Organic Chemistry of Drug Synthesis. Volume 7

facilitate this reaction. The anion is of course not isolated, and is next
quenched withN-fluorobenzenesulfonimide to afford 110 as a mixture
of enantiomers. The ester group in this mixture is then saponified;
the isomers of the resulting carboxylic acid are next separated by way
of their (S)-benzylamine salts. The isomer that corresponds to the
(S)-isomer is then treated with sodium dithionate in order to reduce the
nitro group to the corresponding amine ( 111 ). Treatment of this ortho
amino acid with acid closes the ring to an indolone. Thus, the neuroprotec-
tive agent 112 is obtained.^15
No biologically active compound has arguably had quite the effect on
the governmental regulations that affect the pharmaceutical industry as
has thalidomide. The profound malformations caused in offspring of
women taking this nonbarbiturate sedative caused reappraisal of govern-
ment oversight of pharmaceuticals in most of western Europe. In the
United States, the event provided the final push for a major revision of
the Food and Drug Laws that govern the FDA. The low-level research
that continued on this drug, in spite of its ill repute, unexpectedly
showed that the compound affected immune function. The drug was, for
example, recently approved by the FDA for treatment of complications
from leprosy; it has also been investigated as an adjunct for treating
some malignancies. Recent research on related compounds has revealed
a series that inhibits tumor necrosis factor (TNF-a). Synthesis of the ami-
nosuccinimide moiety starts by cyclization of carbobenzyloxy glutamine
( 113 ) by treatment with carbonyl diimidazole (CDI). Catalytic hydrogen-
ation of the product removes the protecting group. The aromatic moiety

OH

O

NBS OH

O

NO 2 NO 2

Br

CO 2 H

C 6 H 5 CH 2 O 2 CNH CONH2 1. CDI2. H 2

NH

H 2 N O

O

NR 2

NH

N O

O

113 114

(^115116)
117 ; R = O
118 ; R = H
H 2
O
of the target compound is prepared by free radical bromination of the
methyl group in the benzoic acid ( 115 ) to give the bromomethyl derivative
( 116 ). Condensation of this last with the succinimide ( 114 ), leads to
152 FIVE-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING