Synthesis Of The Key Intermediate Of The Anti-HBV Agent Entecavir

As a common and frequently encountered disease, the infectant of Hepatitis B Virus (HBV) has been great hazard to human's health, there are many persons in the world who have infected the HBV, so the infectant of HBV is a important healthy problem in the world. But the clinical the therapeutical effects of anti-HBV drugs are not satisfying. Compared with other anti-HBV agents, entecavir also has many merits such as little dosage, lower resistance with long administration. The important is that administrating entecavir is also efficiency to somebody who has resistance with other anti-HBV agents. Entecavir has potent anti-HBV activity which does not show any apparent toxicity. Besides, the combination of entecavir and other anti-HBV agents can increase therapeutical effects. Entecavir is currently considered as a clinical candidate for treatment of chronic HBV infection. This product was researched by Bristol-Myers Squibb Co., and it was marketed in China in 2006 initially. As a nucleotide analog, synthesization of entecavir not only guides synthesizing other analog, but also is propitious to impolder new nucleotide analog. Many methods of synthesis of the key intermediate of the entecavir were reported, but many of them have some limitation including high cost, long synthesization route and small scale. We designed a relatively proper synthesis route based on references, and improved the synthesis technology. We started from dicyclopentadiene and gained the key intermediate of the carbocyclic compound in a six-step sequence of reactions including depolymerization, alkylation, symmetric hydroboration-oxidation, benzyl protection, etc.; gained the guanine compound 2-amino-6-benzylguanine by displacement reactions.In the synthesis of the key intermediate (1S,2R)-2-[ (benzyloxy) methyl] -3 -cyclopenten-1-ol, we study the influence of dicyclopentadiene to yield, through changing the solvent and manipulation, purification with twice chromatography, we improved the synthesis technology, making the overall yield improve from 21% to 26.5%, and the process becomes more simpler. In the synthesis of the intermediate (1S,2R,3S,5R)-2-[(benzyloxy) methyl]-6-oxabicyclo [3.1.0] hexane-3-ol, we search for the epoxidation catalyst of high stereoselectivity. Based on relatively references and experiment results, we select t-Butyl hydroperoxide / vanadium(v) acetylacetonate as oxidants, the overall yield improve to 73%; In the synthesis of the intermediate (1S,2R,3S,5R)-3-(benzyloxy)-2-[ (benzyloxy) methyl] -6-oxabicyclo [3.1.0]-hexane, we summarize the factors of influence the yield and optimize the reaction conditions, improved the yield to 69%. In the synthesis of the 2-amino-6-benzylguanine, we study the temperature to influence the whole reaction. We replaced chromatography with recrystallization, improved the yield to 68.7%. By aforementioned improvements, the overall yield of the whole synthetic route higher, the cost was lower and the synthesization route was shorter. At the same time, the process is simple and suitable for large-scale production.