Synthesis of a tetrafluorinated analogue of the quinazoline antifolate 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid

Add time:07/31/2019    Source:sciencedirect.com

A synthesis of a tetrafluoro derivative of the quinazoline antifolate 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid is described. 2-Desamino-2-methyl-N10-propargyl-2′,3′,5′,6′-tetrafluoro-5,8-dideazafolic acid (1) has been made in four stages from 4-amino-2,3,5,6-tetrafluorobenzoic acid (2). The reaction of 2 with thionyl chloride followed by diethyl L-glutamate gave N-(4-amino-2,3,5,6-tetrafluorobenzoyl)-L-glutamate (3). Condensation of 3 with propargyl bromide using caesium carbonate as base gave diethyl N-[2,3,5,6-tetrafluoro-4-(prop-2-ynylamino)benzoyl]-L-glutamate (4) which in turn reacted with 6-bromomethyl-3,4-dihydro-2-methyl-4-oxoquinazoline using the same base to give the diethyl ester 5 of 1. Finally, base-catalysed hydrolysis of 5 gave the target product. The sequence differs from other reported syntheses of quinazoline antifolates most notably in the use of an aminobenzoic acid derivative rather than a nitrobenzoic acid derivative as starting material but also in the need for the relatively strongly basic caesium carbonate to effect the two subsequent steps. Evidence for restricted rotation in the intermediate 4 is also presented.

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