University of Groningen Conglomerates surface in new ...
Transcript of University of Groningen Conglomerates surface in new ...
University of Groningen
Conglomerates surface in new resolution strategiesvan der Meijden, Maarten Willem
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.
Document VersionPublisher's PDF, also known as Version of record
Publication date:2012
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):van der Meijden, M. W. (2012). Conglomerates surface in new resolution strategies. s.n.
CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.
Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.
Download date: 13-10-2021
31
Chapter 2 Deracemization – from academic
novelty to practical application
Making use of conglomerate behavior
In this chapter, the theory of deracemization by abrasive grinding is described and the application
of the technique in the synthesis of Clopidogrel.
Part of this work has been published in:
M.W. van der Meijden, M. Leeman, E. Gelens, W.L. Noorduin, H. Meekes, W.J. P. van Enckevort, B.
Kaptein, E. Vlieg, and R.M. Kellogg, Org. Proc. Res. & Dev., 2009, 13, 1195-1198
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, G. Deroover, Org. Proc. Res. & Dev., 2010, 14, 908-
911
CHAPTER 2
32
2.1 Introduction
The racemates (50:50 mixtures of enantiomers) of crystalline organic compounds are found as
racemic compounds, conglomerates or solid solutions. This is illustrated in cartoon fashion in
figure 1.
Figure 1: possible solid states of enantiomers (picture courtesy of M. Leeman (PhD thesis))
Conglomerates
The International Union of Pure and Applied Chemistry, (IUPAC) defines a conglomerate as: “An
equimolar mechanical mixture of crystals each one of which contains only one of the two
enantiomers present in a racemate1”. This means that the enantiomers crystallize separately as
separate phases from each other. In principle they can be separated by crystal picking as in the
pioneering experiment by Louis Pasteur with a salt of tartaric acid. Conglomerates account for ca
5-10% of all crystalline racemates2 (although on surfaces this number seems to be much higher3).
Deracemization – from academic novelty to practical application
33
Racemic compounds
Racemic compounds crystallize as pairs of enantiomers and behave as a single phase. They cannot
be separated without a chirality breaking operation. Most crystalline racemates (90-95%) are
racemic compounds2.
Solid solution
In a solid solution the enantiomers are ordered randomly.
2.2 Background
2.2.1 Resolutions and deracemizations
The separation of enantiomers is called a resolution. As mentioned, in the case of a conglomerate
this can be done in principle by manually separating the crystals with, for instance, a pair of
tweezers (crystal picking) or, more conveniently, by crystallization (entrainment)4. In the case of a
racemic mixture, this is not possible, since in each crystal, the enantiomers are paired. In this case
the separation (resolution) is performed by intervention of a single enantiomer used for
derivatization, formation of a complex with a chiral molecule, or most frequently as the formation
of a diastereomeric salt. In this case the racemate is treated with an enantiopure acid or base to
form a diastereomeric salt. In contrast to the enantiomers of the regular racemate, in the case of
diastereomers, the physical properties are different. In principle, the diastereomers can now be
separated by their difference in solubility using crystallization.
The main disadvantage of resolutions by diastereomeric salt formation is the fact that a 50% yield
at a maximum is obtained unless there is a racemization step in the process, in which case one
has a dynamic absolute resolution. The case where one has a conglomerate becomes especially
interesting. If combined with an in solution racemization, in theory a maximum of 100% yield and
100% enantiomeric purity could be obtained, starting from racemic material without the help of a
chiral auxiliary group.
An example where this combination was used was first described by Havinga5,6. He showed that
upon slow cooling of a supersaturated hot solution of methyl-ethyl-vinylanilinium iodide over
several weeks a suspension of an enantiomerically pure solid was obtained.
CHAPTER 2
34
NI
3
N
+ I
1 2
Figure 2: methyl-ethyl-vinylanilinium iodide
Since compound 3, a conglomerate, slowly racemizes in solution by means of a reversible SN2
reaction, the balance can be tipped completely in favor of only one enantiomer. In this case a
dynamic process of crystal dissolution and crystal growth takes place. The first primary nucleation
event will generate a crystal of single chirality. Secondary nucleation from the crystal propagates
this chirality. Large crystals will grow at the expense of smaller ones, which are more soluble
(Gibbs-Thompson rule7,8) This process is called Ostwald ripening9. Another driving force is that, for
conglomerates, the solubility of the racemate is usually double that of the enantiomerically pure
compound. This so-called “Meyerhoffer double solubility rule” also holds for conglomerates
under racemizing conditions as has been shown recently10. As predicted by Frank11 once the
balance is tipped, and provided amplification is possible, it will move towards one of both
enantiomers (although the time frame may be indefinite).
Although the scale was small (1 mmol) Havinga unambiguously showed that this technique led to
a spontaneous resolution. Equally striking as the results was Havinga’s understanding of how this
process worked! He also briefly mentioned a possible relation between his discovery and the
origin of chirality, a topic which would also find huge interest in the scientific community over the
time to come. Havinga realized that the process should be stochastic; the chance of formation of
either enantiomer was equal.
Almost 50 years later Kondipudi et al.12 investigated the crystallization of NaClO3. Although this
compound is achiral, it crystallizes as cubic crystals in chiral space-group (P21313) and is therefore
a conglomerate. As soon as the crystals dissolve, they lose the chirality (a process that has been
referred to as “chiral amnesia”14) Primary nucleation leads to a crystal of one or the other chirality
(see figure 3). Dissolving NaClO3 in water and then slowly evaporating the water to achieve
supersaturation while stirring at ~100 rpm led to complete deracemization of the material.
Interestingly, without stirring a statistical mixture of crystals of opposite handedness are formed.
Deracemization – from academic novelty to practical application
35
Figure 3: suspension of an achiral compound that crystallizes as mirror images (picture courtesy of
M. Leeman (PhD thesis))
This experiment was again performed, but in a different way, by Viedma15. Viedma did not start
from a (supersaturated) solution of NaClO3, but from a suspension. The suspension was “ground
towards one enantiomer”. The system is nearly at equilibrium rather than “far from equilibrium”,
the situation that pertains at supersaturation. He found that stirring the suspension for several
days did not change the balance between the two enantiomers, and therefore the suspension
remained racemic. However when he started to perform the deracemization by attrition (grinding
with glass- or ceramic beads) the suspension was deracemized completely within 24 h. He also
showed that the rate of deracemization was dependent on the amount and size of the glass beads
and of the rate of stirring. This was later confirmed by the group of Cheung16 who performed
similar experiments on ethylenediammonium sulfate, another achiral compound that crystallizes
as a conglomerate. The clear advantage is that this method is faster and can be performed at
higher concentrations than the previous techniques.
The examples done previously were performed on inorganic compounds or salts of simple organic
molecules. The question was if this technique can be applied to more complex systems of
pharmaceutical interest. The requirements for the technique were already described by Havinga
in 1941:
“1. With crystallization, separate l- and d-crystals are formed, therefore not a racemic compound
or mixed crystals…
2. The compound shows in solution the phenomenon of racemization, for example due to the
presence of a catalyst which can drastically improve the rate of the transition l ↔ d
CHAPTER 2
36
3. The speed with which the crystal seeds are formed in solution is small, the speed of growth of
the crystals and the speed of racemization is high.”20
Upon discussing the Viedma results, a consortium of the Radboud University Nijmegen, Imperial
College London, DSM and Syncom BV decided to test this method for amino acid derivatives that
complied to the requisites as described above. They chose the Schiff bases of phenylglycineamide.
This compound met the criteria postulated by Havinga: it is a crystalline solid (unlike the ester
derivative). Due to the low pKa, the compound is easily racemized using a strong organic base like
DBU and the chosen compound 4 is a conglomerate. Furthermore, it’s easy to prepare. After
searching for a conglomerate (the screening of which is described in this chapter) it was found
that (E)-2-(2-methylbenzylideneamino)-2-phenylacetamide 4 is indeed a conglomerate and is
easily racemized.
NNH2
O
4
Figure 4: (E)-2-(2-methylbenzylideneamino)-2-phenylacetamide
This compound was subjected to conditions similar to those described by Viedma and this
resulted in complete deracemization.17,18,19. The striking feature in this step was that it was
completely non-stochastic towards the (R)-enantiomer in three different labs. The bias could be
circumvented by addition of a (tailor made) additive20. Irradiation with circularly polarized light
(CPL) followed by grinding, also leads to deracemization.21 In the latter case, irradiation of the
Schiff base with CPL is sufficient to direct the outcome of the reaction.
2.2.2 Theory with deracemization
The thermodynamics of the deracemization are in part the same as for the Havinga system
mentioned in chapter 2.2.1. However, in the method used for the deracemization of imine 4, a
suspension of a conglomerate is stirred using grinding, while racemization takes place in solution.
