2,4-Diamino-5-benzylpyrimidines as Antibacterial Agents. 4. 6-Substituted Trimethoprim Derivatives from Phenolic Mannich Inetrmediates. Application to the Synthesis of Trimethoprim and 3,5-Dialkylbenzyl Analogues

Article abstract of DOI:10.1021/jm00179a012

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 deg 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.