quaternary bromide apparent loses hydrogen bromide under reaction
conditions to give the unsaturated quinolone ( 71 ). Treatment of 71 with
the anion obtained from N-methylimidazole and butyllithium leads to
addition of that heterocycle to the ketone. The thus formed carbinol ( 72 )
is then treated with ammonia. The quaternary carbinol then in essence sol-
volyses so as to replace the hydroxyl group by a primary amine forming
tipifarnib( 73 ).13,14
O HNOH
74Cl O H
O NO OO HNOOCH 3OCH 3NH 2 OCH^3
OCH 3OHNH757677Agents that increase the force of contraction of the heart, often called
positive inotropic agents, play an important role in treatment of congestive
heart failure. Many of the currently available drugs also increase heart rate,
an undesired side effect. A compound that is based on a quinolone is said
to increase force of contraction without speeding up the heart rate. The final
steps of synthesis on this agent closely parallel those used to prepare
b-blockers. Thus, reaction of the carbostiryl ( 74 ) with epichlorohydrin
affords the glycidic ether ( 75 ). Treatment of this intermediate with the
benzylamine ( 76 ), opens the epoxide to afford the aminoalcoholtorbori-
none( 77 ).^15
C. Quinolone Antibacterial Agents
Research on the quinolone antibacterial agents crested a decade ago, as
indicated by the fact that Volume 5 in this series described the synthesis
of no fewer than 11 drugs in this structural class. The level of activity
then, not surprisingly, declined so that only four quinolones were described
in Volume 6, which was published in 1999. Two of the three quinolones
discussed below were actually prepared before that year; their absence in
the book is due to the circumstance that they had not yet, for some
172 SIX-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING