Biomedical Engineering Reference
In-Depth Information
O
OMe
H
Negishi
coupling
Skraup
A-224817.0 1A (racemate)
198
FIGURE 2.16
Retrosynthetic analysis of A-224817.0.
1.
n
-BuLi, ZnCl
2
THF, 0°C, 2 h
OMe
OMe
CO
2
Me
6 steps
28%
198
CO
2
Me
2.
Br
OMe
OMe
200
NO
2
199
NO
2
201
1.2 mol% Pd(PPh
3
)
2
Cl
2
THF, rt, 30 min
90%
SCHEME 2.47
Large-scale preparation of the biaryl system of A-224817.0
198
.
The scalable process was based on a very efficient Negishi cross-coupling to
afford a biarylic system. Hence, 1,3-dimethoxybenzene
was lithiated with
n
-BuLi, transmetalated with ZnCl
2
, and cross-coupled with ethyl 2-bromo-5-
nitrobenzoate (
199
201
precipitated out from the reaction mixture after 2 h and was obtained in 90% yield
after simple filtration (Scheme 2.47). The Negishi cross-coupling conditions proved
to be much more efficient than the Suzuki's: using 2,6-dimethoxyboronic acid as
the starting material instead of 1,3-dimethoxybenzene (
201
), the cross-coupling
product
200
) in the presence of Pd(0) catalyst. The biaryl derivative
was obtained in 58% yield, after long reaction time and tedious
chromatographic purification.
202
2.3.2. Phosphodiesterase Inhibitor PDE472
Multikilogram quantities of the potent phosphodiesterase type 4D inhibitor PDE472
202
were prepared for phase I batch on pilot plant scale after optimization of the
reaction conditions, paying attention to eliminate or minimize the risks generally
associated with processes chemistry [101] (Figure 2.17).
The Negishi coupling was the key step in this synthesis, allowing the formation
of the aryl-aryl bond between the benzoxadiazole heterocycle and the biarylic
N
MeO
Negishi coupling
N
O
N
PDE472
202
FIGURE 2.17
Retrosynthetic analysis of PDE472
202
.
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