifuge, filter, wash the filtrate with petroleum ether three times (200mL*3), collect the lower layer; add ethanol 2 to 3 times the amount of the solution to the filtrate, centrifuge, filter, Concentrate the filtrate to dryness, then add 200ml of ethanol, centrifuge, filter, adjust the pH value of the filtrate to 2-5 with hydrochloric acid, evaporate the filtrate to dryness, add pure water to the concentrate and dissolve it completely, and use a super-acidic ion exchange resin to collect the purity greater than 95%. The taurochenodeoxycholic acid component is concentrated to obtain about 9.8 g of taurochenodeoxycholic acid.

[0048] (2) step is the same as (2) step of embodiment 1.

[0049] (3) step is the same as (3) step of embodiment 1.

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Abstract

The invention discloses a tauroursodeoxycholic acid synthesis method. The method includes: taking poultry bile as a raw material, and performing process steps of dissolving, decontaminating, degreasing, deproteinizing, acidifying, treatment through ion-exchange resin and the like to obtain high-purity taurochenodeoxycholic acid; performing 7-hydroxyl selective oxidation of the taurochenodeoxycholic acid to obtain 3alpha-hydroxyl-7-keto-cholan-24-oyl-N-taurine; performing 7-keto selective reduction of 3alpha-hydroxyl-7-keto-cholan-24-oyl-N-taurine to obtain N-(3alpha,7beta-dihydroxy-5-beta-cholan-24-oyl)-taurine; finally performing re-crystallization and purification to obtain high-purity tauroursodeoxycholic acid. Cheap raw materials are adopted for acquisition of high-additional-value tauroursodeoxycholic acid through two-step reaction, short chemical synthesis route, high yield, high target product purity, simple and controllable process, few impurities, reduction of acid and alkaline emission and environmental friendliness are realized, industrialization can be realized beneficially, and the method has a promising application prospect in the pharmaceutical field.

Description

technical field [0001] The invention relates to the field of pharmaceutical raw materials, in particular to a method for synthesizing tauroursodeoxycholic acid. Background technique [0002] Tauroursodeoxycholic acid was developed by the Italian Besidy Pharmaceutical Company in 1991 and was first listed in Italy. It is mainly used clinically for the treatment of gallbladder cholesterol stones, primary sclerosing cholangitis, primary biliary cirrhosis and chronic Hepatitis C, etc. From the perspective of molecular structure, tauroursodeoxycholic acid is formed by combining ursodeoxycholic acid and taurine through amide bonds. The key step of chemical synthesis is the formation of amide bonds between the two substances. [0003] At present, the synthetic methods of tauroursodeoxycholic acid mainly contain three types: (1) take ursodeoxycholic acid as raw material, first form mixed anhydride or active ester with ethyl chloroacetate, then react with taurine to synthesize taurou...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J41/00
CPCC07J41/0061
Inventor 康健陈新颖
Owner GUANGZHOU YINGYU PHARMA TECH CO LTD
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