Biomedical Engineering Reference
In-Depth Information
DBU
Dioxane/
t
-BuOH (2:1)
Cl
Br
CaCO
3
, 30 min
80°C
Cl
DMAP
NMe
2
NCO
CH
2
Cl
2
Cl
HN
O
O
N
152
154
N
DMF
H
Br
(not isolated)
(automated
solvent switch)
Br
Si
SO
3
H
N
NH
2
HN
153
O
155
N
N
(not isolated)
N
30 min, 150°C
N
N
HN
N
O
H
2
N
H
2
O
Waste
N
N
Gleevec
®
158
(32% after chromatography)
N
156
t
-BuONa
Dioxane/
t
-BuOH (2:1)
NH
2
Pd
L
157
(10 mol%)
SCHEME 11.48
A flow process for the synthesis of imatinib
158
.
route has been developed that uses a reverse coupling strategy to the batch route but
was more suitable to continuous processing (Scheme 11.48) [52].
Acid chloride
152
was preloaded onto immobilized DMAP and a solution of
aniline
153
was then passed through the column to release the amide
154
. The output
from this stream was collected by an automatic fraction collector (triggered by a UV
detector) after scavenging the acid byproduct with immobilized dimethylamine.
Collecting fractions in this manner enabled only the most concentrated output peak
area to be collected and subsequently aliquoted directly into a vial containing
methylpiperazine in DMF. This process also facilitated the automated solvent switch
(from chloroform to DMF) and produced a homogeneous mixture of known relative
stoichiometry ready to form amide
. The stream was passed through a basic
calcium carbonate column maintained at 80
C and scavenged with isocyanate to
remove excess methylpiperazine. The stream was then directed into a column
containing silica-immobilized sulfonic acid for catch-and-release purification.
Intermediate
155
was released from the silica-supported sulfonic acid by
elutionwith a DBU solution directly into the subsequent Buchwald-Hartwig coupling
with
155
. Fortunately, at the elevated
temperatures required, no decomposition of the catalyst to Pd black was observed.
The addition of a water stream aided dissolution of the NaBr precipitate. A series of
scavenging columns at the end of the coupling sequence was envisaged to clean up
the reaction stream and furnish pure material. However, analysis revealed that the
output stream contained not only product
156
using the BrettPhos Pd precatalyst
157
158
but also unreacted starting materials.
Differentiating between thesewas problematic so the reactor output was concentrated
in vacuo
and directly loaded onto a silica samplet cartridge for automated flash
chromatography to give
158
in 32% yield with better than 95% purity.
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