Organic Chemistry of Drug Synthesis. Volume 7

with chloroacetonitrile affords 174. Treatment of 174 with Raney nickel
reduces the cyano group to the corresponding primary amine; this
product then undergoes internal ester–amine interchange to yield the
cyclized amide 175. Lithium aluminum hydride then serves to reduce
the amide to an amine; the ester on the other ring is converted to a carbinol
in the process, affording the amino alcohol ( 176 ). The basic function is
next alkylated with 2-chloropyrimidine ( 177 ). Reaction of the alcohol
in 178 with methanesulfonyl chloride leads to the mesylate; this group is
next displaced by means of sodium azide and the newly introduce azide
group reduced to the primary amine. Resolution of this last product as
its mandelate salt then yields 179 as a single enantiomer. Reaction of
179 with succinic anhydride converts the pendant amine to a succinimide
affording the anxiolytic agentsunepitron( 180 ).^25

N

CO 2 H

HO 2 C

171

SOCl 2

CH 3 OH

N

CO 2 CH 3

CH 3 O 2 C

172

H 2

NH

CO 2 CH 3

CH 3 O 2 C

173

CN

Cl CN

N

CO 2 CH 3

CH 3 O 2 C

174

Ni

CH N

3 O 2 C

175

NH

O

LiAlH 4

N

176

NH

HO

N

N ClNN

N

178

N

HO

1. CH 3 SO 2 Cl


2. NaN 3


3. N 2 H 4


4. ResolveN
   N
   N
   179

N

H 2 N

N

N

N

N

H H

180

N

O

O

O

O

O

177

The principal metabolite of one of the more recent antipsychotic drugs,
risperidone, has significant dopamine blocking activity in its own right. As
is often the case, where a metabolite has the same effect as the ingested
drug, this opens the possibility that the metabolite is responsible for the
observed effect. Condensation of acetoacetamide ( 182 ), arguably available
in several steps from risperidone intermediate 181 ,^26 with the cyclic
imidate ( 183 ) affords the metabolite as its O-methyl ether 184. Cleavage
of that ether, for example, with boron tribromide, would then afford
paliperidone( 185 ).^27

2. COMPOUNDS WITH TWO FUSED SIX-MEMBERED RINGS 209