Development of an Improved Process To Prepare a Key Intermediate in the Manufacture of Sotorasib
Sotorasib is a first-in-class KRASG12C inhibitor with a unique carbon–nitrogen atropisomer. Described herein is the development of an improved second-generation process to manufacture a key sotorasib intermediate, rac-4. Notable improvements to the second-generation process include the development of a three-step fully telescoped sequence in acetonitrile and the use of phosgene as an isocyanating agent, which allowed for dichloromethane, aqueous extractive work-ups, and distillations to be completely removed from the process. Compared to the first-generation process, these process improvements led to a 97% reduction in organic solvent usage and a 71% reduction in wastewater generation and still maintains a 75% yield and >99.5% purity of rac-4 in the overall process.
Authors
- Daniel J. Griffin (ORCID: https://orcid.org/0000-0002-5051-2069)
- Michael T. Corbett (ORCID: https://orcid.org/0000-0002-1704-489X)
- Vilmalí López-Mejías (ORCID: https://orcid.org/0000-0003-2138-8414)
- Joshua Bolger
- Laslo Farkaš Višontai
- John Colyer (ORCID: https://orcid.org/0000-0001-8281-5550)
- Yongbo Dan
- Austin Smith (ORCID: https://orcid.org/0000-0001-8795-8681)
- Jo Anna Robinson
- Yeongcheol Han (ORCID: https://orcid.org/0000-0002-1729-7870)
- Maria Victoria Silva Elipe (ORCID: https://orcid.org/0000-0002-8429-9534)
- Michał Achmatowicz (ORCID: https://orcid.org/0009-0000-1920-2049)
- Kyle W. Quasdorf (ORCID: https://orcid.org/0000-0003-0151-6511)
- Derek B. Brown (ORCID: https://orcid.org/0000-0002-7909-0867)
- Jason S. Tedrow (ORCID: https://orcid.org/0000-0002-5663-2360)
- Padmini K. Ananthoji
- Andrew T. Parsons (ORCID: https://orcid.org/0000-0002-0320-0919)
- Brian M. Cochran (ORCID: https://orcid.org/0000-0002-4842-2259)
- Seb Caille
- Hsiao‐Wu Hsieh (ORCID: https://orcid.org/0000-0002-0443-4223)
- William Powazinik
- Xi‐Jie Dai (ORCID: https://orcid.org/0000-0002-4899-6359)
- Ying Chen (ORCID: https://orcid.org/0000-0002-6594-1579)
- Kai Liu (ORCID: https://orcid.org/0000-0003-1633-7188)
- Tianhui Shi
- Zhenlü Wang (ORCID: https://orcid.org/0000-0001-9862-5057)
- Junlong Chen (ORCID: https://orcid.org/0000-0003-3931-8190)
- Amanda E. Stahl
- Brendan Dalbey
Institutions
- Amgen (United States) (US)
- HEM Technologies (United States) (US)
- Université Bourgogne Franche-Comté (FR)
Publication Details
- Journal
- Organic Process Research & Development
- Published
- 2025-06-02
- DOI
- https://doi.org/10.1021/acs.oprd.5c00043
- Citations
- 1
- Primary Topic
- Thermal and Kinetic Analysis
- Type
- article
- Field-Weighted Citation Impact
- 0.52