Collect. Czech. Chem. Commun. 1999, 64, 242-256

Synthesis of Quaternary 1-[2-(Phosphonomethoxy)ethyl] Derivatives of 2,4-Diaminopyrimidine and Related Acyclic Nucleotide Analogs

Antonín Holýa,*, Miloš Buděšínskýa, Jaroslav Podlahab and Ivana Císařováb

a Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 166 10 Prague 6, Czech Republic
b Department of Inorganic Chemistry, Charles University, 128 40 Prague 2, Czech Republic


Quaternization of 2,4-diaminopyrimidine (2) by diisopropyl 2-chloroethoxymethanephosphonate (3) followed by bromotrimethylsilane treatment and subsequent hydrolysis gave zwitterionic N1-[2-(phosphonomethoxy)ethyl] derivative, hydrogen {[2-(2,4-diaminopyrimidin-1-io)ethoxy]methyl}phosphonate (5). Its structure was confirmed by X-ray crystallography. The same product was obtained from 2-amino-4-[(dimethylaminomethylene)amino]pyrimidine (6) by an analogous reaction sequence followed by an aqueous ammonia treatment after the transsilylation reaction. Also the quaternizations of 4,6-diaminopyrimidine (7) and 2,4,6-triaminopyrimidine (8) with the halo derivative 3 afforded the zwitterionic N1-substituted compounds 9 and 10, respectively. In contrast to this regiospecific reaction, 2-aminopyrimidine (11) gave on treatment with compound 3 and following deprotection the exo-N2-isomer 13. This compound was also obtained by the reaction starting from 2-[(dimethylaminomethylene)amino]pyrimidine (12) which was prepared by treatment of compound 11 with dimethylformamide dineopentyl acetal. Also 2,3-diaminopyridine (14) gave by the above reaction a mixture of 2-amino-3-{[2-(phosphonomethoxy)ethyl]amino}pyridine (15) and quaternary N1-[2-(phosphonomethoxy)ethyl] derivative (16). None of these analogs of the antiviral PMEDAP exhibited any antiviral activity against DNA viruses or retroviruses, nor any cytostatic activity.

Keywords: Acyclic nucleotide analogs; Pyrimidines; Phosphonates; Antivirals; PMEDAP; NMR spectroscopy, 1H and 13C; Crystal structure.