First use of the Taylor pteridine synthesis as a route to polyglutamate derivatives of antifolates

Abstract

The di- through penta-γ-L-glutamates of 2-desamino-2-methylaminopterin, a new antifolate with a novel mechanism of action requiring γ-polyglutamylation for biological activity, were prepared. α-tert-Butyl γ-methyl L-glutamate was condensed with 4-nitrobenzoyl chloride, the methyl ester selectively hydrolyzed with base, and the product condensed with di-tert-butyl L-glutamate to obtain tri-tert-butyl N-(4-nitrobenzoyl)-γ-L-glutamyl-L-glutamate. This is the first example of the preparation of the polyglutamates of an antifolate via the Taylor pteridine synthesis