Method for preparing ursodesoxycholic acid on basis of chemical oxidation and enzyme catalysis combination technology

A technology of ursodeoxycholic acid and chemical oxidation is applied in the field of preparing ursodeoxycholic acid based on the combined technology of chemical oxidation and enzyme catalysis, and can solve the problems of lack of market competitiveness, high pollution, high energy consumption and the like

Active Publication Date: 2017-03-22
陕西岳达德馨生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The traditional chemical synthesis method of UDCA has a series of problems such as complex reaction process, low selectivity, harsh reaction conditions, high energy consumption, and large pollution, so the industrialization process of UDCA is limited
[0004] In addition, the method of preparing ursodeoxycholic acid based on combined enzyme catalysis technology is currently relatively common. The biological combined enzyme catalysis method overcomes various shortcomings of traditional chemical methods, but the biological combination The cost of oxycholic acid is relatively high, and the price of ursodeoxycholic acid produced by biological combination enzyme catalysis is relatively expensive, so there is no market competitiveness
Based on several traditional methods for preparing ursodeoxycholic acid, we have improved the preparation scheme of ursodeoxycholic acid, which overcomes the disadvantages of chemical methods such as danger, high energy consumption, large pollution, and low selectivity, and combines the Based on the advantages of high selectivity of biocatalytic method, a new idea and new method for preparing ursodeoxycholic acid with high efficiency and low cost are proposed

Method used

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  • Method for preparing ursodesoxycholic acid on basis of chemical oxidation and enzyme catalysis combination technology
  • Method for preparing ursodesoxycholic acid on basis of chemical oxidation and enzyme catalysis combination technology
  • Method for preparing ursodesoxycholic acid on basis of chemical oxidation and enzyme catalysis combination technology

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Experimental program
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Effect test

Embodiment 1

[0009] The method for oxidizing chenodeoxycholic acid to generate intermediate 7-carbonyl-lithocholic acid by chemical oxidation method specifically comprises the following steps:

[0010] (1) Dissolve 6 g of chenodeoxycholic acid in 10 times the volume of acetone aqueous solution. The volume ratio of acetone to water is 2.7:1. After it is completely dissolved, add 4 g of NBS and stir at 30 ° C for 1.5 h. After the reaction is complete, add 40% NaHSO 3 , Diluted with 500ml of water to precipitate the product.

[0011] (2) Filter the reaction solution I, dry the product, and dry it to obtain white and loose 7-carbonyl-lithocholic acid powder I.

Embodiment 2

[0013] Content Analysis of Raw Material CDCA

[0014] Take about 0.1g of powder I in a 50ml volumetric flask, add an appropriate amount of methanol, and dissolve it by ultrasonication (power 300W, frequency 25kHz) for 5 minutes, dilute to the mark with methanol, shake well, filter, take the filtrate, 10l, pass through high performance liquid chromatography instrument, using a vapor luminescence scattering detector, to record the chromatogram figure 1 , the chromatogram is analyzed, and the percentage content of CDCA is 98%. The control substance CDCA comes from the China Institute for the Control of Pharmaceutical and Biological Products.

Embodiment 3

[0016] Content Analysis of 7K-LCA in Powder Ⅰ after Reaction Liquid Ⅰ Treatment

[0017] Take about 0.1g of powder I in a 50ml volumetric flask, add an appropriate amount of methanol, and dissolve it by ultrasonication (power 300W, frequency 25kHz) for 5 minutes, dilute to the mark with methanol, shake well, filter, take the filtrate, 10l, pass through high performance liquid chromatography instrument, using a vapor luminescence scattering detector, to record the chromatogram figure 2 , the chromatogram is analyzed, and the percentage content of 7K-LCA is 99%. The reference substance 7K-LCA was from the China Institute for the Control of Pharmaceutical and Biological Products.

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Abstract

The invention discloses a new thought of generating 7-carbonyl-lithocholic acid by virtue of chenodeoxycholic acid dissolved by NBS acetone peroxide, and carrying out catalytic synthesis on the 7-carbonyl-lithocholic acid (7k-LCA) in combination with biological enzyme catalysis to obtain ursodesoxycholic acid (UDCA). The new thought is characterized by comprising the following steps: generating a catalytic enzyme (7 beta-HSDH) with high purity, high activity and high stability by virtue of the characteristics of high efficiency and low cost of the method of generating 7-carbonyl-lithocholic acid by virtue of chenodeoxycholic acid dissolved by NBS acetone peroxide and in combination with high-density fermentation of recombinant escherichia coli, and selectively catalyzing 7k-lithocholic acid in an aqueous phase to generate the ursodesoxycholic acid (UDCA). The synthesis process is simple, short in synthesis route, high in conversion rate and low in cost, and is a novel method for preparing ursodesoxycholic acid on the basis of a chemical oxidation and enzyme catalysis combination technology.

Description

technical field [0001] The present invention relates to the comprehensive field of chemical oxidation and biotechnology, in particular to a method for preparing ursodeoxycholic acid by a combination of chemical oxidation and biological enzyme catalysis redox method, the method is based on the oxidation of chenodeoxycholic acid in acetone by NBS to generate 7-carbonyl-lithocholic acid, and then use the 7β-hydroxysteroid dehydrogenase (7β-HSDH) produced by the high-density fermentation of recombinant Escherichia coli, combined with the role of coenzymes, to catalyze the conversion of 7-carbonyl-lithocholic acid into ursodeoxy cholic acid method. Background technique [0002] Ursodeoxycholic acid, English name: ursodesoxycholic acid (UDCA), is a commonly used bulk medicinal material. It is recorded in the "Chinese Pharmacopoeia" and the American Pharmacopoeia. Use a lot. Domestically, it is mainly used for the treatment of gallstones, cholecystitis, cholangitis, biliary dyspe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P33/00
CPCC12P33/00
Inventor 张天杨眉
Owner 陕西岳达德馨生物制药有限公司
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