THE SYNTHESIS OF N-PYRIMIDIN-5-YL)ETHYL>BENZOYL>-L-GLUTAMIC ACIDS AS ANTINEOPLASTIC AGENTS

Article abstract of DOI:10.3987/COM-92-S(T)65

A series of N-<2-amino-4-substituted <(pyrrolo<2,3-d>pyrimidin-5-yl)ethyl>benzoyl>-L-glutamic acids were synthesized.In this current synthesis, compound 2-amino-4-chloro-pyrrolo<2,3-d>pyrimidine (4) was selected as an important precursor for the preparation of key intermediates such as 5b, 10b, 15a and 15b.These highly functionalized pyrrolo<2,3-d>pyrimidines were then later coupled with either 4-ethynylbenzoylglutamate or 4-iodobenzoylglutamate in a palladium catalyzed Heck reaction and thus provided the basic skeleton of the targeted molecules.The availability ofthe chlorine atom at the 4-position of the pyrrolopyrimidine nucleus has allowed us to introduce different substituents at this position efficiently.By this approach, we were able to prepare a variety of 4-substituted pyrrolo<2,3-d>pyrimidine based folate antagonists (2a-2g) which are closely related to the novel thymidylate synthase inhibitor LY231514.In vitro analysis has demonstrated that some of these agents are highly cytotoxic against human leukemic cells (CCRF-CEM) in culture.