Organic Chemistry of Drug Synthesis. Volume 7

skeleton ( 136 ). Saponification of the acetate group on the pendant side
chain then affords the PDE V inhibitor 137.^20
Moving one of the imidazole nitrogen atoms found in xanthines into the
ring junction provides the nucleus for another PDE 5 inhibitor. The other
substituents in this compound more closely resemble those found in
sildenafil (aka Viagra) than those used in dasantafil. The convergent
scheme starts with the acylation of alanine ( 138 ) with butyryl chloride.
The thus-produced amide ( 140 ) is again acylated, this time with the half
acid chloride from ethyl oxalate in the presence of DMAP and pyridine
to afford intermediate 141. In the second arm of the scheme, the benzoni-
trile ( 142 ) is reacted with aluminate 143 , itself prepared from trimethyl-
aluminum and ammonium chloride, to form the imidate ( 144 ). Treatment
of 144 with hydrazine leads to replacement of one of the imidate nitrogen
atoms by the reagent in an addition–elimination sequence to form
145. Condensation of 145 with 141 leads to formation of the triazine
( 146 ). Phosphorus oxychloride then closes the second ring to afford 147.
Reaction of this last intermediate with chlorosufonic acid affords the
corresponding sulfonyl chloride. Treatment of this compound with
N-ethyl piperazine forms the sulfonamide and thusvardenafil( 148 )is
obtained.21,22

O

CN

142

AlCH 3 ClNH 2

Al(CH 3 ) 3 + NH 4 Cl

143

O

144

NH 2

NH

H 2 NNNH 2

O

145

NH

NH

NH 2

HO 2 C

138

+ClOC

139

TMSCl

Et 3 N

NH 2

HN

HO 2 C

O

Cl

O OC 2 H 5

O

N

HO 2 C

O

C 2 H 5 O

O

O

140 141

O

N

HN

N

O

NH

O

O

146

POCl 3

O

N

HN

N

O

N

O

N

HN

N

O

N 1. ClSO 3 H

N

O S

O

N

N 147

HN

2.

148

1. COMPOUNDS WITH FIVE-MEMBERED RINGS FUSED TO SIX-MEMBERED RINGS 205