Synthesis of potential prodrugs and metabolites of 9-(S)-(3-hydroxy-2-phosphonylmethoxypropyl)adenine

Abstract

Reaction of 9-(S)-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (I) with N,N'-dicyclohexylcarbodiimide afforded the cyclic phosphonate II. The same compound was also obtained by controlled alkaline hydrolysis of 3'-O-chloromethanephosphonyl-9-(S)-(2,3-dihydroxypropyl)adenine (III). Methanolysis of compound II or III by sodium methoxide gave methyl ester VII. Isomeric cyclic ester V and methyl ester VIII were obtained from 3'-O-phosphonylmethyl ether IV or 2'-O-chloromethanephosphonyl ester VI by the same reactions. Compound I was transformed into morpholide IX which afforded the P-diphosphoryl derivative X by treatment with inorganic diphosphate. The P-phosphoryl derivative XII was obtained from compound I by successive protection with dimethoxytrityl chloride, activation with diphenyl chlorophosphate, treatment with inorganic phosphate and acid deprotection.