Organic Chemistry of Drug Synthesis. Volume 7

proceeds to give exclusively to the (E) olefin isomer. Acid hydrolysis
removes the acetyl protection. Reaction of that intermediate with the
cyanoimidate 148 leads to displacement of one phenoxy groups by the
amine in 147. This reagent may be viewed formally as the phenol
acetal of cyanamide formate. Reaction of the intermediate 149 with
tert-butylamine displaces the remaining phenoxy group to form the
corresponding cyanoguanidine. Thusterbogrel( 150 ) is obtained.^24

O

N

CH 3 CONH

144

(C 6 H 5 ) 3 P(CH 2 ) 4 CO 2 H N

145 CH^3 CONH

CO 2 H

H 2 N N

CO 2 H

H+

146 147

C 6 H 5 O OC 6 H 5

N

148

N N

H

CO 2 H

149

C 6 H 5 O

CNN

NC

N N

H

CO 2 H

150

(CH 3 ) 3 CNH 2

CNN

(CH 3 ) 3 CNH 2

tBuOK

6. MISCELLANEOUS MONOCYCLIC AROMATIC

COMPOUNDS

Damage to peripheral nerves, termed peripheral neuropathy, is among one
of the more common consequences of diabetes; it may also be caused by
Parkinson’s disease or various toxins. Neurophilins are agents that reverse
that condition and encourage new nerve growth. The small moleculetim-
codar( 157 ) has shown promising activity in animal models and several
early clinical trials. Aldol condensation of pyridine-4-carboxaldehyde
( 152 ) with acetone dicarboxylic acid ( 151 ) proceeds to the keto acid
( 153 ). This transient intermediate decarboxylates under reaction conditions
to afford the bis(enone) 154. Hydrogenation over platinum proceeds to
give the saturated ketone ( 155 ). Treatment of 155 with benzylamine in
the presence of cyanoborohydride leads to the product from reductive
amination ( 156 ). Acylation with hydrocinnamoyl chloride affords the
amide 157.^25

60 MONOCYCLIC AROMATIC COMPOUNDS