Cocrystallization-Induced Spontaneous Deracemization: A General Thermodynamic Approach to Deracemization

Article abstract of DOI:10.1002/anie.202002464

Processes leading to enantiomerically pure compounds are of utmost importance, in particular for the pharmaceutical industry. Starting from a racemic mixture, crystallization-induced diastereomeric transformation allows in theory for 100 percent transformation of the desired enantiomer. However, this method has the inherent limiting requirement for the organic compound to form a salt. Herein, this limitation is lifted by introducing cocrystallization in the context of thermodynamic deracemization, with the process applied to a model chiral fungicide. We report a new general single thermodynamic deracemization process based on cocrystallization for the deracemization of (R,S)-4,4-dimethyl-1-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)pentan-3-one. This study demonstrates the feasibility of this novel approach and paves the way to further development of such processes.

Full text of DOI:10.1002/anie.202002464

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Accepted Article
Title: Co-crystallization induced spontaneous deracemization: A
general thermodynamic approach to deracemization.
Authors: Michael Guillot, Joséphine de Meester, Sarah Huynen,
Laurent Collard, Koen Robeyns, Olivier Riant, and Tom
Leyssens
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202002464
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Co-crystallization induced spontaneous deracemization: A
general thermodynamic approach to deracemization.
Michael Guillot‡, Joséphine de Meester‡, Sarah Huynen‡, Laurent Collard‡, Koen Robeyns‡, Olivier
Riant*, Tom Leyssens*
[*]
Prof. T. Leyssens & Prof O. Riant
Department of Molecular Chemistry, Materials and Catalysis
Institute of condensed Matter and Nanosciences Université Catholique de Louvain
Place Louis Pasteur, 1 bte L4.01.06, BE-1348 Louvain-La-Neuve, Belgium
E-mail: tom.leyssens@uclouvain.be & olivier.riant@uclouvain.be
M. Guillot, J de Meester, S. Huynen, L.Collard, K. Robeyns
[‡]
Department of Molecular Chemistry, Materials and Catalysis
Institute of condensed Matter and Nanosciences Université Catholique de Louvain
Place Louis Pasteur, 1 bte L4.01.06, BE-1348 Louvain-La-Neuve, Belgium
Supporting information for this article is given via a link at the end of the document.
between two diastereomeric salts and does therefore not require
the formation of such a conglomerate.
Abstract: Processes leading to enantiopure compounds are of
utmost importance, in particular for the pharmaceutical industry.
Starting from
a
racemic mixture, Crystallization Induced
theoretical 100%
Diastereomeric Transformation allows for
a
As highlighted by a 2006 literature revue CIDT can only be
performed on salt-forming compounds with the vast majority of
studied systems combining a carboxylic acid with an amine[20]. For
non-salifiable compounds, to the best of our knowledge, no
thermodynamically based deracemization method has been
reported and thus many racemizable compounds are left with no
viable option for deracemization. We are the first, to introduce
here such a method, based on co-crystallization, expanding the
scope of thermodynamically based deracemization processes to
all racemizable compounds (scheme 1). Co-crystallization
typically relies on strong intermolecular interactions like hydrogen
transformation of the desired enantiomer. However, this method has
the inherent limiting requirement for the organic compound to form a
salt. In this contribution, this limitation is lifted by introducing co-
crystallization in the context of thermodynamic deracemization, with
the process applied to a model chiral fungicide. We here report a new
general single thermodynamic deracemization process based on co-
crystallization for the deracemization of (R,S)-4,4-dimethyl-1-(4-
fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-Pentan-3-one.
This
work
presents the feasibility of this novel approach and paves the way to
further development of such processes.)
or halogen bonding[21]
, which are more universal. Co-
crystallization was recently explored by us and others in the
context of chiral resolution, targeting several racemic drug
systems[22-25]. Based on these methods, and drawing a parallelism
to CIDT, we set out to go beyond chiral resolution targeting a Co-
crystallization Induced Spontaneous Deracemization (CoISD)
process. The process developed here is innovative, industrially
friendly and scope-expanding. It is a thermodynamic process
applicable to all, non-salt as well as salt forming compounds, and
both to conglomerate or racemic compound forming systems,
hereby making it a general process compared to all the other
crystallization based deracemization processes.
