Industry-Oriented Route Evaluation and Process Optimization for the Preparation of Brexpiprazole

Efforts toward route evaluation and process optimization for the preparation of brexpiprazole ( 1 ) are described. Starting from commercially available dihydroquinolinone 11, a three-step synthesis route composed of O -alkylation, oxidation, and N -alkylation was selected for industry-oriented process development aiming to reduce side reactions and achieve better impurity profiles. The reaction conditions of the three steps were investigated, and the control strategy for the process-related impurities was established. The optimized process was validated on the kilogram scale and now is viable for commercialization, with the results of not less than 99.90% purity of 1 (by HPLC) and not more than 0.05% of persistent impurities 15 and 16 .