The method uses glass beads to grind the crystals and to keep the particle size small. Since the
solid state of both enantiomers is in equilibrium with their dissolved form and the enantiomers
Deracemization – from academic novelty to practical application
37
are in turn racemized and therefore in equilibrium with each other in solution, the system as a
whole is in equilibrium. This means that the previously mentioned Meyerhoffer double solubility
rules also applies here10.
Figure 5: Suspension of a chiral conglomerate, racemizing in the liquid phase (Picture courtesy of
M. Leeman (PhD thesis)
If an imbalance is formed or is introduced, the system can be pushed to a single enantiomer. This
imbalance can be a result of a natural chiral impurity or by seeding with either one of the
enantiomers, or by a (tailor made) additive which can inhibit the nucleation of one of the
enantiomers. The Eve-crystal (first crystal), from the first nucleation event, must provide one or
the other chirality. This crystal is subsequently ground into large amounts of smaller crystals,
which can act as seeds for secondary nucleation.22 A contributing factor may be that as the
growth of the initial enantiomer proceeds, the solution will be depleted of material, lowering the
concentration, and thereby lowering the rate of nucleation to almost zero5,6,12.
CHAPTER 2
38
Figure 6: schematic depiction of attrition enhanced deracemization (picture courtesy of Michel
Leeman (PhD.).
In contrast to the Havinga experiment, the deracemization in this system is further enhanced by a
process called Ostwald ripening. The definition of Ostwald ripening is “Dissolution of small crystals
or sol particles and the redeposition of the dissolved species on the surfaces of larger crystals or
sol particles. The process occurs because smaller particles have a higher surface energy, hence
higher total Gibbs energy, than larger particles, giving rise to an apparent higher solubility.”23 An
everyday example of Ostwald ripening is the change of texture in old ice cream to more gritty and
coarse.24 In the case of the deracemizations, this will mean that if the “undesired” enantiomer
crystallizes in a suspension of predominantly the other enantiomer, this compound will re-
dissolve and instead grow on the larger crystals already present. The constant grinding will
enlarge the total surface and will create new nuclei on which growth make take place.
Deracemization – from academic novelty to practical application
39
2.3 Clopidogrel
2.3.1 Background and introduction
We desired to show the power and applicability of the new grinding method by using this method
in the synthesis of a blockbuster drug. As a target, we chose Clopidogrel (Plavix)
N
S Cl
OO
Figure 7: Clopidogrel (Plavix)
Clopidogrel (Plavix) is a platelet aggregation inhibitor used for reducing ischemic strokes, heart
attacks and in atherosclerosis and for the prevention of thrombosis after placement of
intracoronary stent. The compound is marketed by Bristol-Myers Squibb and Sanofi-Aventis under
the trade name Plavix, by Sun Pharmaceuticals under the trade name Clopilet, by Ranbaxy
Laboratories under the trade name Ceruvin, and under the name "Clavix" by Intas
Pharmaceuticals. The sales of Plavix were $5.9 billion in 2005 and in 2007 sales were $7.3 billion, a
growth of 20.5%.25
The patent procedures use resolution of the final product Clopidogrel with camphor sulfonic
acid26, or resolution of the intermediate 2-chlorophenylglycine ester with tartaric acid.27 In both
cases racemization can be used to recycle the undesired enantiomer.
The route we envisaged does not require the use of a resolving agent and has a dynamic
resolution step incorporated in the deracemization process. The approach described in this
chapter can be generally used for the deracemization of amino acid derivatives.
CHAPTER 2
40
Scheme 1: retrosynthetic route towards Clopidogrel (5)
On examination of the structure of Clopidogrel, we could envisage this compound being built up
from ester (S)-6. This ester can be obtained from amide (S)-7. These phenylglycine amide
derivatives have been used previously (vide supra) by us to prepare Schiff bases as 8. These
compounds meet all our requirements for deracemization: they are crystalline and easily
racemized. The final requirement is that the compound needs to be a conglomerate.
2.3.2 Synthesis of and screening of a suitable conglomerate
We used this strategy to prepare Clopidogrel. Commercially available 2-chlorophenylglycine 9 was
esterified using SOCl2 and MeOH. In the next step, ester 6.HCl was converted to the amide using
concentrated aqueous ammonia. From the resulting amide 7, the Schiff bases were prepared
using aromatic aldehydes and Na2SO4 as dehydrating agent.
