THE SYNTHESIS OF N-(2-AMINO-4-SUBSTITUTED LO[2,3-D]-PYRIMIDIN-5-YL)ETHYL]BENZOYL)-L-GLUTAMIC ACIDS AS ANTINEOPLASTIC AGENTS

A series of olo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic acids w ere synthesized. In this current synthesis, compound 2-amino-4-chloro- pyrrolo[2,3-d]pyrimidine (4) was selected as an important precursor fo r the preparation of key intermediates such as 5b, 10b, 15a and 15b. T hese highly functionalized pyrrolo[2,3-d]pyrimidines were then later c oupled with either 4-ethynylbenzoylglutamate or 4-iodobenzoylglutamate in a palladium catalyzed Heck reaction and thus provided the basic sk eleton of the targeted molecules. The availability of the chlorine ato m at the 4-position of the pyrrolopyrimidine nucleus has allowed us to introduce different substituents at this position efficiently. By thi s approach, we were able to prepare a variety of 4-substituted pyrrolo [2,3d]pyrimidine based folate antagonists (2a-2g) which are closely re lated to the novel thymidylate synthase inhibitor LY231514. In vitro a nalysis has demonstrated that some of these agents are highly cytotoxi c against human leukemic cells (CCRF-CEM) in culture.