1453851-79-0Relevant articles and documents
Kumada-Corriu Heteroaryl Cross-Coupling for Synthesis of a Pharmaceutical Intermediate: Comparison of Batch Versus Continuous Reaction Modes
Linghu, Xin,Wong, Nicholas,Jost, Vera,Fantasia, Serena,Sowell, C. Gregory,Gosselin, Francis
, p. 1320 - 1325 (2017/09/23)
Pyridone 1, a key intermediate in the preparation of ERK inhibitor GDC-0994, was synthesized via a cross-coupling/hydrolysis sequence from commercially available starting materials. C-C bond formation was achieved via an efficient palladium catalyzed Kumada-Corriu cross-coupling reaction. However, the 4-pyridylmagnesium halide reagent generated in situ was found to be unstable at the reaction temperature, leading to inconsistent results on scale. In order to address process robustness issues associated with the cross-coupling reaction, we investigated both flow chemistry and a low temperature Kumada-Corriu coupling reaction. Finally, a basic hydrolysis process of 2-fluoropyridine was developed to avoid formation of toxic and corrosive hydrofluoric acid, resulting in a safe and scalable process toward 1.
Development of a Practical Synthesis of ERK Inhibitor GDC-0994
Linghu, Xin,Wong, Nicholas,Iding, Hans,Jost, Vera,Zhang, Haiming,Koenig, Stefan G.,Sowell, C. Gregory,Gosselin, Francis
, p. 387 - 398 (2017/03/24)
The process development of a synthetic route to manufacture ERK inhibitor GDC-0994 on multikilogram scale is reported herein. The API was prepared as the corresponding benzenesulfonate salt in 7 steps and 41% overall yield. The synthetic route features a biocatalytic asymmetric ketone reduction, a regioselective pyridone SN2 reaction, and a safe and scalable tungstate-catalyzed sulfide oxidation. The end-game process involves a telescoped SNAr/desilylation/benzenesulfonate salt formation sequence. Finally, the development of the API crystallization allowed purging of process-related impurities, obtaining >99.5A% HPLC and >99% ee of the target molecule.
Discovery of highly potent, selective, and efficacious small molecule inhibitors of ERK1/2
Ren, Li,Grina, Jonas,Moreno, David,Blake, James F.,Gaudino, John J.,Garrey, Rustam,Metcalf, Andrew T.,Burkard, Michael,Martinson, Matthew,Rasor, Kevin,Chen, Huifen,Dean, Brian,Gould, Stephen E.,Pacheco, Patricia,Shahidi-Latham, Sheerin,Yin, Jianping,West, Kristina,Wang, Weiru,Moffat, John G.,Schwarz, Jacob B.
, p. 1976 - 1991 (2015/04/27)
Using structure-based design, a novel series of pyridone ERK1/2 inhibitors was developed. Optimization led to the identification of (S)-14k, a potent, selective, and orally bioavailable agent that inhibited tumor growth in mouse xenograft models. On the basis of its in vivo efficacy and preliminary safety profiles, (S)-14k was selected for further preclinical evaluation.
