The Synthesis Of Mycophenolic Acid

Immunosuppressive drugs take more and more important role in organ transplantation. During recent years, the success ratio of organ transplantation has been more improved by the using of powerful and lower toxicity immunosuppressive drugs. Mycophenolic acid is a novel immunosuppressive drug. It has strong immunosuppressive effects on various rejections to allograft or xenograft, and on autoimmune diseases, and has the features of higher potency and lower toxicity. However, the known methods for preparing it are somewhat difficult to industrialize.For the purpose of finding an economical and feasible method to synthesize mycophenolic acid, a new synthesis of mycophenolic acid has almost been accomplished from the starting material of ethyl acetoacetate and ethyl crotonate. In this thesis, the synthesis of 5,7-dimethoxyphthalide (27) and 7-hydroxy-5-methoxy -4-methyl-6-prenylphthalide (100) was studied. The problem that the cost was too high in the synthesis of 5,7-dimethoxyphthalide (27) from the starting material of 4,6-dibromo-5,7-dihydroxyphthalide (42) has been solved. Two methods have been studied: (1) First methylation then debromination by hydrogenolysis. (2) First debromination by hydrogenolysis then methylation. The method (2) was better than method (1). The catalyst about the synthesis of 7-hydroxy-5-methoxy-4-methyl-6 -prenylphthalide (100) from 5-methoxy-4-methyl-7-prenoxyphthalide (99) has been studied. The optimum catalyst was ZnCl2.Two new key intermediates in the synthesis of mycophenolic acid were prepared in this thesis. The Structures of some key compounds were confirmed by 1HNMR spectra.