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

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

Weiming Chen^†‡, Jin Suo^§, Yongjian Liu^∥, Yuanchao Xie^§, Mingjun Wu^∥, Fuqiang Zhu^∥ , Yifeng Nian^∥, Haji A. Aisa*^† , and Jingshan Shen*^§ 

^†Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, South Beijing Road 40−1, Urumqi, Xinjiang 830011, P. R. China

^‡University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P. R. China

^§CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China

^∥Topharman Shanghai Co., Ltd., Building 1, No. 388 Jialilue Road, Zhangjiang Hitech Park, Shanghai 201209, P. R. China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00438

*Tel: +86-0991-3835679. Fax: +86-0991-3835679. E-mail: haji@ms.xjb.ac.cn., *Tel: +86-21-20231000-2407. Fax: +86-21-20231000-2407. E-mail: shenjingshan@simm.ac.cn.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00438