Organic Chemistry of Drug Synthesis. Volume 7

CH 3 OC O

OCH 3

(CH 3 ) 3 Si Si(CH 3 ) 3 Cl

O

(CH 3 ) 3 Si

O NaBH (^4) (CH
3 ) 3 Si
OH
AlCl 3
CH 3 O 2 C OH
CH 3 O
OCH 3

1. CH 2 Cl 2 ,' PPh 3 ,DEAD

84 85 86 87

88

2. HF

Heat

CH 3 OC

CH 3 O

OCH 3

89

O=HC O

CH 3 O

OCH 3

90

O

CH 3 O

OCH 3

NC O

NC NHC^6 H^5

C 6 H 5 NH

NH 2

NH 2

HN

CH 3 O

OCH 3

N O

N

NH 2

H 2 N

CH 3 O

91 93

CH 3 O

OCH 3

NC O

C 6 H 5 NH

92

tBuOK

The search for endothelin antagonists as potential compounds for treat-
ing cardiovascular disease was noted in Chapter 5 (seeatrasentan). A com-
posed with a considerably simpler structure incorporates a pyrimidine ring
in the side chain. Condensation of benzophenone ( 94 ) with ethyl chloro-
acetate and sodium methoxide initially proceeds to addition of the
enolate from the acetate to the benzophenone carbonyl. The alkoxide
anion on the first-formed quaternary carbon then displaces chlorine on
the acetate to leave behind the oxirane in the observed product ( 95 ).
Methanolysis of the epoxide in the product in the presence of boron triflor-
ide leads to the ether–alcohol ( 96 ). Reaction of this with the pyrimidine
( 97 ) in the presence of base leads to displacement of the methanesulfonyl
group by the alkoxide from 96. Saponification of the ester group in that
product gives the corresponding acid,ambrisentan( 98 ).^14

O

94

Cl CO 2 C 2 H 5

NaOCH 3

O CO 2 C 2 H 5

95

CH 3 OH

BF 3

OCH 3

96

OH

CO 2 C 2 H 5 N

N

CH 3

CH 3

N

N

CH 3 SO 2

CH 3

CH 3

97

OCH 3

O

CO 2 H

98

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