The scale-up of continuous biphasic liquid/liquid reactions under super-heating conditions: Methodology and reactor design

Article abstract of DOI:10.1039/c6gc02840c

Biphasic liquid/liquid reactions are commonplace, however their scale-up under super-heating conditions is not. Even more challenging efforts have to be expected in the case of a large scale continuous production process, which also includes the development at a lab scale, the selection and design of the continuous reaction equipment. However, by running chemistry above the boiling point of the solvent, the solvent selection can be widened to include green solvents and continuous processing guarantees a limited and safe footprint. Herein is reported a systematic methodology for the development and scale-up of a biphasic reaction under super-heating conditions, as well as the design of a continuous reactor column suitable for handling such conditions. Taking the alkylation of benzylamine with 1,5-dibromopentane as a model reaction, kinetic determination and fluid dynamic characterization of the biphasic media have been instrumental for a successful scale-up concept which was proven in a custom-made hastelloy reactor column.

Full text of DOI:10.1039/c6gc02840c

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Scale-up of continuous biphasic liquid/liquid reactions under super-heating conditions:
methodology and reactor design
Francesca Mandrelli, Alessia Buco, Lorenzo Piccioni, Florian Renner, Bertrand Guelat,
Benjamin Martin, Berthold Schenkel and Francesco Venturoni*
† Novartis Pharma AG, Chemical and Analytical Development, WSJꢀ042, 4002 Basel,
Switzerland.
francesco.venturoni@novartis.com
1

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ABSTRACT: Biphasic liquid/liquid reactions are commonplace, however their scaleꢀup under
superꢀheating conditions are not. An even more challenging effort has to be expected in case of a
large scale continuous production process, which also includes the development in lab scale, the
selection and design of the continuous reaction equipment. However, by running chemistry
above the boiling point of the solvent, the solvent selection can be widened to include green
solvents and continuous processing guarantee a limited and safe footprint. Herein is reported a
systematic methodology for the development and scaleꢀup of a biphasic reaction under superꢀ
heating conditions, as well as the design of a continuous reactor column suitable for handling
such conditions. Taking the alkylation of benzylamine with 1,5ꢀdibromopentane as model
reaction, kinetic determination and fluid dynamic characterization of the biphasic media have
been instrumental for a successful scaleꢀup concept which was proven in a customꢀmade
hastelloy reactor column.
2

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INTRODUCTION
Expanding chemical operating space by employing more drastic temperatures and pressures
has received a great deal of attention over the past years.1 Ever more efficient use of energy and
processing time has become fundamental to the economic value of a process, such that access to
elevated pressure and temperature is now considered a valuable principle for the development of
green processes.2 Under such conditions solvents can be used above their boiling point, and the
range of solvents available to chemists is thereby expanded and can better include those
established as more environmentally friendly.3 Regarding process optimization, reduced reaction
times are to be expected and increased selectivity has also been demonstrated in selected cases.4
Microwave technology5 and continuous flow chemistry6 represent a convenient method to
explore these nonꢀconventional conditions on the laboratory scale. Over the last decades
microwave technology has found great application in laboratory scale reactions and in particular
in the discovery chemistry environment, where high temperatures and pressures can be explored
in total safety.5b,7 Batch microwave technology has limited scaleꢀup potential however, and
conventional thermal batch approaches may require access to nonꢀconventional batch equipment
which is associated with safety risks due to elevated pressures at high volumes. In this context,
continuous flow chemistry6 and the combination of microwave with flow chemistry8 have
recently been highlighted as a solution for such scaleꢀup exercises. The limited footprint of
continuous equipment from laboratory to commercial scale allows for more limited hazards and
reduces the complexities of safety measures. This is captured in the principles of green
engineering, in particular the maximization of timeꢀspace efficiency (principle no. 4) as well as
the ability to integrate superꢀheated steps into material flows encompassing numerous sequential
operations (principle no. 10).3
3

