Manufacturing Process for 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine, a Key Intermediate in the Synthesis of KRAS G12C Inhibitor Divarasib
Jeff Shen, Nicholas A. White, Qingping Tian, Lauren E. Sirois*, Haiming Zhang* and Francis Gosselin,
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引用次数: 1
Abstract
The densely functionalized heterocycle 6-bromo-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (1) represents a key intermediate in the atroposelective synthesis of the potent KRAS G12C covalent inhibitor divarasib (GDC-6036). The first-generation manufacturing process of 1 comprised 9 steps, including tedious protecting group manipulations and a superstoichiometric copper-mediated trifluoromethylation of the corresponding iodopyridine using Chen’s reagent. Additional process research and development enabled an improved, scalable second-generation route furnishing 1 in only 3 steps from the readily available and inexpensive starting material 2,6-dichloro-4-methylnicotinic acid (13) via a deoxofluorination, a chlorine-to-bromine halogen exchange, and a regioselective SNAr amination.
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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