Organic Chemistry of Drug Synthesis. Volume 7

reaction. Thus, reaction of the intermediate with carbon tetrabromide and
triphenyl phosphine presumably converts the alcohol to a bromide; internal
displacement by the primary amine forms the five-membered ring.
Alkylation of that amine with the complex bromo amide 32 affords the
endothelin antagonistatrasentan( 33 ).^3

N

O

N

Br

O

N

O

O

OCH 3

32

OHNH^2

O

O

CO 2 CH 3

CO 2 CH 3

CO 2 CH 3

OCH 3

CBr 4

(C 6 H 5 ) 3 P N

H

O

O

OCH 3

(^3031)
33
29
H 2
Research on anticholinergic compounds has experienced something of a
resurgence as a result of their utility in treating conditions such as urinary
incontinence. The structures of these compounds are quite varied as shown
bydarfenacin( 44 ), which differs considerably from other compounds in
this class, for example, tolterodine (Chapter 3). The synthesis of this com-
pound ( 44 ) is also designed to produce a single enantiomer. Heat induced
decarboxylation of proline ( 34 ) affords the key intermediate 35 as a pure
enantiomer. The amino group is then converted to its tosylate ( 36 ) with
tosyl chloride; the hydroxyl group interestingly does not react under
those conditions. Converting that group to its derivative is accomplished
by the Mitsonobu reaction with methyl tosylate to give the doubly deriva-
tized intermediate 37. Condensation of 37 with the anion from diphenyl
acetonitrile ( 38 ), produced by reaction with sodium hydride, yields the
alkylation product 39. Treatment of this intermediate with hydrogen
bromide removes the protecting group on nitrogen. The nitrile is then
converted to the corresponding amide with sulfuric acid. In a converging
scheme, acylation of benzofuran ( 41 ) with chloroacetyl chloride and

1. COMPOUNDS WITH ONE HETEROATOM 87