Dutch resolution of racemic 4-hydroxy- and 4-fluorophenylglycine with mixtures of phenylglycine and (+)-10-camphorsulfonic acid

Article abstract of DOI:10.1016/S0957-4166(00)00048-3

4-Hydroxyphenylglycine and 4-fluorophenylglycine can be resolved with (+)-10-camphorsulfonic acid only if DL- or D-(-)-phenylglycine is added. When using DL-phenylglycine this is co-resolved in this process. In this resolution process mixed crystals are formed of the (+)-10-camphorsulfonic acid salts of the D-(-)-enantiomers of phenylglycine and the para substituted phenylglycines. In the crystal lattice of the mixed salts approximately 25- 30% of the D-(-)-phenylglycine molecules can be randomly replaced by D-(-)- para substituted phenylglycines, resulting in the desired resolution. The overall non-stoichiometric composition of the mixed crystals reflects to some extent the composition in solution. This behaviour is typical for solid solutions. The solid solution behaviour in this so called 'Dutch resolution' is proven by differential scanning calorimetry (DSC), X-ray crystal structure determination and powder diffraction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00048-3

Tetrahedron: Asymmetry 11 (2000) 1343±1351
Dutch resolution of racemic 4-hydroxy- and 4-¯uoro-
phenylglycine with mixtures of phenylglycine and
(+)-10-camphorsulfonic acid
Bernard Kaptein,a,* Henk Elsenberg,a Reinier F. P. Grimbergen,b
Quirinus B. Broxterman,a,* Lumbertus A. Hulshof,c Kees L. Pouwerd and Ton R. Vriesd
aDSM Research, Organic Chemistry and Biotechnology Section, PO Box 18, 6160 MD, Geleen, The Netherlands
bDSM Research, Centre for Particle Technology, PO Box 18, 6160 MD, Geleen, The Netherlands
cDSM Fine Chemicals, PO Box 81, 5900 AB, Venlo, The Netherlands
dSYNCOM BV, Nijenborgh 4, 9747 AG, Groningen, The Netherlands
Received 21 January 2000; accepted 27 January 2000
Abstract
4-Hydroxyphenylglycine and 4-¯uorophenylglycine can be resolved with (+)-10-camphorsulfonic acid
only if dl- or d-(^)-phenylglycine is added. When using dl-phenylglycine this is co-resolved in this process.
In this resolution process mixed crystals are formed of the (+)-10-camphorsulfonic acid salts of the d-(^)-
enantiomers of phenylglycine and the para substituted phenylglycines. In the crystal lattice of the mixed
salts approximately 25±30% of the d-(^)-phenylglycine molecules can be randomly replaced by d-(^)-
para substituted phenylglycines, resulting in the desired resolution. The overall non-stoichiometric com-
position of the mixed crystals re¯ects to some extent the composition in solution. This behaviour is typical
for solid solutions. The solid solution behaviour in this so called `Dutch resolution' is proven by di€erential
scanning calorimetry (DSC), X-ray crystal structure determination and powder di€raction. # 2000 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Classical resolution is an important technology for the preparation of enantiopure compounds
on an industrial scale. However, ®nding a suitable resolution method is still a method of trial and
error,1 and very often hampered by the formation of (end) solid solution behaviour of the dia-
stereomeric salts.2±5 If so, an e€ective resolution can only be accomplished by subsequent
recrystallisations resulting in a substantial loss of product and resolving agent. In extreme cases,
in which the diastereomeric salts show solid solution behaviour over the entire range of various
* Corresponding authors. E-mail: bernard.kaptein@dsm-group.com, rinus.broxterman@dsm-group.com
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00048-3

