Dansu Li*, Song Xue, Jill A. Caputo, Sarah M. Pound, Yuly Chiang Yu, Peng Yang, Quanfang Hu, John Kremers, Hong Zhao, Zhengping Xiong, Xiaolan Yang, Robert Livingston and Angelos Dovletoglou,
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Scalable Synthesis of Lunresertib, a Selective PKMYT1 Inhibitor
PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. Lunresertib is the first PKMYT1 inhibitor to enter clinical trials for the treatment of various solid tumors. We hereby describe the process development of an efficient, robust, and scalable synthetic route that allows the rapid production of large quantities of lunresertib drug substance (RP-6306). The synthesis features two Pd-mediated couplings, a novel chiral resolution of atropisomers, a one-pot hydration/demethylation sequence, and a recrystallization that upgrades enantiomeric purity. Screening and optimization of the resolution and reactions and control of impurities are 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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