N4-Substituted derivatives of HPMPC were synthesized in four-step synthesis which included treatment of 4-methoxypyrimidin-2(1H)-one (1) with (S)-[(trityloxy)methyl]oxirane in DMF. Condensation of intermediary 1-[2-hydroxy-3-(trityloxy)propyl]-4-methoxypyrimidin-2(1H)-one (2) with (diisopropoxyphosphoryl)methyl tosylate in the presence of sodium hydride resulted in fully protected 4-methoxypyrimidin-2(1H)-one derivative 3 which gave on reaction with an appropriate primary amine in dioxane N4-substituted products 4a-4i. The reaction with bromotrimethylsilane simultaneously cleaved the trityl group and deprotected the phosphonate residue and gave the title HPMP analogues substituted at the cytosine amino group in position N4 5a-5i. Compound 4j was prepared from 4-methoxypyrimidin-2(1H)-one (1) by reaction with cyclopropylamine in dioxane. The intermediary 4-(cyclopropylamino)pyrimidin-2(1H)-one (6) then reacts with (S)-[(trityloxy)methyl]oxirane in DMF. Fully protected phosphonate 4j and its deprotected counterpart 5j was obtained by the same sequence of reactions as in the case of compounds 5a-5i.