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Preparation method of ursodesoxycholic acid

A technology of ursodeoxycholic acid and cholic acid, which is applied in the field of preparation of ursodeoxycholic acid, can solve the problems of high cost, pollution, and long process route, and achieve the effects of low cost, less side reactions, and shortened production process

Pending Publication Date: 2021-07-02
四川百特芳华医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] In this environment, cholic acid is gradually emerging to replace chenodeoxycholic acid as raw material to synthesize ursodeoxycholic acid, such as patent CN201910657023, but the patent has a long process route, which leads to high cost and dangerous use in the process. Higher Raney Ni uses mercaptan derivatives with a strong smell and serious pollution. The synthetic route is as follows:

Method used

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  • Preparation method of ursodesoxycholic acid
  • Preparation method of ursodesoxycholic acid
  • Preparation method of ursodesoxycholic acid

Examples

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Effect test

Embodiment 1

[0031] A preparation method of ursodeoxycholic acid, comprising the following preparation steps:

[0032] (1) Preparation of 7,12-keto-lithocholic acid

[0033] Add 25 grams of cholic acid to 175 ml of water, add 2.52 grams of sodium hydroxide, stir and dissolve to obtain an aqueous solution of cholic acid;

[0034] Prepare 1000ml of aqueous solution containing 7α-HSDH enzyme, 12α-HSDH enzyme, riboflavin reductase, and NAD coenzyme. The concentration of 7α-HSDH enzyme activity in the solution reaches 20U / ml, 12α-HSDH enzyme 20U / ml, Enzyme activity is 40U / ml, NAD coenzyme concentration is 0.04g / L; add 0.3g riboflavin, control temperature at 28±2°C, feed air at a flow rate of 1L / min; control pH at 8.0-8.3, add bile Aqueous acid solution, continue to ventilate and stir to react to generate 7,12-keto-lithocholic acid. After 2 hours of addition, the conversion rate is monitored by HPLC every hour until the conversion rate is ≥97%;

[0035] When the conversion rate is ≥97%, filter...

Embodiment 2

[0044] A preparation method of ursodeoxycholic acid, comprising the following preparation steps:

[0045] (1) Preparation of 7,12-keto-lithocholic acid

[0046] Add 50 grams of cholic acid to 350 ml of water, add 3.42 grams of sodium hydroxide, stir and dissolve to obtain an aqueous solution of cholic acid;

[0047] Prepare 1000ml of aqueous solution containing 7α-HSDH enzyme, 12α-HSDH enzyme, riboflavin reductase and NAD coenzyme. The concentration of 7α-HSDH enzyme activity in the solution reaches 40U / ml, 12α-HSDH enzyme 40U / ml, Enzyme activity 60U / ml, NAD coenzyme concentration 0.06g / L; then add 0.5g riboflavin, control the temperature at 28±2°C, let in air, control the dissolved oxygen at 10%~70%; control the pH at 8.0~ 8.3, add the aqueous solution of cholic acid, continue to ventilate and stir the reaction to generate 7,12-keto-lithocholic acid, after 2 hours after the addition, monitor the conversion rate by HPLC every hour until the conversion rate is ≥98%;

[0048] Wh...

Embodiment 3

[0057] A preparation method of ursodeoxycholic acid, comprising the following preparation steps:

[0058] (1) Preparation of 7,12-keto-lithocholic acid

[0059] Add 75 grams of cholic acid to 500 ml of water, add 7.15 grams of sodium hydroxide, stir and dissolve to obtain an aqueous solution of cholic acid;

[0060] Prepare 1000ml of aqueous solution containing 7α-HSDH enzyme, 12α-HSDH enzyme, riboflavin reductase, and NAD coenzyme. The concentration of 7α-HSDH enzyme activity in the solution reaches 80U / ml, 12α-HSDH enzyme 80U / ml, Enzyme activity 100U / ml, NAD coenzyme concentration 0.08g / L; then add 0.6g riboflavin, control the temperature at 28±2°C, feed air at a flow rate of 1.5L / min; control the pH at 8.0-8.3, add Cholic acid aqueous solution, continue to ventilate and stir to react to generate 7,12-keto-lithocholic acid. After 2 hours of addition, the conversion rate is monitored by HPLC every hour until the conversion rate is ≥98%;

[0061] When the conversion rate is ...

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Abstract

The invention discloses a preparation method of ursodesoxycholic acid. The preparation method is characterized by comprising the following preparation steps: (1) carrying out an oxidation reaction on cholic acid under the action of 7alpha-hydroxysteroid dehydrogenase, 12alpha-hydroxysteroid dehydrogenase, coenzyme, a coenzyme regeneration system and an aqueous solution to obtain 7,12keto-lithocholic acid; (2) carrying out a reduction reaction on the 7,12 keto-lithocholic acid under the action of 7beta-hydroxysteroid dehydrogenase, coenzyme and the coenzyme regeneration system to obtain 12keto-ursodesoxycholic acid; and (3) removing a 12-site carbonyl group of the 12 keto-ursodesoxycholic acid to obtain the ursodesoxycholic acid. The process for preparing ursodesoxycholic acid takes cholic acid as a starting raw material, is sufficient in raw material supply, low in cost, suitable for industrial large-scale application, short in production flow, mild and safe in technological process and few in side reaction.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a preparation method of ursodeoxycholic acid. Background technique [0002] Ursodeoxycholic acid, referred to as UDCA, is the main component of bear bile, a precious traditional Chinese medicine. It can increase the secretion of bile acids, inhibit the synthesis of cholesterol, increase the activity of catalase in the liver, and reduce the concentration of triacylglycerol in the liver and serum. Immunomodulatory in liver diseases, therefore, used in the treatment of gallstones, cholestatic liver disease, fatty liver, primary biliary cirrhosis, various types of hepatitis, toxic liver disorders, cholecystitis, cholangitis and biliary digestion Adverse, bile reflux gastritis, eye diseases, etc. [0003] At present, the preparation methods of ursodeoxycholic acid are mainly as follows: 1. Bear bile extraction: initially the traditional Chinese medicine bear bile is made by harve...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P33/02C12P33/06
CPCC12P33/02C12P33/06
Inventor 张翔董强黄清东袁伟向世明邓治荣
Owner 四川百特芳华医药科技有限公司
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