Effect of ultrasound-assisted crystallization in the diastereomeric salt resolution of tetramisole enantiomers in ternary system with O,O′-dibenzoyl-(2R,3R)-tartaric acid

Article abstract of DOI:10.1016/j.ultsonch.2016.02.015

The diastereomeric salt resolution of racemic tetramisole was studied using ultrasound irradiation. We examined the effect of power and duration of ultrasonic irradiation on the properties of the crystalline phase formed by ultrasound-assisted crystallization and the result of the whole optical resolution. The results were compared with reference experiment without using ultrasound. The US time (5-30 min) caused higher enantiomeric excess. Although yield was lower continuously high resolving efficiency could have been reached through ultrasound. We had the best results with 4.3 W ultrasound power when resolvability was even higher than the best of reference. Furthermore, we accomplished a deep and thorough examination of the salts that possibly could form in this resolution. One of the four diastereomeric salts, which have been identified by powder X-ray diffraction, FTIR-spectroscopy, and differential scanning calorimetry (DSC) in the ternary system of the two tetramisole enantiomers and the resolving agent, namely the bis[(S)-tetramisole]-dibenzoyl-(R,R)-tartrate salt have been proven the key compound in the resolution process, and presented the highest melting point of 166 °C (dec.) among the four salts. The originally expected diastereomeric bitartrate salts with 1:1 M base:acid ratio [(S)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt and (R)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] and their 'racemic' co-crystal [(RS)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] showed somewhat lower melting points (152, 145, and 150 °C, respectively) and their crystallization was also prevented by application of ultrasound. Based on the melting points and enthalpies of fusion measured by DSC, all the binary and ternary phase diagrams have been newly established and calculated in the system with help of classical modelling equations of liquidus curves.

Full text of DOI:10.1016/j.ultsonch.2016.02.015

Ultrasonics Sonochemistry 32 (2016) 8–17
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultson
Effect of ultrasound-assisted crystallization in the diastereomeric
salt resolution of tetramisole enantiomers in ternary system
0
with O,O -dibenzoyl-(2R,3R)-tartaric acid
a,
⇑
a
a
a
a
Zsolt Szeleczky , Erzsébet Kis-Mihály , Sándor Semsey , Hajnalka Pataki , Péter Bagi ,
b
a
c
a
c
Emese Pálovics , György Marosi , György Pokol , Elemér Fogassy , János Madarász
a
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
Research Group for Organic Chemical Technology, Hungarian Academy of Sciences, 1521 Budapest, Hungary
Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, 1521 Budapest, Hungary
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
The diastereomeric salt resolution of racemic tetramisole was studied using ultrasound irradiation. We
examined the effect of power and duration of ultrasonic irradiation on the properties of the crystalline
phase formed by ultrasound-assisted crystallization and the result of the whole optical resolution. The
results were compared with reference experiment without using ultrasound. The US time (5–30 min)
caused higher enantiomeric excess. Although yield was lower continuously high resolving efficiency
could have been reached through ultrasound. We had the best results with 4.3 W ultrasound power when
resolvability was even higher than the best of reference. Furthermore, we accomplished a deep and thor-
ough examination of the salts that possibly could form in this resolution. One of the four diastereomeric
salts, which have been identified by powder X-ray diffraction, FTIR-spectroscopy, and differential scan-
ning calorimetry (DSC) in the ternary system of the two tetramisole enantiomers and the resolving agent,
namely the bis[(S)-tetramisole]-dibenzoyl-(R,R)-tartrate salt have been proven the key compound in the
resolution process, and presented the highest melting point of 166 °C (dec.) among the four salts. The
originally expected diastereomeric bitartrate salts with 1:1 M base:acid ratio [(S)-tetramisole-
dibenzoyl-(R,R)-hydrogen-tartrate salt and (R)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] and
their ‘racemic’ co-crystal [(RS)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] showed somewhat
lower melting points (152, 145, and 150 °C, respectively) and their crystallization was also prevented
by application of ultrasound. Based on the melting points and enthalpies of fusion measured by DSC,
all the binary and ternary phase diagrams have been newly established and calculated in the system with
help of classical modelling equations of liquidus curves.
Received 27 October 2015
Received in revised form 1 February 2016
Accepted 9 February 2016
Available online 13 February 2016
Keywords:
Diastereomeric salt
Optical resolution
Sonocrystallization
Ternary and binary phase diagrams
Tetramisole (Levamisole)
Ó 2016 Elsevier B.V. All rights reserved.
1
. Introduction
Molecules which cannot be arranged in a supposable configura-
substances [1,2]. There are many ways enantiomers could be pro-
duced including chiral chromatography in the presence of a chiral
molecule [3], asymmetric synthesis or enzyme-catalytic reactions
[4,5]. However, in the industry the most cost-effective way is the
separation of the racemic mixture (a blend with equal amounts
of enantiomers).
tion with their mirror image are chiral molecules and these are
called enantiomers. The majority of compounds in the human body
and the macro-molecules made of them are chiral and this is the
reason why enantiomers could have very different biological
effects. So, if a new potential drug has more stereoisomers and dur-
ing synthesis a mixture is produced or they could transform into
each other in the body it is compulsory all around the world to iso-
late enantiomers and study their pharmaceutical activity, toxicity
and metabolism separately. Drugs sold today are mainly chiral
Nevertheless, the best method is still the diastereomeric salt
resolution or ‘‘classical resolution” invented by Pasteur [6], when
⁄
another chiral base (or acid) (R ) is added to racemic acids (or
⁄
⁄
bases) (RS) thus diastereomers form (RR and SR ) and during frac-
tionated crystallization enantiomers get enriched in different
phases. Decomposing the diastereomers yields enantiomeric mix-
ture therefore various refining methods (recrystallization, partial
precipitation, salting out etc.) are needed to obtain the pure enan-
tiomers [7–12].
⇑
Corresponding author.
E-mail address: szeleczky@mail.bme.hu (Z. Szeleczky).
http://dx.doi.org/10.1016/j.ultsonch.2016.02.015
350-4177/Ó 2016 Elsevier B.V. All rights reserved.
1

Z. Szeleczky et al. / Ultrasonics Sonochemistry 32 (2016) 8–17
9
In the course of diastereomeric salt resolution we have to take
many crystallization parameters in account. Some parameters are
already proven to have significant impact on the outcome of the
resolution. These are: crystallization time [13–18], temperature
ter Gedeon Plc. which was dissolved in 5 M NaOH then an extrac-
tion with dichloromethane (DCM) followed by evaporation
resulted in the free base form (NMR spectra in Section 2.5). The
pure
(S)-2,3,5,6-Tetrahydro-6-phenylimidazo[2,1-b]thiazole
[
19,20] and cooling profile [21]. Mixing has an important role as
hydrochloride salt [(S)-TETꢀHCl] was purchased from Richter
Gedeon Plc. as well. The pure (R)-2,3,5,6-Tetrahydro-6-phenylimi
dazo[2,1-b]thiazole [(R)-TET] was made by recrystallization and
decomposition of the diastereomeric salt from the resolution of
well although we haven’t found any example for its methodical
analysis.
Properties of the crystalline product can be modified by the use
of ultrasound through crystallization. During sonocrystallization a
sonotrode, which is capable to create ultrasound at a specific fre-
quency (20–200 kHz), is inserted in the solution. Cavitation (made
by the ultrasound [22]) and acoustic streaming decrease the induc-
tion time and accelerate the primary nucleation, while ultrasound
has also a slight effect to the crystal growth mainly via decreasing
the aggregation of the crystals [23,24]. Consequently, as a result of
the shortened induction time, increased nucleation rate and
decreased aggregation rate, sonocrystallization generates smaller
and more homogeneous crystal products than crystallization with-
out sonication. In addition, particle size, particle size distribution
and structure of the formed crystals could depend principally on
frequency and intensity of the ultrasonic treatment and geometry
and immersion depth of the sonotrode [25].
0
racemic (RS)-TET with O,O -dibenzoyl-(S,S)-tartaric acid [(S,S)-
0
DBTA] as resolving agent. The resolving agent O,O -dibenzoyl-(R,
R)-tartaric acid [(R,R)-DBTA] anhydride was purchased from Fluka
Chemicals, (S,S)-DBTA anhydride from Sigma–Aldrich and dichlor-
omethane (DCM), HPLC-grade water and acetonitrile from Merck.
2.2. Reference experiments without ultrasound
We have used equal amounts for each experiment. 4.08 g
(20 mmol) (RS)-tetramisole [(RS)-TET] was dissolved in 10 ml
dichloromethane (DCM) and 8 ml water at 40 °C and 2.365 g
(6.6 mmol) (R,R)-DBTA in 14 ml dichloromethane (DCM) at 40 °C
as well. The two solutions was mixed and cooled to 5 °C with ice
(Fig. 1). Without ultrasound the homogenization was made by
magnetic stirrer at 500 rpm. After the precipitation of the first crys-
tal we let the diastereomeric salt to crystallize for different time
periods (1, 10, 20 and 30 min). Then we filtered and washed the
crystals with 1 ml distiled water. The diastereomeric salt was anal-
ysed by chiral reverse-phase HPLC. The salt was decomposed by
50 ml 5 M NaOH solution then extracted with dichloromethane
(3 times 50 ml). The organic phase was further extracted with
Ultrasonic irradiation was applied in producing and separating
chiral compounds already as well as asymmetric synthesis
[
26,27] and enzyme-catalysed kinetic resolutions [28]. Kinetic con-
trol was achieved by ultrasound in crystallization of different
enantiomeric mixtures [29].
