A New Route For Synthesis Of The New Anti-HBV Agent Entecavir

In this dissertation we report a new route for synthesis of the new anti-HBV agent Entecavir. Entecavir is a novel carbocyclic 2'-deoxyguanosine analog, which can effectively inhibite the hepatitis B virus replication. This product was researched by Bristol-Myers Squibb Co., and it was marketed in America in March, 2005, and was marketed in China in March this year initially.The new route which we report started from dicyclopentadiene and eventually finished the total synthesis work (including the synthesis of one side chain) in a seventeen-step sequence of reactions including depolymerization, 1,4 bromic addition, acetoxyl-replacement, hydrolyzation, Johnson-Claisen rearrangement, hydrolyzation-cyclization, Prins reaction of important intermediate (1S,5R)-Corey lactone, Methanolysis, benzyl protection, a-hydroxycarbonylzation of cyclic lactone, reduction with LiAlH4, dioxolanation, Mitsunobu reaction, oxidation with NaIO4, reduction, dehydration-methylenation, etc. In this route, there are two new intermediates have not been reported before. And all the analytic datum of the T.M had pass the examination of ShangHai Food&Drug Administration.In the synthesis of the key intermediate (1R, 5S)-Corey lactone (E), we changed the reaction temperature and catalyzer, and used the bibulous reagent to improve the yield from 30% to 71.4% of total two steps. In the synthesis of key intermediate (4R, 5S)-5-benzyloxy-4-benzyloxymethyl-3-hydroxy-hexahydro-cyclopenta[b]-furan -2-one (I), we replaced expensive chiral ligand with indigenous metal ligand MoOPH, and made progress of the treatment of reactions, making the yield improved obviously. In the synthesis of the key intermediate 6-benzyloxy-9-[(1S, 2S, 3R, 4S)-4-benzyloxy-3-benzyloxymethyl-2-(2,2)-dimethy-[1, 3]-dioxolan-4-yl)-cyclopentyl-9H-purin-2-amine(L), we used the modified Mitsunobu reaction and the modification of group substituentes of the carbocyclic core to obtain high chiral purity production, and in addition, making the yield improved. While preparing 6-benzyloxy-9-[(1S, 3R, 4S)-4-benzyloxy-3-benzyloxymethyl-2-methylenecyclopentyl-9H-purin-2-amine (N) from [(1S, 2R, 3S, 5S)-5-(2-amino-6-benzyloxy-9H-purine-9-yl)-3-benzyloxy-2-benzyloxymethyl-cyclopentyl]-methanol (M), we tried many dehydrate reagents and found the best way of dehydration for M, which gave N in high yield. In the synthesis of the terminal material, Entecavir, we made progress of the conditions and treatments of reaction, not only making the process become simpler, but also enhancing the yield. By aforementioned...