Organic Chemistry of Drug Synthesis. Volume 7

N

CH 3 O OCH 3

OCH 3

H 2 O 2

N

CH 3 O OCH 3

OCH 3

(^1415)
HO

1. [O]


2. NaBH 4

N

CH 3 O OCH 3

OCH 3

16

HO

Ac 2 O

BF 3

N

CH 3 O OH

OCH 3

17

HO

O

N

CH 3 O OH

OCH 3

HO

O

18

HO

H Cl

+

N NaH

CH 3 O

OCH 3

HO

O

19

Cl

O

N

HO

OH

HO

O

20

Cl

O

BBr 3

CH 3 O 2 CCl

B 2 H 6

The continuing search for better tolerated antipsychotic drugs has led to
the examination of subtype dopamine receptors in the hope that selectivity
might avoid the side effects that come with indiscriminate receptor block-
ade. A benzopyran compound that shows preferential binding to the D 4
dopamine receptors showed promising results in the laboratory; this
agent, however, subsequently failed in the clinic. The benzopyran nucleus
is formed in a single step. Thus, reaction of phenethyl alcohol ( 21 ) with the
acetal ( 22 ) in the presence of strong acid initially leads to the transient
intermediate ( 23 ) in which one of the methoxy groups has been replaced
by the hydroxyl group from the phenethyl reagent. The carbocation
formed under the strongly acidic conditions by loss of the remaining meth-
oxyl then attacks the aromatic ring to form a pyran ( 24 ). Alkylation of the
secondary amine in the piperazine ( 25 ) with the halogen in 24 then affords
26. This last is resolved to affordsonepiprazole( 27 ).^6

OCH 3

OH

21

OCH 3

22

+

CH OOCH^3

3 SO 3 H

O

Cl Cl

Cl

N

HN

SO 2 NH 2

25

O

23 24

N N SO 2 NH 2

26

O

N N SO 2 NH 2

27

resolve

166 SIX-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING