Synthesis of 9-(2-phosphonylmethoxyethyl)adenine and related compounds

Abstract

Diethyl 2-hydroxyethoxymethanephosphonate ( VIII ) was converted into diethyl 2-halogenoethoxymethanephosphonates IXa and IXb by reaction with triphenylphosphine and tetrachloromethane or tetrabromomethane; analogous reaction of VIII with p -toluenesulfonyl chloride afforded diethyl 2-( p -toluenesulfonyloxy)ethoxymethanephosphonate ( IXc ). Reaction of sodium salt of adenine with compounds IX led to 9-(2-diethoxyphosphonylmethoxyethyl)adenine ( X ). Compound X was converted into 9-(2-phosphonylmethoxyethyl)adenine ( II ) by treatment with bromotrimethylsilane whereas alkaline hydrolysis of X gave ethyl ester Vb . Reaction of 9-(2-hydroxyethyl)adenine ( IIIa ) or its N 6 -benzoyl derivative IIIb with dimethyl p -toluenesulfonyloxymethanephosphonate ( IV ) in the presence of sodium hydride, followed by alkaline hydrolysis yielded methyl ester Va . Morpholide XI reacted with an inorganic phosphate and diphosphate to give 9-(2-phosphorylphosphonylmethoxyethyl)adenine ( XII ) and 2-(diphosphorylphosphonylmethoxyethyl)adenine ( XIII ), respectively.