university of groningen conglomerates surface in new

University of Groningen

Conglomerates surface in new resolution strategiesvan der Meijden, Maarten Willem

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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.


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


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.


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


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%


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.


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.


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.


49

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