Development of Adagrasib’s Commercial Manufacturing Route
David R. Snead, Yonghong Gan, Thomas Scattolin, Dinesh J. Paymode, Michał Achmatowicz, Duane E. Rudisill, Ephraim S. Vidal, Tawfik Gharbaoui, Phil Roberts, Jianbo Yang, Zhangbing Shi, Wei Liu, Joshua Bolger, Zhen Qiao, Cheng‐yi Chen
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 S N Ar 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.
Topics & Concepts
RegioselectivityYield (engineering)Nucleophilic aromatic substitutionIodideCatalysisPalladiumCombinatorial chemistryChemistryOrganic chemistryMaterials scienceNucleophilic substitutionMetallurgyCancer Treatment and PharmacologyChemical Reactions and IsotopesHER2/EGFR in Cancer Research