Organic Chemistry of Drug Synthesis. Volume 7

2. COMPOUNDS WITH FOUR FUSED RINGS

The serious side effects associated with long-term use of dopamine anta-
gonist antipsychotic agents have led to the continuing search for better
tolerated drugs. This research has to some extent been encouraged by
the identification of ever more subtypes of dopamine receptors; this
raises the possibility there may be drugs found that act on a subtype recep-
tor more specific for treating schizophrenia than for the receptors associ-
ated with side effects. Ecopipam ( 101 ) which differs markedly in
structure from most of the widely used antipsychotic drugs, is specific
for D1 dopamine receptors. Though this compound was found to be not
particularly effective for treating schizoid patients, it does have an effect
against addictive behaviors. One of several routes to this compound
starts with the decalin trans aminoalcohol ( 93 ). This compound is then
alkylated with the methyl acetal ( 94 ) from bromoacetaldehyde. The ring
hydroxyl in 95 is then converted to its chlorophenylsulfonate ( 96 ). This
intermediate spontaneously closes to the aziridinium salt ( 97 ) by displace-
ment of the sulfonate by the adjacent amine. Condensation of 97 with
Grignard reagent 98 leads to addition at the tertralin 1 position with con-
comitant ring opening to yield 99. Treatment of 99 with strong acid
leads to attack of the newly revealed aldehyde on the aromatic ring and
thus formation of the azepine ring. The double bond formed in the
course of this last reaction is then reduced with diborane ( 100 ). Scission
of the methyl ether with boron trichloride the affords ( 101 ).^11

93

H 3 CNH

OHBr OCH

3

OCH 3 N

H 3 C

OH

94

95

H 3 CO OCH 3

H 3 CN

OSO 2 C 6 H 4 Cl

96

CH 3 O OCH 3

N+

H 3 CO OCH 3

97

Cl

CH 3 O

CH Cl

3 O

MgBr

98

H N OCH 3

H

CH 3

CH 3 OCH 3

99

N 1. CH 3 SO 3 H

H

HCH 3

2. BH 3
   100

Cl

CH 3 O

N BCl 3

H

HCH^3

Cl

HO

101

Yet another potential antipsychotic drug with an unusual pattern of
receptor affinity consists of a dibenzoxapine. This compoundasenapine

228 POLYCYCLIC FUSED HETEROCYCLES