Christopher Brearley, Robert David Bright, James Clarke*, Douglas J. Critcher, Susana Torres, Ingrid Edwards, Harriet Fenton, Shanjun Huang, Rebecca Amy Johnson, Ricky A. Jones, Suju P. Mathew, Rhys Norster, Kathryn Alice Starbuck, Amelia Taylor-Young, William Waddington, Robert Walton and Jimmy Wang,
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引用次数: 0
Abstract
Emprumapimod was a p38α MAPK inhibitor developed for LMNA-related dilated cardiomyopathy. One key modification from the discovery synthesis to the manufacturing synthesis involved moving the biaryl ether formation toward the end of the synthetic sequence. Herein, we discuss the redesigned route to suit large-scale manufacture. The development of a copper-catalyzed biaryl etherification reaction is detailed, including high-throughput experiments, process development and optimization, and purification. Subsequent amide formation afforded desired emprumapimod, delivering 82 kg of API across three batches. We anticipate this report will further support the utilization of nonprecious metal catalysis in pharmaceutical manufacture processes.
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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