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Synthesis of a tetrafluorinated analogue of the quinazoline antifolate 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid by Michael Jarman; Graham M.F. Bisset; Timothy J. Thornton is a Chemistry article available to read on EtoBox.

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A synthesis of a tetrafluoro derivative of the quinazoline antifolate 2-desamino-2-methyl-N"'-propargyL5,%dideazafolic acid is described. 2-Desamino-2-methyl-N lo-propargyl-2',3',5',6'-tetrafluoro-5,8-dideazafolic acid (1) has been made in four stages from 4amino-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)-~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-~u~ate (4) which in turn reacted with 6-bromomethyl-3,4-dihydro-2-methyl-4-oxoquinazoline using the same base to give the diethyl ester 6 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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Author

Michael Jarman; Graham M.F. Bisset; Timothy J. Thornton

Publisher

Elsevier Science; Elsevier ; Elsevier BV (ISSN 0022-1139)

Published

1993

Language

EN

Field

Chemistry (Physical Sciences)