Plenary Session, SCS Award Lecture
PS-004

Sandmeyer Award Lecture 2025: Organometallic Chemistry at Scale - A Highly Atroposelective Negishi Coupling Enables the Commercial Manufacturing Process of Divarasib

S. Bachmann1, R. Bigler1*, D. Kaldre1*, D. Kummli1*, R. Lebl1*, D. Linder1*, C. Ochs1*, U. Orcel1*, I. Prévot1*, J. Sedelmeier1*, E. Trachsel1*, J. Xu2*, H. Zhang2*
1Synthetic Molecules Technical Development, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland, 2Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States

The first example of a highly atroposelective Negishi coupling at manufacturing scale, allowing for the isolation of (Ra)-4 as a single isomer without chromatography,1 will be presented. The implementation of a continuous process for the metalation steps of the Negishi coupling allowed for the elimination of the cryogenic reaction conditions from the manufacturing process of divarasib (1),2 a highly potent KRAS G12C inhibitor currently undergoing Ph III clinical trials.3

More detailed investigations as to the identification and characterization of the best catalyst, the role of the additive and the reaction kinetics of the Negishi coupling will be presented.

[1]  J. Xu, L. Ngiap-Kie, J. Timmerman, J. Shen, K. Clagg, U. Orcel, R. Bigler, E. Trachsel, R. Meier, N. A. White, J. Burkhard, L. E. Sirois, Q. Tian, R. Angelaud, S. Bachmann, H. Zhang, F. Gosselin, Org. Lett., 2023, 25, 3417-3422.
[2]  S. M. Kelly, R. Lebl, T. C. Malig, T. Bass, D. Kummli, D, Kaldre, U. Orcel, L. Tröndlin, D. Linder, J. Sedelmeier, S. Bachmann, C. Han, H. Zhang, F. Gosselin, Org. Process Res. Dev. 2024, 28, 1546-1555.
[3]  D. Brazel, M. Nagasaka, Targeted Oncology 2024, 19, 297-301.