intermediate ( 65 ). Construction of the heterocyclic ring involves reaction
of 65 with ammonium acetate. The reaction can be viewed for bookkeeping
considerations as proceeding through the initial reaction of ammonium ion
with the ketone to form an imine. This imine cyclizes with the adjacent car-
bonyl on the acetate to afford 66. Treatment of 66 with chlorosulfonic acid
gives the sulfonyl chloride; that sulfonyl chloride is immediately allowed
to react with ammonia to yield the corresponding sulfonamide. This com-
pound then affords the COX-2 inhibitor 67.^9
ClOBr
+Pd(PPh 3 ) 4
ZnFOFFOBr(^61626364)
F
O
OCOCH 3
Br 2
NaOCOCH 3
65
O
N
F
66
- ClSO 3 H CH 3 NH 4 COCH 3
- NH 3
ONF
67CH 3H 2 NO 2 SThe large number of compounds that have been reported illustrate
the wide selection of heterocyclic five-membered rings that are com-
patible with COX-2 inhibitory activity. The oxazole ring can, for
example, be replaced by an isoxazole. Reaction of deoxybezoin ( 68 )
with hydroxylamine affords the oxime ( 69 ). Treatment of this intermediate
with 2 equiv of butyllithium followed by acetic anhydride goes to the
hydroxyl isoxazoline ( 71 ). The transform can be rationalized by assuming
that this proceeds via theO-acylated intermediate ( 70 ). The anion from
the benzylic position would add to the acetyl carbonyl group to afford
the observed product. Reaction of this compound with chlorosulfonic
acid results in sulfonation of the aromatic ring nearest nitrogen.
The first step probably comprises dehydration of tertiary alcohol in 71
under the strongly acidic conditions to give 72. Subsequent addition of
ammonia converts the chlorosulfonic acid to the corresponding sulfona-
mide and thusvaldecoxib( 73 ).^10 Reaction of 73 with acetic anhydride
leads to acylation of the amide nitrogen, which increases the acidity of
that already acidic function. Treatment with base affords the water
soluble salt parecoxib( 74 ),^11 which is suitable for use in injectable
formulations.
92 FIVE-MEMBERED HETEROCYCLES