Combining Incompatible Processes for Deracemization of a Praziquantel Derivative under Flow Conditions

Article abstract of DOI:10.1002/anie.202013502

An efficient deracemization method for conversion of the racemate to the desirable (R)-enantiomer of Praziquantel has been developed by coupling incompatible racemization and crystallization processes. By a library approach, a derivative that crystallizes as a conglomerate has been identified. Racemization occurs via reversible hydrogenation over a palladium on carbon (Pd/C) packed column at 130 °C, whereas deracemization is achieved by alternating crystal growth/dissolution steps with temperature cycling between 5–15 °C. These incompatible processes are combined by means of a flow system resulting in complete deracemization of the solid phase to the desired (R)-enantiomer (98 % ee). Such an unprecedented deracemization by a decoupled crystallization/racemization approach can readily be turned into a practical process and opens new opportunities for the development of essential enantiomerically pure building blocks that require harsh methods for racemization.

Full text of DOI:10.1002/anie.202013502

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Accepted Article
Title: Combining incompatible processes for deracemization of a
Praziquantel derivative under flow conditions
Authors: Richard Morrison Kellogg
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Combining incompatible processes for deracemization of a
Praziquantel derivative under flow conditions
Giulio Valenti,[a] Paul Tinnemans,[b] Iaroslav Baglai,[c] Willem L. Noorduin,[c] Bernard Kaptein,[d] Michel
Leeman,[a] Joop H. ter Horst,[e] and Richard M. Kellogg*[a]
[a]
Mr. G. Valenti, Dr. M. Leeman, Prof. Dr. R. M. Kellogg
Symeres, Kadijk 3, 9747 AT Groningen, The Netherlands
E-mail: r.m.kellogg@symeres.nl
[b]
[c]
[d]
[e]
Dr. P. Tinnemans
Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands
Dr. I. Baglai, Dr. W. L. Noorduin
AMOLF, Science Park 104, 1098 XG Amsterdam, The Netherlands
Dr. B. Kaptein
InnoSyn BV, Urmonderbaan 22, 6167 RD Geleen, The Netherlands
Prof. J.H. ter Horst
EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation (CMAC), Strathclyde Institute of Pharmacy and Biomedical
Sciences, Technology and Innovation Centre, University of Strathclyde, 99 George Street, Glasgow G1 1RD, U.K.
E-mail: joop.terhorst@strath.ac.uk
Abstract: An efficient deracemization method for conversion of the
racemate to the desirable (R)-enantiomer of Praziquantel has been
developed by coupling incompatible racemization and crystallization
processes. By a library approach a derivative that crystallizes as a
conglomerate has been identified. Racemization occurs via reversible
hydrogenation over a palladium on carbon (Pd/C) packed column at
130 °C, whereas deracemization is achieved by alternating crystal
growth/dissolution steps with temperature cycling between 5-15 °C.
These incompatible processes are combined by means of a flow
system resulting in complete deracemization of the solid phase to the
desired (R)-enantiomer (98% ee). Such an unprecedented
deracemization by a decoupled crystallization/racemization approach
can readily be turned into a practical process, and opens new
opportunities for the development of essential enantiomerically pure
building blocks that require harsh methods for racemization.
Figure 1. Racemic praziquantel 1 ((R)-1: (S)-1 = 1 : 1) is used for treatment of
Bilharzia whereas the active enantiomer is (R)-1.
Attrition enhanced deracemization (Viedma ripening)[6] and
related temperature cycling techniques[7] are effective practical
methodologies for total conversion of a racemate into the pure
enantiomer in the solid phase (Figure 2). There are prerequisites:
a) the compound must crystallize as a conglomerate;[8] b) a
suitable method for liquid phase racemization is required for total
deracemization, and c) the racemization conditions must be
compatible with the crystallization conditions required for
deracemization.[9]
Around 200 million people suffer from schistosomiasis (Bilharzia
or snail fever), an infection caused by blood flukes.[1] Praziquantel
(Biltricide) 1 (Figure 1) is used as racemate almost exclusively for
treatment. The drug affects the permeability of membranes of the
parasite towards calcium ions. The (R)-enantiomer is responsible
for the pharmacological effect and tastes significantly less bitter
than the cheaper racemate.[2]. Large and, especially for children,
difficult to swallow bitter tablets of racemic 1 are currently used to
obtain the desired therapeutic effect.
Pure enantiomers of Praziquantel can be obtained via classical
resolution of precursor Praziquanamine 2 (Scheme 1) or its N-
3]
benzoyl derivative.[2a,
Praziquantel has been resolved by
diastereomeric co-crystal formation with L-malic acid.[4] Recently,
1 has been resolved on semipreparative scale using simulated
moving bed chiral chromatography.[5] These resolution
procedures are all limited to a maximum yield of 50%. An efficient
method to convert the racemate to enantiomerically pure (R)-
Praziquantel is of obvious interest.
