Development of Adagrasib’s Commercial Manufacturing Route

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 meth...

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Published inOrganic process research & development Vol. 27; no. 3; pp. 530 - 538
Main Authors Snead, David R., Gan, Yonghong, Scattolin, Thomas, Paymode, Dinesh J., Achmatowicz, Michal, Rudisill, Duane E., Vidal, Ephraim S., Gharbaoui, Tawfik, Roberts, Phil, Yang, Jianbo, Shi, Zhangbing, Liu, Wei, Bolger, Joshua, Qiao, Zhen, Chen, Cheng-yi
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 17.03.2023
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Applied
Chemistry, Organic
Physical Sciences
Science & Technology
KRAS-G12C
targeted covalent inhibitor
Adagrasib
oncology
AMINATION
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Summary: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.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.2c00386