Synthetic Technology Of Obeticholic Acid

At present,liver disease has become a threat to human survival and social development.Liver diseases like hepatitis,fatty liver still can not be effectively treated.Therefore,looking for a better drug for treatment of liver disease is imminent.Obeticholic acid is a farnesol X receptor agonist,through the activation of farnesol X receptor,indirect inhibition of cytochrome 7A1(CYP7A1)gene expression.Because CYP7A1 is the rate-limiting enzyme for biosynthesis of cholic acid,it can promote the synthesis of cholic acid for the treatment of primary biliary cirrhosis and non-alcoholic fatty liver disease.Starting from chenodeoxycholic acid,via oxidation,esterification,electrophilic addition,catalytic hydrogenation,hydrolysis,obeticholic acid was obtained.The total product yield was 35%.The structure of the target product as well as that of the intermediates of each reaction were confirmed by 1HNMR and MS.Comparing to the reaction conditions of each step,optimal conditions were that:In oxidation reaction,chenodeoxycholic acid was oxidized by N-bromosuccinimide,n(chenodeoxycholic acid):n(N-bromosuccinimide)=1:1.5;In electrophilic addition reaction,tert-Butyldimethylsilyl chloride was used as group protection first,and then with acetaldehyde in addition reaction,n(3?-hydroxy-7-cheto-5?-cholan-24-oate):n(triethylamine):(tert-Butyldimethylsilyl chloride)=1:2:2.2;In reduction reaction,the first was hydrogenation,then was reduction with sodium borohydride carbonyl,and finally was hydrolysis by sodium hydroxide,n(3 a-hydroxy-6-ethylidene-7-cheto-5 p-cholan-24-oate):n(sodium borohydride)= 1:6.The product is a new drug for the primary biliary cirrhosis and nonalcoholic fatty liver.This paper describes a new synthetic technology of obeticholic acid.The method has the following advantages:(1)We didn't use LDA and other hazardous substances,the reaction conditions are mild,we improved the condition in the low-temperature environment,and we can operate at atmospheric pressure without hydrogenation,operation was simple and it was easy for experiment Chamber preparation and industrial production.(2)We used metacetaldehyde as a precursor of acetaldehyde to solve the purity of acetaldehyde and difficulty of store.(3)The separation and purification of each step reaction product was simple,the yield was higher.(4)Our raw materials were required by the industrial production,their price was low and they were easy to get.