Study On Proess Of The Synthesizing Entecavir

This dissertation relates to research into route of synthesizing a new anti-HBV agent Entecavir, which chemical name is [1S-(la,3a,4β)]-Amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethhhyl)-2-methylene-cyclopentyl]-6H-purin-6-one.Entecavir is a novel carbocyclic2’-deoxyguanosine analog,which can effectively inhibite the hepatitis B virus replication.This product was reasearched by Bristol-Myers Squibb Co.,and it was marketed in America in march2005.The synthesis of Entecavir was described in the dissertation.we started from dicyclopentadiene and eventually finished the total synthesis work in a fifteen-step sequence of reactions including depolymerization, alkylation, asymmetric hydroboration-oxidation,epoxidation,benzyl protection, ring-opening of epoxide, p-methoxyphenyldipheny methyl protection, oxidation, methylenation, etc.The route of synthesizing sodium cyclopentadienide was improved by the reaction between dicyclopentadiene and sodium in high temperature, and the yield was99%..By improved the synthesis of5-[(benzyloxy)menthyl]cyclopentediene and the separation, we reseached the mechanism of by-product, validated the by-product’s structure by1HMR and avoid the side reaction. in the synthesis of (1S,2R)-2-[(benzyloxy)methyl]-3-cyclopenten-l-ol.By combined with the separation of epoxidation and benzyl protection,the two steps’yield was improved from61%to70%. The final result of this research was to improve the Synthesis Technology of the route before the synthese of [1S-(1α,2β,3α,5β)]-5-[2-Amino-6-(phenylmethoxy)-9H-purin-9-yl]-3-(phenylmethoxy)-2-[(phenylmethoxy)methhyl]cyclopentanol. Intermediates was validated by1HMR and melting point. The research will be more beneficial to the enlargement in industrial production,and provide the important guiding significance.