Matthew L. Maddess*, Ed Cleator*, Mariko Morimoto, Adrian Goodyear, Alejandro Dieguez-Vazquez, Andrew Gibb, Andy Kirtley, Melodie Christensen, Chaohui Song, Feng Peng, Mahbub Alam, Stephen P. Keen and Steven F. Oliver,
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Process Development of a Tricyclic Diazepine-Based IDH1 Mutant Inhibitor
Process development to improve synthetic access to a potent, selective, and brain-penetrant tricyclic diazepine clinical candidate that inhibits mutant IDH1 is described. A variety of disconnections were evaluated to determine the preferred sequence of fragment coupling. The optimized route involves a metal-catalyzed C–N coupling/reductive cascade to form the central diazepine core, improved entries to both the zigzag morpholine and cyclohexyl acid peripheral pieces, and an efficient end-game sequence of acylation, C–N coupling, and deprotection. In addition, a dynamic acylation process that enables selective acylation at N6 of an unprotected diazepine core is described.
期刊介绍：
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.
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