SF F
Br+ S BuLi
(Ph 3 P) 4 .Pd(^5556)
NBS
S
F
57
Br
OH
(Ph 3 P) 4 .P, PPH 3 , CuI
S
F
58
OH
HN O
CO 2 C 6 H 5
Ph 3 P, DEAD
S
F
NH 3
C 6 H 5 O
O
CO 2 C 6 H5
O
OC 6 H 5
S
O
NH 2
59
60
N OH
N O
2. COMPOUNDS WITH TWO HETEROATOMS
A. Oxazole and Isoxazoles
The discovery that non-steroid antiinflammatory agents (NSAID) owe their
efficacy to inhibition of cyclooxygenase (COX), the enzyme that catalyzes
the formation of prostaglandins was followed some time later by the
finding that the enzyme occurred in several subtypes. The almost simul-
taneous discovery of specific inhibitors of COX-2, promised NSAIDS
that reduced inflammation that spared the production of prostaglandins
that maintain integrity of the stomach wall. The enormous success of the
first agent on the market celecoxib, led to detailed investigation of the
structure–activity relationship (SAR) of this class in competing labora-
tories. Minimum requirement for activity seemed to involve two aromatic
rings on adjacent positions on a five-membered heterocyle. The very recent
entry,tilmacoxib( 67 ), shows that one of those benzene rings can be
replaced by cyclohexane. Condensation ofm-fluorobenzyl bromide ( 62 )
with the acid chloride ( 61 ) from cyclohexane carboxylic acid in the pre-
sence of the Heck reagent affords the ketone ( 63 ) that incorporates the
requisite two rings. Bromination proceeds on the benzylic position to
afford 64. This reactive halogen is displaced with acetate to give the key
- COMPOUNDS WITH TWO HETEROATOMS 91