Organic Chemistry of Drug Synthesis. Volume 7

from 2-chloroethyl diidopropyl amine ( 136 ) to afford the benzhydrol
( 137 ). Hydrogenolysis over palladium would then afford tolterodine
( 138 ).^22
The release of large amounts of the neurotransmitter glutamate during a
stroke lead to flood nerve cell receptors, such as that forN-methyl-D-
aspartate (NMDA) causing excessive stimulation. The NMDA receptor
antagonists have as a result been investigated as agents for preventing
some of the injury from strokes. Relatively small changes in the structure
of tolterodine, lead to an NMDA antagonist. Condensation of 3,3-difluoro-
benzophenone ( 139 ) with the lithio reagent from acetonitrile yields the
benzydrol ( 140 ). The nitrile group is then reduced to the corresponding
amine by means of diborane. Treatment with acid leads to loss of the
tertiary hydroxyl group and formation of the olefin ( 141 ). The double
bond is reduced by catalytic hydrogenation ( 142 ).^23 The primary amino
group can then be converted to theN-methyl derivative by any of a
number of procedures, such as, treatment with formaldehyde and formic
acid. Then the NMDA receptor antagonistdelucemine( 143 ) is obtained.

O

F F

139

LiCH 2 CN

F HO F

CN

1. BH 3
   2. H+ F F

140 NH 2

141

H 2

F F

NH 2

142

F F

NHCH 3

143

The first product from one of the branches of the arachidonic acid
cascade comprises a bridged bicylic compound where a pair of oxygen
atoms form one of the rings. One route from this leads to the
familiar five-membered ring prostaglandins; an alternate path leads to
thromboxanes, one of the principal injurious products of the cascade.
Compounds that block thromboxanes would be useful in treating the vaso-
constricting and platelet aggregating action of this compound. The
synthesis of a recent thromboxanes A 2 receptor antagonist starts with the
Wittig condensation of the ylide fromv-phosphinocarboxylic acid ( 145 )
with the ketone ( 144 ) to give the olefin ( 146 ). The reaction apparently

5. DIARYLMETHANES 59