Development of a Commercial Manufacturing Process for Vepdegestrant, an Orally Bioavailable PROTAC Estrogen Receptor Degrader for the Treatment of Breast Cancer
A commercial process for vepdegestrant (1), the most advanced PROTAC protein degrader in human clinical trials, has been developed to support clinical and commercial needs. The process features an efficient convergent synthetic strategy through the final reductive amination of two advanced chiral intermediates, as well as several highly efficient telescoped processes and robust crystallization for purity control. The final commercial process of vepdegestrant (1) consists of seven proposed regulatory GMP steps with five isolations in an overall yield of 29%.
Authors
- Nitinchandra D. Patel (ORCID: https://orcid.org/0000-0001-9571-6658)
- Michael R. Reeve
- Truong N. Nguyen (ORCID: https://orcid.org/0000-0002-6414-827X)
- Jorge López (ORCID: https://orcid.org/0000-0003-0807-6096)
- Maciej Kalinowski (ORCID: https://orcid.org/0000-0002-6729-1506)
- Robert Pritchard (ORCID: https://orcid.org/0000-0003-3782-3249)
- Jean‐Nicolas Desrosiers (ORCID: https://orcid.org/0000-0003-3859-2390)
- John A. Grosso
- Jamie M. Buske (ORCID: https://orcid.org/0009-0004-5676-8163)
- Herman Chen
- Chase A. Salazar (ORCID: https://orcid.org/0000-0002-2221-4865)
- Teri Shanklin Hochdorfer (ORCID: https://orcid.org/0000-0002-0842-7549)
- Amber M. Johnson (ORCID: https://orcid.org/0000-0002-6202-6113)
- Tyler J. Potter
- Noalle Fellah (ORCID: https://orcid.org/0000-0002-5561-4064)
- Emily Tweed (ORCID: https://orcid.org/0000-0001-6659-812X)
- Doris Chen (ORCID: https://orcid.org/0000-0001-8835-0280)
- S. K. Avery
- Paul G. Wahome
- Xin Chen (ORCID: https://orcid.org/0009-0005-9066-8868)
- David F. Fernández (ORCID: https://orcid.org/0000-0003-3482-0894)
- Robert S. Simpson
- Katherine D. Launer-Felty
- Lu Han (ORCID: https://orcid.org/0000-0003-4228-768X)
- Hanqing Dong
- Ethan Wood (ORCID: https://orcid.org/0009-0005-1562-5382)
- John J. Salisbury (ORCID: https://orcid.org/0009-0001-8202-9020)
- Zhihui Peng (ORCID: https://orcid.org/0000-0002-7447-3893)
- Anil M. Rane
- Andrew R. Davidson (ORCID: https://orcid.org/0009-0009-3329-407X)
- Teresa W. Makowski
- Brian P. Jones
- Carolyn Mastriano
- Margaret C. Richins
- Liza Tabshey
- Nancy Walsh-Sayles
- Jordan A. Willie
Institutions
- Pfizer (United States) (US)
- Arvinas (United States) (US)
Publication Details
- Journal
- Organic Process Research & Development
- Published
- 2024-11-05
- DOI
- https://doi.org/10.1021/acs.oprd.4c00362
- Citations
- 11
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 2.57