Discovery and development of a commercial synthesis of azafenidin
A commercial synthesis of the DuPont herbicide azafenidin is described. Discovery of a novel synthesis of the triazolinone ring system and a practical, environmentally benign process to 5-cyanovaleramide were critical breakthroughs in enabling azafenidin to be manufactured at an acceptable cost. The process began with the selective hydrolysis of DuPont's nylon intermediate, adiponitrile, to 5-cyanovaleramide. This was converted via Hofmann rearrangement and Pinner-type cyclization to afford the key amidine carboxylate intermediate containing both carbon atoms of the triazolinone ring. The preservation of all six carbon atoms of adiponitrile set up a 2 + 3 cyclocondensation with arylhydrazines, which replaced a costly 4 + 1 cyclocondensation of an amidrazone with phosgene or a phosgene surrogate used in the original route. This new triazolinone process was optimized to afford the commercial product in a highly efficient and economical fashion.
Shapiro, Rafael,DiCosimo, Robert,Hennessey, Susan M.,Stieglitz, Barry,Campopiano, Onorato,Chiang, George C.
p. 593 - 598
(2013/09/07)
Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity
Subsequent to the discovery of 4-[(2,4-dichlorophenyl)amino] -6,7-dimethoxy-3-quinolinecarbonitrile (1a) as an inhibitor of Src kinase activity (IC50 = 30 nM) several additional analogues were prepared. Optimization of the C-4 anilino group of la led to lc which contains a 2,4-dichloro-5-methoxy- substituted aniline. Replacement of the methoxy group at C-7 of 1c with a 3-(morpholin-4-yl)propoxy group provided 2c resulting in increased inhibition of both Src kinase activity and Src-mediated cell proliferation. Analogues of 2c with other trisubstituted anilines at C-4 were also potent Src inhibitors and the propoxy group of 2c was preferred over ethoxy butoxy or pentoxy. Replacement of the morpholine group of 2c with a 4-methylpiperazine group provided 31a which had an IC50 of 1.2 nM in the Src enzymatic assay an IC50 of 100 nM for the inhibition of Src-dependent cell proliferation and was selective for Src over non-Src family kinases. Compound 31a which had higher 1 and 4 h plasma levels than 2c effectively inhibited tumor growth in xenograft models.