title: 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.
abstract: 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 Eschericia coli dihydrofolate 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 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.
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D001419:Bacteria / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D005493:Folic Acid Antagonists; D066298:In Vitro Techniques; D008352:Mannich Bases; D010636:Phenols; D051381:Rats; D013329:Structure-Activity Relationship; D014295:Trimethoprim / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D005493:Folic Acid Antagonists; D008352:Mannich Bases; D010636:Phenols; D014295:Trimethoprim