Exploration of a Nitromethane-Carbonylation Strategy during Route Design of an Atropisomeric KRASG12C Inhibitor.

Route design and proof of concept synthesis was conducted on a synthetically challenging atropisomeric KRASG12C inhibitor to support clinical API manufacture. Improvements to the synthesis of a chiral piperazine fragment gave reduced step count and streamlined protecting group strategy via the formation and methanol ring opening of an N-carboxy-anhydride (NCA). The complex atropisomeric nitroquinoline was accessed via an early stage salt-resolution followed by a formal two-part nitromethane-carbonylation, avoiding a high temperature Gould-Jacobs cyclization that previously led to atropisomer racemization. The substrate scope of the formal nitromethane-carbonylation strategy was further explored for a range of ortho-substituted bromo/iodo unprotected anilines.

Citation

James J Douglas, Matthew R Tatton, Daniël de Bruin, David Buttar, Calum Cook, Kuangchu Dai, Catalina Ferrer, Kevin Leslie, James Morrison, Rachel Munday, Thomas O Ronson, Hucheng Zhao. Exploration of a Nitromethane-Carbonylation Strategy during Route Design of an Atropisomeric KRASG12C Inhibitor. The Journal of organic chemistry. 2022 Feb 18;87(4):2075-2086

Mesh Tags

Substances

PMID: 34652911

search → result