Diastereoselective synthesis of fluorinated piperidine quinazoline spirocycles as iNOS selective inhibitors |
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| Authors: | Chris Walpole Ziping Liu Ernest E. Lee Hua Yang Fei Zhou Nicole Mackintosh Magnus Sjogren David Taylor Jinyu Shen Robert A. Batey |
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| Affiliation: | 1. AstraZeneca R&D Montreal, 7171 Frederick-Banting, Ville Saint-Laurent (Montreal) Quebec, Canada H4S 1Z9;2. Department of Chemistry, University of Toronto, 80 St. George St., Toronto, Ontario, Canada M5S 3H6;3. AstraZeneca R&D Innovative Medicines Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA;4. AstraZeneca Process R&D Södertälje, 151 85 Södertälje, Sweden;5. AstraZeneca R&D, Silk Road Business Park, Charter Way, Macclesfield, Cheshire SK10 2NA, UK |
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| Abstract: | A diastereoselective synthesis of fluoropiperidine quinazoline spirocycles has been developed through a silyl triflate mediated intermolecular coupling of difluorobenzamidine and racemic N-protected 3-fluoropiperidine dimethyl ketals or piperidones. Combination of the silyl reagents together with Lewis acids (such as BF3·OEt2, ZnCl2, InCl3, etc.) accelerated the coupling reaction to afford the desired fluorospirocycles in good yields (40–83%) and high diastereoselectivity. A ratio of the two diastereoisomers of up to 10:1 in favor of the desired isomer can be achieved. |
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