Continuous synthesis and purification by direct coupling of a flow reactor with simulated moving-bed chromatography

Article abstract of DOI:10.1002/anie.201202795

Continuous synthesis meets continuous purification to produce pure products from crude reaction mixtures. In the nucleophilic aromatic substitution of 2,4-difluoronitrobenzene with morpholine the desired monosubstituted product can be continuously separated from the byproducts in a purity of over 99 % by coupling a flow reactor to a simulated moving bed (SMB) chromatography module (see scheme). Copyright

Full text of DOI:10.1002/anie.201202795

Angewandte
Chemie
DOI: 10.1002/anie.201202795
Flow Chemistry
Continuous Synthesis and Purification by Direct Coupling of a Flow
Reactor with Simulated Moving-Bed Chromatography**
Alexander G. OꢀBrien, Zoltꢁn Horvꢁth, FranÅois Lꢂvesque, Ju Weon Lee, Andreas Seidel-
Morgenstern, and Peter H. Seeberger*
Continuous-flow reactors have increased the scale of reac-
tions that can be carried out in the laboratory, and can ease
the transition from the research to production environment.[1]
Performing a reaction in flow can be advantageous in cases
where heat, mass, or light-transfer influence reactivity, or
where hazardous reagents are used at high temperature and
pressure.[2] However, purification is often a bottleneck in
synthesis and can negate the benefits ascribed to flow
reactors, unless side-products can be removed by crystalliza-
tion or liquid–liquid extraction.[3] In-line solid-supported
reagents that scavenge undesired byproducts[4] have finite
lifetimes and cannot be operated in a continuous manner
without regeneration. Additionally, separating complex mix-
tures of products often necessitates recourse to batch column
chromatography. Simulated moving-bed (SMB) chromatog-
raphy,[5,6] a form of continuous counter-current chromatog-
raphy widely used industrially, offers a solution. Based on
efforts to integrate both enzymatic and crystallization pro-
cesses with SMB chromatography[7,8] we envisioned that
a flow reactor could be coupled with SMB chromatography to
synthesize and purify complex molecules in a single, contin-
uously operated system. Herein, we report the first successful
coupling of flow synthesis and SMB chromatography to
continuously produce pure product.
transformation would likely differ from those for purification.
In an initial experiment using a commercially available flow
reactor (Vapourtec,[11] R2/R4 see the Supporting Informa-
tion), solutions of 1 and morpholine in ethanol were mixed
and heated to 1008C in a 10 mL stainless steel loop connected
to an 8 bar back pressure regulator to give a mixture of ortho-
2, para-2 and disubstituted product 3 (Figure 1a, Condi-
Figure 1. a) SNAr reaction of 2,4-difluoronitrobenzene (1) with morpho-
line under continuous flow conditions. b) Plan of the flow system.
The nucleophilic aromatic substitution (SNAr) reaction of
2,4-difluoronitrobenzene (1) with morpholine (Figure 1a)
affords a mixture of products and thus was selected to
demonstrate the approach. The reaction can be performed in
a range of solvents at various temperatures and concentra-
tions.[9,10] From the outset we were mindful of the fact that the
ideal solvent, concentration, and flow rates for the synthetic
tions 1). In these preliminary experiments, salt byproduct 4
was removed by batch aqueous extraction. Classical four-zone
SMB chromatography,
a binary separation technique,
requires that the target elutes either as the first or last
component. The target product, ortho-2 eluted last in
reversed-phase chromatography (hydrophobic stationary
and hydrophilic mobile phases) and was selected for separa-
tion from all the other reaction components.
[*] Dr. A. G. O’Brien, Dr. F. Lꢀvesque, Prof. Dr. P. H. Seeberger
Department for Biomolecular Systems
Max-Planck Institute for Colloids and Interfaces
Am Mꢁhlenberg 1, 14476 Potsdam (Germany)
SMB chromatography employs four zones of columns
connected end to end in series. A counter-current between the
mobile and stationary phases is simulated by periodically
shifting the two inlet and outlet ports in the direction of the
mobile phase flow after a certain time (the “shift time”).
Eluent and the feed mixture to be purified are fed at opposite
points in the system while the strongly retained product
(extract) and the remaining weakly retained byproducts
(raffinate) are collected at the two remaining positions. A
separate pump drives each zone: our design assumed that the
flow reactor provides the feed input to the system (Figure 2).
Criteria for successful operation were not only high yield and
purity, but also the continuous and robust operation of the
coupled reactor and SMB system.
Prof. Dr. P. H. Seeberger
Freie Universitꢂt Berlin
Arnimallee 22, 14195 Berlin (Germany)
E-mail: peter.seeberger@mpikg.mpg.de
Homepage: http://www.mpikg.mpg.de
Z. Horvꢃth, Dr. J. W. Lee, Prof. Dr. A. Seidel-Morgenstern
Max-Planck Institute for Dynamics of Complex Technical Systems
Sandtorstrasse 1, 39106 Magdeburg (Germany)
[**] We thank the Max-Planck Society and AstraZeneca UK for generous
financial support. F.L. is the recipient of a postdoctoral fellowship
from Fonds quꢀbꢀcois de la recherche sur la nature et les
technologies (FQRNT).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202795.
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Angewandte
Communications
and the product distribution was determined. The extract
contained only ortho-2 (over 99% purity by HPLC) and the
system reached cyclic steady state after three cycles. The
raffinate contained the remaining products, accompanied by
a small amount of ortho-2 (Figure 3).[17]
Figure 2. Schematic diagram of the directly coupled system.
HPLC separation of the product mixture using both
normal (YMC PAK SIL, 30 mm, n-hexane/EtOH, 75:25 v/v)
and reversed (LiChrosorb 25–40 mm, H2O/EtOH, 25:75 v/v)
phases highlighted the poor performance of ethanol as
a mobile phase for purification. Low solubility of the product
mixture in the former case and poor reproducibility in the
latter case prompted use of tert-butyl methyl ether (MTBE; 2-
methoxy-2-methyl propane) and EtOAc as alternatives,
although the insoluble salt by-product 4 clogged the reactor
