The Synthesis And Process Improvement Of Prednisolone

Prednisolone is one of the valuable steroid drugs, which has anti-inflammatory, antiallergic and immunosuppressive efficacy etc. In this paper, based on the research of traditional synthetic route for prednisolone (prednisone acetate as the starting material, through ketone carbonyl group protection of C3and C20, C11reduction, C3and C20deprotection and ester hydrolysis to obtain the final product, prednisolone), a novel synthetic route is proposed.First, the influence of pH on the prednisolone product yield of the traditional route is analyzed. At the same time, the content of each component of the intermediates are measured by HPLC. The conditions of the traditional synthetic route are optimized. It was found within pH of4.2-5.2, the optimum yield is78.6%.Second, the reaction differences of different ketone carbonyl sites of prednisone acetate are analyzed, and the law is summarized. The structure optimization of the raw material and intermediate are carried out at B3LYP/6-31g (d, p) level using ChemBioOffice2008, Gaussian03W on a Dell E08S Server, and the charge density distribution of different ketone carbonyl groups, bond lengths, bond angles and other structural parameters are calculated. In addition, the nucleophilic substitution differences of three ketone carbonyl are evaluated. And the order of activity is C11> C20> C3. Therefore, in order to reduct C11ketone carbonyl group, the more active C20ketone carbonyl group need to be protected, however, the less active C3ketone carbonyl group needn’t to be protected. The new routine was proposed using prednisone acetate as the starting material, and the esterification of C17location by acetic anhydride was conducted to protect C20by the steric protection (this step yield is95.0%). Subsequently, through C11reduction and hydrolysis of the ester under alkaline condition, the final product, prednisolone was obtained.Finally, the purification of the intermediate,2-(17-acetoxy-10,13-dimethyl-3,11-dioxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[oc]phenanthren-17-yl)-2-oxoethyl acetate, and final product, prednisolone, was conducted by re-crystallization and silica gel chromatography and the final yield is about60%. The intermediate and the final productare characterized by MS, NMR and IR. Based on the literature and computer simulation, it is determined that the product is prednisolone. The new synthetic route can be conducted in mild reaction conditions and easy to operate with less by-products. It has some prospects for industrial application.