In this paper, a practical process for convergent synthesis of the title compound raltitrexed, a specific inhibitor for thymidylate
synthase, was developed. Condensation of 6-(bromomethyl)-3,4-dihydro-2-methyl-4-oxo-quinazoline with diethyl N-<5-(N-methylamino)-2-thenoyl>-L-
glutamate, followed by hydrolysis under basic condition gave the title compound raltitrexed, which was confirmed by IR, ()~1H-NMR, MS as well as element analysis and qualified for the standrand for clinic study. 6-(Bromomethyl)-3,4-dihydro-2-methy 4-oxoquinazoline, one of the key intermediates for
preparing raltitrexed, was prepared from 2-amino-5-methylbenzoic acid by N-acetylation with acetic anhydride, cyclization with ammonium (acetate) as well as bromination with N-bromosuccini mide (NBS) in 69.1% yield. Diethyl N-(5-(N-methylamino)-2-thenoyl)-L-glutamate, another key intermediate for preparing raltirexed, was prepared from (2-thenoylcarboxaldehyde) via direct nitration by the mixture of nitric acid and acetic anhydride, oxidation with hydroperoxide in room temperature, chlorination with thionyl chloride, condensation with the chiral synthon diethyl L-glutamate, reduction with iron in acetic acid, and N-methylation with methyl iodide in 25.4% yield. The improved process is more suitable for indrustrial preparation.