Figure 2. The prerequisites for deracemization.
Unfortunately, Praziquantel is not a conglomerate (prerequisite
a); it crystallizes as a stable racemic compound.[10] However, this
prerequisite can be met by synthesis and search of a covalent
library of crystalline derivatives.[11] We prepared a library of 30
1
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crystalline derivatives 3a-ad obtained by reaction of 2 with acyl
and aryl chlorides (Scheme 1, Figure S1 SI). Derivatives 3 may
be hydrolyzed and converted back to 1 (Scheme 1).[2a]
pumped to the racemization unit and racemized at 130 °C in a
closed system. A filter was connected upstream to the pump and
submerged into the slurry in order to deliver the mother liquor free
of solids to the racemization unit. In order to drive deracemization
in the direction of the desired enantiomer, (R)-3u, a small initial
excess of the desired (R)-enantiomer must be present in the initial
solid phase.
Scheme 1. Reversible derivatization of 2 for generating a library of compounds
3 as candidates for conglomerate screening. (Scheme 1, Figure S1 SI).
Second harmonic generation (SHG) was used for preliminary
conglomerate screening.[12] Four compounds with positive
responses were identified of which only the pivaloyl derivative 3u
proved to be a conglomerate (SI). This assignment was confirmed
by Differential Scanning Calorimetry (DSC) measurements, X-ray
powder diffraction (XRPD) and by crystal structure determination
of a single crystal: orthorhombic non-centrosymmetric P212121
space group (SI).
Prerequisite b: racemization methods for 1 and related structures
13]
are limited and require harsh conditions.[3,
Treatment with
potassium tert-butoxide (t-BuOK) has been reported to racemize
Praziquantel (1) and Praziquanamine (2). The reaction must be
run at -15 °C in an apolar solvent under anhydrous conditions.[13b]
A one-pot racemization of precursor 2 has been reported at
130 °C with palladium supported on carbon under H2
atmosphere.[3, 13a] Long reaction times (48 hours) as well as high
temperature and pressures are necessary.
Figure 3. Schematic illustration of the decoupled system for deracemization.
Attrition enhanced deracemization (Viedma ripening) was first
15]
attempted to promote deracemization.[6c,
Unfortunately, this
Prerequisite c: compatibility of prerequisites a and b, requires that
both crystallization and racemization occur simultaneously. The
was unsuccessful owing to the slow growth rate relative to the rate
of attrition that led to formation of extremely small and difficult to
filter crystals. These crossed the filter submerged into the slurry,
leading to a rise in pressure and clogging.
Alternatives to the attrition involved in Viedma ripening are
crystallization induced asymmetric transformation (CIAT)[16] and
temperature cycling-induced deracemization (TCID).[7a, 7d] Forced
attrition is no longer necessary and, as a result, larger crystals
form.
reported racemization conditions are incompatible with
crystallization process required for deracemization of 3u.
Nevertheless, reversible dehydrogenation-hydrogenation
a
racemization remains an attractive approach if it can be separated
from the crystallization.[13a] The reactivity of the hydrogen bound
to the stereogenic center in 1, 2 and 3u is increased by the
adjacent aryl group.[3,14] We found that compound 1 could be
racemized cleanly in a flow system over a packed bed reactor
filled with Pd supported on carbon, previously activated with H2 at
130 °C, with just 2 minutes of residence time in the packed bed
reactor (SI). Similar conditions were applied to 3u. Racemization
again proceeded cleanly (SI).
Toluene was first checked as solvent in
a single step
crystallization induced asymmetric transformation (CIAT) process.
Roughly 10% seed crystals of the (R)-enantiomer, compared to
the total amount of racemic 3u, were added to the saturated
solution, and the crystallization temperature was decreased from
15 to 5 °C over a 3 h period. In two CIAT experiments (R)-3u in
approximately 90% ee was harvested in 12% and 32% yields,
respectively, corrected for the seed mass used (entries 1 and 2,
Table 1). However, from the complete material balance in Table
1 it is clear that in entry 1 little, if any, deracemization occurred.
For entry 2, for which the ratio between the total volume of the
system and the dead volume of packed bed reactor (total
volume/dead volume ratio) was decreased (SI) significant
deracemization did occur. However, for both entries 1 and 2 the
mother liquors remained enriched in (S)-enantiomer (Table 1),
probably owing to over-hydrogenation of the catalyst, which
slowed the racemization rate.
Trace amounts of the putative achiral dehydro- intermediate 4
were observed during reaction (Scheme 2, SI). Intermediate 4
was isolated and identified. No other side products were detected.
Scheme 2. Liquid phase racemization in a loop through a flow system.
