title: A practical synthesis of 5-lipoxygenase inhibitor MK-0633.
abstract: 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).
authors.affiliation: Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 Route Transcanadienne, Kirkland, Québec, Canada H9H 3L1. francis_gosselin@merck.com
authors.forename: Francis
authors.initials: F
authors.lastname: Gosselin
authors.forename: Robert A
authors.initials: RA
authors.lastname: Britton
authors.forename: Ian W
authors.initials: IW
authors.lastname: Davies
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Dolman
authors.forename: Danny
authors.initials: D
authors.lastname: Gauvreau
authors.forename: R Scott
authors.initials: RS
authors.lastname: Hoerrner
authors.forename: Gregory
authors.initials: G
authors.lastname: Hughes
authors.forename: Jacob
authors.initials: J
authors.lastname: Janey
authors.forename: Stephen
authors.initials: S
authors.lastname: Lau
authors.forename: Carmela
authors.initials: C
authors.lastname: Molinaro
authors.forename: Christian
authors.initials: C
authors.lastname: Nadeau
authors.forename: Paul D
authors.initials: PD
authors.lastname: O'Shea
authors.forename: Michael
authors.initials: M
authors.lastname: Palucki
authors.forename: Rick
authors.initials: R
authors.lastname: Sidler
mesh_terms: D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry; D001557:Benzenesulfonates / Q000138:chemical synthesis* / Q000737:chemistry; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D001557:Benzenesulfonates; D001578:Benzopyrans; D016859:Lipoxygenase Inhibitors; C552157:MK-0633 p-toluenesulfonate; D010069:Oxadiazoles; D001094:Arachidonate 5-Lipoxygenase; C029501:4-toluenesulfonic acid