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 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).
Gosselin
Francis
F
Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 Route Transcanadienne, Kirkland, Québec, Canada H9H 3L1. francis_gosselin@merck.com
Britton
Robert A
RA
Davies
Ian W
IW
Dolman
Sarah J
SJ
Gauvreau
Danny
D
Hoerrner
R Scott
RS
Hughes
Gregory
G
Janey
Jacob
J
Lau
Stephen
S
Molinaro
Carmela
C
Nadeau
Christian
C
O'Shea
Paul D
PD
Palucki
Michael
M
Sidler
Rick
R
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
D001557:Benzenesulfonates; D001578:Benzopyrans; D016859:Lipoxygenase Inhibitors; C552157:MK-0633 p-toluenesulfonate; D010069:Oxadiazoles; D001094:Arachidonate 5-Lipoxygenase; C029501:4-toluenesulfonic acid