Scalable Atroposelective Synthesis of MRTX1719: An Inhibitor of the PRMT5/MTA Complex

Abstract

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 = Simultaneous Processing of Antagonistic Chemical Events) 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(2H)-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.

Access to Cyclopropanol via Supply-Centered Synthesis

“…MRTX1719 is a clinical drug candidate for cancer treatment . The compound contains several structural features of note, including an axis of chirality, a pentasubstituted benzene ring, and a pendant cyclopropyl ether.…”

Semicontinuous Temperature Cycle-Induced Deracemization Using an Axially Chiral Naphthamide

“…This racemization converts the mother liquors back into a racemic mixture, which is subsequently crystallized . Furthermore, this technique has been studied in crystallization-induced diastereomeric transformation, − in particular the epimerization of an axially chiral compound, which was successfully scaled in industrial applications . Although deracemization processes based on the batch-mode are becoming more successful, skill gaps still remain to realize continuous crystallization.…”

Stereodynamic Strategies to Induce and Enrich Chirality of Atropisomers at a Late Stage

“…As discarding the undesired enantiomer is inefficient, the authors developed a thermal racemization process where the undesired enantiomer (( P ) - 1.2 ) was racemized at 315 °C in flow, which could be followed with iterative rounds of classical resolution and thermal recycling . A similar approach was also utilized for the scalable synthesis of MRTX1719, where the resolution conditions were incompatible with temperature required for racemization. , The authors performed iterative crystallization and racemization operations to decouple these incompatible processes and achieve a stepwise dynamic kinetic resolution.…”