Regioselective synthesis of acyclovir and its various prodrugs

High-yield regioselective synthesis of 9-[(2-hydroxy-ethoxy)methyl]guanine (Acyclovir 1, Scheme 1) was achieved from guanine via trisilylated guanine. N-2-acylacyclovir 9a-9b were prepared from N-2, O-diacylacyclovir (4, 8b-8d) using regioselective deacylation procedure. N-2- Acylacyclovir 11 and 13 were prepared via protection of primary hydroxyl groups. Three amino acid esters of acyclovir were synthesized as water-soluble prodrugs, which form protonated cations in pH 7.4 phosphate buffer. Two water-soluble ester prodrugs with free carboxylic acids, which form anionic species in pH 7.4 phosphate buffer, were also synthesized.