With the increasing number of enantiopure chiral drugs
developed every year[1] and regulatory instances encouraging the
development of enantiopure compounds[2], processes allowing
access to these, are of utmost importance. In spite of significant
advances in asymmetric synthesis (in particular asymmetric
catalysis), the most prominent way to enantiopure drugs
nowadays still involves formation of a racemic compound[3] and
separation of the unwanted enantiomer through a resolution
process[4-8], or its transformation into the desired enantiomer, in a
so-called
deracemization
process.
Crystallization-based
resolution processes are less costly than eg. chromatographically
based techniques and therefore industrially wide-spread. Typical
crystallization based resolution processes are preferential
crystallization[9-11] and diastereomeric resolution.[12-14] Going
beyond separation, crystallization based deracemization
processes aim at transforming the unwanted enantiomer
(distomer) into the desired one (eutomer). Over the recent years,
different deracemization tools were developed. The kinetic
We used a model system to develop the CoISD process.
The racemic target compound (R,S)-4,4-dimethyl-1-(4-
fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-Pentan-3-one [RS-BnFTP]
belongs to a family of fungicidal compounds[26], for which a
conglomerate forming system has already successfully been
deracemized through the kinetic Viedma ripening procedure.[27,28]
Combining BnFTP with the chiral co-former, S-3-Phenylbutyric
acid (S-PBA), a diastereomeric pair of co-crystals can be obtained.
Each diastereomer crystallizes in a chiral space group with the
asymmetric unit only containing one enantiomer of the target
compound alongside S-PBA[23,25,29]. The diastereomers crystallize
in the P212121 and P21 space groups for [(S)-BnFTP-(S)-3-
Phenylbutyric acid] (fig. 1.A) and [(R)-BnFTP-(S)-3-Phenylbutyric
acid] (Fig. 1.B) respectively. The former will be referred to as the
(S,S)-co-crystal and is the energetically favored diastereomer1.
process of Viedma Ripening (VR) [15,16] and Dynamic Preferential
[17]
Crystallization (DPC)
require a conglomerate forming
racemate and are therefore inherently limited to 5-10% of all
compounds. Crystallization Induced Diastereomeric
Transformation--CIDT[18,19]
on the other hand, is
,
a
thermodynamical approach, based on the differences in solubility
1 When mixing both racemic RS-BnFTP and RS-PBA, a mixture of the (R,R)
and (S,S) co-crystals are formed instead of the (R,S) – (S,R) mixture, showing
a higher stability of the (S,S) with respect to the (R,S) diasteriomer.
1
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As a consequence, this diastereomer has a lower solubility
compared to the (R,S)-co-crystal .
Scheme 1 State of the art regarding deracemization and how CoISD redistributes the cards and opens new possibilities in the world of deracemization.
Figure 1. A. Asymmetric unit of the (S)- 4,4-dimethyl-1-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-Pentan-3-one-(S)-3-Phenylbutyric acid-co-crystal. B. Asymmetric
unit of the (R)- 4,4-dimethyl-1-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)-Pentan-3-one-(S)-3-Phenylbutyric acid-co-crystal. Displacement ellipsoids are drawn at the
50% probability level. Hydrogen bonds are shown as black dashed lines. Disorder is left out for clarity.
increase in S-BnFTP will lead to a solution that is supersaturated
with respect to the (S,S)-cocrystal2, which continues to crystallize
The principle behind CoISD (Scheme 2) taps into this
solubility difference.[30] Given the right conditions addition of S-
PBA (4 pink crescents) to a racemic mixture of BnFTP (3 orange
squares for R and three red squares for S) will selectively lead to
crystallization of only the (S,S)-cocrystal (2 purple cubes). This
induces a solution enantiomeric excess towards R-BnFTP (3
orange squares for only 1 red square in solution). Addition of a
racemizing agent will pull the solution imbalance towards the
racemic equilibrium once more, implying a net transformation in
solution of R-BnFTP to S-BnFTP (number of squares are evened
with 2 red and 2 orange ones). The associated concentration
as long as a sufficient amount of co-former is present in solution
(1 more purple cube appears). This process is purely
thermodynamic and eventually leads to spontaneous full
deracemization3. The main challenges in developing a CoISD are
comparable to those of the kinetic deracemization processes and
relate to the identification of a suitable chiral coformer and to the
combination of crystallization and racemization conditions. The
former often require low temperature to increase the yield,
whereas the latter often require opposite conditions as illustrated
below.