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B. Kaptein et al. / Tetrahedron: Asymmetry 11 (2000) 1343±1351
diastereomeric compositions, only by repetitive and time consuming fractional crystallisation can
enantiopure product be obtained.6,7
Recently we have described the use of mixtures (family) of resolving agents in classical resolu-
tions.8,9 We have coined the name `Dutch resolution' for this technology. Use of this classical
resolution technology improves the success rate of ®nding a suitable resolution for most race-
mates tested.
In this paper we describe the use of this alternative Dutch resolution method for the prepara-
tion of enantiopure d-(^)-4-hydroxyphenylglycine (d-Hpg) and d-(^)-4-¯uorophenylglycine (d-Fpg)
using (+)-10-camphorsulfonic acid ((+)-CSA) as a resolving agent. Racemic Hpg is resolved on an
industrial scale with (+)-3-bromocamphor-8-sulfonic acid. However, this resolving agent is
expensive and dicult to recycle. On the other hand, racemic phenylglycine (dl-Phg) is resolved
with the much cheaper (+)-CSA on a multi-ton scale.10 The d-enantiomers of both amino acids
are widely used for the production of semi-synthetic antibiotics.11
4-Fluorophenylglycine (Fpg), especially the l-(+)-enantiomer, has recently received attention as
intermediate for substance P analogues.12 The resolution of dl-Fpg with various resolving agents
results only in racemic salt mixtures. Only after esteri®cation could the methyl ester be resolved
using 0.25 equiv. of (+)-dibenzoyl tartaric acid.13
The resolution of dl-Hpg is hampered by the formation of mixed crystals with a full solid
solution behaviour of both diastereomers. In fact, as can be seen in Fig. 1, the diastereomeric salts
form a Roozenboom II type of solid solution14 in which an approximately 1:1 mixture of the
diastereomers has the lowest solubility. In this case even fractional crystallisation is unsuccessful
since the racemate of Hpg tends to crystallise. In fact, the solubilities of both diastereomerically
.
pure Hpg (+)-CSA salts are so high that they could not be determined.
Since neither dl-Hpg nor dl-Fpg can be directly resolved with (+)-CSA we decided to test the
principle of Dutch resolution using mixtures of racemates for these two compounds in combina-
tion with the dl-Phg resolution with (+)-CSA.
2. Results and discussion
2.1. Dutch resolution of dl-4-hydroxyphenylglycine
Initially, mixtures of dl-Hpg and dl-Phg were crystallised in various ratios with 0.75 equiv. of
(+)-CSA in 1N hydrochloric acid (according to the method of Pope and Peachey15). The results of
this crystallisation study are shown in Table 1. In all (Dutch) resolution experiments crystalline
1:1 salts are formed consisting of a mixture of enantiomerically enriched d-(^)-Phg and d-(^)-Hpg
with (+)-CSA.16 The e.e. of both phenylglycines can be improved to above 99% by recrystallisation.

B. Kaptein et al. / Tetrahedron: Asymmetry 11 (2000) 1343±1351
1345
Figure 1. Solubility phase diagram of salts of dl-Hpg and (+)-CSA (solubility curve in red; tie lines in blue; * starting
composition; * end composition of saturated solution and solid)
Table 1
Resolution of dl-Hpg with dl-Phg and (+)-CSA

