University of Groningen
Scaling Up Attrition-Enhanced Deracemization by Use of an Industrial Bead Mill in a Route to
Clopidogrel (Plavix)
Noorduin, W.L.; Asdonk, P. van der; Bode, A.A.C.; Meekes, H.; Enckevort, W.J.P. van; Vlieg,
E.; Kaptein, B.; Meijden, M.W. van der; Kellogg, R.M.; Deroover, G.
Published in:
Organic Process Research & Development
DOI:
10.1021/op1001116
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Noorduin, W. L., Asdonk, P. V. D., Bode, A. A. C., Meekes, H., Enckevort, W. J. P. V., Vlieg, E., Kaptein,
B., Meijden, M. W. V. D., Kellogg, R. M., & Deroover, G. (2010). Scaling Up Attrition-Enhanced
Deracemization by Use of an Industrial Bead Mill in a Route to Clopidogrel (Plavix). Organic Process
Research & Development, 14(4), 908-911. https://doi.org/10.1021/op1001116
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Scaling Up Attrition-Enhanced Deracemization by Use of an Industrial Bead Mill in a
Route to Clopidogrel (Plavix)
W. L. Noorduin,†,¶ P. van der Asdonk,† A. A. C. Bode,† H. Meekes,*,† W. J. P. van Enckevort,† E. Vlieg,*,† B. Kaptein,‡
M. W. van der Meijden,§
R. M. Kellogg,§
and G. Deroover⊥
Radboud UniVersity Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, the Netherlands,
DSM InnoVatiVe Synthesis BV, PO Box 18, 6160 MD Geleen, the Netherlands, Syncom BV, Kadijk 3,
9747 AT Groningen, the Netherlands, and Agfa-GeVaert N.V., Septestraat 27, B-2640 Mortsel, Belgium
Abstract:
The recently discovered technique of deracemization by means of
grinding a racemic conglomerate in contact with a solution wherein
racemization occurs has been scaled up using an industrial bead
mill to demonstrate the practical applicability. The time needed
to reach the enantiopure end state is drastically reduced as a result
of the efficient grinding that can be achieved using bead mills.
Recently, a remarkably simple way to transform racemic
mixtures of conglomerates into an enantiomerically pure
crystalline phase was discovered.1-11
The process involves
subjection of the crystals in a slurry to continuous grinding under
conditions whereby racemization in solution takes place. The
practical execution is very easy and offers an attractive route
to enantiomerically pure compounds including those of interest
for the production of pharmaceuticals. Although this deracemization
process has been explored for various racemizable
conglomerates, thereby confirming its general applicability, so
far most of the experiments as described above have been
conducted with no more than 8-20 mL total volumes. To
demonstrate the practical value of this method, scale-up is
therefore a key requirement. Here, we show that by employment
of industrial mills attrition-enhanced deracemizations can be
scaled up readily with dramatically shorter times needed to reach
the enantiopure end state.
In general, scale-up of chemical processes from the small
amounts of material and volumes that are used in the initial
stages of research to the large volumes that are required for
commercially beneficial processes is not straightforward.12,13
Mixing properties and heat control are notoriously troublesome
parameters in scale-up of chemical processes, although there
are also advantages in increasing the size of reaction systems.13
For the deracemization process, we were particularly interested
in the high abrasion that can be achieved in large-scale bead
mills (or bead mill reactors), since we know from previous
results that the intensity of the abrasive grinding of the crystals
is a crucial factor in the time it takes to transform all the solid
material of an almost racemic solid phase into the enantiomerically
pure form.3
The grinding causes the ablation of small
fragments from the crystals. According to the Gibbs-Thomson
effect the smaller crystals have a higher solubility than the larger
crystals.14
As a result the smaller crystals dissolve, thereby
nurturing the larger crystals, a process called Ostwald ripening.15
However, the incorporation of molecules alone is not sufficient
to explain the asymmetric transformation during grinding.
Uwaha already postulated that the reincorporation of subcritical
clusters in the crystals of the same handedness might be
crucial.16 The cluster reincorporation results in an experimentally
measurable accumulation in the solution of the enantiomer that
forms the minor population in the solid phase.17
The solution
phase racemization reaction erodes this solution phase enantiomeric
excess, resulting in a net flux of molecules from crystals
of the minor handedness towards crystals of the major one. The
rate at which the initially enriched solid phase enantiomeric
excess, ee(0), increases as a function of the time t is determined
by the rate constant k, according to the relation:3,18
* Authors to whom correspondence may be sent. E-mail: hugo.meekes@
science.ru.nl; e.vlieg@science.ru.nl.
† Radboud University.
‡ DSM Innovative Synthesis BV.
§ Syncom BV.
⊥ Agfa-Gevaert N.V.