H2N
Cl
OH
O
ClH.H2N
Cl
O
O
SOCl2MeOH
95%H2N
Cl
NH2
O
NH4OH
81%
RCHO
Na2SO4
N
Cl
NH2
OR
879 6.HCl
Scheme 2: synthesis of imine 8.
As already explained, for the deracemization to work, the imine needs to be a conglomerate. The
downside is that a reliable method to design conglomerates is not yet available; therefore we
needed to find a fast method of screening for conglomerates. Our approach was twofold: we used
Second Harmonics Generation (SHG) as well as small scale deracemization experiments. As stated
Deracemization – from academic novelty to practical application
41
above, ca 5-10% of all racemates crystallize as conglomerates. We therefore made a small library
of compounds and screened them. The results are summarized in table 1.
Entry R = SHG[a] e.e. in first test
1 Ph Large SHG effect 33% 2 2-tolyl No SHG effect 0% 3 2-chlorophenyl Large SHG effect 0% 4 2-bromophenyl Large SHG effect 0% 5 2-nitrophenyl Small SHG effect [b] 6 2-benzyloxyphenyl No SHG effect 0% 7 1-naphthyl Small SHG effect 0% 8 2-pyridyl Small SHG effect [b] 9 2,5-difluorophenyl No SHG effect [b] 10 2,5-dihydroxyphenyl [b] [b]
[a] Second Harmonics Generation [b] not enough pure material
Table 1: Analysis of Schiff bases
The first series of Schiff bases contained three possible conglomerates according to SHG-analysis.
However, upon testing the compounds in deracemisation experiments, only one provided any e.e.
The failure of the other two may be due to too fast crystallization. Further investigation has not
been carried out. However, the result with benzaldehyde imine (entry 1) was promising, since it is
the cheapest of all tested aldehydes and it already gave 33% e.e. in the first test. The combination
of positive SHG result and some ee in the deracemization indicated that the compound is indeed a
conglomerate (a fact which was confirmed by X-ray analysis).
For the deracemization, in general two techniques can be used. The first is the method as used by
Viedma and Noorduin. In this method the racemic suspension is in contact with a strong base and
is ground with glass beads, and optionally sonication. At room temperature deracemization takes
24 h to several days.
The second method is the Havinga-Kondipudi-Leeman approach in which a suspension of the
racemate is in contact with a strong base and is heated until complete dissolution. The mixture is
then slowly cooled with temperature programming to room temperature whilegrinding with glass
beads. The first crystal (Eve-crystal) is then ground to form many nuclei, all of the same
handedness. This prevents primary nucleation and favors secondary nucleation. The cooling
makes sure that the saturation level is kept constant and the nuclei present ensure that only one
handedness is obtained. Ostwald ripening corrects the occasional other handedness which is
probably also formed in small amounts. This results in complete deracemization in several hours
to overnight (see figure 6).
CHAPTER 2
42
2.3.3. Comparison of the two methods for attrition enhanced deracemization
The advantage of Viedma/Noorduin method is that it is isothermal and therefore does not need
heating or cooling programs. One of the disadvantages, however, is that it is fairly slow and
therefore the practical (industrial) application might be limited. This was recognized by Leeman et
al. at Syncom and he therefore designed an adaption of the methods by Havinga and Kondipudi,
as described above.28
We used the Havinga-Kondipudi-Leeman approach for our imine deracemization. The mixture was
heated with DBU as racemizing agent until complete dissolution at 70°C and then slowly cooled
with a cooling rate of 0.1 deg./min while stirring vigourously with glass beads. This resulted in ca.
93% e.e. overnight and >98% e.e. after stirring for an additional day. This result was obtained
without seeding or addition of a nucleation inhibitor. The method provided either enantiomer,
depending on the sign of the seed. Using seeding, an e.e. of >99.5% with a yield of 80% was
obtained overnight. The imine appears to show non-stochastic behavior, which was especially
evident in grinding experiments at room temperature. Under these conditions, all 5 tests gave
only the (S)-enantiomer. However, when using the Havinga-Kondipudi-Leeman approach, in one
case also the (R)-enantiomer was found. Non-stochastic type of behavior has been reported
previously5,6 and might be explained by minute chiral contaminants that act as a nucleation
inhibitor. It was already shown29 that the manner in which the deracemization is performed can
influence the outcome of the chirality. Strangely, in the case of imine 4, non-stochastic behavior
leads to the sole formation of the (R)-enantiomer.
