A Novel Synthetic Approach Of Alloursodeoxycholic Acid And Ursodeoxycholic Acid

The Steroids are widely found in nature and have exhibited significant biological activities. Ursodeoxycholic acid (UCDA) is naturally occurring hydrophilic bile acid. UCDA is found in minute quantities in human bile and in larger quantities in the bile of certain species of bears. Due to the limited resources of the bear and it is our duty to protect them, the price of natural bear bile powder is very expensive and difficult to obtain. The ursodeoxycholic acid is known as a product of considerable interest in human therapy, it is of great significance to synthesize it by chemical methods. hydeoxycholic acid (HDCA) and chenodeoxycholic acid (CDCA) are natural steroids from bile which are abundant in nature. To synthesize ursodeoxycholic acid from the low-priced and natural abundant Hydeoxycholic acid has the advantages of low cost, simple operation and good yields. The chenodeoxycholic acid and the ursodeoxycholic acid has a great similarity in the structure. It has the advantages of short synthetic steps, good stereoselectivity to synthesize ursodeoxycholic acid from chenodeoxycholic acid. Both synthetic route to ursodeoxycholic acid from chemical methods is of great importance for ursodeoxycholic acid drugs and biochemical product development In order to use the natural abundant bile acid effectively as well as meet the needs for ursodeoxycholic acid, the thesis aims at the studies on the semisynthesis of ursodeoxycholic acid and alloursodeoxycholic acid from low-priced and natural abundant hydeoxycholic acid or chenodeoxycholic acid. Thethesis mainly included the following aspects of work:1、Introduce the structure, the classification, pharmacological activity, clinical application of the steroidal compounds and the prior synthesis methods of ursodeoxycholic acid briefly.2、A novel and highly efficient synthetic approach of alloursodeoxycholic acid, starting from hydeoxycholic acid in9steps with overall yield25%, was reported. The key intermediate4was prepared in good yield by improved allylic oxidation of3. The critical steps to stereoselectively inverse the configuration of5and α,β-unsaturated carbonyl reduction of6were realized under Mistunobu coditions and Luche reduction respectively. The synthetic approach have the advantages of easy availability of starting materials, highly stereoselective, easily work-up and good overall yield, so it has considerable practical value.3、A novel and highly efficient synthetic approach of ursodeoxycholic acid, starting from chenodeoxycholic acid in4steps with overall yield61%, was reported. The key intermediate10was prepared in good yield by using ethyl chloride to selectively acylated C3hydroxy of compound9.The critica step of the synthesis reaction is the configuration transformation of the compound10in Mistunobu conversion conditions. The synthesis route has the advantages,such as fewer synthetic steps, high yield and suitable for industrial production.4、We also research on the effects of independent variable such as temperature, solvent and feeding sequence on the yield of the key intermediate and the final product, and by comparing the result, we improve the conditions of the reaction and hence increase the yield. The structures of the synthesized compounds have been confirmed by1HNMR,13CNMR, MS and IR.