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

Route design and proof of concept synthesis was conducted on a synthetically challenging atropisomeric KRAS 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 -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 -substituted bromo/iodo unprotected anilines.