| Abstract
| - Alkylation of various primary amines with crotyl bromide, followed by DMAP-promoted acylationwith methyl malonyl chloride to 4 and then manganic triacetate dihydrate/cupric acetate inducedradical cyclization, gave 1-substituted-4-vinyl-3-carbomethoxy-2-pyrrolidinones (5). Thiation to thethiolactams 6 and guanidine cyclization then gave a series of 2-amino-3,4-dihydro-4-oxo-5-vinyl-7-substituted pyrrolo[2,3-d]pyrimidines (7). Palladium-catalyzed C−C coupling with diethyl 4-iodobenzoylglutamate led in one step via an unexpected redox reaction to the diethyl esters 9 of aseries of 7-substituted derivatives of ALIMTA (LY231514, MTA), from which the target analogues10 were readily prepared by saponification. Attempted deprotection at position 7 was successful inonly one case (9d, R = CH2C6H3(OMe)2(-3‘,4‘), which resulted in a known pentultimate precursor(9, R = H) of ALIMTA. The 7-substituted derivatives 10 proved to be inactive in vitro as inhibitorsof cell division.
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