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7-ketolithocholic acid intermediate and preparation process and application thereof

A preparation process and a technology for an intermediate, which are applied to a 7-ketolithocholic acid intermediate and its preparation process and application field, can solve the problems of waste of resources, environment, separation difficulties, pollution and the like, achieve mild reaction conditions, simplify the reaction route, The effect of high safety factor

Active Publication Date: 2019-11-08
成都百途医药科技有限公司 +1
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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-ketolithocholic acid intermediate and preparation process and application thereof
  • 7-ketolithocholic acid intermediate and preparation process and application thereof
  • 7-ketolithocholic acid intermediate and preparation process and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] In this example, R 1 is methyl, R 2 is trimethylsilyl, R 3 For methanesulfonyl.

[0064] The preparation technology of 7-keto lithocholic acid intermediate comprises the following steps:

[0065] 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;

[0066] Step 2: Dissolve 2kg of intermediate 1 in 20kg of dichloromethane, add 2kg of trimethylchlorosilane and 1.2kg of triethylamine, heat up to reflux and stir for 2 hours, TLC monitors that 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;

[0067] Step ...

Embodiment 2

[0074] In this example, R 1 is methyl, R 2 is dimethyl tert-butylsilyl, R 3 For methanesulfonyl.

[0075] The preparation technology of 7-keto lithocholic acid intermediate comprises the following steps:

[0076] 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;

[0077] Step 2: Dissolve 2kg of intermediate 1 in 20kg of toluene, add 2kg of dimethyl tert-butylchlorosilane and 1.3kg of imidazole, heat up to reflux and stir for 2 hours, TLC monitors that the reaction is complete, stop the reaction, concentrate to remove the solvent, and a large amount of solid Precipitation, filtration to obtain intermediate 2, 2.1 kg of white solid dried in vacuum at 50°C;

[0078] Step 3: Dissolve 1kg ...

Embodiment 3

[0085] This embodiment is based on embodiment 1 or embodiment 2, and the difference with embodiment 1 or embodiment 2 is:

[0086] The second step: the preparation of intermediate 5:

[0087] Dissolve 10g of intermediate 4 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 solution was dropped into 400 g of deionized water, a large amount of solids were precipitated, and intermediate 5 was obtained by filtration, and dried in vacuum at 50° C. to obtain 6.8 g of white solids.

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Abstract

The invention discloses a 7-ketolithocholic acid intermediate and a preparation process and an application thereof. Hyocholic acid is utilized as a starting material, an esterification reaction is carried out first, then a silane protection group protects a 3-hydroxyl group with high selectivity, then a specific spatial structure of 6,7-hydroxyl group of the hyocholic acid is utilized, a conventional protection method can be selectively connected to a strong leaving group at 6-position to obtain the 7-ketolithocholic acid intermediate, and the 7-ketolithocholic acid intermediate is subjected to oxidation, removal, reduction, and hydrolysis to remove a protection group to obtain a target product 7-ketolithocholic acid. The 7-ketolithocholic acid prepared by the process is high in degree ofpurity, is also simple in process step, enables a synthetize route to be greatly simplified, and enables the industrialization cost to be saved.

Description

technical field [0001] The invention relates to the field of preparation technology of important intermediates of cholic acid drugs, in particular to a 7-ketolithocholic acid intermediate and its preparation technology and application. 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 limitati...

Claims

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Application Information

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IPC IPC(8): C07J31/00C07J9/00
CPCC07J9/005C07J31/006Y02P20/55
Inventor 袁华杰赵卫许日泉蒋宁
Owner 成都百途医药科技有限公司
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