Study On Hydroxyl Oxidation Activity Of Bile Acid And Synthesis Of Ursodeoxycholic Acid

Bile acid is a natural steroidal organic compound with very important biological functions.Ursodeoxycholic acid(UDCA)is the main component of bear bile and has the functions of sterilization,anti-inflammation and dissolving gallstones,so it has become the preferred drug for the treatment of liver diseases.UDCA was initially extracted from bear bile.Because of the limited resources of live bears and the violation of animal protection methods,it was synthesized from cholic acid(CA)after a large number of clinical applications.Because the process of synthesizing UDCA from chenodeoxycholic acid(CDCA)is simpler than that from CA,and the production cost is lower,with the maturity of extraction technology of CDCA and large-scale production,CDCA has gradually replaced CA as the main raw material for the production of UDCA.However,there are still some shorcomings in the industrial application of the synthesis of UDCA from CDCA.In order to find a more suitable production process for industrial application,this paper carried out the research of the synthesis of UDCA from CDCA.In order to determine the optimum conditions of the synthesis of UDCA and provide the organic basis for the synthesis of UDCA from different bile acids,the oxidation activity sequence of hydroxyl groups on steroid skeleton of different bile acids was also studied in this paper.Finally,the organic synthesis process with simple operation,high chemical yield,good stereo selectivity and simple product separation was selected to complete the synthesis of UDCA.Specific work and achievements are as follows:1.Using NBS as oxidant,the oxidation order of hydroxyl groups on the steroidal skeleton of bile acid was obtained.The order of hydroxyl oxidation activity of HDCA was C3>C6;that of CDCA was C7>C3;that of CA was C7>C3>C12;and that of BCA was C7>C3>C12.2.UDCA was synthesized from CDCA by esterification,3a-OH acetylation protection,7a-OH configuration conversion and alkali hydrolysis.In the process of esterification,the effects of catalyst,feed ratio and reaction time on the yield were studied.The optimum conditions were as follows:p-toluene sulfonic acid as catalyst,the feed ratio was 1:0.1 g/g,the reaction time was 2 h,and the yield was 98%.In the process of acetylation to protect 3a-OH,the effects of hydroxyl protection group,feed ratio and reaction time on the yield were studied.The optimum conditions were as follows:acetic anhydride as hydroxyl protection group,the feed ratio was 1:1.5 g/g,the reaction time was 7 h,and the yield was 92%.In the process of 7a-OH configuration conversion,the effects of feed ratio and reaction time on the yield were studied.The optimum conditions were as follows:the feed ratio was 1:0.8 g/g,the reaction time was 24 h,and the yield was 85%.In the process of alkali hydrolysis to obtain UDCA,the effects of solid-liquid ratio and reaction time on the yield were studied.The optimum conditions were as follows:the solid-liquid ratio was 1:20 g/mL,the reaction time was 1.5 h,and the yield was 80%,the purity was 92%.3.The structures of the synthesized products were characterized by IR,IHNMR and XRD.