Organic Chemistry of Drug Synthesis. Volume 7

removal of chromium by iodine gave the product in high yield. Removal
of thet-BOC protecting group with trifluoroacetic acid (TFA) completes
the synthesis of ( 166 ).^26

HO

NH 2

OH

158

HO 2 C Cl

HO

NH

OH

O NH

O

OH

159

Cl

O

160

Red-Al

NH

O

OH

161

N

O

OH

162 OCOtBu

N

O=HC O

OCOtBu

[O]

(C 6 H 5 ) 2 Zn

N

O

OCOtBu

OH

164 163

OC 2 H 5

F

(CO) 3 Cr

165

NH

O

O

166

OC 2 H 5

2. TFA

tBuOK tBuOCOCl

Many, if not most, cancer chemotherapy agents can be considered
selective toxins with a rather narrow therapeutic index. The administration
of these agents is quite frequently accompanied by nausea and vomiting,
the reflex whereby the body seeks to reject toxins. Classical antiemetic
compounds, such as the phenothiazines, have little effect on chemo-
therapy induced emesis. The more recently introduced serotonin antagon-
ists are far more effective. They however, are, not universally effective
and elicit severe CNS side effects in some patients. A pair of closely
related antiemetics act by a very different mechanism: these drugs
oppose emesis by acting as antagonists at tachykinin receptors. The syn-
thesis of the common moiety starts with aldol-like condensation of the
anion from the acetonitrile ( 168 ) generated with a strong base with the
ester group on the piperidine ( 167 ). Heating the product ( 169 )from
that reaction with strong acid leads to hydrolysis of the nitrile group to
the corresponding acid. The transient intermediate then decarboxylates
to afford the ketone ( 170 ). Reaction of 170 with bromine then gives the
bromoketone ( 171 ). This undergoes spontaneous internal displacement
of bromine by the piperidine nitrogen. The formation of this bridge
leads to the quinuclidine ( 172 ) as a quaternary salt. The benzyl protecting
group on nitrogen is then removed by hydrogenolysis over palladium
to yield the substituted quinuclidone ( 173 ). Reductive amination with
2-methoxy-4-isopropylbenzylamine ( 174 ) affordsezlopipant ( 175 ); the
same reaction using 2-methoxy-4-tert-butylylbenzylamine leads to
maropitant( 176 ).27,28

62 MONOCYCLIC AROMATIC COMPOUNDS