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Method for purifying ursodeoxycholic acid

A technology of ursodeoxycholic acid and a purification method, which is applied in the field of purification of ursodeoxycholic acid, can solve the problems of high energy consumption, prolonged production cycle, and many steps, and achieve good selectivity, low reagent consumption, and easy operation. simple effect

Inactive Publication Date: 2020-01-10
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Chenodeoxycholic acid, but the solubility of the two kinds of cholic acid in ethyl acetate is very small, and it needs to use a large amount of solvent for multiple purifications to remove the chenodeoxycholic acid, which consumes too much energy
In organic solvents such as ethanol, the solubility of the two bile acids is very large, and the difference in solubility between the two is not obvious when the temperature is changed, and they cannot be crystallized.
U.S. Patent (US4282161) once reported a method for purifying ursodeoxycholic acid, using methanol to process crude ursodeoxycholic acid to generate ursodeoxycholic acid methyl ester, then crystallize with ethyl acetate, and then use alkaline Alkali saponification produces alkali metal ursodeoxycholic acid, and finally acidifies to obtain pure ursodeoxycholic acid. This invention includes three processes of esterification, saponification and hydrolysis. There are many steps, which will lead to prolongation of the production cycle and the product Large loss, not suitable for industrial production
Another Chinese patent (CN106928306A) discloses purification of crude ursodeoxycholic acid by triethylamine treatment, the main disadvantage is that it is difficult to reach the pharmaceutically acceptable limit of triethylamine

Method used

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  • Method for purifying ursodeoxycholic acid
  • Method for purifying ursodeoxycholic acid
  • Method for purifying ursodeoxycholic acid

Examples

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Embodiment 1

[0024] Dissolve 10 g of crude ursodeoxycholic acid containing 95% in 100 mL of tetrahydrofuran, stir and heat up to 55 ° C, add 3.29 g of diisopropylethylamine, and react at 65 ° C for 1 hour, then cool the resulting slurry to 0-5°C, suction filter the crystals, rinse the filter cake with an appropriate amount of tetrahydrofuran, and dry under reduced pressure at 55-60°C to obtain 13 g of ursodeoxycholic acid diisopropylethylammonium salt.

[0025] Suspend the above diisopropylethylammonium ursodeoxycholic acid in 260mL of ultrapure water, add 20% aqueous sodium hydroxide solution, adjust the pH to 12.0 at 25-30°C; then extract the solution with dichloromethane Finally, put it into the reaction bottle, stir and heat up to 45°C, add 5% dilute hydrochloric acid dropwise to adjust the pH to 2.0, cool the slurry to 20°C, crystallize, filter with suction, rinse the residual acid solution with ultrapure water, collect and dry, and obtain Pure ursodeoxycholic acid 9.2g.

Embodiment 2

[0027] Dissolve 10 g of crude ursodeoxycholic acid containing 85% in 100 mL of tetrahydrofuran, stir and heat up to 60 °C, add 3.25 g of diisopropylethylamine, and react at 65 °C for 40 min, then cool the resulting slurry to 0 -5°C, the crystals were suction-filtered, the filter cake was washed with an appropriate amount of tetrahydrofuran, and dried under reduced pressure at 55-60°C to obtain 12.5 g of ursodeoxycholic acid diisopropylethylammonium salt.

[0028] Suspend the above diisopropylethylammonium ursodeoxycholic acid in 250mL ultrapure water, add 20% aqueous sodium hydroxide solution, adjust the pH to 12.2 at 25-30°C; then extract the solution with dichloromethane Finally, put it into the reaction bottle, stir and heat up to 48°C, add 5% dilute hydrochloric acid dropwise to adjust the pH to 2.4, cool the slurry to 25°C, crystallize, filter with suction, rinse the residual acid solution with ultrapure water, collect and dry, and get Pure ursodeoxycholic acid 8.9g.

Embodiment 3

[0030] Dissolve 10 g of crude ursodeoxycholic acid containing 80% in 100 mL of tetrahydrofuran, stir and heat up to 50 ° C, add 3.3 g of diisopropylethylamine, and react at 65 ° C for 1.5 hours, then cool the resulting slurry to 0-5°C, suction filter the crystals, rinse the filter cake with an appropriate amount of tetrahydrofuran, and dry under reduced pressure at 55-60°C to obtain 13.2 g of ursodeoxycholic acid diisopropylethylammonium salt.

[0031] Suspend the above diisopropylethylammonium ursodeoxycholic acid in 250mL ultrapure water, add 20% aqueous sodium hydroxide solution, adjust the pH to 12.5 at 25-30°C; then extract the solution with dichloromethane Finally, put it into the reaction bottle, stir and heat up to 50°C, add 5% dilute hydrochloric acid dropwise to adjust the pH to 2.5, cool the slurry to 22°C, crystallize, filter with suction, rinse the residual acid solution with ultrapure water, collect and dry, and obtain Pure ursodeoxycholic acid 8.7g.

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Abstract

The invention discloses a method for purifying ursodeoxycholic acid. The method comprises: 1) dissolving a ursodeoxycholic acid-containing mixture in tetrahydrofuran, adding diisopropylethylamine, andcarrying out a reaction to prepare a ursodeoxycholic acid diisopropylethylammonium salt-containing solution; 2) cooling the ursodeoxycholic acid diisopropylethylammonium salt-containing solution at 0-5 DEG C to crystallize the solution, and then performing separation to obtain ursodeoxycholic acid diisopropylethyl ammonium salt; and 3) hydrolyzing the ursodeoxycholic acid diisopropylethyl ammonium salt. The method has the advantages of simplicity in operation, low reagent consumption, high selectivity, and high purity of the obtained ursodeoxycholic acid.

Description

technical field [0001] The invention relates to the field of fine chemicals, in particular to a method for purifying ursodeoxycholic acid. [0002] technical background [0003] Ursodeoxycholic acid (UDCA), also known as 3a,7β-dihydroxy-5β-cholestane-24-acid, is one of the active ingredients of traditional Chinese medicine bear bile, which has the functions of improving eyesight, clearing away heat, calming the liver, etc. Important functions. For centuries, ursodeoxycholic acid has been used to treat liver and gallbladder diseases, especially for the treatment of cholesterol-type gallstones, and can maintain the dynamic balance of enterohepatic circulation in the body. So far, ursodeoxycholic acid is the only drug approved by the US Food and Drug Administration (FDA) for the treatment of primary biliary cirrhosis. [0004] Given the importance of ursodeoxycholic acid, there is an increasing demand for its clinical application. At first, it was mainly extracted from natural...

Claims

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Application Information

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IPC IPC(8): C07J9/00
CPCC07J9/005
Inventor 郭鹏郭梦芹张艺铭
Owner WUHAN UNIV
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