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Synthesis method of 3[alpha],7[beta]-dihydroxy-5[alpha]-cholanic acid

A technology of deoxycholic acid and its synthesis method, which is applied in the field of biomedicine and can solve the problems that the production of ursodeoxycholic acid cannot satisfy human beings.

Inactive Publication Date: 2021-05-18
ZHONGSHAN BAILING BIOTECHNOLOGY CO LTD
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  • Abstract
  • Description
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Problems solved by technology

[0003] With the deepening of human understanding of ursodeoxycholic acid, the use of ursodeoxycholic acid has increased significantly. The output of ursodeoxycholic acid synthesized from cholic acid and chenodeoxycholic acid extracted from chicken bile has been reduced. inability to meet human needs

Method used

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  • Synthesis method of 3[alpha],7[beta]-dihydroxy-5[alpha]-cholanic acid

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Experimental program
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preparation example Construction

[0033] Such as figure 1 Shown, a kind of synthetic method of ursodeoxycholic acid comprises the following steps:

[0034] a. Oxidation of allochodeoxycholic acid (ACDCA)

[0035] Put the bechenodeoxycholic acid into the reaction container, add the phosphate buffer with the mass volume ratio of bechenodeoxycholic acid 1g:10ml, and the concentration of the substance is 50-100mmol / L to adjust the pH of the solution to 7.5-7.8 , stirred and dissolved, then added 0.15% nicotinamide adenine dinucleotide phosphate (NADP), 0.15-0.18% lactate dehydrogenase (LDH), 0.30-0.35% 7 - α-steroid dehydrogenase (7-αHSDH), 30-35% sodium pyruvate, control the solution temperature at 25-30°C, and react at pH 7.5-8.0 until the residue of chenodeoxycholic acid in the solution The amount is less than 1%;

[0036] After the reaction is completed, raise the temperature of the solution to 50-55°C, stir for 30 minutes, and then cool down to 25-30°C;

[0037] b. Reduction reaction of allo-7-ketolithoch...

Embodiment 1

[0042] Add 10g of chenodeoxycholic acid in a 500ml reaction bottle, add 100ml of phosphate buffer solution with a substance concentration of 50mmol / L to adjust the pH of the solution to 7.8, stir and dissolve, then add 15mg NADP, 15mg LDH, 30mg 7-αHSDH, 3.3 g of sodium pyruvate, control the solution temperature at 25-30° C., and react at pH 7.5-7.8 for 5 hours, and take a sample to measure the residual amount of chenodeoxycholic acid in the solution to be 0.73%. After the reaction was completed, the temperature was raised to 55°C and stirred for 30 minutes, and then the temperature was lowered to 25-30°C.

[0043] Add 4.5g of L-sodium malate, 0.18g of MDH, and 15mg of 7-βHSDH to the above reaction solution, control the temperature of the solution at 25-30°C, and the pH to 6.8-7.2 to react for 3 hours, and take samples to detect allo-7-ketolithiasis Acid residues are less than 0.06%.

[0044] After the reaction is completed, add a small concentration of 10% sodium hydroxide to...

Embodiment 2

[0047] Add 10g of chenodeoxycholic acid to a 500ml reaction bottle, add 100ml of phosphate buffer solution with a concentration of 75mmol / L to adjust the pH of the solution to 8.0, stir and dissolve, then add 15mg of NADP, 18mg of LDH, 35mg of 7-αHSDH, 3.5 g of sodium pyruvate, the temperature of the solution was controlled at 25-30° C., and the pH was 7.5-7.8 to react for 5 hours, and the residual amount of chenodeoxycholic acid in the solution was measured to be 0.66% by sampling. After the reaction was completed, the temperature was raised to 50°C and stirred for 30 minutes, and then the temperature was lowered to 25-30°C.

[0048] Add 4.6g of L-sodium malate, 0.18g of MDH, and 16mg of 7-βHSDH to the above reaction solution, control the temperature of the solution at 25-30°C, and react at a pH of 6.8-7.2 for 3 hours, and take samples to detect allo-7-ketolithiasis Acid residues are less than 0.05%.

[0049] After the reaction is completed, add a small amount of 10% sodium hy...

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Abstract

The invention discloses a synthesis method of 3[alpha],7[beta]-dihydroxy-5[alpha]-cholanic acid. The method takes allochenodeoxycholic acid as an initial raw material and includes the following steps: adding phosphate buffer, nicotinamide adenine dinucleotide phosphate, lactate dehydrogenase, 7-[alpha]hydroxysteroid dehydrogenase and sodium pyruvate, performing reaction, and performing cooling after enzyme was inactivated through high temperature; additionally adding L-sodium malate, malate dehydrogenase and 7-[beta]hydroxysteroid dehydrogenase to react, and performing cooling to room temperature after the enzyme was inactivated through high temperature; and obtaining the 3[alpha],7[beta]-dihydroxy-5[alpha]-cholanic acid through filtration, washing and drying. The overall process of the method includes the oxidation and reduction steps of the allochenodeoxycholic acid and the synthesis of the 3[alpha],7[beta]-dihydroxy-5[alpha]-cholanic acid. The whole reaction of the method is conducted in an aqueous solution without using organic solvents; the method is simple in technology and easy to operate; and the purity of the obtained 3[alpha],7[beta]-dihydroxy-5[alpha]-cholanic acid can reach more than 98.5%, and the obtained 3[alpha],7[beta]-dihydroxy-5[alpha]-cholanic acid can be used as samples of pharmaceutical properties such as toxicology and pharmacology in pharmaceutical research institutions and can also be used as impurity reference substances during quality research of ursodeoxycholic acid.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a method for synthesizing ursodeoxycholic acid. Background technique [0002] Ursodeoxycholic acid UDCA is a non-toxic hydrophilic cholic acid, which can competitively inhibit the absorption of toxic endogenous cholic acid in the ileum, by activating the signaling network composed of calcium ions and protein kinase C, and by activating the cleavage activity Protein-based enzymes to increase the cholestatic effect. Ursodeoxycholic acid can also competitively replace toxic cholic acid molecules on cell-running organelles, preventing hepatocytes and cholangiocytes from being damaged by more toxic cholic acids. Clinically, ursodeoxycholic acid is mainly used to dissolve cholesterol gallstones, primary biliary cirrhosis PBC, chronic hepatitis C, and also used for alcoholic liver disease, non-alcoholic fatty liver, benign recurrent intrahepatic Cholestasis, congenital...

Claims

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Application Information

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IPC IPC(8): C12P33/00C12P33/02
CPCC12P33/00C12P33/02
Inventor 秦和平张和平祝国祥林志锋凌芬娜
Owner ZHONGSHAN BAILING BIOTECHNOLOGY CO LTD
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