Collect. Czech. Chem. Commun. 2005, 70, 2053-2065

Synthesis of Some N4-Substituted Derivatives of 1-[(S)-3-Hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC, Cidofovir)

Šárka Chalupová*, Antonín Holý and Milena Masojídková

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic


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.

Keywords: HPMPC; Cidofovir; Acyclic nucleoside phophonates; Nucleotides; Aminolysis; Cytosine; Pyrimidines.

References: 12 live references.