Development of Adagrasib’s Commercial Manufacturing Route

Abstract

A commercial route to adagrasib (1) was developed to support clinical and commercial needs. Yield was improved to 32% over six chemical steps. A doubly regioselective SNAr reduced consumption of a chiral intermediate, reaction optimization led to parts per million palladium catalysis, and a new method to deprotect Cbz-groups were developed to mitigate risk associated with benzyl iodide.

Stereochemical Editing via Coupled Epimerization and Optical Resolution to Sustainably Manufacture a Key Adagrasib Building Block

“…( S )-Mandelic acid was identified as an optical resolution candidate based on structural similarity to related molecules, and it worked quite successfully in this application (Figure ). Piperazine was recovered with high enantiopurity and recovery (48.2% recovery, 99.64:0.32 er ( S : R )).…”

“…Adagrasib is an FDA-approved KRAS G12C inhibitor. The commercial and second-generation routes of manufacturing were recently disclosed. The piperazine building block is required at the metric ton scale, and accessing this fragment was unsatisfying in both cases (Figure , highlighted in blue).…”

“…We wondered whether the minor piperazine epimerization (1–2%) encountered during adagrasib manufacturing might present an opportunity (Figure ). Perhaps a short, racemic synthesis could be quickly developed, relying upon optical resolution to provide enantiopurity. Epimerization is generally an equilibrium-based process, and so this could provide a pathway to increase the yield if the process of making the undesired isomer were reversible, amplified, and able to be switched on upon command.…”

“…Is epimerization a nuisance to be avoided or a valuable tool for designing asymmetric syntheses? Advances place epimerization processes in the spotlight, yet industrial examples adopting this strategy remain scarce when dynamic kinetic resolution (DKR) and crystallization-induced diastereomeric transformations (CIDT) are not feasible.…”

Development of a Streamlined Manufacturing Process for the Highly Substituted Quinazoline Core Present in KRAS G12C Inhibitor Divarasib

“…Since the seminal report by Shokat et al a decade ago, it has been widely demonstrated that previously considered undruggable KRAS G12C mutations can now be targeted with high potency. In fact, several small molecules have been successfully developed as selective KRAS G12C inhibitors to treat cancer patients, including recently U.S. Food and Drug Administration (FDA) approved sotorasib and adagrasib as well as clinical candidates ARS-2102, JDQ443, and BI-0474 (Figure ). Genentech’s divarasib (GDC-6036, 1 ), a highly potent and selective small-molecule KRAS G12C covalent inhibitor, is currently being investigated in phase III clinical trials.…”