Organic Chemistry of Drug Synthesis. Volume 7

N

CO 2 C 2 H 5

167

NC

N

+

Base

O

NC

H+

N

O

N

O

Br 2

Br

N+

O

N H 2

O

168 169

170

173 172 171

N NH

175

OCH 3

H3C

CH 3

H 2 N

OCH 3

H 3 C

CH 3

174

N NH

176

OCH 3

H 3 C

H 3 CCH3

Most paradigms for treating Parkinson’s disease involve increasing dopa-
mine levels at synapses in the brain. Administration of dopamine itself is
ruled out since the polarity of this compound prevents it from crossing the
blood–brain barrier. Dopamine, like most neurotransmitters, is taken back
by the presynaptic fiber after it has triggered action. A compound that inhibits
this process would as a consequence increase levels of dopamine in the synap-
tic cleft. The starting material ( 177 ) for a dopamine reuptake inhibitor in fact
comprises the free acid form of cocaine. Hydrolysis in mild acid serves to
remove the benzoate ( 178 ). Reaction of this hydroxyl acid with phosphorus
oxychloride leads to loss of the hydroxyl and formation of the conjugated
acid. This compound is then converted to its methyl ester ( 179 ).
Condensation with the Grignard reagent from 3,4-dichlorobromobenzene in
the presence of copper leads to conjugate addition of the organometalic

6. MISCELLANEOUS MONOCYCLIC AROMATIC COMPOUNDS 63