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B. Kaptein et al. / Tetrahedron: Asymmetry 11 (2000) 1343±1351
There is a strong preference for the incorporation of d-(^)-Phg over d-(^)-Hpg in all crystal-
lisations. Actually, on repeated crystallisation d-(^)-Hpg is slowly lost and diastereomerically
.
pure d-(^)-Phg (+)-CSA remains.
The resolution of racemic Hpg can be improved by gradual replacement of dl-Phg in the
simultaneous resolution with half of the amount of enantiomerically pure d-(^)-Phg. As can be
seen from Table 2 the (inert) fraction of l-(+)-Phg can be omitted without a considerable in¯u-
ence on the Hpg resolution performance (for example, compare entry 3 in Table 1 with entry 1 in
Table 2).
Table 2
Resolution of dl-Hpg with d-(^)-Phg and (+)-CSA
In a typical multi-gram scale experiment the resolution of a 1:1 mixture of dl-Hpg (8.4 g, 50
mmol) and d-(^)-Phg (3.8 g, 25 mmol) with 0.67 equiv. (11.6 g, 50 mmol) of (+)-CSA (40 wt% in
1N HCl solution) produced 7.4 g of mixed crystalline salt (Hpg:Phg 26:74, e.e.Hpg 84%). After
this ®rst crystallisation step a second crop of mixed salt can be obtained from the mother liquor
upon addition of a second portion of d-(^)-Phg (3.8 g). Thus, another 7.1 g of mixed salt are
obtained with a somewhat lower Hpg content (Hpg:Phg 15:85) but with an even higher e.e. of 88%.
2.2. DSC measurements and X-ray di€raction of the mixed crystals
To get more insight into the nature of the simultaneous resolution, diastereomerically pure
mixed crystals of d-(^)-Hpg and d-(^)-Phg with (+)-CSA were prepared for di€erential scanning
calometry (DSC) and X-ray analysis (ratio Hpg:Phg 26:74). DSC measurements reveal that the
mixed crystals have a congruent melting point which is only slightly lower than that of the pure
.
d-(^)-Phg (+)-CSA salt (see Table 3). On the other hand, the heat of fusion (ÁHf) of the mixed
crystals is considerably lower than that of the pure d-(^)-Phg salt, indicating that the pure
.
d-(^)-Phg (+)-CSA salt is more stable than the mixed salt. This is in agreement with the obser-
vation that d-(^)-Hpg is lost after repetitive crystallisations. The fact that the mixed crystals show
one (sharp) melting point is typical for solid solution behaviour of quasi-racemates with a
homogeneous composition of the solid state.17±19 This is con®rmed by single crystal X-ray ana-
.
lysis (vide supra). Also the single melting point of dl-Hpg (+)-CSA con®rms the solid solution
behaviour observed earlier (Fig. 1).
.
.
The X-ray crystal structures of d-(^)-Phg (+)-CSA and of a d-(^)-Hpg/d-(^)-Phg (+)-CSA
mixed crystal (ratio 26:74) are determined and shown in Figs. 2 and 3. The crystallographic data
can be found in Table 4. Comparisons of the two unit cells are shown both in Table 4 and Fig. 4.

B. Kaptein et al. / Tetrahedron: Asymmetry 11 (2000) 1343±1351
1347
Table 3
.
DSC data of d-(^)-Hpg/d-(^)-Phg (+)-CSA mixed crystals (ratio 26:74)
.
.
compared with d-(^)-Phg (+)-CSA and dl-Hpg (+)-CSA crystals
.
Figure 2. X-Ray crystal structure of d-(^)-Phg (+)-CSA
.
Figure 3. X-Ray crystal structure of d-(^)-Hpg/d-(^)-Phg (+)-CSA mixed crystals

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B. Kaptein et al. / Tetrahedron: Asymmetry 11 (2000) 1343±1351
Table 4
.
.
Crystal data and details of the structure determination of d-(^)Phg (+)-CSA and d-(^)Hpg/d-(^)Phg (+)-CSA mixed
crystals
.
.
Figure 4. Unit cells of (a) d-(^)-Phg (+)-CSA and (b) d-(^)-Hpg/d-(^)-Phg (+)-CSA mixed crystals
In the mixed crystal d-(^)-Phg and d-(^)-Hpg are randomly distributed in the crystal lattice,
which is typical for solid solution behaviour. From the X-ray crystal structures it can be seen that
the Phg and Hpg units appear superimposed and occupy positions with orientations also
.
observed for Phg in the d-(^)-Phg (+)-CSA crystal structure. In addition to all of the Phg±CSA
interactions in the crystal lattice, the Hpg units form an additional hydrogen bond to the
CSA sulfonate group. Due to the incorporation of Hpg the unit cell parameters of the mixed
.
salt slightly di€er from the d-(^)-Phg (+)-CSA salt. The random incorporation of Hpg is also

