Study On Novel Process For Synthesis Of Immunosuppressive Agent Azathioprine

Azathioprine is widely used as immunosuppressive agent, and its intermediate are important pharmaceutical and chemical raw material.Based on the analysis and evaluation of bibliographer, the applications of azathioprine and its intermediates were reviewed. The processes for synthesis of them were summarized.Starting from diethyl ethaneioate and methylamine (aq) N,N'-Dimethyloxalamide was prepared. The mechanism of the reaction of the preparation was studied. The yield was 85.2%.5-Chloro-1-methylimidazole nitrate could be obtained immediately by adding nitric acid in acetone solvent, in which 5-chloro-1-methylimidazole dissolved. And 5-chloro-1-methyl-imidazole was synthesis from N,N'-Dimethyloxalamide and PCl5. The total yield was 77.5%.The nitration of imidazole and derivatives was discussed, and the mechanism of nitration about 5-chloro-1-methylimidazole nitrate was studied. The 5-chloro-1-methyl-4-nitroimidazole was obtained by heating 5-chloro-1-methylimidazole nitrate in certain ratio of acetic acid to sulfuric acid, and the yield was 92.9%.P₂S₅ and Lawesson's reagent were used as the curing ingredient, and 6-mercaptopurine was prepared by the reaction with hypoxanthine in yield 65.2% and 90.0%. The reaction mechanism of Lawesson's reagent and hydroxyl groups was studied.Azathioprine was synthesized by 6-mercaptopurine and 5-Chloro-1-methyl-4-nitroimidazole with a yield 94.6%, and sodium bicarbonate was selected as catalyst.The structures of the product and intermediates were identified and confirmed by IR, NMR and MS. Furthermore, the methods of analysis were studied.It provided the theoretical basis and the feasible process parameters for the industrialization of azathioprine and its intermediate.