A scalable synthesis of (R)-3-(2-aminopropyl)-7-benzyloxyindole via resolution |
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| Institution: | 1. Chemistry Research Laboratories, Drug Research Division, Dainippon Pharmaceutical Co., Ltd., Enoki, 33-94, Suita, Osaka 564-0053, Japan;2. The 1st Laboratories, Research & Development Center, Nagase & Co., Ltd., 2-2-3 Murotani, Nishi-ku, Kobe 651-2241, Japan;1. Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China;2. Humanwell Healthcare (Group) Co,. Ltd, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, Hubei, China;3. Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China;1. Center for Marine Natural Products and Drug Discovery, School of Earth and Environmental Sciences, Seoul National University, NS-80, Seoul 151-747, Republic of Korea;2. Department of Chemistry and Nano Science, Global Top 5 Program, Ewha Womans University, Seoul 120-750, Republic of Korea;3. Research Institute of Oceanography, Seoul National University, NS-80, Seoul 151-747, Republic of Korea;4. College of Pharmacy, Yeungnam University, 214-1 Dae-dong, Gyeongsan 712-749, Republic of Korea |
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| Abstract: | (±)-3-(2-Aminopropyl)-7-benzyloxyindole 1, assembled from 7-benzyloxyindole 3 in 59% overall yield, is resolved with O,O′-di-p-toluoyl l-(2R,3R)-tartaric acid 7 into (R)-1, a key intermediate of AJ-9677 2 (selective adrenaline β3-agonist) in 99.5% e.e. and 36% overall yield. The unwanted enantiomer (S)-1 (61.9% e.e.; recovered in 57% yield from the crystallization filtrate) can be reused in another round of resolution after its enantiomeric purity is lowered to 3.7% by Raney Co treatment under a hydrogen atmosphere. |
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