Patent ID: 7034152

Claim:
A process for the preparation of entecavir having the formula comprising: (a) treating an ester of the formula wherein R a is allyl, phenyl, C 1 to C 6 alkylphenyl, or C 1 to C 6 alkoxyphenyl; R b is C 1 to C 6 alkyl; and R is C 1 to C 4 alkyl or benzyl; with an enol ether of acetone and an acid to protect the hydroxy group, followed by treatment with a hydride reagent to reduce the carboxylic acid ester moiety, and then alkylating the resulting alcohol with a benzyl halide and removing the enol ether hydroxy protecting group to give an allylic alcohol of the formula (b) epoxidizing the product from step (a) with a diastereoselective epoxidation to give a cyclopentane epoxide having the formula (c) treating the cyclopentane epoxide from step (b) with an alkali metal salt of a purine compound of formula wherein X is Cl, I, or benzyloxy, to give a compound of formula (d) when X is Cl or I, eliminating the vicinal diol of formula 78 to the methylene compound of formula, (e) hydrolyzing the benzyl ether moiety on the primary alcohol of compound 94 and transforming the silane moiety of compound 94 to a hydroxy moiety via protodesilylation and oxidation, to give a compound of formula, and (f) hydrolyzing the chloro or iodo moiety X to provide the compound of formula 21; or (d′) when X is benzyloxy, eliminating the vicinal diol of formula 78 to form the methylene compound of formula and (e′) hydrolyzing the benzyl ether moiety on the primary alcohol of compound 79 and transforming the silane moiety to a hydroxy moiety via protodesilylation and oxidation, to provide the compound of formula 21; or (a″) epoxidizing the ester of formula 66 with a diastereoselective expoxidation followed by reduction, to give a cyclopentane epoxide having the formula (b″) treating the cyclopentane epoxide from step (a″) with an alkali metal salt of the purine compound of formula 28 to give a compound of formula (c″) when X is Cl or I, eliminating the vicinal diol of formula 73 to the methylene compound of formula (d″) transforming the silane moiety of compound 92 to a hydroxy moiety via protodesilylation and oxidation, and hydrolyzing the chloro or iodo moiety X to provide the compound of formula 21; or (c′″) when X is benzyloxy, eliminating the vicinal diol of formula 73 to form the methylene compound of formula and (d′″) transforming the silane moiety of compound 71 to a hydroxy moiety via protodesilylation and oxidation, to provide the compound of formula 21.