in these solvents. Possible accumulation of 4 on the columns
under normal-phase conditions prompted further exploration
of reverse-phase conditions, which revealed THF/water
(40:60 v/v) as an ideal eluent. Upon changing the reaction
solvent to THF higher selectivity for ortho-2 was observed.
Increased temperature (1658C),[12] ensured complete con-
sumption of the starting material (Figure 1a, Conditions 2).[13]
A second set of pumps was used to dilute the product stream
with THF/water and thereby provide the SMB unit with
a feed of appropriate concentration and eluent composition.
Thermodynamic and kinetic parameters for SMB design were
obtained from preliminary batch chromatography experi-
ments. Operating conditions were estimated using the follow-
ing constraints: a total feed concentration of 5.5 gLÀ1, feed
flow-rate of 10 mLminÀ1, and both purity and yield of the
target product greater than 99%. The migration velocity of
the solute in the chromatographic column depends on the
mobile-phase velocity and the partition ratio. Linear adsorp-
tion isotherms were applied. During SMB separations, the
stationary-phase movement is simulated by shifting the ports.
The shifting time represents the counter-current stationary
phase velocity. Each SMB zone has a designated flow-rate
ratio (m), that is, the ratio of net liquid-phase flow to
simulated solid-phase flow. A specific component moves in
the liquid flow direction if the zone flow-rate ratio is larger
than the Henry constant of this component. The well-
established short-cut triangle method[14] was used to identify
the region of possible operating conditions (see the Support-
ing Information). A detailed evaluation of these conditions
was performed by separating the output of the reactor prior to
direct connection of the two instruments. The product
distribution in the feed leaving the flow reactor as analyzed
by off-line HPLC remained constant.[15]
Figure 3. Concentration profiles at the a) extract port in the uncoupled
system; b) raffinate port in the uncoupled system.
With effective separation conditions established, we
sought to directly couple the instruments, replacing the
SMB feed pump with a capillary from the flow reactor and
the dilution pumps. During initial attempts, the flow reactor
did not tolerate the high pressure generated in the SMB
system and the feed flow rate was reduced to 5.0 mLminÀ1 by
decreasing the dilution-pump flows. The reduced feed flow
rate was compensated for by recalculation of the operating
conditions. Feed throughput was maintained by the resulting
increase in feed concentration. Aliquots of the feed were
analyzed at every cycle. The system took longer to reach
steady state under these conditions but continuous operation
was achieved (Figure 4a,b). The extract contained ortho-2 in
over 99% purity, even before steady state was achieved
(Figure 4c,d). Comparison of the input and output concen-
trations and flow rates allowed calculation of the steady state
yield. In the final cycle 89% of ortho-2 was obtained. Extract
The mixture from the flow reactor was then fed into the
SMB system that was arranged in a six column (1-2-2-1)
configuration.[16] Fractions of the extract and raffinate were
collected after every cycle (six port shifting intervals, 171 s)
Figure 4. Concentration profiles at the a) extract port in the coupled
system; b) raffinate port in the coupled system; c) chromatogram of
the feed composition from the flow reactor; d) chromatogram of
extract fraction over the final shift in the coupled system.
2
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Chemie
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contained ortho-2 in equivalent purity.
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In summary, we have developed a system for the
continuous flow synthesis and purification of complex reac-
tion mixtures using SMB chromatography. The system can be
operated continuously to provide the target compound in high
yield. Based on linear adsorption isotherms the method can
be applied to other purification problems in the synthesis of
complex organic molecules. This system is one of the very first
truly continuous flow-purification systems and should prove
of wide applicability for the synthesis of complex molecules
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Received: April 11, 2012
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Published online: && &&, &&&&
Keywords: continuous synthesis · flow chemistry ·
.
nucleophilic aromatic substitution · purification ·
simulated moving-bed chromatography
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[11] Vapourtec Ltd. (http://www.vapourtec.co.uk) is gratefully
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systems.
[12] At temperatures above 1658C, decomposition of the reaction
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[15] The UV absorptions of compounds 2 and 3 varied. Individual
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[16] To enhance separation, two columns were used in each of the
two separation zones of the SMB system. The remaining two
zones consisted of one column each.
[17] These separation conditions were also successfully applied to the
purification of the less-pure product mixture deriving from the
reaction in EtOH (Figure 1a, Conditions 1).
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Angew. Chem. Int. Ed. 2012, 51, 1 – 4
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Angewandte
Communications
Communications
Flow Chemistry
A. G. O’Brien, Z. Horvꢁth, F. Lꢂvesque,
J. W. Lee, A. Seidel-Morgenstern,
P. H. Seeberger*
&&&& — &&&&
Continuous Synthesis and Purification by
Direct Coupling of a Flow Reactor with
Simulated Moving-Bed Chromatography
Continuous synthesis meets continuous
purification to produce pure products
from crude reaction mixtures. In the
nucleophilic aromatic substitution of 2,4-
difluoronitrobenzene with morpholine
the desired monosubstituted product can
be continuously separated from the
byproducts in a purity of over 99% by
coupling a flow reactor to a simulated
moving bed (SMB) chromatography
module (see scheme).
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 4
These are not the final page numbers!