Another application was in diastereomeric salt resolution: in
the resolution of an intermediate of silodosin with (S)-mandelic
acid the yield of the diastereomeric salt was increased from 10%
to 34% by 30 min of ultrasonic irradiation [30]. However, ultrasonic
power and irradiation time were not mentioned.
One of our aims with present paper was to analyse the effect of
intensity and duration of ultrasonic irradiation on the properties of
the diastereomeric salt formed by fractionated crystallization and
the result of the whole resolution.
Diastereomeric salt resolutions are made in aqueous or alco-
holic solvents predominantly (65% of all resolutions [8]) but some-
times an immiscible solvent mix is a better choice [31]. In these
cases homogenization of the phases is harder to achieve by
mechanical mixing. Hence, we chose a model resolution with a
biphasic solvent mixture where we assume the contact between
the two phases would be improved by ultrasonic cavitation. The
resolution of racemic 2,3,5,6-Tetrahydro-6-phenylimidazo- [2,1-
4
30 ml brine and dried on MgSO then evaporated. The yield of
the enantiomeric mixture was calculated on the basis of half the
initial (RS)-TET. The efficiency of resolution was described by the
value of resolvability – or Fogassy-parameter (F), which is the pro-
duct of the enantiomeric excess (ee) and yield (Y) of the enan-
tiomeric mixture made from the diastereomeric salt; thus a value
between 0 and 1. For each parameter setting we carried out 3 par-
allel experiments and we averaged the results.
2.3. Experiments with ultrasound
We have used equal amounts for these experiments as well.
4.08 g (20 mmol) (RS)-TET was dissolved in 10 ml dichloromethane
and 8 ml water at 40 °C and 2.365 g (6.6 mmol) (R,R)-DBTA in
14 ml dichloromethane at 40 °C as well. When the solutions were
added together, ultrasonic irradiation and cooling (5 °C) was
started straightaway. We used a Bandelin Sonopuls HD 2200 ultra-
sonic homogenizer equipped with MS 72 booster horn probe
(diameter 2 mm, length 191 mm; shape: exponential taper; reso-
nance frequency of the equipment is 20 kHz). The sonotrode was
placed at the same location during the runs: in a vertical position
with its tip on the water–dichloromethane phase interface. The
temperature was controlled throughout the whole experiment to
avoid the warming effect of ultrasound. The duration of sonication
was varied between 1, 5, 10, 20 and 30 min. Then we filtered the
diastereomeric salt and washed with 1 ml distiled water (Fig. 2).
The salt was analysed with chiral reverse-phase HPLC. We used dif-
ferent ultrasonic power and the real power was measured by the
calorimetric method.
0
b]-thiazole ((RS)-tetramisole [(RS)-TET]) with O,O -dibenzoyl-(R,
R)-tartaric acid [(R,R)-DBTA] as resolving agent was carried out
successfully in water/dichloromethane non-miscible solvent mix.
So we selected this resolution as our model. The (RS)-TET is an
anthelmintic for warm-blooded animals and humans as well. The
(
S)-TET is known to be responsible for all of the pharmaceutical
activity. On the other hand the systematic toxicities of (R)-TET
and (S)-TET are approximately on the same order. It follows that
administration of pure (S)-TET gives anthelmintic activity with
substantially reduced risk of toxic reactions [32]. The S-isomer
was given the name Levamisole.
The (RS)-TET can compose acidic and neutral salts also with (R,
R)-DBTA so our other goal was a deep and thorough examination of
the salts that possibly could form in this resolution.
The calorimetric ultrasonic power measurement was made in
water which gives a different value for our water/dichloromethane
biphasic solvent. Therefore, the ultrasonic power determined with
water is a nominal value but the value should be closely correlated
with the actual one. In the present study all of the experiments
were executed at a condition of constant volumetric ratio of water
and dichloromethane solution. Thus, we used the nominal ultra-
sonic power as a guide to express the change of ultrasonic powers
2
. Materials and methods
2.1. Materials
The racemic 2,3,5,6-Tetrahydro-6-phenylimidazo [2,1-b]
thiazole hydrochloride salt [(RS)-TETꢀHCl] was acquired from Rich-

1
0
Z. Szeleczky et al. / Ultrasonics Sonochemistry 32 (2016) 8–17
Fig. 1. Schematic procedure of experiments without ultrasound.
Fig. 2. Arrangement of experiments with ultrasound.
[
33]. The further processing of the salt went the same way as the
salt and optical rotations of the enantiomeric mixtures. The specific
rotations of the optically active samples were determined on a PER-
KIN ELMER 245 MC polarimeter using a sodium lamp (589 nm). The
specific rotation of (S)-tetramisole found in the literature is
reference experiments. For each parameter setting we conducted
3
parallel runs then averaged the results.
2
5
a
¼ ꢂ100 (c = 1; ethanol) [35].