¶ Present address: School of Engineering and Applied Sciences, Harvard
University, Cambridge, MA, U.S.A.
(1) (a) Viedma, C. Phys. ReV. Lett. 2005, 94, 065504. (b) Viedma, C.
Astrobiology 2007, 7, 312.
(2) Noorduin, W. L.; Izumi, T.; Millemaggi, A.; Leeman, M.; Meekes,
H.; van Enckevort, W. J. P.; Kellogg, R. M.; Kaptein, B.; Vlieg, E.;
Blackmond, D. G. J. Am. Chem. Soc. 2008, 130, 1158.
(3) Noorduin, W. L.; Meekes, H.; van Enckevort, W. J. P.; Millemaggi,
A.; Leeman, M.; Kaptein, B.; Kellogg, R. M.; Vlieg, E. Angew. Chem.,
Int. Ed. 2008, 47, 6445.
(4) Kaptein, B.; Noorduin, W. L.; Meekes, H.; van Enckevort, W. J. P.;
Kellogg, R. M.; Vlieg, E. Angew. Chem., Int. Ed. 2008, 47, 7226.
(5) Viedma, C.; Ortiz, J. E.; de Torres, T.; Izumi, T.; Blackmond, D. G.
J. Am. Chem. Soc. 2008, 130, 15274.
(6) Tsogoeva, S. B.; Wei, S.; Freund, M.; Mauksch, M. Angew. Chem.,
Int. Ed. 2009, 48, 590.
(7) Noorduin, W. L.; Kaptein, B.; Meekes, H.; van Enckevort, W. J. P.;
Kellogg, R. M.; Vlieg, E. Angew. Chem., Int. Ed. 2009, 48, 4581.
(8) Noorduin, W. L.; Vlieg, E.; Kellogg, R. M.; Kaptein, B. Angew. Chem.,
Int. Ed. 2009, 48, 9600.
(9) van der Meijden, M. W.; Leeman, M.; Gelens, E.; Noorduin, W. L.;
Meekes, H.; van Enckevort, W. J. P.; Kaptein, B.; Vlieg, E.; Kellogg,
R. M. Org. Process Res. DeV. 2009, 13, 1195.
(10) Noorduin, W. L.; Bode, A. A. C.; van der Meijden, M.; Meekes, H.;
van Etteger, A. F.; van Enckevort, W. J. P.; Christianen, P. C. M.;
Kaptein, B.; Kellogg, R. M.; Rasing, T.; Vlieg, E. Nat. Chem. 2009,
1, 729.
(11) Noorduin, W. L.; Meekes, H.; van Enckevort, W. J. P.; Kaptein, B.;
Kellogg, R. M.; Vlieg, E. Angew. Chem., Int. Ed. 2010, 49, 2539.
(12) Sharrett, P. N. Handbook of Batch Process Design; Blackie/Chapman
and Hall: London, 1997.
(13) Hoyle, W. Pilot Plants and Scale-up of Chemical Processes; Royal
Society of Chemistry: London, 1999; Vol. 2, pp 40-61.
(14) Gibbs, J. W.; The Collected Works of J. Willard Gibbs: in Two
Volumes; Yale University Press: New Haven, CT, U.S.A., 1948; Vol.
I - Thermodynamics.
(15) Ostwald, W. Z. Phys. Chem. 1900, 34, 495.
(16) Uwaha, M. J. Phys. Soc. Jpn. 2004, 73, 2601.
(17) Noorduin, W. L.; van Enckevort, W. J. P.; Meekes, H.; Kaptein, B.;
Kellogg, R. M.; Tully, J. C.; McBride, J. M.; Vlieg, E. Submitted.
Organic Process Research & Development 2010, 14, 908–911
908 • Vol. 14, No. 4, 2010 / Organic Process Research & Development 10.1021/op1001116  2010 American Chemical Society
Published on Web 06/22/2010
The rate constant k is strongly dependent on the attrition
intensity.3
A search for methods for more efficient attrition
brought us to the pigment and coating industries, which have
long experience in the grinding of solids, both on small and
large scale.19
One of the devices that is often used for this
purpose is a so-called bead mill (see Figure 1). The high number
of revolutions per minute (up to 4000 rpm) in combination with
very hard yttrium-stabilized ZrO2 beads should allow more
intense grinding.
