Organic Chemistry of Drug Synthesis. Volume 7

Elastase is an inflammatory protease associated with lung injury caused
by infection or any of a number of other tissue insults. Inhibitors of this
enzyme would thus be expected to aid in treatment of lung injuries. A com-
pound that includes a sulfonamide linkage has shown activity against
neutrophil elastase. Protection of the phenol inp-hydroxyphenylsulfonate
( 90 )asitstert-butyl ester ( 91 ), comprises the first step in the construction
of an elastase inhibitor. The sulfonate function is then activated as the sul-
fonyl chloride ( 92 ) by reaction with thionyl chloride. In the other arm of
the convergent scheme, condensation of o-nitrobenzoyl chloride ( 93 )
with glycine benzyl ester ( 94 ) leads to the second half of the molecule.
The nitro group in this intermediate is then reduced to an amine with
iron in the presence of acid. Reaction of the newly revealed amino group
with sulfonyl chloride in 92 yields the corresponding sulfonamide ( 97 ).
Hydrogenolysis of the benzyl protecting group affords the free acid and
thussivelestat( 98 ).^16

OH

NaO 3 S

(CH 3 ) 3 COCl

90

O

NaO 3 S

91

C(CH 3 ) 3

O

SO 2 Cl O

ClO 2 S

92

C(CH 3 ) 3

O

NO 2

COCl

93

+ H 2 N O

O

CH 2 C 6 H 5

94

NO 2

O

O

HN CH 2 C 6 H 5

O

HN

O

O

HN CH 2 C 6 H 5

O

O

SO 2

C(CH 3 )

O

95

NH 2

O

O

HN CH 2 C 6 H 5

Fe/HCl O

96

92

97

HN

OH

O

HN

O

O

SO 2

C(CH 3 )

O

98

H 2

The potential antimetastatic activity of inhibitors of metalloproteinases
has generated considerable work in the area as noted in the discussion of
tanomastat ( 34 ). The very different structure of the inhibitorprinomastat
( 107 ) illustrates the considerable structural freedom that seems to exist for
inhibitors of these enzymes. Displacement of halogen in 4-chloropyridine
( 99 ) by phenoxide leads to the diaryl ether ( 100 ). Reaction of inter-
mediate 100 with chlorosulfonic acid affords the sulfonyl chloride ( 101 ).

54 MONOCYCLIC AROMATIC COMPOUNDS