2 The co-crystal solubility product depends on the concentration of both
components in solution Ksp= [S-BnFTP]*[(S)-PBA]
3 Full deracemization does not imply a 100% transformation of R into S. The
final solution still contains a mixture of R- and S-BnFTP. The lower the solubility
of the co-crystal, the higher the overall deracemization.
2
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Scheme 2 Principle of the Cocrystallization Induced Spontaneous Deracemization process.
much weaker carboxylate base. This latter is not strong enough
to induce racemization under the initial conditions studied. A
similar situation is often encountered in CIDT-processes for which
a temperature increase is typically required for the racemization
to occur.[32,33] Keeping this in mind, we performed racemization in
presence of the coformer (and sub-stoichiometric amounts of
DBU) at higher temperatures. After 12 hours at 110°C, the filtrate
obtained from the resolution fully racemized while 2h at 90°C
partially racemized it. The racemization kinetics are slower
compared to those typically observed for CIDT. For this latter,
however one partner fulfills the role of the acid/base required for
racemization, leading to the high kinetics observed. As DBU
interacts with the acidic coformer, the quantity of base cannot be
increased in the current system. For systems where such an
interaction does not occur, faster racemization can be achieved.
Temperature increases are usually counterproductive with
respect to crystallization processes. To allow for a reasonable
yield, we decided to physically separate both processes working
with a crystallization vessel at 10°C and a racemization vessel at
Toluene was selected as crystallization solvent, as the
(S,S)-cocrystal behaves congruently in this solvent and
furthermore shows low solubility. On top, this solvent allows the
BnFTP racemization reaction to run without major difficulty.
Moreover, there is a substantial solubility difference between both
diastereomers. Chiral resolution conditions in toluene (SI), allow
to crystallize the (S,S)-cocrystal with a 32% yield4 and an ee of
98.6% (Fig. 2) starting from the RS-BnFTP racemate. This
process leaves a solution imbalance in favor of R-BnFTP
(ee=58.6%).
5
90°C. The liquid from the crystallization vessel with an
enantiomeric imbalance in favor of the distomer is continuously
transferred to the racemization vessel and the racemic solution
from the racemization to the crystallization vessel, as shown in
Fig. 3.
Figure 2. (a) Chiral chromatography of the cake (b) and the filtrate obtained
from the RS-BnFTP chiral resolution process in toluene.
Besides induction of a solution enantiomeric imbalance, a
racemization reaction is also a prerequisite for the development
of a deracemization process. In our case, racemization is based
on the keto-enol equilibrium of BnFTP using either a Brønsted
acid or base.[31] BnFTP racemizes freely in the presence of weak
bases but does not in presence of weak or strong acids. 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) was chosen as the
racemizing agent since the use of one equivalent of DBU at room
temperature led to full racemization in 30 minutes, whereas a 5
mol% catalytic amount of DBU was shown to induce complete
racemization in 6h (SI). Unfortunately, addition of the base to a
solution containing both BnFTP and co-former no longer led to
racemization at this temperature. This can easily be understood,
as DBU (less than 1eq with respect to BnFTP and co-former) will
deprotonate the carboxylic acid of the coformer, producing a
Figure 3. Sketch of the single process deracemization process set-up.
4 Maximum yield for a resolution is 50%
5 For a process which does not require high temperatures, a one-pot method
combining crystallization and racemization is fully achievable.
