Organic Chemistry of Drug Synthesis. Volume 7

Adding yet another large substituent to the imidazole ring restores PDE
inhibiting activity. The resulting compounddasantafil( 137 ) blocks PDE 5
and thus joins the growing list of agents that address erectile disfunction.
The synthesis of this compound begins with the formation of the reductive
amination product ( 129 ) from anisaldehyde ( 128 ) and glycine. This
product is then treated with reagent 130 , obtained from reaction of triethyl
orthoformate and cyanamide in the presence of strong base. For bookkeep-
ing purposes formation of the imidazole ( 131 ) can be rationalized by
assuming initial addition–elimination of the amine in 129 to the reagent
130 ; addition of the enolate from 129 to the nitrile then closes the ring.
Condensation of the product ( 131 ) from this reaction with diethylcarba-
mate again in the presence of strong base forms the pyrimidinedione
ring to afford the xanthine ( 132 ) after neutralization. The nitrogen at
position 1 is next alkylated with bromoethyl acetate ( 133 ). Reaction of 133

OCH 3

O=HC

1.H 5 C 2 OCCH 2 NH 2 OCH^3

H 5 C 2 O 2 C

2. NaBH 4
   128

NCNH 2 +CH(OC 2 H 5 ) 3

NH

129 130

OCH 3

N

HO N

H 2 N

O

131

tBuOK

NCN OC 2 H 5

1. C 2 H 5 NHCO 2 C 2 H 5
   tBuOK


2. AcOH

OCH 3

N

N N

NH

O

O

132

OCH 3

N

N N

N

O

O

BrCH 2 CH 2 OAc

OAc

K 2 CO 3

133

NBS

OCH 3

N

N N

N

O

O

OAc

Br

134

Br OH

H 2 NOH

OCH 3

N

N N

N

O

O

OAc

Br

136

NH

NaHCO 3 OH

OCH 3

N

N N

N

O

O

OH

Br

137

135 NH

with NBS results in bromination on both the aromatic ring and the carbon
on the fused imidazole ring ( 134 ). Displacement of the latter bromine atom
with chiral aminocyclopentanol ( 135 ) completes construction of the

204 BICYCLIC FUSED HETEROCYCLES