Organic Chemistry of Drug Synthesis. Volume 7

( 148 ) affords the acyl bromide. The product is then converted to the ester
( 149 ), by treatment with methanol in the presence of acid. Catechol esters
undergo ready electrophillic attack as a result of the high electron density
in the ring. Thus, reaction of diethyl catechol with isothiocyanate in the
presence of acid leads to ring substitution. The initially formed thiocyanate
hydrolyzes to the observed thiourea ( 150 ) under reaction conditions. In a
classic method for forming heterocyclic rings, reaction of bromoketone
( 149 ) with the thiourea ( 150 ) proceeds to the thiazole 151.
Saponification of the ester then affordstetomilast( 152 ).^24

HO 2 C N

O

148

1. Br 2


2. CH 3 OHCH^3 O^2 C N O
   149

Br

KSCN

H+

OC 2 H 5 OC^2 H^5

OC 2 H 5

OC 2 H 5

OC 2 H 5 OC 2 H 5

OC 2 H 5

H 2 N OC 2 H 5

S 150

S

N

CH 3 O 2 C N

151

S

N

CH 3 O 2 C N

152

NaOH

Heterocyclic compounds bearing nitro groups were among some of the
earliest antiparasitic agents. A nitrothiazole has recently been approved for
treating diarrhea due to such infections. This rather venerable compound,
nitazoxanide( 155 ) is prepared in a single step by reaction of the acid
chloride ( 153 ) from aspirin with the aminonitrothiazole ( 154 ).^25

S N

O 2 N

H 2 N

154

OCOCH 3

O Cl

S N

O 2 N

+

OCOCH 3

O NH

153

155

Many peptides contain reasonably reactive amines, as well as an
occasional free guanidine function. By the same token, the sugars that

2. COMPOUNDS WITH TWO HETEROATOMS 101