A novel synthetic route to 7-substituted derivatives of the antitumor agent LY231514 (MTA)

This paper describes a further synthesis of the pyrrolo[2,3-d]pyrimidine an titumor agent MTA (LY231514). Manganic triacetate dihydrate-induced radical cyclization of methyl N-crotyl-N-(3',4'-dimethoxybenzyl)malonamide (4d) yi elded the 3-carbomethoxy-2-pyrrolidinone 5d that was then thiated with P2S5 to the corresponding thiolactam (6d). Cyclization with guanidine gave the 7-substituted 2-amino-4(3H)-oxo5,6-dihydro-pyrrolo[2,3-d]pyrimidine (7d). P d-catalyzed coupling with diethyl 4-iodobenzoylglutamate yielded (in a sing le step) the diethyl ester 9d. Deprotection with H2SO4/TFA followed by sapo nification then gave MTA. Several additional 7-substituted derivatives of M TA were prepared by use of this methodology. In contradiction to a publishe d claim, these 7-substituted derivatives proved to be devoid of any signifi cant cell growth inhibitory activity. (C) 1999 Elsevier Science Ltd. All ri ghts reserved.