Nicholas R. Deprez*, Jonathan M. E. Hughes*, Shorouk O. Badir, Stasik Popov, Teresa Andreani, Rachel S. Bade, Clara Hartmanshenn, Thomas Tai-min Kwok, Donald R. Gauthier Jr., Nastaran Salehi Marzijarani, Zeinab Sakhaei, Riki Drout, Steve Castro, David J. Schenk, Charles Wolstenholme, Nilusha Padivitage, Cody Welch, Jason R. Kowalski, Brittany Kassim, Yong Liu, Ryan D. Cohen, Alex M. Confer, Guilherme Dal Poggetto, Andrew P. J. Brunskill, Feng Peng, Ji Qi, Jing Xu, Mingxiang Lin and Jamie M. McCabe Dunn,
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引用次数: 0
Abstract
We describe the rapid end-game process development for the first good manufacturing process (GMP) delivery of the 3C-like protease inhibitor MK-7845 (1), an experimental treatment for SARS-CoV-2. Three operations, including an amide-coupling, oxidation, and crystallization, were rapidly developed and implemented on a kilogram scale to enable critical safety studies and phase 1 clinical trials to move forward on a highly accelerated timeline. Key to the success of this undertaking was our focus on purging key impurities formed in the amide-coupling step, identifying a safe and scalable TEMPO/NaOCl oxidation to access 1, and developing an active pharmacutical ingredient (API) crystallization that addressed challenges associated with gumming, oiling, and agglomeration. Notably, this delivery was completed within an approximately six-week time frame, and challenges associated with this highly accelerated delivery are also discussed.
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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