Optimization and Scale-Up of a Novel Process for 2-Aminoindan Hydrochloride Production

Abstract

The need for an economical process for producing 2-aminoindan hydrochloride, a key starting material in manufacturing novel bioactive molecules, motivated development of a novel synthetic route using an inexpensive reactant, ninhydrin. The synthesis, involving oximation of ninhydrin followed by catalytic reduction of the resulting oxime intermediate to give 2-aminoindan, was demonstrated successfully, and a product purification scheme was developed to isolate 2-aminoindan as the hydrochloride salt form. Subsequent process development optimized the reduction step by identifying regimes of fast and slow reaction (corresponding to reduction of oxime and diketone functions, respectively), and tailoring reaction conditions to use mild conditions during the fast exothermic regime to ensure process safety followed by more severe conditions for the slower reaction. The process was successfully scaled up 100-fold in a pilot plant, with excellent yield and product quality agreement between laboratory and pilot plant.