Organic Chemistry of Drug Synthesis. Volume 7

elimination of methyl mercaptan to afford the guanidine ( 20 ). Reaction of
20 with the indole aldehyde ( 21 ) affords ( 22 ).^3
Much of the damage that results from stroke is attributable to increases
of glutamate orN-methyl-D-aspartate (NMDA), which follow the local
anoxia that accompany this event. Agents that inhibit the activity of the
resulting abnormal levels of these neurotransmitters would, at least in
theory, protect nerves. The NMDA antagonist gavestinel ( 28 ), has a
powerful neuroprotective in animal models of stroke. This finding
seems not to have held up in the clinic.^4 Condensation of 2,5-dichlorophe-
nylhydazine ( 23 ) with ethyl pyruvate affords the hydrazone ( 24 ).
Treatment of this intermediate with phosphoric acids leads to rearrange-
ment to the indole ( 25 ). The indole is treated withN-methyl-N-phenylfor-
mamide in a classic Vilsmeyer reaction. This reaction introduces a formyl
group on the remaning open position on the fused pyrrole ring ( 26 ).
Condensation of 26 with the ylide from the amide phosphonium salt
leads to the chain extended product 27. Saponification of the ester
group then affords 28.^5

Cl

Cl NHNH^2

23

+ CO^2 C^2 H^5

O

Cl

Cl NHN CO^2 C^2 H^5

24

H 3 PO 3

NH

CO 2 C 2 H 5

Cl

Cl

25

C 6 H 5 N

CH 3

CH=O

PO 3 Cl

NH

CO 2 C 2 H 5

Cl

Cl

26

O NHC 6 H 5 CH=O

Ph 3 P

NH LDA

CO 2 C 2 H 5

Cl

Cl

27

O NHC

6 H 5

NH

CO 2 H
Cl

Cl

O NHC 6 H 5

NaOH

28

Oglufanide( 31 ), at one time called thymogen, is a dipeptide isolated
from calf thymus. The imunnomodulatory properties of both the natural
product and the subsequent synthetic version have been extensively
studied as agents that enhances immune function. The compound currently
is undergoing clinical trials in patients infected with the hepatitis C virus.
In the absence of specific references one may imagine that this dipeptide is
obtained using standard peptide chemistry where tryptophan 29 with a pro-
tected carboxylic acid is condensed with suitably protected glutamate,
( 30 ). Removal of the protecting groups would the afford ( 31 ).

142 FIVE-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING