Synthesis of pyrazolo 3,4-pyrimidine analogues of the potent agent N-4-2-2-amino-4 3-oxo-7-pyrrolo 2,3-pyrimidin-5-yl ethylbenzoyl-L-glutamic acid (LY231514)

Several pyrazolo[3,4- d ]pyrimidine analogues of the potent antitumor agent N -{4-[2-(2-amino-4(3 H )-oxo-7 H -pyrrolo[2,3- d ]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic acid (LY231514, 5) have been prepared. A principal synthetic step proved to be a palladium-catalyzed CC coupling of the 5-halo-substituted pyrazolo[3,4- d ]pyrimidines 12–15 with dimethyl 4-ethynylbenzoyl-L-glutamate (16). An additional pyrazolo[3,4- d ]pyrimidine analogue of 5 possessing an isofolic acid bridge unit (-NHCH2-) was prepared by reductive alkylation of diethyl 4-formylbenzoyl-L-glutamate (31) with 2-methyl-5-amino-4(3 H )-oxo-7 H -pyrazolo[3,4- d ]pyrimidine (30). Only compound 26 proved to have in vitro cell growth inhibitory activity.