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Preparation method of ursodesoxycholic acid EP impurity I

A technology of ursodeoxycholic acid and impurities, applied in the field of medicine, to achieve the effects of high product purity, convenient product quality control, mild and simple preparation method

Pending Publication Date: 2022-03-01
ZHONGSHAN BAILING BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, no patents and technical literature reports on the preparation of ursodeoxycholic acid EP impurity I have been found, so the preparation of high-purity ursodeoxycholic acid EP impurity I and its research have certain significance

Method used

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  • Preparation method of ursodesoxycholic acid EP impurity I
  • Preparation method of ursodesoxycholic acid EP impurity I
  • Preparation method of ursodesoxycholic acid EP impurity I

Examples

Experimental program
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Effect test

Embodiment 1

[0025] The preparation method of the ursodeoxycholic acid EP impurity I (UA triol) of the present embodiment comprises the steps:

[0026] (1) Weigh 25g of UDCA, pour it into a 1000ml three-neck flask, add 75ml of methanol, 0.6g of concentrated sulfuric acid, stir and react for 2h, add 60ml of methanol, 90ml of water to cool down to about 0°C, stir for 1h, filter to obtain a wet product, and 100°C Dry for more than 4 hours to obtain 23.4g of 3α,7β-dihydroxy-5β-cholesteric acid methyl ester;

[0027] (2) Add 23.4g of 3α,7β-dihydroxy-5β-methylcholesterate and 530ml of tetrahydrofuran into a 1000ml three-neck flask, stir to dissolve, slowly add 5.96g of lithium aluminum hydride in portions, and keep Stir for about 6 hours;

[0028] (3) Add 23ml of 1:1 hydrochloric acid to quench the reaction, filter, wash the filter cake filtrate with 20ml of tetrahydrofuran at 50-55°C and concentrate in vacuum to a paste, add 180ml of acetone, stir and pulverize, cool to 4°C, stir for 1h, filte...

Embodiment 2

[0030] The preparation method of the ursodeoxycholic acid EP impurity I (UA triol) of the present embodiment comprises the steps:

[0031] (1) Weigh 25g of UDCA, pour it into a 1000ml three-necked flask, add 100ml of ethanol, 2.0g of concentrated hydrochloric acid, stir for 2 hours, add 150ml of ethanol, 90ml of water, cool down to about 0°C, stir for 1h, filter to obtain a wet product, and 100°C Dry for more than 4 hours to obtain 24.25 g of 3α,7β-dihydroxy-5β-cholesteric acid ethyl ester;

[0032] (2) Add 3α,7β-dihydroxy-5β-cholesteric acid ethyl ester and tetrahydrofuran 600ml into a 1000ml three-necked flask, stir to dissolve, cool down to 10°C, slowly add 7.5g lithium aluminum hydride in portions, and stir for about 6 hours.

[0033] (3) Add 30ml of 1:2 hydrochloric acid to quench the reaction, filter, wash the filter cake filtrate with 20ml of tetrahydrofuran at 50-55°C and concentrate in vacuum to a paste, add 220ml of acetone, stir and pulverize, cool to 10-15°C, stir ...

Embodiment 3

[0036] The preparation method of the ursodeoxycholic acid EP impurity I (UA triol) of the present embodiment comprises the steps:

[0037] (1) Weigh 25g of UDCA, pour it into a 1000ml three-neck flask, add 75ml of propanol and 1.0g of p-toluenesulfonic acid, stir for 2 hours, add 150ml of propanol, 90ml of water, cool down to about 0°C, stir for 1 hour, and filter to get wet product, dried at 100°C for over 4 hours to obtain 26.25 g of 3α,7β-dihydroxy-5β-cholesteric acid ethyl ester;

[0038] (2) Add 3α,7β-dihydroxy-5β-cholesteric acid ethyl ester and 700ml tetrahydrofuran into a 1000ml three-necked flask, stir to dissolve, cool down to 10°C, slowly add 7.5g of lithium aluminum hydride in portions, and stir for about 6 hours;

[0039] (3) Add 50ml of 1:10 hydrochloric acid to quench the reaction, filter, wash the filter cake filtrate with 20ml of tetrahydrofuran at 50-55°C and concentrate in vacuum to a paste, add 250ml of acetone, stir and pulverize, cool down to 10-15°C, sti...

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Abstract

The invention discloses a preparation method of an ursodesoxycholic acid EP impurity I. The ursodesoxycholic acid EP impurity I is prepared by taking ursodesoxycholic acid as an initial raw material through the following steps: dissolving ursodesoxycholic acid in small molecular alcohol, adding a catalyst for reaction, and crystallizing to obtain a compound B; adding the compound B into tetrahydrofuran, stirring and dissolving, slowly adding lithium aluminum hydride for reaction by several times, stirring, adding diluted hydrochloric acid for quenching reaction, filtering, washing with tetrahydrofuran, and performing vacuum concentration on filtrate to obtain paste, namely a compound C crude product; adding the crude product of the compound C into acetone, stirring, pulverizing, cooling, filtering to obtain a wet product of the compound C, and drying until the weight is basically unchanged to obtain the dried ursodesoxycholic acid EP impurity I; wherein the small molecular alcohol is straight-chain alcohol or branched-chain alcohol containing 1-4 carbon atoms; the catalyst is sulfuric acid, hydrochloric acid or p-toluenesulfonic acid. The preparation method disclosed by the invention is mild and simple, the prepared product is relatively high in purity, and the product quality is more convenient to control.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically refers to a preparation method of ursodeoxycholic acid EP impurity I. Background technique [0002] Ursodeoxycholic acid (3α,7β-dihydroxy-5β-cholesteric acid), English name: Ursodeoxycholic Acid (UDCA for short), is a non-toxic hydrophilic cholic acid, which is the 7-position of chenodeoxycholic acid The isomer can competitively inhibit the absorption of toxic endogenous bile acids in the ileum, increase the effect of cholestasis by activating a signaling network composed of calcium ions and protein kinase C, and by activating cleavage-active protein-based enzymes. 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, chroni...

Claims

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Application Information

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IPC IPC(8): C07J9/00
CPCC07J9/00
Inventor 沈惠宾罗海露皮念忠杨峻基
Owner ZHONGSHAN BAILING BIOTECHNOLOGY CO LTD
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