B. Kaptein et al. / Tetrahedron: Asymmetry 11 (2000) 1343±1351
1349
translated into a slightly higher (apparent) thermal movement and refraction index
(R(F)=0.0253 and 0.0584, respectively).
2.3. Dutch resolution of dl-4-¯uorophenylglycine
Identical to the Dutch resolution of dl-Hpg described above, the resolution of racemic Fpg was
performed with (+)-CSA and various amounts of dl-Phg (see Table 5). Also in these experiments
.
the d-(^)-Fpg/d-(^)-Phg (+)-CSA mixed salt preferentially crystallises. However, the e.e.s of
d-(^)-Fpg are somewhat lower compared to the Hpg experiments and there is a stronger preference
for inclusion of d-(^)-Phg.
Table 5
Resolution of dl-Fpg with dl-Phg and (+)-CSA
After recrystallisation of a primarily obtained mixed salt, the diastereomerically pure d-(^)-
.
Fpg/d-(^)-Phg (+)-CSA mixed salt could be obtained, although with only low contents of d-
(^)-Fpg. Consequently, the resolution eciency is rather low, but resolution is not possible
without addition of racemic Phg.13 No further resolution experiments with addition of enantio-
merically pure d-(^)-Phg were performed.
3. Conclusions
From all of the results above it can be concluded that d-(^)-Hpg and d-(^)-Fpg show solid
solution behaviour with d-(^)-Phg in the crystalline salts with (+)-CSA, with a preference for the
incorporation of d-(^)-Phg. The ratio between d-(^)-Hpg/d-(^)-Phg or d-(^)-Fpg/d-(^)-Phg is
always non-stoichiometric and no preferred/stable composition is found. Repeated crystallisation
.
results in pure d-(^)-Phg (+)-CSA crystals with loss of d-(^)-Hpg and d-(^)-Fpg. The latter can be
isolated from the mother liquor.
In addition to the presented Dutch resolution of dl-Hpg and dl-Fpg other derivatives of
phenylglycine also show the same behaviour. Preliminary experimental results show that the
methyl ester of Hpg as well as the amide of Phg can be resolved with (+)-CSA and racemic Phg

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B. Kaptein et al. / Tetrahedron: Asymmetry 11 (2000) 1343±1351
also forming mixed crystals. X-Ray powder di€raction con®rms the formation of mixed crystals
.
with unit cell parameters identical with the d-(^)-Phg (+)-CSA salt.
4. Experimental
4.1. Resolution experiments
All resolution experiments were performed on a 10±100 mmol scale by mixing the various
phenylglycines and (+)-10-camphorsulfonic acid at room temperature in water or 1N HCl solu-
tion with starting concentrations and ratios as described in Tables 1, 2 and 5. The mixture was
heated at 70±100ꢀC to dissolve the salts and then slowly cooled under stirring to room tempera-
ture. In all experiments spontaneous crystallisation started on cooling. The mixtures were left
stirring at room temperature for 5±18 h to reach (thermodynamic) equilibrium. Crystalline salts
were ®ltered o€ and air-dried to constant weight. The composition and enantiomeric excess were
determined by chiral HPLC. Column: C-18 Nucleosil 12.5 cm in series with a Chrompack CR(+),
eluent: 0.10 M HClO4 solution, ¯ow: 0.8 ml/min, temp.: 25ꢀC, sample concentration: 30 mg/100
ml, injection volume: 20 ml, detection: UV 254 nm.
4.2. DSC
DSC thermograms were determined using a Netzsch DSC200 instrument, calibrated with In,
Pb, Zn and Sn. Samples (7±10 mg) were weighed with an accuracy of 0.01 mg and encapsulated in
reusable high pressure stainless steel pans (40 ml, Perkin±Elmer, sealed under nitrogen). Thermo-
grams were recorded at a scanning rate of 5ꢀC/min, with an empty pan as reference under a
nitrogen atmosphere. With broad lines the onset temperature was taken as the start of the melting
point (solidus line); the top of the peaks were taken as the end of melting (liquidus line).
4.3. Crystal structure determination
.
Single crystal X-ray di€raction of a d-(^)-Phg (+)-CSA crystal (parallelepiped, size
.
0.25Â0.28Â0.50 mm) and of a d-(^)-Phg/d-(^)-Hpg (+)-CSA mixed crystal (parallelepiped, size
0.13Â0.36Â0.38 mm) was performed on an Enraf±Nonius CAD-4F di€ractometer, interfaced to
an INDY (Silicon Graphics) UNIX computer (Mo tube, 50 kV, 40 mA, monochromated Mo±Ka
radiation, Áo=1.20+0.34 tg y). Unit cell parameters can be found in Table 4; additional infor-
mation is available from Cambridge Crystallographic Data Bank.
Acknowledgements
The authors thank Auke Meetsma and Adri Minnaard (University of Groningen) for the
determination of the X-ray structures and for fruitful discussions. We thank Eric van der Vegte
(DSM Research) for the DSC measurements.

B. Kaptein et al. / Tetrahedron: Asymmetry 11 (2000) 1343±1351
1351
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