D
2
.4. HPLC analysis
The enantiomeric excess of tetramisole were investigated using
2.5. NMR spectroscopy
a Gilson HPLC system featuring a Gilson 306 high-pressure pump, a
Gilson 806 pressure detector and an Applied Biosystems 783A UV
detectors at 254 nm. The reverse-phase HPLC separations were per-
Routine H and 13C NMR spectra were recorded on a BRUKER AV
1
300 spectrometer. Proton chemical shifts are reported in ppm.
formed on
50 mm ꢁ 4.6 mm) packed with 5
34]. The mobile phase, a 20 mM NH HCO
3
fer (pH: 8.8): acetonitrile mixture with a rate of 40:60, was run at a
flow rate of 0.5 ml/min at 20 °C. The diastereomeric salt was dis-
solved in the eluent and introduced into the device by a Rheodyne
a
Lux Cellulose
2
l
column (dimensions:
m sorbent (Phenomenex)
+ 0.1% diethylamine buf-
2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole
sole): H NMR (300 MHz, CDCl
3
(tetrami-
) d 2.99 (t, 1H, J = 8.7 Hz); 3.12
(dd, 1H, J = 15.1, 8.3 Hz); 3.27–3.43 (m, 1H); 3.43–3.59 (m, 1H);
3.57–3.76 (m, 2H); 5.46 (t, 1H, J = 8.8 Hz); 7.17–7.49 (m, 5H) 13
1
2
[
4
C
3
NMR (75 MHz, CDCl ) d 34.1; 49.1; 58.4; 76.6; 126.5; 127.2;
128.4; 142.8; 174.3.
7
725i injector. The sample volume injected was 20
l
l. The retention
Diastereomeric salt representative NMR spectra: 1H NMR
(500 MHz, D2O:CD3CN) d 3.75–3.78 (dd, 2H, J = 10.4, 8.3 Hz);
3.84–3.96 (m, 4H); 4.01–4.13 (m, 4H); 4.34 (t, 2H, J = 10.5 Hz);
time for (R)-tetramisole was 16.5 min for (S)-tetramisole 17.9 min.
The peaks were identified by pure (S)-tetramisole hydrochloride

Z. Szeleczky et al. / Ultrasonics Sonochemistry 32 (2016) 8–17
11
Fig. 3. Enantiomeric excess (A), yield (B) and resolvability (C) of tetramisole enantiomeric mixture made from the diastereomeric salt regarding crystallization time without
ultrasound (average of 3 parallel experiments with standard deviation).
Fig. 4. Enantiomeric excess (A), yield (B) and resolvability (C) of tetramisole enantiomeric mixture made from the diastereomeric salt regarding crystallization time with
4
.3 W ultrasonic treatments (average of 3 parallel experiments with standard deviation).
Fig. 5. Enantiomeric excess (A), yield (B) and resolvability (C) of tetramisole enantiomeric mixture made from the diastereomeric salt regarding crystallization time with
.5 W ultrasonic treatments (average of 3 parallel experiments with standard deviation).
6
Fig. 6. Enantiomeric excess (A), yield (B) and resolvability (C) of tetramisole enantiomeric mixture made from the diastereomeric salt regarding crystallization time with
1 W ultrasonic treatments (average of 3 parallel experiments with standard deviation).
1
5.77 (s, 2H); 5.81–5.83 (dd, 2H, J = 10.4, 8.3 Hz); 7.70–7.59 (m,
1
0H); 7.64–8.22 (m, 10H) 13C NMR (125 MHz, D2O:CD3CN) d
36.7; 48.2; 55.2; 67.6; 75.6; 126.8; 129.1; 129.5; 129.6; 129.9;
130.2; 134.2; 138.7; 167.6; 172.2; 177.0.
were measured in hermetically sealed Al-pans with a heating rate
of 10 K/min.
2.7. Powder X-ray diffraction (XRD) and FTIR spectroscopy
2.6. Differential scanning calorimetry (DSC)
Powder XRD patterns were recorded with a PANalytical X’pert
Pro MPD (PANalytical Bv., The Netherlands) multipurpose X-ray
diffractometer using Cu K radiation, Ni filter, X’celerator detector,
and ‘zero background’ single crystal silicon or ‘‘top-loaded” sample
DSC measurements were performed on a DSC 2920 device (TA
Instruments Inc., New Castle, DE USA). The samples (1.2–4.6 mg)
a

1
2
Z. Szeleczky et al. / Ultrasonics Sonochemistry 32 (2016) 8–17
Table 1
Melting point and enthalpy of fusion of starting materials (data applied in our equilibrium calculations).
