Organic Chemistry of Drug Synthesis. Volume 7

product with piperidine under somewhat more forcing conditions with
replaces the terminal chlorine on the ether-linked side chain to complete
the synthesis of 189.^27

183

CH 3 O

HO

CO 2 C 2 H 5

185 ; R = O

186 ; R = H

Cl OTs

184

CH 3 O

O

CO 2 C 2 H (^5) 1. HNO 3

2. SnCl 2

CH 3 O

O

CO 2 C 2 H 5

NR 2

1, HCONH 2

2. SO 2 Cl

CH 3 O

O N

NH

Cl

187

NH

N

OHN OCH(CH 3 ) 2

CH 3 O

O N

NH

N

N

O HN OCH(CH 3 ) 2

Cl Cl

Cl Cl

CH 3 O

O N

NH

N

N

O HN OCH(CH 3 ) 2

N

188

189

Piperidine

C. Miscellaneous Benzo-Fused Heterocycles

Aldose reductase inhibitors are expected to protect long-term diabetic
patients from the consquences of the accumulation of sorbitol that is one
of the consequences of the disease [see lidorestat (Chapter 7)]. A quinazo-
lodione provides the nucleus for another potential drug in this class. The
sequence for the preparation of this agent starts with the heterocycle
( 190 ), which is in essence simply the cyclic carbonate of the corresponding
anthranilic acid. Heating the compound with the substituted benzylamine
( 191 ). Result in formation of the ring-opened amide with loss of carbon
dioxide 192. The ring is close again this time as a quinolodione ( 193 );
the requisite carbonyl carbon is restored by means of carbonyl diimidazole.
The anion from reaction of this last intermediate with sodium hydride is
then alkylated with ethyl bromoacetate. Saponification of the ester com-
pletes the preparation ofzenarestat( 194 ).^28

184 SIX-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING