Continuous Consecutive Reactions with Inter-Reaction Solvent Exchange by Membrane Separation

Article abstract of DOI:10.1002/anie.201607795

Pharmaceutical production typically involves multiple reaction steps with separations between successive reactions. Two processes which complicate the transition from batch to continuous operation in multistep synthesis are solvent exchange (especially high-boiling- to low-boiling-point solvent), and catalyst separation. Demonstrated here is membrane separation as an enabling platform for undertaking these processes during continuous operation. Two consecutive reactions are performed in different solvents, with catalyst separation and inter-reaction solvent exchange achieved by continuous flow membrane units. A Heck coupling reaction is performed in N,N-dimethylformamide (DMF) in a continuous membrane reactor which retains the catalyst. The Heck reaction product undergoes solvent exchange in a counter-current membrane system where DMF is continuously replaced by ethanol. After exchange the product dissolved in ethanol passes through a column packed with an iron catalyst, and undergoes reduction (>99 % yield).

Full text of DOI:10.1002/anie.201607795

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201607795
German Edition: DOI: 10.1002/ange.201607795
Synthesis Design
Continuous Consecutive Reactions with Inter-Reaction Solvent
Exchange by Membrane Separation
Ludmila Peeva, Joao Da Silva Burgal, Zsofia Heckenast, Florine Brazy, Florian Cazenave, and
Andrew Livingston*
Abstract: Pharmaceutical production typically involves multi-
ple reaction steps with separations between successive reac-
tions. Two processes which complicate the transition from
batch to continuous operation in multistep synthesis are solvent
exchange (especially high-boiling- to low-boiling-point sol-
vent), and catalyst separation. Demonstrated here is membrane
separation as an enabling platform for undertaking these
processes during continuous operation. Two consecutive
reactions are performed in different solvents, with catalyst
separation and inter-reaction solvent exchange achieved by
continuous flow membrane units. A Heck coupling reaction is
performed in N,N-dimethylformamide (DMF) in a continuous
membrane reactor which retains the catalyst. The Heck
reaction product undergoes solvent exchange in a counter-
current membrane system where DMF is continuously
replaced by ethanol. After exchange the product dissolved in
ethanol passes through a column packed with an iron catalyst,
and undergoes reduction (> 99% yield).
temperature, and solvent environment. In reality, synthetic
sequences are usually split into two or more shorter sequences
with product isolation occurring between the sequences. One
reason for dissecting a multistep flow synthesis can be the
[3a]
need for a switch between solvents. Solvent exchange by
distillation is straightforward when the solvent to be removed
has a lower boiling point than the replacement solvent, and
[
4]
[5]
semi-batch and continuous solvent exchange from low- to
high-boiling solvent in flow has been demonstrated. However,
a solvent exchange in the opposite direction (reverse boiling-
point order) is typically difficult, and is associated with
significant energy consumption and large quantities of
intermediate solvent mixtures. Aside from economic effects,
thermal operations may degrade the APIs and/or catalysts if
they are thermally labile. Reverse boiling-point-order solvent
exchange has been reported by catch-and-release techniques
in which the desired product of a solution-phase reaction is
selectively trapped onto a functionalized support material.
The compound is subsequently released from the support by
pumping in the replacing solvent along with an appropriate
T
he production of typical active pharmaceutical ingredients
APIs) involves multiple reaction steps with separations
workup) between successive reactions, and is dominated by
[
3a,6a]
(
(
releasing agent.
However, this approach relies on batch
trap and release cycles, thus introducing operating and control
complexity.
batch operations. However pharmaceutical manufacturers are
actively investigating converting their processes into contin-
uous production, thus seeking cost savings of 10 to 20% as
Furthermore, if two reaction steps utilize different cata-
lysts which can interfere with each other, catalyst removal is
essential between sequential stages. Catalyst incompatibility
can be minimized by using solid-phase-bound and/or immo-
[1]
compared to batch manufacturing, reduced energy and
[2]
carbon footprints, and improved overall safety. In contrast
to batch processing, multistep reaction sequences can be
conducted employing several flow reactors in series, com-
bined with packed-bed materials chemically functionalized
with catalysts, or reagents for exploiting purification with
solid-phase scavengers, chromatographic separation, or
liquid/liquid extraction. A benefit is that intermediates are
not isolated but are directly transferred into the next flow
[6]
bilized catalysts. However there are limitations on the
[7]
practicality of these systems. Thus in many cases the use of
homogeneous catalysts is favored together with an appropri-
[
8]
ate catalyst recycling technique, such as using scavenging
columns or scavenging agents in solution, liquid–liquid
biphasic conditions, or organic solvent nanofiltration (OSN).
Membrane unit operations are well suited for continuous
processes because of their ease of operation in flow,
scalability, and the absence of phase transitions or biphasic
[
3]
reactor.