0
(S)-tetramisole [(S)-TET]
(RS)-tetramisole [(RS)-TET]
O,O -dibenzoyl-(R,R)-tartaric acid [(R,R)-DBTA]
mixture of monohydrate and anhydrate forms)
(
Formula
C
11
H
12
2
N S
C
11
H
12
2
N S
18 14 8
C H O
Formula weight
Melting point (°C, decomposition, by DSC analysis)
204.29
61.3
204.29
93.0
358.30
155.9
Specific enthalpy of fusion
D
H
f
(J/g)
96.41
19.696
136.3
27.845
60.13
21.545
Molar enthalpy of fusion
D
H
f
(kJ/mol)
Fig. 7. DSC curve of (R,R)-DBTA measured in hermetically sealed Al crucible (initial
mass 3.035 mg).
Fig. 8. XRD patterns of the four diastereomeric salts (a–d) with different
stoichiometry and composition found in the ternary system of (S)-tetramisole
and (R)-tetramisole with (R,R)-DBTA together with that of a usual precipitation (e)
in the resolution processes from DCM/H O. The pattern of the latter sample (e)
2
highly resembles to that of Salt No. 1 (d), except some significant differences in
holders in the range of 2h = 4–44°. Fourier transform infrared spec-
tra of the solid samples were measured by Excalibur Series FTS
3
4
000 (Biorad) FTIR spectrophotometer in KBr between 400 and
relative intensities caused by preferred crystal orientations.
ꢂ1
000 cm
.
Table 2
Melting point and enthalpy of fusion of the four identified diastereomeric salts in the resolution system (data applied in our equilibrium calculations).
Base:acid ratioa
Melting point [°C]
b
Specific enthalpy of fusion
[J/g]b
Identified diastereomeric salts
Labels
DH
f
bis[(S)-tetramisole]-dibenzoyl-(R,R)-tartrate salt
[(S)-TET]
Salt No. 1
2
ꢀ(R,R)-DBTA
2:1
1:1
1:1
1:1
166.1
(decomposition)
152.1
(decomposition)
149.9
(decomposition)
145.1
50.71
56.18
52.00
44.59
(S)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt
(RS)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt
(R)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt
(S)-TETꢀ(R,R)-DBTA
Salt No. 2
(SR)-TETꢀ(R,R)-DBTA
Salt No. 3
(R)-TETꢀ(R,R)-DBTA
Salt No. 4
(decomposition)
a
The ratio was determined by NMR.
Determined by DSC analysis.
b

Z. Szeleczky et al. / Ultrasonics Sonochemistry 32 (2016) 8–17
13
2.8. Screening for and preparation of pure diastereomeric salts of the
3.2. Resolution of tetramisole with ultrasound (4.3W)
system in EtOH
During ultrasonic experiments we experienced precipitation of
crystals immediately. After 1 min of ultrasonic treatment (power
was 4.3 W) we got tetramisole mixture from the diastereomeric
salt with 39% enantiomeric excess and 84% yield – which was less
than the reference. However, by increasing the irradiation time we
could produce the mixture with 54–64% enantiomeric purity and
78–93% yield. Resolvability was between 0.43 and 0.55 according
to 5–30 min of ultrasonic homogenization (Fig. 4).
Either enantiomeric S- or racemic tetramisole was dissolved in
EtOH and mixed with a similar solution (R,R)-DBTA in molar ratios
of base:acid = 3:1, 2:1, and 1:1. Crystalline phase purity or phase
composition of both the precipitations filtered out immediately
and solid products obtained after gentle evaporation to dryness
was compared and evaluated pairwise by means of XRD phase
analysis.
3.3. Resolution of tetramisole with ultrasound (6.5W)
3
. Results and discussion
As we changed the power to 6.5 W we found similar results to
3.1. Resolution of tetramisole without ultrasound
the lower power runs. After 1 min of crystallization we had tetra-
misole with 48% enantiomeric purity and 55% yield which were
still lower than the reference. Then we used longer ultrasonic
treatment and we could have extracted tetramisole from the
diastereomeric salt with enantiomeric excess between 57 and
Without ultrasound the first crystals appeared after 15–20 min.
After 1 min of crystallization we were able to isolate (S)-TET with
8% enantiomeric excess (ee) and 91% yield (Fig. 3). By increasing
the crystallization time we had a rising yield but a declining enan-
tiomeric purity. In the case of 30 min crystallization time enan-
tiomeric purity decreased to 12% though yield increased by a few
percent (90% to 96%). Resolvability (F-value) – which is the product
of enantiomeric excess and yield – showed a significant drop (from
4
6
9% and 62–70% yield while resolvability ranged between 0.40
and 0.46 (Fig. 5).
3.4. Resolution of tetramisole with ultrasound (11.0W)
0
.44 to 0.12).