3
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observed by looking at the total R/S ratio at the end of the
experiments, with in the case of experiment 2, the 50/50 R/S
mixture being thermodynamically transformed into a 87/13
mixture. From the follow-up of experiment 2 (SI), racemization
kinetics were shown faster than crystallization kinetics. For this
reason, heating was decreased for the third experiment with
racemization becoming the limiting factor, yielding less
deracemization over the same period of time. With these 3
experiments, we are the first to demonstrate that deracemization
can be thermodynamically induced to yield enantiopure co-
crystalline solid with high purity. Depending on the co-former’s
handedness used, one can select the desired enantiomer. As for
the kinetic Viedma Ripening procedure, the process runs over
multiple days. Process productivity is therefore not very high, as
we are limited by the amount of DBU present. However, higher
productivities are expected for systems which show a more
suitable interplay between crystallization and racemization
kinetics. The development of an optimized process is ongoing,
requiring a full understanding of all process parameters.
In this paper, we pioneer in showing the success of the
CoISD process through 3 experiments. Each experiments is
performed using a 1 equivalent mixture of RS-BnFTP and co-
former and 7.5% mol of DBU. After each experiment, the solid in
suspension was filtered and the cake washed with toluene (SI).
Tubing and reactor vessels were flushed with acetone, and
solutions added to the filtrate. This latter was evaporated and the
weight of the cake and solid recovered from the filtrate were
determined. Both were further analyzed by chiral HPLC to check
the ratio of R vs. S-BnFTP. Combining these measurements
allowed for a full mass balance. Results are given in table 1. In all
cases, the cake was found to be enantiopure. Expectedly, starting
with the S-coformer leads to crystallization of S-BnFTP while the
R enantiomer can be crystallized using the co-former of opposite
handedness. Experiment 1, led to a recovered yield of over 50%,
inherently implying that we went beyond mere resolution (max.
yield of 50%). The full mass balance, showed a deracemization to
have occurred (bold numbers) for all experiments as can be
Experiment
C(BnFTP-
PBA)
VDBU / %mol
Yield6
(cake)
50.7%
eecake
eefiltrate
Ratio R/S total
Trac.
runtime
1 (S-PBA)
2 (R-PBA)
3 (R-PBA)
0.20 mol/L
203µL / 7.5%
254µL / 7.5%
305µL / 7.5%
0.999 [S]
1.00 [R]
0.97 [R]
0.276 [S]
0.54 [R]
0.246 [S]
18/82
87/13
38/62
90°C
90°C
75°C
4 days
5 days
5 days
0.25 mol/L
0.30 mol/L
44.6%
38.7%
Table 1 Key parameters and results for each of the three deracemization experiments. For each experiment, the same volume of toluene was used, 90mL. For the
enantiomeric excess (ee), the enantiomer in excess is given in brackets. Yield is calculated with respect to the total mass retrieved at the end of the experiment.
In conclusion, we report an innovative thermodynamic
Acknowledgements
deracemization process coupling selective co-crystallization to a
racemization reaction. We successfully deracemized RS-BnFTP
targeting either the S- or R-enantiomer based on choice of the co-
former handedness. Unlike kinetic processes such as Viedma
Ripening or dynamic preferential crystallization, CoISD can target
conglomerate as well as racemic compounds, and contrary to
CIDT, CoISD can be used for those compounds that do not form
salts. Overall, this makes CoISD a general deracemization
process, which in the future we will likely see applied to a
multitude of compounds. Further studies are currently ongoing to
optimize the process parameters and understand underlying
racemization and crystallization kinetics.
The authors would like to thank the UCL and FNRS for financial
support. The authors would also like to thank the FNRS (PDR
T.0149.19 – M. Guillot is a FRIA research fellow) for financial
support.
Keywords: Deracemization • Co-crystal • Thermodynamic •
Process • CoISD
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5
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Entry for the Table of Contents
Offering the first general approach to deracemization, co-crystallization induced spontaneous deracemization takes advantage of the
universal dimension of co-crystallization to create a pair of diastereomers and combines it to the racemization reaction in solution. This
model was successfully applied to a fungicide, previously unable to be deracemized with the current methodologies, opening new path
for further developments.
6
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