Synthesis Of Anti-HBV New Drug Entecavir

Hepatitis B is a serious disease, which is infected by the hepatitis B virus(HBV), and it has been great hazard to human’s health. As it is statisticed by the World Health Organization, there are more than 2 billion persons in the world who have infected the HBV, in which 360 million persons are chronic Hepatitis B virus Carriers. China has more hepatitis B patients than any other country in the world. Entecavir is a nucleoside analog, and it is quite effective to anti-hepatitis B virus and has high specificity to the hepatitis B virus.The synthesis of Entecavir was described in the dissertation. We started from dicyclopentadiene, it was synthesized the CpNa. The CpNa was eventually synthesized the intermediate (IS,3R,4S)-N-[(4-Methoxy-phenyl)diphenyl-methyl]-6-(phenylmethoxy)-9-[2-methylene-4-(phenylmeth-oxy)-3-[(phenylmethoxy)methyl]-cyclopentyl]-9H-purin-2-amine by alkylati-on,asymmetric hydroboration-oxidation, epoxidation, benzyl protection, ring-opening of epoxide, p-methoxyphenyldiphenylmethyl protection, Dess-Martin oxidation, methylenation.In the synthesis of the key intermediate (1S,2R)-2-[(benzy-loxy)methyl]-3-cyclopenten-1-ol(D), the route of synthesiszing sodium cyclopentadienide and chiral boron reagent (-)-Ipc2BH were improved, and the intermediate C was purified. In the epoxidation process, witho-ut purifying with chromatography, we made the overall yield improved and the process became more simpler. In the ring-opening of epoxide process, by changing the mol ratio and increasing the reaction temperature to 145℃, we made the overall yield improved. In the p-methoxyphenyldiphenylmethyl protection process, we found out a conven-ient detecting method for TLC, and immediately purifying with fast chromatography, we made the overall yield improved and the process became more simpler. In the Dess-Martin oxidation process, we made the Dess-Martin periodinane validated by melting point successfully. In order to avoid the leave of the p-methoxyphenyldiphenylmethyl, we used the pyridine instead of tert-butyl alcohol to catalytic reaction. In the methylenation process, we made the effective methylenation reagent using ultrasonic in the base of modified Lombardo method. The. interm-ediate(1S,3R,4S)-N-[(4-Methoxyphenyl)diphenyl-methyl]-6-(phenylmeth-oxy)-9-[2-methylene-4-(phenylmethox-y)-3-[(phenylmethoxy)methyl]-cyclop-entyl]-9H-purin-2-amine(J) was validated by MS and 1H-NMR. By these improvements, the overall yield of the whole synthetic route became higher, and the cost was lower. At the same time, the process is simple and suitable for large-scale production.