Organic Chemistry of Drug Synthesis. Volume 7

by assuming initial displacement of terminal chlorine by the amine to give
the transient intermediate 112. This amino group then takes part in an
ester–amide interchange in the presence of base to form the new ring.
Thus, 113 is obtained.^13

NH NH^2

108

CO 2 CH 3

+

CH = O

O

O

109

HCl NH

NH

CO 2 H 3

O

O

ClOC Cl

110

N N

H

CO 2 H 3

O

O

111

Cl

O

CH 3 NH 2

N N

H

CO 2 H 3

O

O

112

NH

O

N N

H

O

O

113

N

O

O

3. COMPOUNDS WITH FIVE OR MORE FUSED

RINGS: CAMPTOTHECINS

Though the potent cytotoxic activity of camptothecin ( 114 ) was recognized
by the middle 1960s, the drug was not used in the clinic until just over a
decade ago. The very poor solubility of the compound initially led to
the use in clinics of the ring opened acid. It was later found that the
intact lactone was essential for activity. Clinical trials in the early 1990s
confirmed that finding. The mechanism of action of this drug as an inhibi-
tor of topoisomerase I sets it aside from many other widely used com-
pounds, such as the anthracyclines that act on topoisomerase II.
A number of analogues that mainly include the addition of solubilizing
functions, such as topotecan, lurtotecan, and irinotecan, and have
been approved for use in patients. An intermediate on the way to a
compound that includes a solubilizing amino group has interestingly
been assigned a nonproprietary name. This compoundcamptogen( 115 )
is available from the natural product in a single step using classical
nitration conditions.^14

230 POLYCYCLIC FUSED HETEROCYCLES