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

Article abstract of DOI:10.1016/S0040-4039(99)00959-4

This paper describes a further synthesis of the pyrrolo[2,3- d]pyrimidine antitumor agent MTA (LY231514). Manganic triacetate dihydrate- induced radical cyclization of methyl N-crotyl-N-(3',4'- dimethoxybenzyl)malonamide (4d) yielded 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)-oxo-5,6- dihydro-pyrrolo[2,3-d]pyrimidine (7d). Pd-catalyzed coupling with diethyl 4- iodobenzoylglutamate yielded (in a single step) the diethyl ester 9d. Deprotection with H₂SO₄/TFA followed by saponification then gave MTA. Several additional 7-substituted derivatives of MTA were prepared by use of this methodology. In contradiction to a published claim, these 7-substituted derivatives proved to be devoid of any significant cell growth inhibitory activity.