Research And Optimization Of The Synthesis Process Of Obeticholic Acid

In 2016,a new class of new drug structure,Obeticholic acid,developed by Intercept Pharmaceuticals Inc.of the United States,was approved by the FDA.Obeticholic acid is a farnesol X receptor(FXR)agonist and the first drug used in clinical treatment of primary biliary cirrhosis(PBC)and nonalcoholic fatty liver disease(NAFLD)in the past 20 years.With the improvement of China's economic level,the prevalence of PBC and NAFLD in China has increased rapidly,and the demand for Obeticholic acid has also increased rapidly.Intercept's patent for Obeticholic acid will expire in 2022.In order to reduce medical expenses,improve patients' quality of life,and meet domestic clinical needs,it is of great practical significance to develop a process route suitable for industrial production.Based on the publicly reported synthetic process,this paper chooses the source of rich and inexpensive chenodeoxycholic acid as raw material.The process is as follows: 1)firstly selectively oxidize the 7-hydroxyl group of chenodeoxycholic acid(III)with 1.4 times equivalent of NBS at 0 ° C in the dark;2)using concentrated sulfuric acid Catalytic reaction of methanol with compound II to form 3?-hydroxy-7-oxo-5?-cholanoic acid-24-methyl ester(IV);3)nitrogen protection,compound IV and trimethyl in the presence of LDA The chlorosilane is reacted at-45 °C to form 3?,7-bis(trimethylsiloxy)-6-ene-5?-cholanoic acid-24-methyl ester(V);4),after nitrogen protection at-45 °C Under the conditions,compound V and acetaldehyde reacted under the action of boron trifluoride diethyl ether to form 3?-hydroxy-6-ethylidene-7-one-5?-cholanoic acid-24-methyl ester(VI);5)room temperature conditions Reduction of the carbonyl group of compound V to a hydroxyl group using sodium borohydride to form 3?,7?-dihydroxy-6-vinyl-5?-cholanoic acid-24-methyl ester(VII);6)further use of palladium carbon for olefin Hydrogenation to form 3?,7?-dihydroxy-6-ethyl-5?-cholanoic acid-24-methyl ester(VIII);7)Finally,hydrolysis reaction is carried out under the action of sodium hydroxide to obtain the target product Aobe Cholic acid(6-ethyl goose goes Oxycholic acid,I),confirmed by NMR and HRMS,the total yield was 36.4%.The method used in this paper is cheap,easy to obtain,has good selectivity,simple route,high yield,simple post-treatment of the product,and has the potential for large-scale production.