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Biphasic liquid/liquid reactions are often required when a differing solubility of the reaction
partners is observed. In this case, segmented flow in capillary reactors is a simple but efficient
reactor setup which enables a high massꢀtransfer performance for continuous transformations.10
For a larger production however, larger tube diameters or numbering up of the tubes is limited
regarding mixing, heat transfer and complexity of equipment if long reaction times and low flow
rates are required. In this regard, the presence of inserts or static mixer elements in the tubes may
still not be sufficient to guarantee a homogeneous dispersion of the two liquid phases and as a
consequence intense mass transport between the two phases. Alternatively an active mixing,
which can ensure a homogeneous distribution and a high heat and mass transfer independently
from tube diameters is an effective solution11 and is the one that we selected in this study.
Reaction columns are vertically oriented cascades of continuous stirredꢀtank reactors (CSTRs),
and can be considered the reactor of choice for this type of biphasic transformation. Indeed, this
setup decouples mixing and flow rate, ensuring a homogeneous dispersion of the reaction
mixture in the reactor, maximising mass and heat transfer and is therefore suitable for a
consistent scaleꢀup of biphasic reactions under superꢀheating conditions.12
RESULTS AND DISCUSSION
Establishing a methodology for the scaleꢀup of biphasic mixtures under superꢀheating conditions
started with the design of appropriate hardware. In this case a 13ꢀstage doubleꢀjacketed hastelloy
Cꢀ22 bench scale reactor column (rated up to 40 bar) had been designed and realised inꢀhouse in
collaboration with an internal workshop (Figure 1). In the selected design, the two phases are
pumped via a Tꢀpiece at the inlet present at the bottom of the column. The mixture progresses
between each stage (or chamber) of the column through a small opening, allowing the
conversion to increase with each sequential stage and leading to a biphasic outlet mainly
4

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containing the product of the reaction. The reaction time (residence time in the column) is
defined by tuning the flow rates of the two phases.
Figure 1. Schematic drawing of the reactor column
The design of such a reaction column is critical for the homogeneous mixing of the phases and
for the residence time distribution (backꢀmixing between the stages). The stirrer (design and
rotation speed) and the plate design (free crossꢀsection) are the key parameters.13 In particular, a
fixed chamber diameter of 28 mm was defined for each stage, allowing enough room for
technical modification on the plate. A fixed ratio of height/diameter (0.6)14 defined the volume of
each stage. The number of stages was derived from experience in previous projects, including
simulations of reference reactions and 13 physical stages were considered a good compromise
between operational volume and flow behaviour (number of theoretical CSTRs). The plates were
mounted on three vertical supports which were also acting as baffles. Efficient mixing in each
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stage was ensured by a series of impellers (standard Rushton Turbine agitators) mounted on a
shaft passing through the centre of the plates and connected to a magnetic coupled, high pressure
overhead stirrer (Figure 2).15
a
b
c
Figure 2. Reactor column with overhead stirrer (a, b) and inserts (c)
Among the different structural details a significant one for our endeavour was the design of a
modular system for modifying the stage openings (Figure 3a). The flow between the stages was
ensured by small vertical hollow tube mounted on the horizontal plates defining the stages.
Therefore, just by changing the inner diameter of this tube between the stages it was possible to
modify and explore the impact of backꢀmixing on the homogeneous distribution of the biphasic
mixture along the reactor, Figure 3a (1, 2, and 3 mm tube openings were used in this study).
The main concern while operating with biphasic mixtures was the potential accumulation within
the reactor of one of the phases (heavy or light) in a different ratio compared to the initial feed
solution. With feed inlet at the bottom of the column, accumulation of the heavy phase by gravity
has to be avoided. Considerable accumulation of one phase can significantly influence the
operating conditions because it modifies the ratio between the reagents (if located in two
6

