Organic Chemistry of Drug Synthesis. Volume 7

O

OCH 3

64

HCO 2 C 2 H5

NaOC 2 H5 O

OCH 3

CHO- Na+

CH 3 O CH 2 P(C 6 H 5 ) 3 CH 3 O CH 2 Cl

(C 6 H 5 ) 3 P

65 66 67

O

OCH 3

CH 3 O

68

2.H 2

O AlCl^3

OH

CH 3 O 69

TSA

CH 3 O

70

O N

OH

CH 3 O

Cl N

72

71

H 2

CH 3 O

O N O N

73

BBr 3

HO

74

The more recent synthesis for lasoxifene ( 74 ) takes a very different course.
The first step comprises displacement of one of the halogens in 1,4-dibromo-
benzene by the alkoxide fromN-2-hydroxyethylpyrrolidine 75 in the presence
of 18-crown ether to afford 76. Condensation of the lithium salt from 76
with 6-methoxytetralone ( 77 ) followed by dehydration of the initially
formed carbinol yields intermediate 78 , which incorporates the important
basic ether. Reaction of this compound with pridinium bromide perbromide
leads to displacement of the vinylic proton by halogen and formation of the
bromide 79. Condensation of this product with phenylboronic acid in the pre-
sence of a palladium catalyst leads tocoupling of the phenyl group by formal
displacement of bromine. The product ( 79 ), is then taken on to 74 as above.^12

HO N

Br

Br

+

(^75) Br
O N
76
O
CH 3 O
77
CH 3 O
O N
78
PyBr 3 +
CH 3 O
O N
Br
79
C 6 H 5 B(OH) 2
CH 3 O
O N
74
[Pd]
78 CARBOCYCLIC COMPOUNDS FUSED TO A BENZENE RING