Subscribe to RSS
DOI: 10.1055/s-2008-1042664
Synthesis of an NK-1 Receptor Antagonist (CF-17,493)
Contributor(s):Philip KocienskiPfizer Global R & D, Groton, USA
Process Research and Development of an NK-1 Receptor Antagonist. Enantioselective Trifluoromethyl Addition to a Ketone in the Preparation of a Chiral Isochroman
Org. Process Res. Dev. 2007, 11: 1015-1024
Publication History
Publication Date:
21 February 2008 (online)
Key words
enantioselective trifluoromethylation - formylation - Duff reaction - Friedel-Crafts acylation
Significance
Neurokinin-1 (NK-1) is a small peptide that is upregulated in arthritis, migraine, inflammatory bowel disease, asthma, pain and depression. NK-1 antagonists are potential treatments for these conditions. The synthesis depicted features a nucleophilic trifluoromethylation (A→C) catalyzed by the cinchonine-derived quaternary ammonium fluoride B. For related reactions, see: Tetrahedron Lett. 1994, 35, 3137; Chem. Lett. 2007, 36, 666; Org. Lett. 2007, 9, 3707.
Comment
The nucleophilic trifluoromethylation was best achieved in CH2Cl2 with a catalyst B bearing a free hydroxyl group and a naphthyl derivative on the quaternary nitrogen. Treatment of the TMS ether C with t-BuOK led directly to the formaton of isochroman F possibly via intermediates D and E.
Review
Some Recent Results in Nucleophilic Trifluoromethylation and Introduction of Fluorinated Moieties, B. R. Langlois, T. Billard Synthesis 2003, 185.