title: 2,4-Diamino-5-benzylpyrimidines as antibacterial agents. 4. 6-Substituted trimethoprim derivatives from phenolic Mannich intermediates. Application to the synthesis of trimethoprim and 3,5-dialkylbenzyl analogues.
abstract: The preparation of a wide variety of 6-substituted trimethoprim analogues was readily accomplished by the reaction of 2,4-diamino-6-substituted-pyrimidines with 2,6-dimethoxy-4-[(N,N-dimethylamino)methyl]phenol at 120--160 degrees C. The less reactive 2,6-dialkyl-4-[(N,N-dimethylamino)methyl]phenols reacted successfully with 2,4-diamino-6-(alkylthio)pyrimidines to give 5-(substituted benzyl)pyrimidines. The phenolic groups of the products were alkylated in high yield when a nonreactive 6-substituent was present in the pyrimidine ring. 6-(Alkylthio) groups were easily removed with Raney nickel. Trimethoprim was thus obtained in high yield from its 6-(methylthio) counterpart. The 6-substituted trimethoprim analogues all had low activity as inhibitors of Escherichia coli dihydrofolate reductase and as antibacterial agents.
mesh_terms: D000478:Alkylation; D001419:Bacteria / Q000187:drug effects; D004926:Escherichia coli / Q000201:enzymology; D005493:Folic Acid Antagonists; D008352:Mannich Bases; D008722:Methods; D008958:Models, Molecular; D014295:Trimethoprim / Q000031:analogs & derivatives* / Q000138:chemical synthesis*
chemical_list: D005493:Folic Acid Antagonists; D008352:Mannich Bases; D014295:Trimethoprim