The reaction of 2,5-dimethoxybenzaldehyde (I) with ethyl acetoacetate (II) in a mixture of piperidine and glacial acetic acid in refluxing benzene gives ethyl alpha-acetyl-beta-(2,5-dimethoxyphenyl)acrylate (III), which is hydrogenated in a Parr low-pressure apparatus using 5% palladium on charcoal catalyst in ethyl acetate to yield ethyl alpha-acetyl-(2,5-dimethoxyphenyl)propionate (IV). The condensation of the propionate (IV) with 2,4.6-triaminopyrimidine in diphenylether at 195-230 C provides 2,4-diamino-7,8-dihydro-6-(2,5-dimethoxybenzyl)-5-methyl-7-oxopyrido[2,3-d]pyrimidine (VI). The key intermediate (VI) is converted to the 7-chloro compound (VII) by treatment with a 1:1 complex of N,N-dimethylformamide thionyl chloride, and finally (VII) is hydrogenolyzed with palladium on charcoal in the presence of potassium hydroxide to yield BW-301 U.
The synthesis of [14C]-labeled piritrexim has been described: The condensation of 2,5-dimethoxybenzaldehyde (I) with acetone in aqueous NaOH gives 4-(2,5-dimethoxyphenyl)-3-(E)-buten-2-one (II), which is hydrogenated with H2 over Pd/C in methanol to give 4-(2,5-dimethoxyphenyl)-2-butanone (III). The condensation of (III) with malononitrile (IV) by means of acetic acid-sodium acetate in refluxing toluene yields 2-cyano-5-(2,5-dimethoxyphenyl)-3-methyl-2-pentenenitrile (V), which is condensed with acetic acid diethoxymethyl ester (VI) at 105 C to afford the corresponding diethoxymethyl derivative (VII). The cyclization of (VII) with 32% HBr in acetic acid affords 2-bromo-5-(2,5-dimethoxybenzyl)-4-methylpyridine-3-carbonitrile (VIII), which is finally cyclized again with [14C]-labeled guanidine (IX) by means of NaH in refluxing tert-butyl alcohol.