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

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Abstract Image

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

Key Laboratory of Plant Resources and Chemistry in Arid Regions, Xinjiang Technical Institute of Physics and ChemistryChinese Academy of SciencesSouth Beijing Road 40−1, Urumqi, Xinjiang 830011, P. R. China
University of Chinese Academy of SciencesNo. 19A Yuquan Road, Beijing 100049, P. R. China
§CAS Key Laboratory for Receptor ResearchShanghai Institute of Materia Medica, Chinese Academy of Sciences555 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.
ESI-MS: m/z = 434.22 [M + H].
1H NMR (500 MHz, DMSO-d6) δ (ppm): 11.61 (s, 1H), 7.80 (d, J = 9.4 Hz, 1H), 7.69 (d, J = 5.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 9.4 Hz, 1H), 7.40 (d, J = 5.5 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.84–6.78 (m, 2H), 6.30 (d, J = 9.4 Hz, 1H), 4.05 (t, J = 6.4 Hz, 2H), 3.06 (brs, 4H), 2.61 (brs, 4H), 2.43 (t, J = 7.1 Hz, 2H), 1.86–1.75 (m, 2H), 1.69–1.57 (m, 2H).
13C NMR (125 MHz, DMSO-d6) δ (ppm): 162.35, 160.55, 148.36, 140.76, 140.49, 140.12, 133.47, 129.34, 125.92, 125.19, 121.99, 118.57, 116.73, 113.36, 112.11, 110.96, 98.68, 67.71, 57.47, 53.08, 51.83, 26.66, 22.81.
/////////////Brexpiprazole
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