Aryl <i>H</i>-Phosphonates. 6. Synthetic Studies on the Preparation of Nucleoside <i>N</i>-Alkyl-<i>H</i>-phosphonamidates

Abstract

Various approaches to the synthesis of nucleoside H-phosphonamidates have been investigated. Direct couplings of nucleoside H-phosphonates with amines have been hampered by extensive reactions of the condensing agents with amines. Preactivation of nucleoside H-phosphonates with pivaloyl chloride or chlorophosphates, followed by the addition of amines, notably diminished these side reactions. The most efficient and versatile route to nucleoside N-alkyl H-phosphonates was found to be aminolysis of the in situ-produced aryl nucleoside H-phosphonates with appropriate amines.