2,4-Diamino-5-benzylpyrimidines and Analogues as Antibacterial Agents. 3. C-benzylation of Aminopyridines with Phenolic Mannich Bases. Synthesis of 1- and 3-Deaza Analogues of Trimethoprim.

Article abstract of DOI:10.1021/jm00178a008

Electrophilic substitution of 2,4-diaminopyridine by 2,6-disubstituted-4-<(N,N-dimethylamino)methyl>phenols and by halogens (bromine and fluorine) 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 dihydrof olate reductase than is trimethoprim. 2,6-Diaminopyridine is very readily dibenzylated at the 3,5 positions, as well as on an amino group, by a phenolic Mannich base; use of a fourfold excess of the pyridine provided a 3-benzylated 2,6-diaminopyridine in 50percent 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.