Study on synthesis of Ursodeoxycholic Acid by reduction of 7-Ketolithcholic Acid in Double Aprotic Solvents and Molecular simulations

Abstract

Ursodeoxycholic acid is not only safer than chenodeoxycholic acid in the treatment of hepatobiliary diseases, but also has a wide range of applications in Acute Kidney Injury and Parkinson's Disease.The purpose of this experiment is to improve the conversion rate of 7-ketocholic acid and the yield of ursodeoxycholic acid in Aprotic Solvents during electrochemical reduction process. Three aprotic solvents were investigated as electrolytes, 1,3-Dimethyl-2-imidazolidinone(DMI) has the stable five-membered ring structure, 7K-LCA has undergone two nucleophilic and "Walden" Inversion", the 7K-LCK was stereoselectively reduced to UDCA. hexamethylphosphoramide (HMPA) and 1,3-methyl-3,4,5,6- Tetrahydro-2(1H)-pyrimidinone (DMPU) can be attacked by chloride ions to produce by-products. Molecular simulation based on molecular orbital theory combines experiments to study reducibility of three aprotic solvents(hexamethylphosphoramide(HMPA), 1,3-methyl-3,4,5,6-Tetrahydro-2(1H)-pyrimidinone (DMPU), and 1,3-Dimethyl-2-imidazolidinone(DMI)). Choose the best solvent based on the simulation results, the electrolysis reaction can be carried out by applying current and voltage when lithium chloride is used as electrolytes. and the calculation using Materials studio showed that Cu, Pb, Hg-Cu, and Ni had the largest binding energy to the substrate in this system. Using Cu as the electrode when the solvent is a 1:1 mix of DMI and HMPA ,the conversion rate of 7-ketocholic acid could reach 98%,the yield of ursodeoxycholic acid was up to 80%. Under the same conditions, linear voltammetry was performed on the electrochemical workstation to study the electrolysis behavior, and the obtained results were consistent with the experiment.