For the synthesis of Clopidogrel we needed to convert the deracemized Schiff base (S)-8a into the
corresponding amino ester 6. First direct conversion with H2SO4 was attempted. This was tried
since deprotection of the imine is done under acidic conditions, and the conversion of amide
7.HCl (as free base) has been described using H2SO4 in MeOH.31 However, this reaction gave many
side products, probably due to the benzaldehyde formed, which can undergo condensations with
either of the other reactants. Therefore the benzaldehyde was first removed by treatment with
HCl to give the pure and stable HCl salt 7.HCl in almost quantitative yield.30 The obtained amide
was then treated with H2SO4 in MeOH to give ester 6 whilst the e.e. remained >99%.31 The
obtained amino ester was then allowed to react with dibromide 10 to give Clopidogrel 5 in 95%
yield with an ee >99%
Deracemization – from academic novelty to practical application
43
Scheme 3: Synthesis of Clopidogrel
The synthesis of dibromide has been described in the literature32 in two steps. Although the yield
was slightly lower than described, this route proved satisfactory.
Scheme 4: synthesis of dibromide 10
In the first step thiophene alcohol 11 is condensed with formaldehyde to give cyclic ether 12. In
the second step, the ring is opened and the obtained diol (not shown) is transformed to
dibromide 10. The first step is rather interesting. What probably happens is a three step process:
CHAPTER 2
44
Scheme 5: mechnism of InCl3 ether formation
In the first step, alcohol 11 complexes with InCl3 to give a compound such as 13. A similar mode of
action has been described in the patent literature.33 Then a modified Blanc reaction34 takes place
to insert the hydroxymethylgroup. Finally, cyclisation gives the desired lactone 12 and
regenerates the InCl3.
With an appealing example for pharmaceutical industry, it would be interesting to find out if this
reaction could be performed on large, preferably industrial, scale. To address the scale up, Wim
Noorduin did experiments at the site of Agfa-Gevaert with the use of an industrial bead-mill.35
The method they used for deracemization is an adaption of the Viedma type of isothermal
attrition enhanced deracemization. The bead mill used was a Netzsch MINICER bead mill as
depicted in figure 8.
Deracemization – from academic novelty to practical application
45
Figure 8: Netzsch MINICER bead mill with a volume of 0.25 – 0.5 L(picture courtesy of Netzsch
GMBH)
For the grinding, 0.4-mm-diameter yttrium-stabilized ZrO2 beads were used. Apart from proving
the applicability of this technique for industrial scale, it also showed that the effective grinding
which can be obtained in a bead mill also significantly shortens the deracemization time, up to a
27 fold compared to ultrasonic grinding. This example shows the potential of this powerful new
technique.
2.4 Summary and Conclusions
In this chapter it has been demonstrated that the recent discovery of attrition-induced
deracemization of conglomerates can be readily translated into practical application, namely the
synthesis of Clopidogrel (Plavix). By use of a bead mill for deracemization of the racemic, chiral
component of Clopidogrel, a further step towards upscale has been taken. A pragmatic approach
to the screening for conglomerates has also been developed. We conclude that further
investigation can be performed to broaden the scope of the process by using other means of
racemization and other substrates. Some of the research in this direction is shown in chapter 4
and 5.
CHAPTER 2
46
2.5 Experimental Section
(+/-)-2-Chlorophenylglycine methyl ester hydrochloride(6.HCl). To 2-chlorophenylglycine 9(100
g, 539 mmol) in MeOH (270 mL) was added SOCl2 (47 mL, 647 mmol, 1.2 eq.) dropwise. After
complete addition, the mixture was stirred overnight at room temperature and subsequently
heated with a hot water bath for 3 h. Complete conversion was indicated by NMR analysis. About
50 mL of the MeOH solvent was evaporated, and the remaining reaction mixture was poured in
tert-butyl methyl ether (TBME, 700 mL). The resulting white solid was collected by filtration and
was washed with TBME to give, after drying, ester 6.HCl (120.3 g, 510 mmol, 95% yield) as a white
solid.
1H NMR (DMSO-d6) δ9.36 (2H, b), 7.67(1H, m), 7.57 (1H,m), 7.45 (2H, m), 5.44 (1H, s) 3.76 (3H, s)
13C NMR (DMSOd6) δ168.7, 134.0, 132.1, 131.1, 130.7, 130.5, 128.7, 54.1, 53.0
[M + 1] (TOF/ESI) calculated for C9 H10NO2Cl: 200.05, found: 200.1.
