7-ketolithocholic acid intermediate and its preparation method and application

Abstract

The invention discloses a 7-ketolithocholic acid intermediate and its preparation method and application. The invention uses hyocholic acid as a starting material, first performs esterification reaction, and then adds 2,2-dimethylpropane and hyocholic acid The unique 6,7 hydroxyl structure reacts to form parallel fork protection, and then selectively protects the 3-position hydroxyl group, and then uses the special space structure of hyocholic acid to selectively connect the leaving group to the 6-position to form 7-ketone Keystone cholic acid intermediate, 7-ketolithocholic acid intermediate unique 7-position exposed hydroxyl group, selective oxidation of 7-position hydroxyl group to form α-hydroxy ketone intermediate 6 with 6-position connecting leaving group, this type of hydroxyketone can be directly The hydroxyl group at the 6th position and the leaving group are removed simultaneously to form intermediate 7, and intermediate 7 can be deprotected by simple hydrolysis to obtain the target product 7-ketolithocholic acid. The 7-ketolithocholic acid prepared by the method of the present invention not only has high purity, but also has a simple process flow and no special purification method in the preparation process, which 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...

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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.

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