Based on this decreasing of enantiomeric excess and increasing
One minute of ultrasonic irradiation (11 W) produced a scale-
mic mixture with 49% enantiomeric excess and 65% yield; it was
again lower then without the use of ultrasound (1 min of crystal-
lization after the appearance of precipitation). By longer irradiation
we were able to keep enantiomeric excess and yield relatively high
(56–71% and 62–81% respectively), resolvability varied between
0.39 and 0.46 (Fig. 6).
of yield it seems the formation of the diastereomeric salt with (S)-
TET is the kinematically favoured way. Longer crystallization could
raise the amount of diastereomeric salt with (R)-tetramisole [(R)-
TET)]. Because of sharply falling enantiomeric purity the salt needs
to be filtered extremely quickly for the best possible separation,
which is not an advantage from the technological point of view.
Fig. 9. FTIR spectra of the four identified pure diastereomeric salts with different composition and stoichiometry found in the ternary system of (S)-tetramisole and (R)-
ꢂ1
tetramisole with (R,R)-DBTA. Salt No. 1 (d) exhibits a quite different hydrogen bonding system in the 2100–2800 cm absorption region, compared to that of the other salts.

1
4
Z. Szeleczky et al. / Ultrasonics Sonochemistry 32 (2016) 8–17
3.5. Comparing ultrasonic results
Ultrasound caused crystals to form immediately when we
turned on the device. Without it they needed 15–20 min of cooling
to precipitate. So, faster crystallization could have been experi-
enced in this particular resolution, however there was no change
in crystal habit according to microscopic images. Furthermore, in
the crystalline phase the molar ratios of base:acid was no change
according to NMR spectroscopy as well (representative NMR spec-
tra in Section 2.5).
In every case 1 min irradiation had an unfavourable effect on
the resolution: while the reference experiments gave a mixture
with 48% enantiomeric excess and 91% yield then ultrasound pro-
duced tetramisole mixture with 39–49% enantiomeric purity and
only 54–83% yield. Thus, ultrasonic treatment hasn’t changed the
ratio of diastereomers in this short period but their amount signif-
icantly. Therefore resolvability dropped to 0.26–0.32 from 0.44. Yet
longer irradiation (5–30 min) maintained a higher, even level of
enantiomeric excess so we could have avoided its decrease experi-
enced during the reference runs. It seems, by the use of ultrasound,
precipitation of the later crystallizing less stable and unfavourable
diastereomeric salts can be reduced and consequently higher enan-
tiomeric excess is achievable as long as we treat it for a sufficient
period of time.
Although yield was lower continuously high resolvability (0.40)
could have been reached through ultrasound. We had the best
results with low power (4.3 W) ultrasound when resolvability
(
(
F = 0.50–0.56) was even higher than the best of reference
F = 0.44). In our opinion, in every resolution when a kinetically
favoured, quickly precipitating diastereomeric salt results high
purity after immediate filtering, ultrasonic treatment can be
beneficial.
3.6. Differential scanning calorimetric (DSC), powder X-ray diffraction
(
XRD), and FTIR spectroscopic study of the starting materials and
diastereomeric salts occurred in the ternary system of solid tetramisole
enantiomers and (R,R)-DBTA
3.6.1. XRD and DSC study of the starting materials
The solid racemic tetramisole [(RS)-TET] sample to be resolved
have been found as a ca. 1:1 mixture of its two known polymorphic
modifications (P2 /n and P2 /c in s.g. No. 14) as established by XRD
phase analysis with help of the generated powder diffraction pat-
terns from single crystal coordinates of PIMTAZ [36] (also PIM-
TAZ01 [37], PIMTAZ11 [38]), and PIMTAZ02 [38], respectively,
obtained from the Cambridge Structural Database [CSD, CCDC,
Fig. 10. DSC curves of the four diastereomeric salts with different stoichiometry
and composition found in the ternary system of (S)- and (R)-tetramisole with (R,R)-
DBTA, together with that of a precipitation obtained in the resolution processes
1
1
(
hermetically sealed Al crucible, heating rate of 10 °C/min).
2
25 °C indicating decomposition of the melt. Nevertheless, the pre-
[
39]] by Mercury program [40] as references. Recrystallization
viously observed and reported endothermic and exothermic peaks
at 94 and 107 °C, respectively [42], have not been detected, at all.
from ethanol increased significantly the ratio of the P2 /n poly-
1
morph, which observation was not reported previously [37]. Mean-
while the solid (S)-tetramisole [(S)-TET] sample has been identified
similarly as levamisole (SAWJIJ [37], SAVJIJ10 [38]). The melting
behaviour of pure crystalline tetramisole forms and their mixtures
were similar to those reported earlier ([41], Table 1). We note here,
that previous information, which had been published in Acta Chim.
Acad. Sci. Hung. 102 (1979) 59–65 and was cited in Ref. [9] (on
page 150) about existence of any anomalous racemate, was made
obsolete by Ref. [41]. The solid resolving agent was identified as
a ca. 2:1 M mixture of anhydrous and monohydrate forms of (R,
R)-DBTA according to both XRD and thermogravimetric (TG) mea-
surements, showing agreement with formerly measured patterns
of the two pure forms of the acid ([42]) and a mass loss of 1.66%.
