Hindered Biaryl Bond Construction and Subsequent Diastereomeric Crystallization to Produce an Atropisomeric Covalent KRASG12CInhibitor ARS-2102
- Resource Type
- Article
- Authors
- Yang, Xiaogen; Li, Zhiwen; Xu, Wenwen; Zhu, Guanming; Feng, Xiantong; Zhang, Jun; Zhao, Hongbin; Chen, Yuyin; Kong, Jianshe; Mai, Wanping; Li, Lian-Sheng; Pippel, Daniel J.; Ren, Pingda; Deng, Xiaohu
- Source
- Organic Process Research & Development; January 2023, Vol. 27 Issue: 1 p206-216, 11p
- Subject
- Language
- ISSN
- 10836160; 1520586X
A scaleup route for a first-generation covalent KRASG12Cinhibitor ARS-2102 was devised, featuring an “early cross-coupling” strategy to construct the tetra-substituted atropisomeric biaryl scaffold. An iterative diastereomeric recrystallization enabled an effective chiral resolution of key intermediate 24. A global deprotection followed by chemoselective functionalization afforded ARS-2102 in excellent yield and diastereomeric enrichment. This chromatography-free sequence was successfully executed on kilogram scale.