Organic Chemistry of Drug Synthesis. Volume 7

to an aldehyde ( 160 ) by means of manganese dioxide. Aldol-type conden-
sation of 160 with the active methylene group in thiazolidinedione itself
leads to the unsaturated intermediate 161. Next, catalytic hydrogenation
serves to reduce the double bond. The free phenol in the other ring is then
alkylated witho-fluorobenzyl chloride. Thus, the hypoglycemic agent
netoglitazone( 163 ) is obtained.^26

D. Triazoles

Antifungal activity is retained in compounds in the “conazole” series when
an additional nitrogen atom is inserted into the all-important heterocyclic
ring. The preparation of a triazole-based antifungal agent starts with the
construction of the pyrimidine ring. Thus, condensation ofb-ketoester
( 164 ) with formamidine leads to pyrimidine 165. Treatment of intermedi-
ate 165 with phosphorus oxychloride leads to the corresponding chlori-
nated compound ( 166 ). The key intermediate 168 could be obtained, for
example, by alkylation of 1,2,4-triazole with phenacyl chloride ( 167 ).
Addition of the enolate from treatment of the pyrimidine ( 166 ) with
strong base to addition to the carbonyl group in 168. The resulting tertiary
alcohol ( 169 ) is obtained as a mixture of diastereomers. The chlorine atom,
having served its function, is now removed by catalytic hydrogenation.
Separation of diastereomers followed by resolution of the desired enantio-
mer pair affords the antifungal agentvoriconazole( 170 ).^27

F

OC 2 H 5

O O

+HN NH^2

N NH

F

O

F

N O

F

O

N NH

N

NN

F

Cl

POCl 3

IDA

N

N

F

N N

N N N

F

HO Cl

F F

1. 
   

   H (^2) F

   
   


2. 
   

   Resolve

   
   

F

N N

N NN

F

F

HO

164 165 166

(^167168)
170 169
Cl

2. COMPOUNDS WITH TWO HETEROATOMS 103