Organic Chemistry of Drug Synthesis. Volume 7

2. FIVE-MEMBERED RINGS WITH TWO

HETEROCYCLIC ATOMS

A. Benzimidazoles

Thrombin is an essential intermediate in the formation of blood clots.
Inhibitors of this factor would prove useful in treating and preventing
inappropriate clot formation that potentially leads to stroke and heart
attacks. Reaction of the carboxylic acid ( 143 ) with thionyl chloride leads
to the corresponding acid chloride ( 144 ). Treatment of that intermediate
with the substituted pyridyl amine ( 142 ) leads to the amide ( 145 ).
Catalytic hydrogenation of the product reduces the nitro group to the
primary amine ( 146 ). Condensation of this ortho diamine with the car-
boxylic acid ( 147 ) in the presence of carbonyl diimidazole then forms
the imidazole ring ( 148 ). This reaction proceeds via the amide formed
with the primary amine followed by replacement of the amide carbonyl
oxygen by the adjacent amine. Reaction of the product with ammonium
carbonate leads to addition of ammonia to the nitrile to form an amidine.
Saponification of the side-chain ester affords the thrombin inhibitor
dabigartan( 149 ).^20

NH

NO 2

CH 3

ROC

+

N

NH

CO 2 C 2 H 5

142 143;144; R = OH R = Cl

NH

NR 2

CH 3

N

N

CO 2 C 2 H 5

O

HN CN

HO 2 C

145;R = O

146; R = H

+

147

N

N

CH 3

N

N

CO 2 C 2 H 5

O

HN CN

CDI

1. (NH 4 ) 2 CO 3
   2. NaOH

148

N

N

CH 3

N

N

CO 2 H

O

HN

NH 2

NH

149

Thioazolidinediones have by now achieved a major role in the treatment
of Type II, also called adult onset diabetes. A recent example includes a
benzimidazole moiety as part of the structure. One of the syntheses for
this compound starts by nucleophilic aromatic displacement of fluorine
inp-fluorobenzaldehyde ( 151 ) by the anion from treatment of the hydroxy-
methylbenzimidazole ( 150 ) with strong base. The product ( 152 ) is then

156 FIVE-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING