Organic Chemistry of Drug Synthesis. Volume 7

is alkylated with 3-bromopropionitrile; the terminal cyano group is then
reduced to the primary amine by means of Raney nickel ( 82 ).
Condensation of 82 with the pyridazothiophene ( 81 ) leads to addition of
the amine to the isocyano group to afford the transient coupled urea
( 83 ). The urea nitrogen furthest from the ring then displaces the ethoxide
from the nearby ester group to form a fused pyrimidone ring. Thus, the
a 1 -adrenergic blockerfiduxosin( 84 ) is finally obtained.^9
Anthraquinones have been investigated in some detail over the past
several decades as sources for antitumor agents. Several compounds
whose structure includes this three-ring fragment have gone as far as the
clinic. It has since been established that cytotoxic activity of these com-
pounds is due mainly to their activity on topoisomerase 2. The anthra-
quinone mitoxantrone, was approved by the FDA close to two decades
ago. An analogue in which one of the benzene rings is replaced by pyridine,
perhaps not surprisingly, retains antitumor activity. Reaction of the lithio
reagent from 4-chlorofluorobenzene ( 86 ) with the pyridine equivalent ( 85 )
of phthalic anhydride affords the acylation product ( 87 ). Treatment with
acid leads to internal acylation and formation of the aza-anthraquinone
( 88 ). Condensation of this intermediate with the substituted hydrazine
( 89 ) leads to formation of the fused pyrrazole ( 90 ). The regiochemistry of
this reaction would suggest that the first step involves displacement of
halogen and is thus guided by greater ease of replacing fluorine over
chlorine; ordinary imine formation then closes the ring. Displacement
of chlorine byN,N-dimethylethylenediamine ( 91 ) completes the synthesis
oftopixantrone( 92 ).^10

N O

O

O

85

+

Cl

F

86

BuLi N

HCO 2

O F

Cl

87

N

O F

O Cl

H 2 NNH

NH OH

N

N

O Cl

88

89

N

NH OH

N

N

O

N

NH OH

90

NH 2 N

HN N

91

92

1. COMPOUNDS WITH THREE FUSED RINGS 227