Organic Chemistry of Drug Synthesis. Volume 7

sulfenic acid ( 128 ). Alkylation by means of base and methyl bromide gives
the corresponding aryl methyl sulfone ( 129 ). The carboxylic acid is then
activated as the acid chloride by treatment with thionyl chloride.
Reaction of this intermediate with guanidine gives the aroyl guanidine
( 130 ).^20

5. DIARYLMETHANES

Prolonged treatment of cancer patients with chemotherapeutic agents not
infrequently results in the development of drug resistance. The small
number of malignant cells that survive exposure to the drug proliferate
and become the dominant population. A far more serious case involves
the development of cell lines that develop resistance to more than one
class of drugs, a condition known as multidrug resistance. The structurally
relatively simple compoundtesmilifene( 133 ) has been shown to enhance
the antitumor activity of several classes of chemotherapy agents against
multidrug resistant cancers. The mechanism of action of this drug is as
yet unclear. This compound is prepared by alkylation ofp-benzylphenol
( 131 ) with 2-chlorotriethylamine ( 132 ).^21

OH

+ Cl N(C 2 H 5 )

131

132

133

O N(C

2 H 5 )

Moving the side chain bearing the amino group to the benzylic carbon
leads to compounds with very different activities. Anticholinergic agents
specific for muscarinic receptors have proven to be very useful for treating
urinary incontinence. The synthesis of a recent example speculatively starts
with the Fries rearrangement of the ester ( 134 ) to the benzophenone ( 135 ).
This compound is then treated with the organometallic reagent obtained

CH 3

O O

134

CH 3

OH

135

AlCl (^3) O Cl
NCH(CHCH(CH^3 )^23 ) 2
BuLi
CH 3
OH
N
OH
CH(CH 3 ) 2
CH(CH 3 ) 2
CH 3
OH
NCH(CH^3 )^2
CH(CH 3 ) 2
137
138
136 H^2
58 MONOCYCLIC AROMATIC COMPOUNDS