Synthesis Of Obeticholic Acid And Optimization Of The Preparation Process

Objective:The incidence and prevalence of primary biliary cirrhosis are increasing year by year,but the commonly used usodeoxycholic acid?UDCA?is often limited due to poor response or intolerance,so new developments have been developed.The treatment of primary biliary cirrhosis drugs is particularly urgent.Obeticholic acid?OCA?,developed by Intercept Pharmaceuticals of the United States under the trade name Ocaliva,is a potent agonist of farnesoid X receptor?FXR?and is stimulated by FXR.The body regulates a series of gene expression including cholic acid and cholesterol,and treats primary biliary cirrhosis with poor response or intolerance to ursodeoxycholic acid,and has high safety.On the basis of summarizing and analyzing the synthetic routes reported in many literatures,this paper selects a synthetic route that is cheap and easy to obtain,simple and controllable,and meets the requirements of green industry.The synthesis process of oleic acid is carried out.Improvement and optimization to provide a basis for industrial production.Methods:Obeticholic acid was synthesized from?E?-3-hydroxy-6-ethylene-7-keto-5-cholane-24-acid via the reactions including the double bound hydrogenation,inversion of?-ethyl's configuration,and stereospecific reduction of carbonyl group.Every step was optimized and the crystal form of obeticholic acid was studied.The structure of compounds were confirmed by MS,¹H NMR,¹³C NMR and 2D NMR.The crystal of compound 1,compound 2 and obeticholic acid were cultivated and the chemical structure was confirmed through X-ray diffractometer.The related impurities were prepared to establish the quality standard of obeticholic acid.Results:Optimize the route and find the suitable route for industrial production.The purity of obeticholic acid is not less than 99.5%by HPLC,the single impurity is not more than 0.1%by HPLC,with the overall yield about 72.7%.Five impurities were prepared and confirmed.Conclusion:An industrial process for the preparation of obeticholic acid has been developed,available for the safety and quality control as well as the quality improvement of final products,which could meet the registration requirements of Center for Drug Evalution?CDE?.