Scalable,efficient process for the synthesis of (R)-3,5-bistrifluoromethylphenyl ethanol via catalytic asymmetric transfer hydrogenation and isolation as a DABCO inclusion complex |
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| Affiliation: | 1. Department of Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA;2. Department of Analytical Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA;1. The Key Laboratory of Low-Carbon Chemistry & Energy Conservation of Guangdong Province, Sun Yat-sen (Zhongshan) University, Guangzhou 510275, People׳s Republic of China;2. State Key Laboratory of Optoelectronic Materials and Technologies, Sun Yat-sen (Zhongshan) University, Guangzhou 510275, People׳s Republic of China;3. School of Physics Science and Engineering, Sun Yat-sen (Zhongshan) University, Guangzhou 510275, People׳s Republic of China;4. School of Chemistry and Chemical Engineering, Sun Yat-sen (Zhongshan) University, Guangzhou 510275, People׳s Republic of China;1. Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA;2. NRG Oncology/Gynecologic Oncology Group, Roswell Park Cancer Institute, Buffalo, NY, USA;3. University of California, Irvine Medical Center, Orange, CA, USA;4. University of Arizona Cancer Center and Creighton University at St Joseph''s Hospital and Medical Center, Phoenix, AZ, USA;5. University of Iowa Hospitals, Iowa City, IA, USA;6. Mayo Clinic, Rochester, MN, USA;7. MD Anderson Cancer Center, Houston, TX, USA;8. Oklahoma University Health Science Center, Oklahoma City, OK, USA;9. Vall d''Hebron University Hospital, Vall d''Hebron Institute of Oncology, Barcelona, Spain;10. University of Cincinnati College of Medicine/Women''s Cancer Center at Kettering, Kettering, OH, USA;11. Memorial Sloan-Kettering Cancer Center, New York, NY, USA;12. Michiana Hematology Oncology PC-Mishawaka, Mishawaka, IN, USA;13. Indiana University School of Medicine, Indianapolis, IN, USA;1. Department of Chemistry, Faculty of Science, University of Dicle, TR-21280 Diyarbakir, Turkey;2. Department of Chemistry, Faculty of Science, University of İnönü, 44280 Malatya, Turkey;3. Dicle University, Vocational School, Department of Electronics 21280 Diyarbakir, Turkey |
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| Abstract: | (R)-3,5-Bistrifluoromethylphenyl ethanol 2, a key building block in the synthesis of aprepitant, has been synthesized from ketone 5 via catalytic asymmetric transfer hydrogenation using a simplified catalyst generation procedure. The process uses (1S,2R)-cis-1-aminoindan-2-ol 10 and dichloro(p-cymene)Ru(II)dimer 9 as the chiral ligand and metal source for the reduction. While the reduction provides 2 in 90–92% ee, an isolation of 2 as a 2:1 inclusion complex with DABCO was developed to allow for the upgrade of the enantiomeric excess to >99%. |
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