ketone ( 11 ). The central ring is formed by a newly devised pyridine syn-
thesis. The first step involves reaction of chloroacetic acid ( 12 ) with
dimethylformamide (DMF); the initial adduct is then converted to its hexa-
fluorophosphate salt ( 13 ). Condensation of 13 with ketone 11 involves
initial displacement of one of the dimethylamino groups by the enolate
from 11 to give the open-chain adduct ( 14 ). Reaction with ammonium
hydroxide then closes the ring forming the required pyridine. Thus, the
NSAIDetoricoxib( 15 ) is obtained.^2
B. Reduced Pyridines
Much effort has been devoted over the years to devise long acting forms of
drugs. The occasion does, however, sometimes arise where blood levels of
a drug being administered by infusion need to be cut off abruptly. Several
examples, such as theb-blocker esmolol or the analgesic agent remifenta-
nyl, include in their structure a function that is quickly converted to a car-
boxylic acid. This functional group both inactivates the drug and hastens
its excretion. Dihydropyridines comprise a large group of calcium
channel blockers used to treat angina and hypertension. The short-acting
example,clevidipine( 18 ) incorporates a methoxymethyl ester, a function
that is readily cleaved to the corresponding acid by serum esterases. The
actual experimental details in patents3,4describe the preparation of this
compound by simple alkylation of the monoester ( 16 ) with chloromethyl
butyrate ( 17 ). These sources are, however, mute as to source of the half
ester starting material.
NHOClH 3 C CH 3+ OOCH 3 O OH ClO Cl
OO
K 2 CO 3NHOClH 3 C CH 3CH 3 O OO Cl1617
18A very similar strategy underlies the design of the opiate-like analgesic
alvimopan( 30 ). Ileus, that is paralysis of the gastrointestinal tract, is a
common side effect from surgery. The shock of the operation accompanied
by heavy use of opiates causes a shut down of intestinal peristalsis. The
structure of that drug in effect comprises a very potent synthetic opiate
modified by a polar glycine residue. That last moiety keeps the drug out
of the CNS. Reversing postoperative ileus comprises one of the main
- COMPOUNDS WITH ONE HETEROATOM 117