Organic Chemistry of Drug Synthesis. Volume 7

envisaged as proceeding thorough the aminal ( 95 ) of the glyoxal. Imine
formation with dichloro reagent 94 by displacement of halogen then leads
to imidazole 96. Reaction of that intermediate with iodine in base leads to
the iodo derivative ( 97 ). Displacement of iodine by the anion from dichlorol
sulfide ( 98 ) proceeds to give the thioether ( 99 ). The still-free imidazole
nitrogen is next alkylated with 2-chloromethyl pyridine to afford 101. The
benzyl protecting group on oxygen is then removed by treatment with
strong acid. The thus-revealed carbinol in 102 is condensed with chlorosul-
fonyl isocyanate to form the corresponding carbamate. Thus, the NNRTI
103 is obtained.^16
The imidazole ring takes its place in this example among a wide variety
of heterocyclic rings that serve as the nucleus for COX-2 NSAID anti-
inflammatory compounds. Reaction of sulfonyl chloride ( 104 ), available
from chlorosulfonation of acetanilide withtert-butylamine, gives the corres-
ponding sulfonamide ( 105 ). The acetyl group on nitrogen is then removed
by heating with strong base to give the aniline ( 106 ). Reaction of 106 with
the fluoro anisaldehyde ( 107 ) gives imine 108 , which incorporates the two
adjacent aromatic rings characteristic of COX-2 inhibitors. Reaction of the
imine with toluenesulfonyl isocyanate in the presence of potassium
carbonate leads to what may be viewed as 2þ3 cycloaddition of the nitro-
gen analogue of a ketene to form the imidazole ring ( 109 ). This ring is then
chlorinated withN-chlorosuccinimide (NCS) possibly to adjust the elec-
tron density on the heterocyclic ring. Heating this last intermediate ( 110 )
with acid removes the protecting group to give the free sulfonamide and
thuscimicoxib( 111 ).^17

SO 2 Cl

CH 3 COHN

104

H 2 NC(CH 3 ) 3

CH 3 COHN

KOH SO^2 NHC(CH^3 )^3

H 2 N

O=HC

OCH 3

105 106 107 F

SO 2 NHC(CH 3 ) 3

SO 2 NHC(CH 3 ) 3

N

OCH 3

F

108

TsCH 2 N=C

SO 2 NHC(CH 3 ) 3

N

OCH 3

F

109

NCS N

SO 2 NHC(CH 3 ) 3

N

OCH 3

F

N

Cl

SO 2 NH 2

N

OCH 3

F

N

Cl

HCl K 2 CO 3

111 110

The enzyme dopamine-b-hydroxylase, as the name indicates, catalyzes
hydroxylation of the side chain of dopamine in sympathetic nerves to form

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