Synthesis of quaternary 1-[2-(phosphonomethoxy)ethyl] derivatives of 2,4-diaminopyrimidine and related acyclic nucleotide analogs

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-(phosphonomethoxylethyl] derivative (16). None of these analogs of the antiviral PMEDAP exhibited any antiviral activity against DNA viruses or retroviruses, nor any cytostatic activity.