Organic Chemistry of Drug Synthesis. Volume 7

Saponification of the methyl ester followed by hydrogenolysis of the
benzyl ether completes the synthesis of the leukotriene B 4 antagonist
etalocib( 47 ).^9

CH 3 O OH

35

C 3 H 7 I

BuLi

CH 3 O OH

37

KF

CH 3 O O

F

CN CN

HO O

CO 2 CH 3

1. KOH


2. MeOH

OCH^2 C^6 H^5

OH

O

40

(C 2 H 5 ) 3 SiH

OCH^2 C^6 H^5

OH

41

OCH^2 C^6 H^5

OH

NBSBr

F

B(OH) 3

OCH^2 C^6 H^5

O

44

F

Br Cl

OCH^2 C^6 H^5

O

43

Br

Cl

R

OH

O

F

36 37 38 3. BBr^3

1. 39
   2. NaOH

42

4546 ; R = Cl; R = I

O O

CO 2 H

3. H 2

39

47

The discovery, close to half a century ago that beta adrenergic receptors
fell into two broad classes, led to major advances in drug therapy. Agonists
that act on beta 2 receptors, for example, include the majority agents for
treating asthma. The large number of beta blockers act as beta-1 selective
adrenergic antagonist. The discovery of a third subset of binding sites, the
beta-3 receptors has led to a compound that provides an alternate method
to currently available anticholinergic agents for treating overactive blad-
ders. There is some evidence too that beta-3 agonists may have some
utility in treating Type II diabetes. Synthesis of the compound begins
with construction of the biphenyl moiety. Thus, condensation of methyl
m-bromobenzoate ( 48 ) withm-nitrophenylboronic acid ( 49 ) in the pre-
sence of palladium leads to the coupling product ( 50 ). The nitro group
is then reduced to the corresponding amine ( 51 ). Alkylation of 51 with
thet-BOC protected 2-bromoethylamine ( 52 ) leads to intermediate 53.
Treatment with acid removes the protecting group to give the primary
amine ( 54 ). Condensation of this last product with m-chlorostyrene
oxide leads to formation of 56 , a molecule that incorporates the aryl

2. BIPHENYLS 49