Kinetic and Mechanistic Investigations to Enable a Key Suzuki Coupling for Sotorasib ManufactureWhat a Difference a Base Makes

The process to manufacture sotorasib (AMG 510) employs a Suzuki–Miyaura reaction as a key step in the synthetic sequence. Detailed kinetic and mechanistic investigations into this process were utilized to identify the active catalytic species and rate-determining step, rationalizing current procedur...

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Bibliographic Details
Published in:Organic process research & development 2023-01, Vol.27 (1), p.198-205
Main Authors: Murray, James I., Zhang, Liang, Simon, Adam, Silva Elipe, Maria V., Wei, Carolyn S., Caille, Seb, Parsons, Andrew T.
Format: Article
Language:English
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Summary:The process to manufacture sotorasib (AMG 510) employs a Suzuki–Miyaura reaction as a key step in the synthetic sequence. Detailed kinetic and mechanistic investigations into this process were utilized to identify the active catalytic species and rate-determining step, rationalizing current procedural requirements and process limitations. This knowledge was applied to demonstrate that simple alteration of the base (from KOAc to K2CO3) provided significant process improvements by shifting the rate-determining step and transmetalation pathways. Kinetic modeling was utilized for parameter optimization and resulted in significant reductions in both the Pd catalyst loading and equivalents of boronic acid as well as removing the requirement for slow reagent dosing. This report highlights the distinct mechanistic pathways that may occur upon alteration of the base in Suzuki–Miyaura coupling reactions.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.2c00332