Organic Chemistry of Drug Synthesis. Volume 7

HO

CH=O

+

S

NH

NH

O

S NH

NH

O

NaOAc

AcOH

HO

141 142 143

Uric acid comprises one of the principal products from metabolism of
endogenous nitrogen-containing compounds. Metabolic disorders that
cause this pyrimidine base to accumulate in the bloodstream can cause
gout, a painful condition that results from deposits of uric acid in joints.
The uricosoric thiazolefebuxostat( 147 ), like its venerable predecessor
allopurinol, inhibits the enzyme xanthine oxidase, which is central to the
production of uric acid. Febuxostat, whose structure is significantly differ-
ent from its predecessor, has recently been introduced as treatment for
gout. Reaction of the dinitrile compound ( 144 ) with hydrogen sulfide in
base proceeds to convert the one of the two cyanide groups to the corre-
sponding thioamide ( 145 ). Regioselectivity is speculatively due to reaction
at the less hindered of the two nitriles. Condensation of this with the
diketo-ester ( 146 ) leads to formation of the thiazole ring. Saponification
of the ester completes the preparation of 147.^23

CN

NC

O

144

H 2 S

NaOH NC

O

145

S NH 2

CH 3 O 2 C

O O

2. OH– NC
   O

147

S N

HO 2 C

146

Reactive oxygen species released by neutrophils may play a role in con-
ditions, such as inflammatory bowel disease and chronic pulmonary
obstructive disease. A thiazole that inhibitsin vitroproduction of super-
oxide by human neutrophils is currently being investigated in the clinic.
In a convergent scheme, bromination of acyl pyridine carboxylic acid

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