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

Synthesis of the tided tetrahydropyrimidoazepine-based folate (6a) is descr ibed using a regiospecific gamma-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 isoxaz olinopyrimidoazepine and isoxazolopyrimidoazepine-based folates (7a and 8a respectively) were also prepared (via intramolecular 1,3-dipolar cycloaddit ion chemistry) as conformationally-restricted analogs of 6a. All three comp ounds were prepared as potential antitumor agents based on the known, struc turally related, antitumor agent 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF). Both 7a and 8a were inactive in the human colon carcinoma (GC3cl) cell culture assay. Compound 6a, however, was weakly active (IC50 = 2.0 mu M) in the above assay, (C) 1998 Elsevier Science Ltd. All rights reserved.