To demonstrate the practical importance we turned to
compound 1, recently used by us as an intermediate in a total
resolution process towards clopidogrel by preferential crystallization
under deracemization conditions.9
The blockbuster drug
(S)-clopidogrel (Plavix, Figure 2) was developed and commercialized
by Sanofi-Aventis for the treatment of cardiovascular
diseases and launched in 1993.20
The intermediate
compound 1 is a racemic conglomerate and can be readily
racemized in solution with the organic base diaza(1,3)bicyclo[5.4.0]undecane
(DBU). It is interesting to compare the deracemization
rates between the ‘standard’ small-scale experimental
procedure and the process using the bead mill. For the smallscale
experiment, to a 12-mL reaction vial were added 8.0 g of
glass beads (2.5 mm diameter), 0.3 g of (RS)-1, and 4.7 g of
acetonitrile (MeCN). This solution/solid mixture was ground
in an ultrasonic cleaning bath thermostatted at 23 °C. After 10
min of intense grinding, 0.1 g of the solution-phase racemization
catalyst DBU was added. The progression of the solid-phase
enantiomeric excess (ee) was followed by filtering samples
taken from the slurry and analyzing the composition of the solid
phase using chiral HPLC. As can be observed in Figure 3,
within 6 h the solid phase deracemizes to an enantiomerically
pure state.
For the milling experiments a Netzsch MINICER bead mill
(110 mL free volume) filled with 0.4-mm-diameter yttriumstabilized
ZrO2 beads (660 g) was used. The setup is shown in
Figure 1. We start with a small ee in order to have a rapid
conversion that still allows an accurate determination of the rate.
To overcome blocking of the mill by large crystals, a slurry
was first prepared by partially dissolving 20 g (RS)-1 and 2 g
of (S)-1 in 320 mL of MeCN in a separate reaction vessel. This
mixture was vigorously stirred for 20 min and then poured in
the bead mill that already contained 110 mL of MeCN. After
5 min of grinding at 2000 rpm, 5 g of DBU was added to initiate
the solution-phase racemization. To follow the process, we
continuously sampled the solid phase. As can be seen from
Figure 3, within 45 min the racemate is completely converted
into the desired (S)-1 enantiomer.
To compare quantitatively the deracemizations in the ultrasonic
cleaning bath and in the bead mill, the rate constants for
the process were calculated using eq 1. As can be seen from
Table 1, the deracemization process is approximately 6-7 times
faster in the bead mill compared to that in the ultrasonic cleaning
bath. However, we should realize that in the bead mill the slurry
is continuously circulated through the system and, hence, spends
only a fraction of the time in the milling chamber (110 mL
free volume) where it is subjected to grinding. If we take the
total solution volume (430 mL) and the free volume in the mill
into account (110 mL), the difference in the rates is even more
pronounced. Ignoring further effects of the differences in volume
of the setup, the overall deracemization rate of the bead mill is
more than 25 times faster as compared to the rate for
deracemizations performed in the ultrasonic cleaning bath.
The acceleration of the deracemization is attributed to the
efficient grinding that can be achieved using the bead mill. To
investigate this effect further we varied the stirring rate in the
bead mill, keeping all other conditions constant. Surprisingly,
the rate of the deracemization scarcely increases between 1000
and 2000 rpm and even decreases going to the highest stirring
rate of 3000 rpm (Table 1). This may be attributed to increasing
damage to the crystal packing at these high stirring rates,
resulting in the formation of a substantial amount of amorphous
material, a phenomenon well-known for these industrial mills.21
The formation of amorphous material is indeed observed in the
background of the X-ray powder diffraction patterns (Figure
4). The amorphous surfaces may slow down the deracemization
since the enantioselective crystal growth by Ostwald ripening
is expected to be hampered. An additional effect of the increase
of the grinding intensity may be that the formation of clusters
that dissolve in monomers will start to dominate over the
reincorporation of clusters back into the crystal, thereby
decreasing the overall deracemization rate.
Thus far, most deracemizations have been performed on a
10-mL scale in a single vessel. However, we have previously
described an alternative manner to deracemize larger volumes.
A clear homogeneous solution in which racemization of 1 takes
place is cooled with grinding. The mechanism of deracemization
(18) Noorduin, W. L.; Meekes, H.; Bode, A. A. C.; van Enckevort, W. J. P.;
Kaptein, B.; Kellogg, R. M.; Vlieg, E. Cryst. Growth Des. 2008, 8,
1675–1681.
(19) Breitung-Faes, S.; Kwade, A. Chem. Ing. Technik 2007, 79, 241.
(20) Herbert, J. M.; Frehel, D.; Bernat, A.; Badorc, A.; Savi, P.; Delebassee,
D.; Kieffer, G.; Defreyn, G.; Maffrand, J. P. Drugs Future 1993, 18,
107.
(21) Ksiazek, K.; Wacke, S.; Go´recki1, T.; Go´recki, Cz. J. Phys. Conf.
Ser. 2007, 79, 012022.
ee(t) ) ee(0) exp(kt) (1)
Figure 1. Schematic drawing of the deracemization setup. A
slurry containing a mixture of (R)- and (S)-1 crystals is
circulated through the bead mill. As a result of the vigorous
grinding in the mill, in combination with the cyclic process, in
the end all crystals are converted into a single enantiomer via
the solution-phase racemization reaction.
