A Practical Synthesis of 5-Lipoxygenase Inhibitor MK-0633

Practical, chromatography-free syntheses of 5-lipoxygenase inhibitor MK-0633 p-toluenesulfonate (1) are described. The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second rout...

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Veröffentlicht in:	Journal of organic chemistry 2010-06, Vol.75 (12), p.4154-4160
Hauptverfasser:	Gosselin, Francis, Britton, Robert A, Davies, Ian W, Dolman, Sarah J, Gauvreau, Danny, Hoerrner, R. Scott, Hughes, Gregory, Janey, Jacob, Lau, Stephen, Molinaro, Carmela, Nadeau, Christian, O’Shea, Paul D, Palucki, Michael, Sidler, Rick
Format:	Artikel
Sprache:	eng
Schlagworte:	Analytical chemistry Arachidonate 5-Lipoxygenase - chemistry Benzenesulfonates - chemical synthesis Benzenesulfonates - chemistry Benzopyrans - chemical synthesis Benzopyrans - chemistry Chemistry Chromatographic methods and physical methods associated with chromatography Exact sciences and technology Heterocyclic compounds Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms Lipoxygenase Inhibitors - chemical synthesis Lipoxygenase Inhibitors - chemistry Molecular Structure Organic chemistry Oxadiazoles - chemical synthesis Oxadiazoles - chemistry Preparations and properties Stereoisomerism
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Zusammenfassung:	Practical, chromatography-free syntheses of 5-lipoxygenase inhibitor MK-0633 p-toluenesulfonate (1) are described. The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second route features an inexpensive diastereomeric salt resolution of vinyl hydroxy-acid 22 followed by a robust end-game featuring a through-process hydrazide acylation/1,3,4-oxadiazole ring closure/salt formation sequence to afford MK-0633 p-toluenesulfonate (1).
ISSN:	0022-3263 1520-6904
DOI:	10.1021/jo100561u