Synthese von 4‐halogensubstituierten Analogen von Trimethoprim

The Synthesis of 4‐Halogen‐substituted Analogs of Trimethoprim The four 2,4‐diamino‐5‐(4‐halo‐3,5‐dimethoxybenzyl)pyrimidines 20a‐d have been synthesized along known routes, i.e. form the corresponding aldehydes 17a‐d via the aminomethylidene‐derivatives 18a‐d and 19a‐d , respectively (Scheme 4) . All four aldehydes were prepared from a common intermediate, methyl 4‐amino‐3,5‐dimethoxybenzoate ( 3 ), which was obtained from dimethyl 2,6‐dimethoxyterephthalate ( 2 ) and hydroxylamine in a regioselective Lossen ‐type rearrangement mediated by polyphosphoric acid (Scheme 1) . Under identical rearrangement conditions 2,6‐diethoxyterephthalate ( 12 ) led, in addition to the amine 14 , to the benzoxazolone 15 (Scheme 2) . Scope and mechanism of this reaction are discussed. ‐ The antimicrobial activity of the diamino‐pyrimidines 20a‐d , expressed as the inhibition of E. coli ‐dihydrofolate reductase, has been measured and compared with that of trimethoprim ( 1 ), an established antimicrobial agent.