(+/-)-2-Chlorophenylglycinamide (7). To ester 6.HCl (100 g, 424 mmol) was added concentrated
aqueous ammonia (315 mL), and the resulting mixture was stirred overnight at room
temperature. The mixture was cooled with ice, and the solids were collected by filtration, washed
with water, and stripped 3× with toluene to give 57.2 g of amide 7. The motherliquor was
extracted with dichloromethane (2 × 300 mL), dried over Na2SO4, combined with the solid amide,
and concentrated to give amide 7(63.6 g, 344 mmol, 81% yield) as a white solid.
1H NMR (DMSO-d6) δ7.22-7.46 (5H, m), 7.18 (1H, b), 4.61 (1H, s), 2.31 (2H, b)
13C NMR (DMSO-d6) δ175.3, 141.3, 133.3, 129.8, 129.5, 129.2, 127.8, 56.8
[M + 1] (TOF/ESI) calculated: 185.05, found: 185.1.
(+/-)-2-(Benzylideneamino)-2-(2-chlorophenyl)acetamide(8a). To amide 7(58.7 g, 318 mmol) in
dichloromethane (DCM, 480 mL) was added benzaldehyde (35.3 mL, 350 mmol, 1.1 equiv) and
Na2SO4 (73.4 g, 517 mmol, 1.63 equiv), and the mixture was stirred overnight at room
temperature. The mixture was then heated with a hot water bath, and the solids were removed
by filtration. The residue was washed with warm dichloromethane, and the combined mother
liquors were concentrated to give 88.3 g, 324 mmol crude imine 8a, which was recrystallized from
MeCN (500 mL) to give 8a (77.9 g,286 mmol, 90% yield) as a white solid.
Deracemization – from academic novelty to practical application
47
1H NMR (DMSO-d6) δ8.45 (1H, s), 7.87 (2H, dd), 7.63, (1H, dd), 7.44-7.51 (6H, m), 7.32-7.38 (2H,
m), 5.43 (1H, s)
13C NMR (DMSO-d6) δ172.1, 164.17, 138.1, 136.3, 133.4, 132.0, 130.9, 130.0, 129.8, 129.4, 129.2,
128.0, 73.6
[M + 1](TOF/ESI) calculated: 273.08, found: 273.2.
The imines 8b-i were prepared in a similar manner.
Deracemization following protocol of ref 28. (S)-(E)-2-(Benzylideneamino)-2-(2-
chlorophenyl)acetamide ((S)-8a). In a 1 L round-bottom flask with a 5 × 2 cm stirring egg was
loaded racemic-imine 8a (35 g, 128 mmol), MeCN (315 mL) and the mixture were stirred at 1050
rpm. Glass beads (borosilicate, 0.2 mm, 87.5 g) were added, followed by the addition of DBU (5.1
mL, 38.5 mmol, 0.3 equiv). The mixture was heated to 70°C to form a homogeneous solution and
subsequently cooled to 20 °C with a rate of 0.1 °C/min using a thermostat (Huberministat cc). To
the mixture were added a few milligram-sizedcrystals of enantiopure imine (S)-8a, obtained in a
previous experiment, at 68, 67, 66, and 64 °C. After stirring overnight at 20 °C, chiral HPLC analysis
revealed an ee >99.5%, and the solids were collected by filtration and washed with TBME to give
(S)-8a (115.6 g, including glass beads, 28.1 g, 103 mmol, corrected, 80% yield) as a white solid.
Deracemization following isothermal protocol of ref 17.(S)-(E)-2-(Benzylideneamino)-2-(2-
chlorophenyl)acetamide((S)-8a). A scintillation vial was charged with 2 mm glassbeads (10 g),
Schiff-base 8a (389 mg, 1.43 mmol) and MeCN (3.5 mL). The flask was placed in an ultrasonic
bath, fitted with a thermostat (keeping the temperature at 20 °C), and was sonicated for 5 min.
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU,0.10 g, 0.76 mmol, 0.53 equiv) was added, and the
mixture was sonicated at 20 °C overnight. After 1 night, the ee was >80%, after 2 nights the ee
was 91-98%. This experiment was carried out as described above five times, and each time similar
results were obtained; in all cases the (S)-enantiomer 8a was obtained.