The optimization of a multistep flow process is challeng-
ing. Each reactor unit has to be designed to ensure compat-
ibility with the subsequent unit in terms of flow rate,
[9]
systems. OSN has been demonstrated for solvent exchange
and catalyst recovery for individual processes utilizing
predominantly model compounds. Herein we present the
first example of continuous consecutive reactions where the
catalyst recovery and the solvent exchange are achieved in
membrane units. As a case study we have selected two
consecutive reaction steps from the synthesis of the API [6-
chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]-acetic acid, a selec-
tive cyclooxygenase 2 (COX-2) inhibitor, steps which require
a reverse boiling-point-order solvent exchange from DMF to
[*] Dr. L. Peeva, J. Da Silva Burgal, F. Brazy, F. Cazenave,
Prof. A. Livingston
Department of Chemical Engineering, Imperial College London
Exhibition Road, London SW7 2AZ (UK)
E-mail: a.livingston@imperial.ac.uk
Z. Heckenast
Department of Chemistry, Imperial College London
Exhibition Road, London SW7 2AZ (UK)
[10]
ethanol (Figure 1). The synthesis reported in the literature
has been performed in batch, and the inter-reaction protocol
used for purification and solvent exchange is tedious. Figure 1
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201607795.
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Figure 1. A) Reaction scheme for API synthesis. B) Schematic repre-
sentation of the alternative routes for solvent exchange. DMF=N,N-
dimethylformamide.
Figure 3. A) Schematic representation of the PFR-m-CSTR configura-
tion. Conversion in the PFR and CSTR (B) and palladium concentration
in the permeate stream from the m-CSTR (C) over time at different
residence times and catalyst loadings.
shows it comprises seven steps involving a variety of solvents.
We replace this process with a single step performed in
a membrane cascade unit, and the details are presented in
Figure 2.
10 mol%. A simplified kinetic model was developed in order
to predict the reactor performance (Figure S1). As can be
seen from Figure 3, the shortest RT achievable in the reactor
at about 95% conversion is 10 hours. Reducing the RT to
5
hours resulted in a sharp drop in conversion, as predicted by
the model. It was also possible to achieve conversion above
5% at lower catalyst loadings, however at the expense of
9
a long RT of 53 hours (see the Supporting Information). The
palladium concentration in the permeate remained within the
expected range (< 10% of concentration in the membrane
reactor and below 100 ppm). The palladium contamination of
À1
the product is high (ca. 1880 mgPdkg product, at 10 mol%
catalyst loading) and the final product will need additional
purification. However this product contamination is still
about two times lower than in the process performed in batch
À1
(
ca. 4400 mgPdkg product).
Despite the high catalyst loading used, the product stream
was clear and transparent since the bulk of the palladium was
retained in the membrane reactor (see Figure S2). The
product stream from the m-CSTR was passed through an
air stripper to remove residual TEA and ethyl acrylate. The
product stream obtained at 53 hours RT was further diluted
Figure 2. New concept for a continuous process where the Heck
reaction and the solvent exchange are performed in continuous
membrane units.
À1
À1
with DMF to bring the flow rate up to 0.006 Lh (0.003 Lh
was too low for reliable cascade operation), and passed
through the membrane cascade for solvent exchange. This
initial experiment was performed to evaluate the cascade
operational parameters and also the membrane stability. The
The first reaction, a palladium-catalyzed Heck coupling,
was performed in a continuous unit consisting of a plug flow
reactor and completely stirred membrane reactor/separator
[
11]
[9c]
in series (PFR-m-CSTR; Figure 3). Although the conver-
sion in the PFR reactor is relatively low, our previous studies
have shown that successful pre-activation of the catalyst
cascade was operated in a counter-current mode with the
postreaction mixture being fed in at Stage 1 and the replace-
ment solvent fed in at Stage 3 (feed-to-replacing solvent ratio
1:2.5; Figure 2). The final product dissolved in the replace-
ment solvent was collected as an overflow from Stage 3. The
cascade was operated for about 160 hours with consistent
membrane flux and rejection. The solvent was exchanged
from 100% DMF to 82% EtOH with product dilution of 2.1
and product yield greater than 95% (Figure 4; see Fig-
ure S7A).
[
11]
occurs within the PFR.
Preliminary kinetic experiments
were performed to determine the effect of catalyst loading on
the reaction rate and estimate the minimum residence time
(
(
RT) achievable in the reactor. As can be seen from Figure S1
see the Supporting Information), increasing the catalyst
loading above 10 mol% does not further accelerate the
À1
reaction rate (apparent kinetic constant max 0.66 h ), so our
study focused on catalyst loadings within the range of 0.05 to
2
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Figure 5. A) Schematic representation of the packed-bed column.