DSC investigation of (R,R)-DBTA carried out in hermetically sealed
aluminium crucible reflected also a release of water of crystallisa-
tion from the monohydrate (89 °C) and the formally reported melt-
ing point (156 °C, [42]) of the anhydrous form of (R,R)-DBTA
3.6.2. Analytical (XRD, FTIR and DSC) screening for pure
diastereomeric salts occurring in the ternary solid system of
tetramisole enantiomers and (R,R)-DBTA
To screen for solid forms of pure diastereomeric salts in the sys-
tem, phase composition and identity between the immediately fil-
tered precipitation and the final product of gentle evaporation to
dryness, both obtained from a mixed solution of either enan-
tiomeric (S)-tetramisole or (RS)-tetramisole and (R,R)-DBTA dis-
solved in EtOH in molar ratios of base:acid = 3:1, 2:1, and 1:1,
has been checked and compared in series by XRD phase analysis,
FTIR spectroscopy, and DSC. In this way, we could now identify
three more forms of pure salts in the solid ternary system, beyond
the salt of (R)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate (Salt
No. 4), which was obtained previously in a different way, (Table 2).
The bis[(S)-tetramisole]-dibenzoyl-(R,R)-tartrate salt (Salt No. 1),
(Fig. 7). In addition a sharp endothermic peak was observed at
whose composition is showing a base:acid = 2:1 M ratio of

Z. Szeleczky et al. / Ultrasonics Sonochemistry 32 (2016) 8–17
15
(
S)-tetramisole and (R,R)-DBTA, has been found as the key com-
Previously, only one pair of diastereomeric salts was reported
by Kozma et al. in this resolution system, a ‘p-salt’ with the highest
melting point of 422 K (149 °C) [43,44] was occurred, while the n-
salt had a lower melting temperature of 405 K (132 °C) [44], mean-
while a ‘certain’ mixture of them was reported fusing at 415 K
(142 °C) [44]. Actually, the melting parameters of the four pure
diastereomeric salts of the resolution system – observed and estab-
lished in this study – are listed in Table 2.
pound of resolutions, Actually, Salt No. 1 has usually been accom-
panied - in our experiments carried out in EtOH - by the (RS)-
tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt (Salt No. 3).
The latter salt exhibits
a base:acid = 1:1 M ratio of (RS)-
tetramisole and (R,R)-DBTA, thus Salt No. 3 can also be considered
as a lattice compound with stoichiometric composition, i.e. a 1:1
molecular compound of both the (S)-tetramisole-dibenzoyl-(R,R)-
hydrogen-tartrate salt (Salt No. 2) and Salt No. 4. These latter
two salts were found to be diastereomeric salt pair with base:
acid = 1:1 M ratio of (S)-tetramisole or (R)-tetramisole with (R,R)-
DBTA, respectively (Table 2). The different XRD patterns, FTIR spec-
tra, and DSC curves of all the four diastereomeric salt are presented
in Figs. 8–10, respectively. Each salt has a unique diffraction pat-
tern (Fig. 8a–d), what indicates their different crystalline
structures.
A comparison of the FTIR spectra of the four salts shows, that
those of three salts (Salt Nos. 2–4) with molar ratio of base:
acid = 1:1 are more or less similar to each other, but not the
same. Meanwhile spectrum of Salt No. 1 with molar ratio of
base:acid = 2:1 is rather different (Fig. 9) from those of the other
three. This latter Salt No. 1 exhibits a broad absorption band of
hydrogen bonding system in the 2800–2100 cm wavenumber
range. It shows – beyond the lowest carbonyl stretching of
1
1
vibration of (R,R)-DBTA dianions, not observed in the cases of
the other three 1:1 salts of hydrogen tartrates. We assume that
the overall similarity of spectrum of Salt Nos. 2–4 reflect the
common stoichiometric composition of base:acid = 1:1 M ratio
and – as a consequence – an overall similarity of the hydrogen
bonding systems of theirs, meanwhile Salt No. 1 represents a
much more different and stronger hydrogen bonding system
between the protonated cations of (S)-tetramisole and fully
deprotonated dibenzoyltartrate dianions present in salt with
3.6.3. Complex ternary and some binary phase diagrams of the system
assuming eutectic relations between the components
It was already previously reported [43,44] that the occurring
diastereomeric salts in this system fuse with decomposition. Our
DSC observations on related fusion phenomena indicate, that they
are escorted by a definite exothermic heat effect occurring imme-
diately after the melting endotherm peak. The exothermic effect
probably comes from a decarboxylation reaction of (R,R)-DBTA
unit liquidified by the fusion process. It cannot be excluded, that
the endothermic and the exothermic heat effects are in most of
the cases at least partially overlapping and that makes difficult to
separate them precisely. Nevertheless, we tried to separate and
even quantify the heat of fusion of the pure salts, and we also
assumed that the endothermic peak temperature observed truly
corresponds to the melting point of the given pure crystalline
phase. Another assumption of ours was, that each pair of occurring
crystalline solids in the systems is in a eutectic relation. Thus we
could carry out all the calculations for solid–melt equilibrium
phase diagrams of the various binary crystal mixtures (conglomer-
ates) using the simplified Schröder–van Laar equations [9], except
the binary melting phase diagram of the enantiomeric and racemic
tetramisole pair, what had already been calculated and validated
on the basis of combined application of the Schröder–van Laar
and Prigogine–Defay equations [41,9]. On the basis of eutectic bin-
ary phase relations [45] even the ternary eutectic phase relations
ꢂ1
ꢂ1
708 cm
630 cm
among the four salts – a new stretching band at
probably as carboxylate asymmetric splitting of
ꢂ1
,
(
including the ternary eutectic compositions and ternary eutectic
2
:1 M ratio of [(S)-TET] and (R,R)-DBTA, what results in the high-
temperatures) were calculated [46,47] as estimations for ternary
sub-systems. Finally these data and relations have been merged
est melting point among the four salts (Fig. 10a).
