Antifolate chemistry:: synthesis of 4-{N-[(6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-2-ynyl)amino} benzoic acid via a (propargyl) Co2(CO)6+ complex

A new route to compound 3 (4-{N-[(6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g] quinazolin-6-yl]-N(prop-2-ynyl)amino} benzoic acid), a crucial intermediate for the synthesis of potent inhibitors of thymidylate synthase (TS), is described. In this sequence the C-6-N-10 bond was constructed first, by the reductive amination of 5-acetamido-6-bromoindan-1-one 6 with tert-butyl 4- aminobenzoate, then the cyclopenta[ g] quinazolinone ring was formed and the propargyl group was introduced on the N-10-position using the (propargyl)Co-2(CO)(6)(+) complex as the electrophilic propargyl reagent.