Vol. 14, No. 4, 2010 / Organic Process Research & Development • 909
is analogous to that described for NaClO3.22,23
The solution may
be seeded during the cooling process with crystals of the desired
handedness. In this way it took about 17 h to reach complete
deracemization of 35 g of 1 in a volume of 315 mL.9
Here we
demonstrate that the severe grinding achieved in an industrial
mill can be employed to drastically reduce the deracemization
time, even at constant temperature. Moreover, we show that
the transformation is still effective when the slurry is pumped
through a network of tubes. This should also allow one to pump
the slurry through a cascade of mills and to use a backfeed of
enriched material. As the enantiomeric enrichment follows an
exponential law, the rate is slowest at the onset of the process.
Therefore, it may be attractive to remain in the steep part of
the exponential increase of the ee. To achieve this one can, for
instance, envision a setup with a partial backfeed, such that
enantiomerically highly enriched crystals are used to enrich the
racemic starting material, thus avoiding the slow onset. Recently,
we demonstrated that the racemization reaction for the grinding
process need not be performed in the presence of the crystals.17
Since one can now pump the slurry through a network, this
might allow one to use different racemization conditions (such
as high temperatures, which would dissolve the crystals) or to
use enzymes (which cannot be used in combination with severe
grinding). For instance, this may be implemented by using two
containers (one with crystals that are ground and one container
in which the racemization takes place) that are separated by a
semipermeable membrane that only allows solute molecules to
pass.
In summary, these results demonstrate that scaling up of the
grinding of a slurry of racemic conglomerate crystals with low
enantiomeric excess under racemizing conditions as a route to
(22) Kondepudi, D. K.; Kaufman, R. J.; Singh, N. Science 1990, 250, 975.
(23) McBride, J. M.; Carter, R. L. Angew. Chem., Int. Ed. 1991, 30, 293.
Figure 2. Chemical and physical equilibria during the attrition-enhanced asymmetric transformation of 1.
Figure 3. Progression of the enantiomeric excess in the solid phase during the grinding-induced transformation on a 10-mL
scale using a thermostatted ultrasonic cleaning bath (open symbols) and on a 400-mL scale using the bead mill (closed symbols).
The straight lines are a fit of the data to eq 1. The right graph shows the increase of the chiral purity in the solids of the latter
experiment (blue (S)-1, red (R)-1). The initial ee values after dissolution were 3.40% for the ultrasonic and 5.96% in the
beadmill experiment.
Table 1. Deracemization rates in the various experiments
experiment grinding process rpm
k
(min-1
)
overall k
(min-1
)a
1 ultrasonic bath (10 mL) - 0.012 0.01
2 bead mill (400 mL) 1000 0.076 0.30
3 bead mill (400 mL) 2000 0.080 0.31
4 bead mill (400 mL) 2500 0.081 0.32
5 bead mill (400 mL) 3000 0.069 0.27
a
Final column lists the overall k value that corrects for the fraction of the time
that the slurry is actually ground by the beads, ignoring further effects of the
differences in volumes of the setups.
Figure 4. X-ray powder diffraction patterns of the solids
collected after 20 min of grinding at various stirring rates
(expressed in units of rpm in the inset/legend). The patterns
show a trend of increasing background intensity, indicating the
formation of amorphous material at higher stirring rates.
910 • Vol. 14, No. 4, 2010 / Organic Process Research & Development
enantiomerically pure compounds is possible. Furthermore, we
observe that this route becomes even more efficient on a larger
scale. Using the efficient grinding that can be achieved with an
industrial bead mill, we have explored the limits of the rate at
which this process can be performed.
Experimental Section
Determination of the ee by Chiral HPLC Analysis of the
Solids Samples. Sample preparation 0.5 mg solid in 1.5 mL
of eluent, injection volume 20 µL, HPLC column Chiralpak
AD-H (250 mm × 4.6 mm ID), eluent n-hexane/2-propanol,
85:15 v/v%, flow 1 mL/min, r.t., detection λ ) 254 nm.
Retention times (S)-1 9.3 min, (R)-1 10.5 min.
Acknowledgment
We kindly acknowledge Ivan Vanderhaeghe, Sonny Wynants
and Liesbeth Vranckx (AGFA-Gevaert NV) for their assistance
during the bead mill experiments. The SNN agency (Cooperation
Northern Netherlands) and the European Fund for Regional
Development (EFRO) are acknowledged for partial financial
support of this work. The group from Radboud University
Nijmegen thanks COST Action CM0703 for support.
Received for review April 20, 2010.
OP1001116
Vol. 14, No. 4, 2010 / Organic Process Research & Development • 911