Grace McKenna, Cole Cruz, Bryon Simmons*, James T. Brewster II*, Anna M. Benz-Weeden, Thomas A. Brandt, Quinn A. Bumpers, Adam Cook, Mohamed Saad Abdullah Elsayed, Daniel Golec, Nicholas Lewandowski, Phong Nguyen, Robert W. Pipal, Pavel Savechenkov, Christina E. Wong, Eugene Tarlton, John J. Gaudino, Ronald J. Hinklin* and Tony P. Tang,
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引用次数: 0
Abstract
New synthetic methodologies that access complex saturated building blocks enable the synthesis of drug molecules with unique properties. Here, we report collaborative efforts between Pfizer’s Medicinal Chemistry, Medicinal Chemistry Synthesis Development, and Pharmaceutical Sciences Small Molecule (PSSM) groups for the development of kilogram-scale-enabled synthesis of a type II brain penetrant cMET inhibitor, PF-07907063. The chemistry presented herein demonstrates the importance of implementing a green chemistry approach for developing and applying new transformations throughout the drug development pipeline. Specifically, synthetic planning rooted in the 12 Principles of Green Chemistry led to advancements in deoxygenative photoredox-nickel dual catalysis and cross-electrophile nickel catalysis. The final route significantly lowered the process mass intensity (PMI), increased the yield of the final API, and allowed for the purification of key intermediates through crystallization versus purging impurities via column chromatography, among other improvements.
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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