ether in the antagonist toremifene ( 196 )^32 is replaced by a simple
hydroxyethyl group. This agent is prepared starting with an intermediate
( 192 ) used to prepare 196. Alkylation of the phenol in 192 with
the choroethanol benzyl ether affords 193. The free hydroxyl at
the end of the chain is then converted to the halide ( 194 )by
reaction with carbon tetrachloride and triphenyl phosphine. Removal of
the benzyl group by means of hydrogen over palladium then affords
195.^33
There is some evidence that points to an association between
Alzheimer’s disease and a defict in brain acetylcholine levels.
Considerable attention has thus focused on cholinesterase inhibitors as
potential drugs for treating the affliction. The preparation of a relatively
simple inhibitor is prepared by acylation of the benzylamine ( 197 )
with chloroformamide ( 198 ). The resulting urethane is then resolved
to affordrivastigmine( 199 ).^34
(CH 3 ) 2 N OH
+ (CH^3 )^2 NO N CH
2 CH 3CH 3ON CH
2 CH 3CH 3OCl197 198 199The lipidemic compound ezetimibe ( 207 ), whose structure differs
markedly from the ACAT inhibitor avasamibe ( 125 ), discussed previously,
also inhibits absorption of cholesterol from the gut. The key to the con-
struction of this compound involves formation of an azetidone. Enamine
formation between thep-benzyloxybenzaldehyde ( 200 ) and aniline ( 201 )
provides one of the required reactants, imine 202. This compound is
then treated with a half-acid chloride of ethyl adipate ( 203 ) and triethyl-
amine. In all likelihood, this first dehydrohalogenates under reaction
conditions to form the substituted ketene. The transient intermediate
reacts with the imine in a 2þ2 cylcoaddition to afford a four-membered
ring and thus 204. The reaction proceeds to give the trans isomer almost
exclusively. The ester group is then hydrolyzed by means of lithium
hydroxide. Condensation with the zinc reagent formed in situ from
p-fluoromagnesium bromide and zinc chloride affords the ketone ( 205 ).
The carbonyl group is then reduced with diborane to afford the alcohol
( 206 ). Removal of the benzyl protecting group by hydrogenolysis over
palladium finally affords 207.^35
66 MONOCYCLIC AROMATIC COMPOUNDS