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different phases), as well as reaction time and reaction rate, all factors which can have an impact
on product quality and yield. We therefore wanted to understand which were the main
parameters affecting phase accumulation. A model solvent system of water/ethyl acetate was
initially selected, and a series of experiments initiated where the flow rate, stage opening and
stirring speed were varied systematically (Table 1).16
Table 1. Accumulation studies with model solvent system EtOAc/Water (2.3:1, v/v)
Experiment
Connection tube
Stirring speed
(rpm)
700
Residence time
Accumulation
opening (mm)
(min)
45
1
2
3
4
5
6
1
1
1
2
3
2
17%
16%
11%
9%
900
45
1100
45
1100
45
1100
45
18%
1%
1100
25
This study allowed us to minimize the accumulation of the heavy phase in the column by finding
an optimum of flow rate and stirring speed for a given opening size. Indeed, if average droplet
diameter is larger than the opening size it would reduce the chance of homogeneous flow, while
very small droplets would be subjected to backflow in case the velocity in the tube is not
sufficient (Figure 3b).
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a
b
Figure 3. a) Single stage and tube between the stages (1, 2, and 3 mm); b) schematic
representation of droplet size of dispersed phase vs tube opening size
From this study it was possible to identify conditions where the two liquid phases flow truly coꢀ
currently in the reactor: a residence time in the range of 25 min, operating with an agitation
speed of 1100 rpm and with openings between the stages of 2 mm (ID). The high stirring speed
ensures that the water phase is well dispersed in the organic one. Under these conditions, the two
liquid phases flow truly coꢀcurrently in the reactor. The performance of the column reactor
(yield, quality) can thus be very close to that of an ideal batch reactor. The others parameters to
be evaluated to legitimate the equivalence in performance of a series of CSTRs with an ideal
batch reactor are the backꢀmixing and massꢀtransfer limitation. Minimal backꢀmixing is
guaranteed by the small open cross section of the column (0.5%) and the high number of
theoretical CSTRs (about 20) measured during residence time distribution experiments.
Regarding massꢀtransfer limitations, in the case that experimental data shows that the reaction is
not massꢀtransfer limited, only a slight dispersion of the phases is sufficient to be in the
kinetically limited regime. The reaction column was designed with a high tip speed resulting in a
high energy density compared with standard microwave devices.17 Therefore if massꢀtransfer
limitations are not encountered in batch microwave experiments, the intense mixing of the
phases in the reactor column would certainly ensure a kinetically limited regime.
8

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In summary, once confirmed that accumulation is minimal, that there is no relevant backꢀmixing
and no expected massꢀtransfer limitations then, a reactor column operating at steadyꢀstate would
deliver the same performance and reaction time as a standard batch reactor.18
The model reaction chosen to confirm this relationship was the double alkylation of benzylamine
with 1,5ꢀdibromopentane (Scheme 1). It was already reported that this reaction significantly
benefits from superꢀheating conditions, reducing the reaction time from hours (conventional
batch at reflux) to minutes (microwave batch) with advantages regarding yield and quality.19
Scheme 1. Preparation of Nꢀbenzyl piperidine 3 and competitive sideꢀproducts
The reaction was initially performed according to literature microwave conditions in batch mode
with MeꢀTHF as organic solvent (1.1 eq. of dihaloꢀalkane, 1.1 eq. of base, 120 °C, 20 min.
irradiation).16 Prior to optimizing the reaction conditions, thermal stability of the reaction mixture
was evaluated. Calorimetric SETARAM experiments16 conducted on the reaction mixture
showed a weak exothermal decomposition energy from 150 °C, occurring after the main reaction
heatꢀrelease. Accordingly it was possible to define the maximum process temperature of 135 °C,
setting 15 °C as a safety margin for smallꢀscale lab experiments and continuous flow reactions.
Modified literature conditions were used to evaluate the effect of different bases on the reaction
profile. As a result of this study sodium hydroxide was found to be the base of choice.20 Next, we
9

