Organic Chemistry of Drug Synthesis. Volume 7

O-alkyl product ( 35 ). Reaction of intermediate 35 with oxalyl chloride
proceeds on the only open position of the heterocyclic ring to yield the
acylated derivative ( 36 ) as its acid chloride. Treatment of 36 with
ammonia gives the corresponding amide. The tert-butyl ester is then
cleaved with acid to afford the phospholipase inhibitorvarespladib( 37 ).^6
Retinopathy, that is, diminishing vision to the point of eventual blind-
ness, is one of the many complications that results from uncontrolled
levels of blood sugar that characterize diabetes. The elevated blood
sugar that characterize the disease stimulate the enzyme aldose reductase
that catalyzes an alternate pathway for glucose metabolism. The sorbitol
end-product from this route tends to accumulate in the ocular lens as opa-
cities, a process that leads to increasingly reduced vision and finally total
blindness. There is also some evidence that an effective inhibitor would
find use in fending off diabetic neuropathy. Though many aldose reductase
inhibitors have been identified over the years, few if any have yet achieved
regulatory approval. In a convergent synthesis for a recent entry, the amino
group in the aniline ( 38 ) is first acylated with acetic anhydride. Treatment

F

F

H 2 N F

F

38

(CH 3 CO) 2 O

F

F

NH F

F

O

39

F

F

NH F

F

S

40

F

F

F

NaH N

S

NaOH

F

HS

H 2 N F

F

41

44

NH

CN

42

NaH

BrCH 2 CO 2 C 2 H 5

N

CN

CO 2 C 2 H 5

CF 3 CO 2 H

N

CO 2 C 2 H 5

S

N

F F

F

43

45

NaOH

N

CO 2 H

S

N

F F

F

46

P 4 S 10

of the amide ( 39 ) with tetraphosphorus decasulfide replaces the amide
oxygen with sulfur ( 40 ). Reaction of 40 with sodium hydride produces
the sulfide anion from the enol form of the thioamde. This compound dis-
places the adjacent ring fluorine atom to form a benzothiazole ( 41 ). Base

144 FIVE-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING