Organic Chemistry of Drug Synthesis. Volume 7

N

O NH

181

N

O N

182

O

NH 2

O

N

NH 2

183

OCH 3

F F

ON N O N

F

N OCH 3

N

O N

O

N

F

N OH

185 184

The structure of a recent quinolone antibiotic differs from the majority
of those agents in the nature of the substituent on the fused aromatic ring;
the inclusion of nitrogen in that ring is unusual though not unprece-
dented. This structural feature in fact harks back to the very first
quinolone, nalidixic acid, as well as the compound nofloxacin, which
led to the revival of this field some two decades ago. Synthesis of the
novel side-chain amine comprises the larger part of the preparation of
the quinolone antibioticgemifloxacin( 196 ). The sequence starts with
conjugate addition of glycine ethyl ester 186 to acrylonitrile. Reaction
of 187 with strong base leads to addition of the enolate adjacent to the
nitrile to the ester carbonyl to afford the pyrrolidinone ( 188 ). The
amine is then protected as itstert-butoxycarbamate ( 189 ) by reaction
with bis-t-BOC. Treatment with sodium borohydride serves to reduce
the ring carbonyl to the alcohol. The cyano group is next reduced to
the corresponding primary amine by means of lithium aluminum
hydride and this new function then also protected as itstert-butoxycarba-
mate ( 191 ). Oxydation of the ring alcohol with the sulfur trioxide:
pyridine complex restores the ring carbonyl group ( 192 ). This function
is then converted to its methoxime ( 193 ) by reaction with
O-methylhydroxylamine. Treatment with acid then removes the tert-
butoxycarbamate protecting groups to reveal the basic amino groups
( 194 ). Reaction of 194 with the often used quinolone starting material
195 results in displacement of chlorine by the more basic of the two
amino groups in 194. Thus, the antibiotic 196 is obtained.^28

210 BICYCLIC FUSED HETEROCYCLES