2,4-Diamino-5-benzylpyrimidines and analogs as antibacterial agents. 3. C-Benzylation of aminopyridines with phenolic Mannich bases. Synthesis of 1- and 3-deaza analogs of trimethoprim

Abstract

Electrophilic substitution of 2,4-diaminopyridine by 2,6-disubstituted-4-[(N,N-dimethylamino)methyl]phenols and by halogens (Br and Fl) produces 3-benzyl and 3-halo derivatives, plus a small amount of disubstitution at the 3,5 positions. Treatment of a 2,4-diamino-3-halopyridine with phenolic Mannich bases gives 5- and N-benzylation. 2,4-Diamino-3-bromo-5-(4-hydroxy-3,5-dimethoxybenzyl)pyridine was methylated on the phenolic group in good yield and dehalogenated to produce 3-deazatrimethoprim [2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyridine]. This compound is about 300-fold less active as an inhibitor of Escherichia coli dihydrofolate reductase than is trimethoprim. 2,6-Diaminopyridine is very readily dibenzylated at the 3,5 positions and on an amino group by a phenolic Mannich base; use of a 4-fold excess of the pyridine provided a 3-benzylated 2,6-diaminopyridine in 50% yield; this was inactive as an inhibitor of dihydrofolate reductase at 10-4 M. 2-Amino- and 4-aminopyridines do not produce C-benzylated products under the conditions reported here-.