Biomedical Engineering Reference
In-Depth Information
Negishi
coupling
O
F
N
F
N
N
N
[3+2]-Annulation
221
FIGURE 2.20
Retrosynthesis of mGluR1 antagonist
221
.
In order to disclose a scaled-up procedure to dispose of large amounts of
antagonist for biological studies, a risk assessment study was undertaken and the
results showed that neat organic azides were heat- and shock-sensitive, while diluted
solutions were safe enough to be handled [105]. The synthesis of bioactive compound
221
involved the one-pot cycloaddition reaction/Pd(0)-catalyzed cross-coupling
between bromophthalimidine
223
and 4-magnesiotriazole derivative
224
, generated
in situ
from a solution of arylazide
in methyl
tert
-butyl ether (MTBE) and 1-
propynylmagnesium bromide. However, the cross-coupling conditions [106,107]
using similar systems were not suitable for the lactam ring of the
N
-isopropyl-5-
bromophthalimidine (
222
223
). The problem was circumvented by converting 4-magne-
sio-triazole derivative
224
in the less nucleophilic zincated reagent
225
(
)
. The Negishi coupling afforded the final compound in an 89% assay
yield. After the first crystallization from MTBE, 66 ppm of palladium was still
present. The content could be reduced to 18 ppm after a recrystallization from a
mixture of AcOEt/pentane/PBu
3
(5 equiv with respect to the palladium catalyst).
Scheme 2.52
F
F
N
3
F
H
2
N
F
(25.5 wt% MTBE solution)
222
MgBr
THF, rt
O
F
F
BrMg
N
F
145
N
F
N
N
O
N
N
N
N
221
224
Br
223
ZnCl
2
THF, 20-30°C
Pd
2
(dba)
3
(1.5 mol%)
Xantphos (3.0 mol%)
55°C
89%
O
O
F
(Br)ClZn
3 steps
O
N
N
F
N
62%
N
Br
Br
226
225
SCHEME 2.52
Synthetic pathway towards mGluR1 antagonists.
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