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 KRAS(G12C) 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.

Automated summary

In this study, route design and synthesis of a challenging chirally atropisomeric inhibitor were conducted to improve synthesis efficiency and avoid racemization. The strategy was further validated on other substrates.