A direct method for the preparation of 2-hydroxyethoxymethyl derivatives of guanine, adenine, and cytosine

Abstract

Alkylation of 2-chloro-6-iodopurine with iodomethyl [(trimethylsily)oxy]ethyl ether at -63.degree. C and subsequent treatment of the 9-substituted chloroiodopurine with K2CO3 in aqueous dioxane at 25.degree. C and then with NH3 under pressure at 150.degree. C provided 9-[(2-hydroxyethoxy)methyl]guanine (1a), a potent antiviral agent against Herpes simplex virus type 1, in excellent yield. Its monophosphate (1g), which is enzymatically produced from 1a in the virus-infected [animal] cells was also synthesized. 6-Chloropurine and 4-(methylthio)pyrimidin-2-one anions were similarly alkylated with iodomethyl [(trimethylsily)oxy]ethyl ether, and the products (1f and 2b) were transformed by treatment with methanolic NH3 at 110.degree. C into 9-[(2-hydroxyethoxy)methyl]adenine (1b) and 1-[(2-hydroxyethoxy)methyl]cytosine (2a), respectively. The synthesis of these analogues, heretofore difficult to prepare by a simple procedure were conveniently accomplished.