Synthesis of N-{[4-(2-amino-4(3H)-oxo-5,6,7,8-tetrahydro-(9H)- pyrimido[4,5-b]-azepin-6-yl)methyl]benzoyl}-L-glutamic acid and two of its conformationally-restricted analogs

Article abstract of DOI:10.1016/S0040-4020(98)01060-6

Synthesis of the titled tetrahydropyrimidoazepine-based folate (6a) is described using a regiospecific γ-alkylation reaction between the dienolate generated from 3-carboethoxy-N-2,4-dimethoxybenzyl-1,5,6,7-tetrahydro-(1H)- azepin-2-one (33) and methyl 4-formylbenzoate, as the key step. The isoxazolinopyrimidoazepine and isoxazolopyrimidoazepine-based folates (7a and 8a respectively) were also prepared (via intramolecular 1,3-dipolar cycloaddition chemistry) as conformationally-restricted analogs of 6a. All three compounds were prepared as potential antitumor agents based on the known, structurally related, antitumor agent 5,10-dideaza-5,6,7,8- tetrahydrofolic acid (DDATHF). Both 7a and 8a were inactive in the human colon carcinoma (GC3c1) cell culture assay. Compound 6a, however, was weakly active (IC₅₀ = 2.0 μM) in the above assay.