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experimentally defined (data not shown) the equivalents of 1,5ꢀdibromopentane (2 equiv.) and
the volume ratio between the solvents (water/MeꢀTHF 1:1.25; v/v).
The reaction kinetic was then investigated by varying the temperature in a microwave reactor
(Figure 4).
Figure 4. Kinetic investigations in microwave batch at 110, 120 and 130 °C.
Every reaction was quantitatively analyzed by calibrated HPLC analysis (calibration curves
generated for the different species). The data were then elaborated with the modelling software
DynoChem,21 obtaining from the regression of the experimental results values of rate constant
(k) and the activation energy (Ea).16 The same software was used to predict the optimal set of
reaction conditions, setting the priorities on maximizing yield and reducing the formation of the
byꢀproducts. Variables were equivalents of base, reaction time (< 30 min, to maximize
performance in the reactor column) and temperature (<135 °C). Optimal conditions for batch and
ideal plug flow conditions were predicted to be 3 equivalents of sodium hydroxide, 126 °C and
25 minutes of reaction time, yielding 96% of target compound and only traces of byꢀproduct 4. A
confirmatory reaction under these conditions was then performed under microwave irradiation
affording a yield of 94% and byꢀproduct 4 below 1 mol%, thus confirming the good predictivity
of the kinetic model.
We moved next to the newly designed continuous reactor (Scheme 2). The setup used to perform
the reaction comprised three SyrDos2 continuous syringe pumps, a pressure sensor for each
10

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pump, a heating/cooling system and a backꢀpressure regulator (Equilibar).22 The setup was
controlled by HiTecZang23 software that allowed the setting of safety ranges as well as the online
monitoring of reaction conditions such as flow rates, temperature and pressure.
Scheme 2. Continuous flow preparation of compound 3
By combining the kinetic and fluid dynamic information previously outlined, a residence time of
25 minutes, reaction temperature of 126 °C, stirring speed of 1100 rpm, 7 bar and 2 mm
openings in every stage were the confirmed ideal reaction conditions. The setup was then
operated for 75 minutes at steadyꢀstate with five samples taken after the startꢀup phase. From the
results reported in Figure 5 it was possible to observe a stable behaviour confirming that no
change in heavy/light phase ratio occurred during steady operations.
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Figure 5. Mole profile of reaction components normalized to initial moles of benzylamine 1.
Point zero corresponds to 25 min after starting the pumps (one reactor volume)
The steadyꢀstate fractions were combined and purified by two sequential extractions: first 3
equivalents of HCl(aq.) were added and the nonꢀpolar impurities (excess of dibromopentane and
related components) were removed into the organic phase, then the aqueous phase was
neutralised with NaOH(aq.) and the reaction product was backꢀextracted with fresh organic
solvent. The combined organic phase was concentrated to dryness to obtain 17 g of product (88%
overall yield).
In conclusion we have reported an efficient development methodology and reactor design for
the scaleꢀup of biphasic reaction mixtures under superꢀheating conditions in continuous flow. A
combination of information derived from kinetic modelling and fluid dynamic analysis was key
to maximizing the output and quality of the target reaction in the designed hardware. In
particular, when three criteria are verified (i. no accumulation of one of the phase in the reactor,
ii. no or limited backꢀmixing and iii. no massꢀtransfer limitations) the newly constructed reactor
can be considered as equally efficient as a microwave batch reactor, therefore simplifying the
optimization and scaleꢀup methodology. The alkylation of benzylamine was selected as a proofꢀ
12

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ofꢀconcept and the validity of this methodology was demonstrated with the production of 17 g of
desired compound. Integration of the described methodology into an endꢀtoꢀend manufacturing
chain24 and the plant scaleꢀup of a complete pharmaceutical ingredient will be reported in due
time.
Electronic supplementary information (ESI) available
Acknowledgements
The authors would like to thank Eliseo Madero and Urs Herzig (ISS, CH) for the manufacturing
of the reactor, Pascale Hoehn and Marian Lanz for the safety studies, Michel Aubry, Serbuelent
Sevinc, Silke Schönebeck, Roger Suremann, Andreas Hafner, Julien Haber and Jutta Polenk for
their support during the development process of this project and Fabrice Gallou, Gerhard Penn
and Thierry Schlama for useful discussions. The authors would also like to thank Prof. Antimo
Gioiello at the University of Perugia.
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In this paper we explore and propose a methodology for the scale-up of continuous biphasic liquid/liquid
reactions under super-heating conditions