TCID mode is advantageous because multiple cycles may be
carried out with a single filtration in the end. Owing to solubility
considerations the solvent was changed to methanol (MeOH,
Figure S25, SI). Re-activation of the column was performed at the
The incompatibility issue was resolved with the decoupled flow
system shown schematically in Figure 3. The crystal
growth/dissolution process occurs in the crystallization unit, a
thermostated reactor, and the mother liquor is continuously
2
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10.1002/anie.202013502
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COMMUNICATION
start of every cooling ramp of each temperature cycle by
delivering hydrogen. After initial experimentation we found that if
short and frequent re-activation of the catalyst was not carried out,
the TCID stopped (Figure S9, SI), probably because of lack of
racemization in solution. Virtually complete conversion of the solid
phase to the (R)-enantiomer was achieved after 10 cycles in
about 18 h (Figure 4). The mother liquors were now racemic and
solid (R)-3u harvest was obtained in 98% ee. The recovery of
crystalline (R)-3u corrected for seed is 32% and the total amount
of (R) has increased by 31-32% (Table 1, entry 3). The
temperature cycling protocol closely resembles recently
published guidelines.[17] Deracemization occurs thus readily and
recharging with the mother liquor and fresh enriched (R)-solid
would allow continuity. From the results of entry 3 and 4 it is clear
that the process is reproducible. Recovered deracemized 3u
contained < 0.1 mg Pd per 1000 mg consistent with the absence
of significant leaching from the catalyst.
Enantiomerically pure (R)-3u was hydrolyzed in 92% yield to the
amine (R)-2 in a mixture of ethanol/aq HCl (1N) overnight. The
product was shown to be enantiomerically pure (SI) and was
acylated in near quantitative yield with cyclohexanecarbonyl
chloride to provide enantiomerically pure (R)-Praziquantel as
previously described.[2a]
Modern crystallization induced deracemization methods offer a
simple and efficient method to obtain chiral building blocks of
extremely high enantiomeric purity in virtually quantitative yield.
[19]
Most of these deracemization methods using conglomerate-
based technologies are restricted to cases where racemization
and crystallization occur under mutually compatible conditions in
a single reactor. Recently reported two-flasks combination of
preferential crystallization with “ex-situ” racemization enabled
deracemization of a drug precursor Mefloquine.[20] Racemization
methods compatible with crystallization have remained limited:
base-catalyzed racemization remains the most commonly used
21]
for deracemization,[11b-d,
although application of photo-
chemically and redox induced variants have been reported.[22]
Consequently, the essential requirement to combine racemization
and conglomerate crystallization under mutually compatible
conditions has greatly limited the application potential.
Our flow system approach opens up exciting opportunities for
coupling crystallizations with other hitherto incompatible
racemization reactions to develop new deracemization methods
that were previously impossible.
100
75
50
25
0
20
15
10
5
T, [°C]
ee, [%]
Acknowledgements
0
0
250
500
750
1000
Merck KGaA provided racemic and enantiopure 1 and 2 and Dr
David Maillard (Merck) is thanked for advices. We are grateful to
Prof Wesley Browne (Univ. Groningen) and Kees van der Loo
(Syncom) for fruitful discussions and aid.
t, [min]
Figure 4. Evolution of the solid phase ee in (R)-3u at the end of cooling ramps
as function of time. The gray segment represents the variation of temperature
as function of time. Triangle represents the sample withdrawn at 5 °C, squares
represent samples withdrawn at 5 °C.
Deposition
numbers
1997311-1997314
contain
the
supplementary crystallographic data for this paper. These data
are provided free of charge by the Cambridge Crystallographic
Data Centre and Fachinformationszentrum Karlsruhe Access
Structures service www.ccdc.cam.ac.uk/structures.
Table 1. Results from the deracemization experiments.[18]
Exp
Starting
conditions
Filtrate[a]
Isolated
solid
Enrichment[e]
%
This research received funding as part of the CORE project
(October 2016-September 2020) from the European Union
Horizon 2020 Research and Innovation Program under the Marie
Sklodowska-Curie grant arrangement No 722456 CORE ITN.
Overall
ee %
(R)
Remaining
in
solution %
ee %
(S)
Yield
ee %
(R)
[b]
%
1[c]
2[c]
3[d]
4[d]
8.9
7.3
79
61
58
57
11
6
21
(12)
89
+2
Keywords: Racemization • Chirality • Flow chemistry •
Heterogeneous catalysis • Schistosomiasis
39
(32)
92
97
98
+24
+31
+32
9.6
0
42
(32)
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COMMUNICATION
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4
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Entry for the Table of Contents
DRUGS "R" US.
The (R) enantiomer of Praziquantel is more active against Schistosomiasis (Bilharzia, snail fever). The cheaper, commonly used,
racemate can be deracemized via a conglomerate derivative to this enantiomer, which is obtained in 98% ee using a flow system in
which Pd catalyzed high temperature racemization is coupled to low temperature cycled crystallization. Broad applicability of this
deracemization approach should be possible.
5
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