Biomedical Engineering Reference
In-Depth Information
N
N
N
1.
n
-BuLi, THF/Pentane, -100°C
2. ZnCl
2
(1.4 equiv)
-90°C to 0°C
MeO
2 steps
89%
3. Pd(PPh
3
)
4
(8 mol%)
0°C to 20°C
4.
206
MeO
MeO
Br
B(OH)
2
N
O
203
205
N
38%
B(OH)
2
Br
202
Pd(OAc)
2
(5 mol%)
P(
o-
Tol)
3
(10 mol%)
Na
2
CO
3
, DMF/H
2
O
60°C
Pd(OAc)
2
(5 mol%)
P(
o-
Tol)
3
(10 mol%)
Na
2
CO
3
, DMF/H
2
O
60°C
34%
34%
N
O
N
O
N
N
204
202
206
N
MeO
207
SCHEME 2.48
Laboratory-scale investigation for PDE472
202
preparation.
northern fragment. Two main intermediates, 4-(3-bromo-4-methoxyphenyl)pyridine
(
), were thus prepared on a large scale
(10-20 g) and tested in Pd(0)-catalyzed Suzuki and Negishi coupling reactions
(Scheme 2.48). Hence, when 4-(3-bromo-4-methoxyphenyl)pyridine (
203
) and 5-bromo-2,1,3-benzoxadiazole (
206
203
) was
204
reacted with 2,1,3-benzoxadiazole-5-yl boronic acid (
) under Suzuki reaction
conditions, PDE472
was obtained in low yield. Identical yields were obtained
when coupling the phenylboronic acid derivative
205
with 5-bromo-2,1,3-benzox-
adiazole (
206
); however, the final compound was contaminated by appreciable
quantities of 4-(4-methoxyphenyl)pyridine (
202
). No better results (38% yield) were
obtained under palladium-catalyzed Negishi conditions by reacting arylzinc reagent
derived from
207
. In addition, the reaction proved to
be quite long (16 h) and required the use of pentane as the cosolvent to avoid the
precipitation of the organozinc species at low temperature (
203
with 4-bromobenzofurazan
206
100
C) and the use
of a relatively high quantity of palladium catalyst (8 mol%). Moreover, the final
product was contaminated with critical amounts of palladium (300-800 ppm) even
after chromatography and recrystallization, very far from the content below 2 ppm
required for drug purity. That being said, the Negishi coupling appeared slightly more
advantageous than the Suzuki coupling due to the easier purification of the crude
(Scheme 2.48).
To improve the yield of Negishi cross-coupling, it was necessary to optimize
each step of the reaction, namely, the halogen-metal exchange to afford aryllithium
intermediate
A
, the transmetalation to give arylzinc reagent
B
,andtheactual
coupling between arylzinc derivative
B
and arylpalladium complex
C
(formed
in situ
from the corresponding 4-bromobenzofurazan
) (Scheme 2.49). For
safety and environmental reasons,
n
-BuLi was replaced by hexyllithium. In an ideal
case, 1.0 equiv of hexyllithium would react with 1.0 equiv of arylbromide
206
203
to
A
afford 1.0 equiv of lithiated derivative
and 1.0 equiv of hexylbromide. However, the
concentration of hexylbromide increases progressively as the reaction progresses,
and the latter can react either on the hexyllithium still present to afford dodecane or
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