Preparation of a Tricyclopropylamino Acid Derivative via Simmons–Smith Cyclopropanation with Downstream Intramolecular Aminoacetoxylation for Impurity Control

Abstract

A tricyclopropylamino acid derivative was prepared via Simmons–Smith cyclopropanation of the corresponding alkene. This transformation was plagued by inconsistent conversions, and the opportunity for the removal of the structurally similar alkene contaminant at this stage and downstream via crystallization was limited. These factors combined to make control of the alkene impurity level in the active pharmaceutical ingredient (API) difficult. A removal strategy was developed that utilized downstream, in-process aminoacetoxylation to convert the alkene impurity to structurally dissimilar compounds that purged during crystallization. Using this protocol, the alkene contaminant in the subsequent intermediates, and thus the API, could be controlled to less than 0.1 area percent.