A new route to 7-substituted derivatives of n-[4-(2-[2-amino-3,4-dihydro-4-oxo-7H-pyrrolo(2,3-d)pyrimidin-5-yl]ethyl)benzoyl]-L-glutamic acid [ALIMTA (LY231514, MTA)].
Alkylation of various primary amines with crotyl bromide, followed by DMAP-promoted acylation with methyl malonyl chloride to 4 and then manganic triacetate dihydrate/cupric acetate induced radical cyclization, gave 1-substituted-4-vinyl-3-carbomethoxy-2-pyrrolidinones (5). Thiation to the thiolactams 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 a series of 7-substituted derivatives of ALIMTA (LY231514, MTA), from which the target analogues 10 were readily prepared by saponification. Attempted deprotection at position 7 was successful in only one case (9d, R = CH(2)C(6)H(3)(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 inhibitors of cell division.
Taylor
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Department of Chemistry, Princeton University, Princeton, New Jersey 08655, USA. etaylor@princeton.edu
Liu
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B
D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry; D005971:Glutamates / Q000138:chemical synthesis* / Q000737:chemistry; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D000068437:Pemetrexed
D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D005971:Glutamates; D007202:Indicators and Reagents; D000068437:Pemetrexed; D006147:Guanine