B) Reduction reaction kinetic constant as a function of DMF concen-
tration. C) Conversion in the packed-bed column overtime at different
RTs.
column, and possibly some initial non-uniformity of the
packed bed.
The final challenge was to push the system to its limits by
minimizing the RT. Maximum product flow rate and therefore
the RT, is determined by the Heck reaction, and as mentioned
earlier, the minimum RT in the PFR-m-CSTR required for
greater than 95% conversion is 10 hours (flow rate
À1
0
.015 Lh ). After passing through the gas stripper the
Heck product stream was fed into the membrane cascade,
now without any dilution. A counter-current stream of EtOH
was fed in at Stage 3 of the cascade at 0.0375 Lh (1:2.5
Figure 4. Theoretical and experimental concentration of product (A)
and ethanol (B) as a function of time in the membrane cascade
stages.
À1
ratio). Because of the higher concentrations of the retained
species, the fluxes through the membrane were lower than
that of the first run, thus leading to a slightly higher dilution of
the product stream (3 times vs. 2.1 at the first run). The
solvent exchange was successful, thus transforming the stream
from 100% DMF to 82% EtOH with a product yield of
greater than 99%. The cascade product stream was mixed
Finally we evaluated the effect of residual DMF, present
after solvent exchange, on the second reaction. A series of
batch kinetic experiments were performed varying the DMF
concentration in the reaction mixture. Results indicated that
DMF concentrations of up to 30% do not significantly affect
reaction rate (Figure 5B), thus the 18% residual DMF
achieved by solvent exchange was sufficient. To further
prove the concept, a packed-bed column with iron was
operated in continuous mode, initially using a model solution
of 0.05m 2 in 82% EtOH and 18% DMF. The flow rate
through the column was adjusted to match the product flow
leaving the solvent exchange stage (RTꢀ 52 min). Initially the
conversion was incomplete with large fluctuations in the
conversion numbers, and the RT in the column was increased
to 110 minutes. After about 20 hours of operation the
conversion increased to approximately 100% and remained
stable. The model solution was replaced with the cascade
product stream initially at 110 minutes RT, and since the
conversion remained stable the RT was decreased to
with 0.59m NH Cl aqueous solution at a ratio of 3.5:1 and
4
passed through the packed-bed iron column. Despite the
short 10 minutes RT in the column the reaction proceeded to
about 100% completion. The products of the first and the
1
second reaction were verified by H NMR spectroscopy. The
purity of the crude reaction mixture was greater than 80%.
Unfortunately the membrane selectivity of m-CSTR was not
sufficient to entirely separate the product of the Heck
reaction from the side product Et NBr, unreacted substrate
3
(ca. 5%), and the small amount of the catalyst debris. The
impurities were carried through the solvent exchange and fed
into the second reaction without any significant impact. In the
event of more sensitive reactions, an additional continuous
membrane purification unit could be provided (see Fig-
ure S10). This study proves that a continuously operated OSN
membrane cascade can successfully achieve inter-reaction
reverse boiling-point-order solvent exchange. Process and
membrane optimization could further improve product
5
1
0 minutes. Again the conversion remained steady at about
00% (Figure 5C). This outcome confirmed the robustness of
the second reaction and that the extent of DMF removal in
the solvent exchange was sufficient. The initial fluctuations
[
12]
were attributed to a pre-activation period of the iron in the
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quality and flexibility of the membrane cascade (see Fig-
ures S8 and S9).
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A. S. Myerson, E. M. Revalor, D. R. Snead, T. Stelzer, N.
Weeranoppanant, S. Y. Wong, P. Zhang, Science 2016, 352, 61 –
In summary we have demonstrated a continuous process
that integrates chemical synthesis with catalyst recovery and
reverse boiling-point-order solvent exchange by using OSN
technology. Significantly, the solvent exchange, usually a cum-
bersome process which typically requires energy intensive
and/or biphasic or semi-batch operations, was performed
smoothly in continuous mode and the product was success-
fully processed in the next reaction step. The membrane unit
operations showed excellent operational stability over a pro-
longed period of more than two months.
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Published online: && &&, &&&&
4
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Angew. Chem. Int. Ed. 2016, 55, 1 – 5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Synthesis Design
High to low: Two processes that compli-
cate the transition from batch to contin-
uous operations in multistep synthesis
are solvent exchange (especially high-
boiling- to low-boiling-point solvent) and
catalyst separation. Described herein is
membrane technology as an enabling
platform for coupling these processes in
a continuous operation.
L. Peeva, J. Da Silva Burgal, Z. Heckenast,
F. Brazy, F. Cazenave,
A. Livingston*
&&&& — &&&&
Continuous Consecutive Reactions with
Inter-Reaction Solvent Exchange by
Membrane Separation
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!