Collect. Czech. Chem. Commun. 2006, 71, 579-594

Preparation of C-5 Substituted Cidofovir Derivatives

Marcela Krečmerová*, Milena Masojídková and Antonín Holý

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


1-[(S)-3-Hydroxy-2-(phosphonomethoxy)propyl]cytosine (HPMPC, cidofovir) was modified by substitution on the base moiety in positions C-5 and N4. Key intermediates of these syntheses, diisopropyl esters of (S)-1-[2-(phosphonomethoxy)-3-(triphenylmethoxy)propyl]-5-alkylcytosines (6 and 7) prepared from 5-alkyl-4-methoxypyrimidin-2(1H)-ones were transformed to the corresponding 5-substituted cytosine or N4-alkylcytosine derivatives by the action of ammonia or primary amines, respectively. These fully protected phosphonate esters gave by treatment with bromotrimethylsilane followed by hydrolysis free phosphonic acids: 1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]-5-methylcytosine (5-methyl-HPMPC, 10), 5-ethyl-1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (5-ethyl-HPMPC, 11) and a series of 5-ethyl-HPMPC analogues 17-21 bearing various substituents in N4 position (cyclopropyl, cyclopentyl, 2-hydroxyethyl, allyl, 2-(dimethylamino)ethyl). 5-Ethynyl-1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine (5-ethynyl-HPMPC, 26) was prepared from 5-iodocytosine derivative 23 using Sonogashira coupling with (trimethylsilyl)acetylene, CuI and [PdCl2(Ph3P)2]. None of the prepared compounds exhibited antiviral activity in vitro.

Keywords: Acyclic nucleotide analogues; Phosphonates; Pyrimidines; Nucleosides; 5-Alkylcytosines; Antivirals; HPMPC; Sonogashira cross-coupling.

References: 40 live references.