(S)-2-Chlorophenylglycinamide Hydrochloride (7.HCl).To (S)-8a (28.0 g, 103 mmol) was added a
mixture of concentrated aqueous HCl (10.1 mL) and acetone (1.8 L), andthe resulting mixture was
stirred for 1 h at room temperature.The suspension was decanted from the glass beads from the
previous step, and the solids were collected by filtration, washed with acetone, and dried to give
7.HCl (21.6 g, 97 mmol, 95% yield) as a white solid.
CHAPTER 2
48
1H NMR (DMSO-d6) δ8.60 (3H, b), 7.75 (2H, d), 7.46-7.62 (m, 4H), 5.14 (1H, s)
13C NMR (DMSO-d6) δ168.6, 134.2, 132.4, 131.7, 130.5, 130.2, 128.4, 53.0
[M + 1](TOF/ESI) calculated: 185.05, found: 185.0.
(S)-2-Chlorophenylglycine Methyl Ester ((S)-6). H2SO4 (26.0mL, 487 mmol, 5 equiv) was added
dropwise under ice cooling to MeOH, and the resulting mixture was heated at reflux for 30 min.
Amide (S)-7.HCl (21.6 g, 97 mmol) was added, and the resulting mixture was stirred for 4 h. at
reflux and then overnight at room temperature. After NMR analysis revealed complete
conversion, MeOH was evaporated, and water (175mL) was added. The aqueous layer was
basified with 1 MNaOH and extracted with DCE (3 × 50 mL). The combined organic layers were
washed with water (50 mL), dried over Na2SO4, and concentrated to give (S)-6 (16.9 g, 85 mmol,
94% yield) as a pale oil.
1H NMR (DMSO-d6) δ7.48 (1H, dd), 7.42 (1H, dd), 7.26-7.7.36 (2H, m), 4.84 (1H, s), 3.58 (3H, s)
13C NMR (DMSO-d6) δ174.4, 139.3, 133.0, 130.0, 129.8, 129.6, 128.1, 56.2, 52.7
[M+1] (TOF/ESI) calculated: 200.05, found: 200.1.
(S)-Clopidogrel (5). To 2-(2-bromoethyl)-3-(bromomethyl) thiophene, prepared by a literature
procedure, 12 (4.3 g, 15.1 mmol) in MeCN (45 mL) was added a mixture of ester (S)-6 (3.3 g, 17.8
mmol, 1.18 equiv) and di-isopropylethyl amine (DIPEA, 4.4 mL, 26.7 mmol, 1.77 equiv) in MeCN
(20 mL) dropwise, and the resulting mixture was heated at reflux overnight. The mixture was
concentrated, and the residue was taken up in EtOAc (80 mL) and washed with water (2x 60 mL),
brine (60 mL), dried over Na2SO4, and concentrated to give Clopidogrel 5 (4.3 g, 13.4 mmol, 88%
yield) as a yellow oil with a purity of 94-95% according to HPLC and an ee >99% determined by
chiral HPLC.
1H NMR (CDCl3) δ7.7 (1H, m), 7.41 (1H, m), 7.24-7.32 (2H, m), 7.06 (1H, d), 6.67 (1H, d), 4.93 (1H,
s), 3.61-3.79 (5H, m), 2.89 (4H, bs)
13C NMR (CDCl3) δ171.6, 134.9, 134.1, 133.5, 133.5, 130.2, 130.0, 129.7, 127.4, 125.5, 123.0, 68.1,
52.4, 50.9, 48.5, 25.8
[M+1] (API/ES) calculated: 322.07, found: 322.0.
Deracemization – from academic novelty to practical application
49
1 IUPAC Compendium of Chemical Terminology, online edition, corresponds with the publication
by the Royal Society of Chemistry, 2nd edition, New York, 1997 2 J. Jacques, A. Collet, in Enantiomers, Racemates and Resolutions, Krieger Pub Co, Malabar,
Florida, reprint 1994, pp. 10-20 3 S. Haq, N. Liu, V. Humblot, A.P.J. Jansen, R. Raval, Nature Chem., 2009, 1, 409-414 4 G. Levilain, G. Coquerel, CrystEngCom., 2010, 12, 1983-1992 5 E. Havinga, Chem. Weekblad, 1941, 38, 642 6 E. Havinga, Biochim. Biophys. Acta, 1954, 13, 171 7 C. Viedma, J.E. Ortiz, T. de Torres, T. Izumi, D.G. Blackmond, J. Am. Chem. Soc., 2008, 130,
15274-15275 8 P.J. Skrdla, Cryst. Growth Des., 2011, 11, 1957-1965 9 W.L. Noorduin, E. Vlieg, R.M Kellogg, B. Kaptein, Angw. Chem. Int. Ed., 2009, 48, 9600-9606 10 T. Izumi, D.G. Blackmond, Chem. Eur. J., 2009, 15, 3065-3068 11 F.C. Frank, Biochim. Biophys. Acta, 1953, 11, 459-463 12 D. K. Kondepudi, R. J. Kaufman, N. Singh, Science, 1990, 250, 975 13 D. Xue, S. Zhang, Chem. Phys. Lett., 1998, 287, 503-508 14 D.G. Blackmond, Chem. Eur. J., 2007, 13, 3290-3295 15 C. Viedma, Phys. Rev. Lett., 2005, 94, 065504 16 P.S.M. Cheung, J. Gagnon, J. Surprenant, Y. Tao, H. Xu and L.A. Cuccia, J. Chem. Soc. Chem.
