Scalable Atroposelective Synthesis of MRTX1719: An Inhibitor of the PRMT5/MTA Complex
Michał Achmatowicz, Thomas Scattolin, David R. Snead, Dinesh J. Paymode, Sahar Roshandel, Chen Xie, Guihui Chen, Cheng‐yi Chen
Abstract
High Resolution Image Download MS PowerPoint Slide MRTX1719 was identified as a potent inhibitor of the PRMT5/MTA complex, designed to selectively target MTAP -deleted cancers. A scalable synthesis of this atropisomeric compound and an efficient isolation of the desired isomer were required to support Phase 1 clinical trials, and this was established through further development of the racemic medicinal chemistry route. In the key step, the desired ( M )-atropisomer of MRTX1719 was amplified from racemic API by combining crystallization (20 °C) and racemization (160 °C, 4 min). Concurrent execution of these, ostensibly incompatible, operations was enabled by a continuous flow setup (SPACE = S imultaneous P rocessing of A ntagonistic C hemical E vents) providing 98.4% e.e. of ( M )-atropisomer in 75% yield from racemic API on 12 kg scale. Process development targeting earlier steps of the API synthesis led to several impactful revisions including desymmetrization of 4-chlorobenzamide to access the 6-substituted-4-(aminomethyl)phthalazin-1(2 H )-one ring system, improved borylation conditions (Suzuki–Miyaura or photocatalytic), and demonstration of an economically viable route to the challenging pentasubstituted benzene from 1,4-difluorobenzene and cyclopropyl methyl ketone.