Asymmetric synthesis of warfarin and its analogues on water |
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| Affiliation: | 1. Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland;2. Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland;1. Drug Delivery and Disposition, KU Leuven, Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, Box 921, 3000 Leuven, Belgium;2. Rega Institute, Laboratory of Medicinal Chemistry, Minderbroedersstraat 10, 3000 Leuven, Belgium;3. IVAP, Sint-Rafaël, KU Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium;1. Department of Mechanical & Industrial Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA;2. Process Technologies Department, ExxonMobil Research & Engineering, Annandale, NJ 08801, USA;1. School of Chemistry and Chemical Engineering, Xi’an University of Arts and Sciences, Xi’an, China;2. Department of Pharmacology, School of Pharmacy, the Fourth Military Medical University, Xi’an, China;3. Department of Physics, School of Science, Tianjin University, Tianjin, China |
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| Abstract: | The asymmetric Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones on water without organic co-solvents is reported to be catalysed by organic primary amines. The application of enantiomerically pure (S,S)-diphenylethylenediamine affords a series of important pharmaceutically active compounds in good to excellent yields (73–98%) and with good enantioselectivities (up to 76% ee) via reactions accelerated by ultrasound. In particular, our developments led to an efficient protocol for the ‘solids on water’ formation of the anticoagulant warfarin in both enantiomeric forms. The presented scalable and environmentally friendly organocatalytic approach affords the target drug in enantiomerically pure form. |
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