Selectively 13C-enriched 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine (trimethoprim) and 2,4-diaminopyrimidine

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Abstract
Samples of 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine (Trimethoprim) were synthesized, enriched with 13C at the following positions: 2 and 5; 4 and 6; α and 4-methoxy. For the first two series (having 13C-enrichment at the pyrimidine), appropriately labelled cyanoacetic acid was converted into labelled methyl 2-(3,4,5-trimethoxybenzyl)cyanoacetate and thence to the labelled 6-hydroxy derivative of Trimethoprim. For the last series (having 13C-enrichment at the trimethoxybenzyl moiety), the key reaction was the nucleophilic attack of C–5 of 2,4-diamino-6-hydroxypyrimidine on labelled 3,4,5-trimethoxybenzyl bromide, again yielding the labelled 6-hydroxy derivative of Trimethoprim. The conversion of the 6-hydroxy derivatives into 13C-enriched Trimethoprim was via the 6-chloride. Also synthesized was [6-13C]-2,4-diaminopyrimidine by cyclization of guanidine and [3-13C]-3-anilinoacrylonitrile. The identity, and the site(s) of the 13C label(s) of each final product and intermediate, were established on the basis of 1H and 13C n.m.r. spectral evidence.