with methyl orthoformate in strong acid then introduces a formyl group at
the only open position on the ring ( 92 ). Condensation of this aldehyde with
indolone 85 , as above, leads to formation of the analogue of 86 , which in
addition carries a carboxyl group on the pyrrole ring ( 93 ). Saponfication
then affords the free acid ( 94 ). Reaction of this compound withN,N-diethyl-
ethylenediamine gives the corresponding amide. Thus, the tyrosine kinase
inhibitorsunitinib,( 95 ) is obtained.^13
The neurotransmitter dopamine is closely involved in many aspects of
the central nervous system (CNS). It was demonstrated post-facto that
the majority of antipsychotic agents owe their efficacy by blocking dopa-
mine receptors in the brain. Parkinson’s disease is conversely traceable to a
deficiency of dopamine. Most treatments for that disease involve adminis-
tration of compounds that make up for that deficiency. The indolone
aplindore( 106 ), acts as a partial agonists at the subclass of dopamine
receptors associated with Parkinson’s. The drug is currently in the clinic
for that indication. The compound also interestingly shows some promise
for treating “restless leg syndrome”. The synthesis begins with alkylation of
the free phenol in catechol ( 96 ) with allyl bromide. The methyl ether in 97
is then cleaved with strong base, a reaction specific for methyl ethers, to
afford the phenol ( 98 ). The newly formed hydroxyl is then alkylated with
chiral glycidyl tosylate 99 , to afford the glycidic ether ( 100 ). Heating a
solution of that compound leads first to Claisen rearrangement where the
allyl group moves over to the benzene ring to form transient intermediate
101. The phenol formed as a result of the rearrangement next opens the
O 2 N
OCH 3
OHBr96O 2 NOCH
O
97O 2 NOH
O
98NaOH
DMSOTsO O OO 2 NO(^99) O
100
O
O 2 N
O
OH
101
O 2 N
O
O R
102 ; R = OH
103 ; R = Br
O 2 N
O
O
HO 2 C
Br
104
KMnO
O
HN O Br
O
C 6 H 5 CH 2 NH 2 O
O
HN
HN
(^105) O^106
CBr 4 /PPh 3
150 FIVE-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING