Process Development and Pilot-Plant Synthesis of (S)-tert-Butyl 1-Oxo-1-(1-(pyridin-2-yl)cyclopropylamino)propan-2-ylcarbamate: Studies on the Scale-Up of Kulinkovich-Szymoniak Cyclopropanation

A practical and scalable synthesis of (S)tert-butyl 1-oxo-1-(1-(pyridin-2-yl)cyclopropylamino)-propan-2-ylcarbamate, an intermediate in the manufacture of a lymphocyte function-associated antigen 1 inhibitor, is described. The titled compound is prepared via an efficient one-pot, two-step telescoped sequence starting from readily available materials. A modified Kulinkovich-Szymoniak cyclopropanation of a nitrile followed by in situ amide formation with an activated carboxylic acid derivative afforded the target product in about 50% overall isolated yield and > 97% purity.