Comm., 2008; 44; 987-989 17 W.L. Noorduin, T. Izumi, A. Millemaggi, M. Leeman, H. Meekes, W.J.P. Van Enckevort, R.M.
Kellogg, B. Kaptein, E. Vlieg and D.G. Blackmond, J. Am. Chem. Soc..2008, 130, 1158 18 W.L. Noorduin, H. Meekes, W.J.P. Van Enckevort, A. Millemaggi, M. Leeman, B. Kaptein, R.M.
Kellogg and E. Vlieg, Angew. Chem. Int. Ed..2008, 47, 6445-6447 19 B. Kaptein, W.L. Noorduin, H. Meekes, W.J.P. Van Enckevort, R.M. Kellogg and E. Vlieg, Angew.
Chem. Int. Ed..2008, 47, 7226 20 W.L. Noorduin, P. Van der Asdonk, H. Meekes, W.J.P. van Enckevort, B.Kaptein, M. Leeman,
R.M. Kellogg and E. Vlieg, Angew. Chem. Int. Ed., 2009, 48, 3278-3279 21 W.L. Noorduin, A.A.C. Bode, M.W. van der Meijden, H. Meekes, A.F. van Etteger, W.J.P. van
Enckevort, P.C.M. Christianen, B.Kaptein, R.M. Kellogg, T. Rasing and E. Vlieg, Nature
Chemistry, 2009, 1, 729-732 22 J.M. McBride, R.L. Carter, Angew. Chem. Int. Ed.1991, 293–295 23 IUPAC Gold book, interactive online version. 24 C.Clarke in The Science of Ice Cream, Royal Society of Chemistry, New York, 2005, 19-20 & 78-
80 25 IMS Global insights, from www.imshealth.com 26 a) (Teva Pharmaceutical Industries), U.S.Patent 6,800,759 2004 b) (Teva Pharmaceutical
Industries), U.S.Patent 6,737,411, 2004, c) (Sanofi SA), U.S. Patent 4,847,265, 1989, d) (USV
Ltd.), U.S. Patent, 6,074,242, 2006
CHAPTER 2
50
27 a) (USV Ltd.), U.S. Patent 2004073057, 2004 b) B. Srinivasa Reddy, WO2006003671, 2006 c) S.
Eswaraiah, A. Raghupathi Reddy, G. Goverdhan, M. Lokeswara Rao, U.S. Patent 2007225320,
2007 28 M.Leeman, J.M. de Gooier, K. Boer, K. Zwaagstra, B. Kaptein, R.M. Kellogg, Tetrahedron
Asymm., 2010, 21, 1191-1193 29 W.L. Noorduin, H. Meekes, W.J.P. van Enckevort, B. Kaptein, R.M. Kellogg, E. Vlieg, Angew.
Chem. Int. Ed., 2010, 49, 2539-2541 30 H.L. van Lingen, J. K.W. van de Mortel, K.F.W. Hekking, F.L. van Delft, T. Sonke and F.P.J.T.
Rutjes, Eur. J. Org. Chem., 2003, 317-324 31 (Sanofi-Synthelabo), U.S. Patent 6,670,486, 2005 32 (Hanmi Pharm. Co.), WO200587779, 2005 33 (International Flavors & Fragrances), DE1951001, 1968 34 R.C. Fuson, C.H. McKeever in Organic Reactions vol 1., John Wiley & sons inc., London, 1942,
63-90 35 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, G. Deroover, Org. Proc. Res. & Dev., 2010, 14,
908-911