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7-ketone lithocholic acid intermediate, preparation method and applications thereof

An intermediate and cornerstone technology, applied in the field of 7-ketolithocholic acid intermediate and its preparation, can solve the problems of waste of resources, environment, separation difficulties, pollution, etc., and achieve mild and not harsh reaction conditions, simple process flow, and safety factor high effect

Active Publication Date: 2019-11-12
成都百途医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] my country is a big pork consumption country, and pig gall is rich in resources. At present, the utilization method of pig gall is mainly to extract and utilize chenodeoxycholic acid and hyodeoxycholic acid, which account for nearly 20% of the total bile acid content in pig gall paste. % of pig bile acid has not been effectively utilized, mostly discarded as leftovers, resulting in huge waste of resources and environmental pollution
[0009] In the 1980s, Zhou Weishan’s research group conducted research on the comprehensive utilization of hyocholic acid, expecting to use hyocholic acid to prepare ursodeoxycholic acid (Chinese Science (B Series) [M].1991,7:680) , but this route needs multiple selective protection, deprotection, oxidation and other processes, there will be a variety of impurities obtained due to incomplete selectivity, the reported yield is only 38%, and this method cannot directly prepare 7-ketone Instead, 3,6-diketone-5α-cholanic acid is obtained as the cornerstone cholic acid. When the compound is reduced, some chiral isomers of 3β will appear, which makes separation difficult and difficult for industrial production.

Method used

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  • 7-ketone lithocholic acid intermediate, preparation method and applications thereof
  • 7-ketone lithocholic acid intermediate, preparation method and applications thereof
  • 7-ketone lithocholic acid intermediate, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] In this example, R 1 is methyl, R 2 is acetyl, R 3 For methanesulfonyl.

[0068] The preparation method of 7-keto lithocholic acid intermediate comprises the following steps:

[0069] Step 1: Dissolve 5kg of hyocholic acid in 50kg of methanol, add 300g of sulfuric acid, heat up to reflux and stir for 3 hours, TLC monitors that the reaction is complete, stop the reaction, concentrate to remove the solvent, a large amount of solids are precipitated, filter to obtain intermediate 1, and vacuum-dry Obtain 5kg of white solid;

[0070] Step 2: Dissolve 2kg of intermediate 1 in 20kg of acetone, add 100g of sulfuric acid and 3kg of 2,2-dimethoxypropane, heat up to reflux and stir for 2 hours, TLC monitors the reaction is complete, stop the reaction, concentrate to remove the solvent, a large amount of solid Precipitation, filtration to obtain intermediate 2, 2.1 kg of white solid dried in vacuum at 50°C;

[0071] Step 3: Dissolve 1 kg of intermediate 2 in 10 kg of acetic a...

Embodiment 2

[0079] In this example, R 1 is methyl, R 2 is acetyl, R 3 For methanesulfonyl.

[0080] The preparation method of 7-keto lithocholic acid intermediate comprises the following steps:

[0081] Step 1: Dissolve 5kg of hyocholic acid in 50kg of methanol, add 300g of sulfuric acid, heat up to reflux and stir for 3 hours, TLC monitors that the reaction is complete, stop the reaction, concentrate to remove the solvent, a large amount of solids are precipitated, filter to obtain intermediate 1, and vacuum-dry Obtain 5kg of white solid;

[0082] Step 2: Dissolve 2kg of intermediate 1 in 20kg of toluene, add 100g of methanesulfonic acid and 3kg of 2,2-dimethoxypropane, heat up to reflux and stir for 2 hours, TLC monitors the reaction is complete, stop the reaction, concentrate to remove the solvent, A large amount of solids were precipitated, and Intermediate 2 was obtained by filtration, and 2.1 kg of white solids were dried under vacuum at 50°C;

[0083] Step 3: Dissolve 1 kg of ...

Embodiment 3

[0091]This embodiment is based on embodiment 1 or embodiment 2, and the difference with embodiment 1 or embodiment 2 is:

[0092] The second step: the preparation of intermediate 7:

[0093] Dissolve 10g of intermediate 6 in 200g of methyl isobutyl ketone, add 36.4g of lithium iodide, 16g of fully activated zinc powder and 10g of deionized water, reflux and stir for 72 hours, stop the reaction, TLC monitors that the reaction is complete, stop For the reaction, the reaction liquid was dropped into 400 g of deionized water, a large amount of solids were precipitated, and the intermediate 7 was obtained by filtration, and vacuum-dried at 50° C. to obtain 6.8 g of white solids.

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Abstract

The invention discloses a 7-ketone lithocholic acid intermediate, a preparation method and applications thereof. The preparation method comprises: carrying out an esterification reaction on hyocholicacid as a starting raw material; adding 2,2-dimethylpropane to carry out a reaction with the unique 6,7 synclastic hydroxyl structure to form cross protection; selectively protecting the 3-site hydroxyl group; selectively linking the leaving group to the 6-site to form a 7-ketone lithocholic acid intermediate by using the special spatial structure of hyocholic acid; selectively oxidizing the unique 7-site exposed hydroxyl group of the 7-ketone lithocholic acid intermediate to form an alpha hydroxyketone intermediate with a leaving group linked to the 6-site; simultaneously and directly removing the 6-site hydroxyl group and the leaving group by using the hydroxyketone to form an intermediate 7; and removing the protection group through simple hydrolysis of the intermediate 7 to obtain the7-ketone lithocholic acid. According to the present invention, the 7-ketone lithocholic acid prepared by the method has high purity, and the method has characteristics of simple process and no specialpurification method, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of preparation technology of important intermediates of cholic acid drugs, in particular to 7-ketolithocholic acid intermediates, preparation methods and applications thereof. Background technique [0002] 7-ketolithocholic acid is an important pharmaceutical intermediate, and it is the main starting material for the preparation of ursodeoxycholic acid, obeticholic acid, taurine ursodeoxycholic acid and other cholic acid drugs. [0003] Ursodeoxycholic acid is an important hepatobiliary drug. It has clear curative effect on gallbladder cholesterol stones, cholestatic liver disease, bile reflux gastritis and other hepatobiliary diseases. The ancient preparation method of ursodeoxycholic acid mainly Extracted from bear bile. In recent years, the scheme of directly extracting ursodeoxycholic acid from bear bile has been gradually replaced by the scheme of chemically synthesizing ursodeoxycholic acid due to the limitation...

Claims

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Application Information

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IPC IPC(8): C07J9/00
CPCC07J9/005Y02P20/55
Inventor 蒋宁赵卫袁华杰
Owner 成都百途医药科技有限公司
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