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



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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:, *Tel: +86-21-20231000-2407. Fax: +86-21-20231000-2407. E-mail:
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.

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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 PLUS year tenure till date Feb 2023, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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