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Enzyme process synthesis method of ursodesoxycholic acid

A technology for ursodeoxycholic acid and enzymatic synthesis, which is applied in the field of synthesis, can solve the problems of low yield and purity, and achieve remarkable effects and low production costs

Inactive Publication Date: 2018-11-23
四川百特芳华医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to solve the problem in the prior art that when ursodeoxycholic acid is prepared by using chenodeoxycholic acid, the 3-hydroxyl group is often oxidized simultaneously during the oxidation-reduction process, resulting in low yield and purity; A kind of enzymatic synthesis method of ursodeoxycholic acid that solves the above problems

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] An enzymatic synthesis method of ursodeoxycholic acid, comprising:

[0029] Step 1, making 7-KLCA as shown in formula one;

[0030] Formula 1:

[0031] Step 2, 100g 7-KLCA is added in 500mL phosphate buffer to make reaction liquid, add 55g L-sodium malate, 2g malate dehydrogenase, 0.2g 7-β steroid dehydrogenase in reaction liquid, control The reaction temperature is 25-30°C, the reaction pH is 7.0-7.5, and the reaction is carried out until the residual 7-KLCA is lower than 0.1%. After the reaction is completed, add 10g of NaOH solution with a mass fraction of 30% and heat up to 70°C and stir for 2 hours. Then cool down to normal temperature, filter, add mineral acid to the filtrate until the pH reaches 2-3, and obtain ursodeoxycholic acid after crystallization.

[0032] Wherein, the specific preparation steps of step 1 include:

[0033] Step 1.1, dissolving 100g of chenodeoxycholic acid in 1000mL of methanol solvent to make a mixed solution, adding 1.03g of sodium ...

Embodiment 2

[0039] The difference between this embodiment and embodiment 1 is that the reaction parameters of step 1 are different in this embodiment, and the specific settings are as follows:

[0040] Step 1.1, dissolving 200g of chenodeoxycholic acid in 1500mL of methanol solvent to make a mixed solution, adding 2.10g of sodium bromide to the mixed solution to configure an electrolytic system;

[0041] Step 1.2, add the electrolysis system to the electrolytic cell without diaphragm of graphite electrode, and continue to energize for 12 hours to obtain the oxidation product. The current in the electrolytic cell without diaphragm is 3A, and the reaction temperature is 5°C;

[0042] Step 1.3, add 15.42 g of dilute sulfuric acid solution with a mass fraction of 30% to the oxidation product dropwise, the reaction time is 1 h, and the reaction temperature is 40°C;

[0043] Step 1.4: Suction filtration, washing with pure water, liquid separation, drying, and concentration under reduced pressur...

Embodiment 3

[0046] The difference between this embodiment and embodiment 1 is that the reaction parameters of each step in this embodiment are different, and the specific settings are as follows:

[0047] Step 1.1, dissolving 100g of chenodeoxycholic acid in 1000mL of methanol solvent to make a mixed solution, adding 1.10g of sodium bromide to the mixed solution to configure an electrolytic system;

[0048] Step 1.2, add the electrolysis system to the electrolytic cell without diaphragm of graphite electrode, and continue to energize for 12 hours to obtain the oxidation product. The current in the electrolytic cell without diaphragm is 5A, and the reaction temperature is 0°C;

[0049] Step 1.3, add 9.42 g of dilute sulfuric acid solution with a mass fraction of 30% to the oxidation product dropwise, the reaction time is 1 h, and the reaction temperature is 35°C;

[0050] Step 1.4: Suction filtration, washing with pure water, liquid separation, drying, and concentration under reduced press...

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Abstract

The invention discloses an enzyme process synthesis method of ursodesoxycholic acid, and solves the problems that in the prior art, when chenodeoxycholic acid is used for preparing the ursodesoxycholic acid, in the oxidation reduction process, the condition that 3-bit hydroxyl groups are simultaneously oxidized often occurs, so that the yield and the purity are not high. The method comprises the following steps that 1, 7-KLCA shown as a formula I is prepared; 2, the 7-KLCA is added into phosphoric acid buffer liquid to prepare reaction liquid; L-sodium malate, malic dehydrogenase and 7-beta hydroxysteroid dehydrogenase are added into the reaction liquid; under the conditions that the reaction temperature is controlled to be 25 to 30 DEG C, and the reaction pH is 7.0 to 7.5, reaction is performed until the 7-KLCA residue is lower than 0.1 percent; after the reaction is completed, alkali is added; the temperature is raised to be 60 to 80 DEG C; stirring is performed for 1 to 3h; then, the temperature is lowered to normal temperature; filtering is performed; acid is added into filtering liquid for crystallization; the ursodesoxycholic acid is obtained. The enzyme process synthesis method has the advantages that the yield and the purity are high; the production cost is low, and the like.

Description

technical field [0001] The invention relates to a synthesis method, in particular to an enzymatic synthesis method of ursodeoxycholic acid. Background technique [0002] Chenodeoxycholic acid is the raw material for preparing ursodeoxycholic acid. In the process of preparing ursodeoxycholic acid from chenodeoxycholic acid, ursodeoxycholic acid is made from its 7-position epimer chenodeoxycholic acid. Cholic acid is oxidized to 5β-3α-hydroxyl-7-carbonyl cholic acid (7K-LCA), which is then synthesized by reduction. In the prior art, since the structure of chenodeoxycholic acid contains two hydroxyl groups, one or both of them will be oxidized theoretically during the preparation process. And technicians in this industry usually use NBS, PCC, chromium trioxide and other substances to oxidize chenodeoxycholic acid, and use metal sodium or Pd / C catalytic hydrogenation to realize the reduction of 7-ketolithocholic acid (7-KLCA) . [0003] In the prior art, although the above-me...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P33/00
CPCC12P33/00
Inventor 黄清东张翔向世明宋立波杜烨彭捷刘金凤
Owner 四川百特芳华医药科技有限公司
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