This
work aims to translate a multi-step and multi-phasic cascade reaction
into a one-step and one-phase reaction via a continuous flow process,
exemplified by the synthesis of Rufinamide (1 ) and its analogue
1-(2,6-difluorobenzyl)-4-phenyl-1H -1,2,3-triazole (2 )
(Scheme 1).
Scheme 1. (a) Reaction scheme for the 2-step synthesis of
Rufinamide (1 ) and analogue
1-(2,6-difluorobenzyl)-4-phenyl-1H -1,2,3-triazole (2 ).
(b), (c) Proposed ONE-FLOW processes for the preparation of product1 and 2 .
Results and Discussion
As for the current production of 1 and 2 , multiple
steps are required to obtain the purified product and most of the
published processes are energy intensive and time consuming; meanwhile,
sustainability and circularity issues such as reagent and catalyst
recovery are in most published papers still not
addressed.10-12 For
instance, in previous work from our group, the first step involving the
synthesis of the azide, a 40 min residence time at 160 °C and 7 bar
(yield 93%) was selected as optimized reaction condition in flow,10 following the use of
the ‘novel process windows’ (NPW) concept to boost flow chemistry
reactions.13 In this
work, we used a packed-bed resin-N3 microreactor to
achieve possibly full conversion under moderate reaction conditions. In
the previous study,10also a solvent-free three-step Rufinamide flow process was developed, as
another NPW variant, based on the use of undiluted reactants (omission
of the solvent) with resulting sustainability
benefits.14 Yet the
need for three consecutive steps, each one with a long reaction time,
requires a start-up time for the whole synthesis of a few
hours,15 while in this
work starting up the reaction takes only a few minutes, in combination
with compression of two steps into one and favorable reaction rates. We
have designed a system, which is meant to simplify the whole cascade of
reactors and separators traditionally used in a ONE-FLOW operation
leading directly to the purified solid product. This is achieved by the
selection of a designed solvent, screened by
COSMO-RS,16 which
enables a selective separation of the product simply by temperature
variation; and a designed catalytic nanoreactor based on cross-linked
polymer vesicles, or
polymersomes,17 which
facilitates catalyst recycling.
For the reaction solvent selection, we used a COSMO-RS based selection
to screen out the reaction solvent candidates for the Rufinamide
(1 ) synthesis, as shown in Table 1. Firstly, the solubilities
of the two reactants (benzyl chloride R1, propiolamide
R2) and product (rufinamide P2) at two
temperatures (T1: 25 °C, T2: 65 °C) in
common solvents were calculated separately by an auxiliary
batch-processing program in COSMOthermX.\(\text{Log}_{10}\left(x\right)\) (\(\log S\), Equation S1, in
supporting information) describes the optimized mole fraction of solute
in one solvent and was chosen as the key parameter to characterize
solubility. The maximal value of \(\log S\) is 0, meaning total
dissolution in the solvent; as the values of \(\log S\) decrease,
the solubility tends to be
smaller.18 At 25 °C,
the potential solvent should comprise high values for\(\log S_{R}\), while keeping low \(\log S_{P}\) and\(\log S_{P-R}\). The target was to find a candidate solvent which
can dissolve reactants R1, R2 at 25 °C
but in which product P2 is insoluble. As the key
scenario constraint, the cut-off values of the following four parameters
were chosen as \(\log S_{R1}>-1\) (freely
soluble),19\(\ \log S_{R2}>-1\), \(\log S_{P2}<-1\),\(\log S_{P2-R1}<-1\), \(\log S_{P2-R2}<-1\). It decreased the
total solvent candidates from 11957 to 1833. Next the difference in
product solubility at different temperatures was used as the second main
constraint. The aim was to find a solvent in which the product dissolves
at higher reaction temperature 65 °C to achieve homogeneous conditions
and precipitates automatically while cooling down to 25 °C. The chosen
values were \(\log S_{P2}^{65}>-1.5\) sparingly
soluble),19\(\log S_{P2}^{65}-\log S_{P2}^{25}>-0.5\). With the above
screening step, the number of solvents that satisfied this condition was
reduced to 356. To improve on the current synthetic processes, three
commonly used solvents for this reaction were used as benchmark solvents
and only solvents with more favorable characteristics (37 candidates,
Table S1, in supporting information) were considered for the next
step.20,21To narrow the screening space further, other chemical and physical
properties and the economic effect of the solvents were considered.
Finally, acetonitrile (ACN) was recognized as the top solvent and its
suitability was validated with solubility tests.
Table 1. Number of solvents in different screening steps.