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.