Fig. 11. The overall ternary and some of the binary phase diagrams of (S)-tetramisole–(R)-tetramisole–(R,R)-DBTA ternary system. Sub ternary systems are also defined by
triplets of components, including the solid crystalline compounds as racemic tetramisole and four supramolecular salts (Salt Nos. 1–4, I - Salt No. 1, II - Salt No. 2, III - Salt No.
0
3
, IV - Salt No. 4), which are the co-crystallized compounds of the enantiomeric tetramisoles and O,O -dibenzoyl-(R,R)-tartaric acid. The overall three-component T–x phase
diagram has been assembled from ternary sub diagrams of the observed crystalline phase-associations assuming eutectic behaviour among the crystalline solids and validity
of Schröder–van Laar equations. The bottom binary phase diagram of (R)- and (S)-tetramisole corresponds to that of Ref. [41].

1
6
Z. Szeleczky et al. / Ultrasonics Sonochemistry 32 (2016) 8–17
Fig. 12. Estimation of the binary eutectic phase diagram of (a) Salt Nos. 1 and 3 (where x
1
is molar fraction of the higher melting Salt No. 1) according to the Schröder–van
Laar equation and (b) Salt Nos. 2, 3 and 4 (where x is overall molar fraction of (R)-tetramisole in the 1:1 type salt mixtures of Salt Nos. 2–4). In the letter case, the calculations
4
of liquidus curves around Salt No. 3 are done – formally – by application also of Prigogine–Defay equation.
into the total phase diagram of ternary phase system of (S)-
tetramisole and (R)-tetramisole with (R,R)-DBTA, as shown in
Fig. 11. Note, the tartrate Salt No. 1 is the key compound of the
resolution, while hydrogen-tartrate Salt No. 3 can be considered
as
a ‘racemic’ intermolecular compound of diastereomeric
bitartrate Salt Nos. 2 and 4 .
3.7. Joint DSC and XRD study of solid precipitations obtained from
resolution trials carried out in two phase system of DCM and water by
icy cooling, with or without ultra sound
A characteristic DSC curve – measured in sealed aluminium cru-
cible – of solid samples from resolution experiments using ultra-
sound is shown in Fig. 10e. It is reasonable to assume that the
overall composition of these samples is within the ternary sub sys-
tem of Salt Nos. 1, 3, and (R)-tetramisole. The DSC curve contains
only two endothermic heat effect reflecting the first two gradual
melting phenomena of this ternary eutectic solid subsystem. The
first small endothermic peak centred at 57 °C might correspond
to the melting of a minute amount of ternary eutectics, which tem-
perature (calculated as 59 °C) is expected to be lower than the reg-
ular melting temperature of (R)-tetramisole (61 °C), what
explained by the dominating presence of the other two salt compo-
nents occurring either in partially crystalline or amorphous forms
during the resolution procedure. The second heat effect at around
Fig. 13. Enantiomeric excess (ee) of tetramisole enantiomeric mixture made from
the diastereomeric salt regarding crystallization time with 4.3 W US irradiation and
without US.
R)-DBTA in molar ratio of base:acid = 3:1 and 2:1. These XRD
observation give us an implication that Salt No. 3 would be
expected to occur also in case of DCM/H O solvent system, but
2
most probably only in an amorphous form. Actually, we could
never observe any of expected third endothermic effects corre-
sponding to the final dissolution of the excess of Salt No. 1, but
when the co-dissolution of Salt Nos. 3 and 1 had started it was
immediately followed by an exothermic melt degradation reaction
indicated by all the DSC-measurements. Most probably an oxida-
tive decarboxilation of tartrates started in both Salts Nos. 3 and 1.
1
42 °C may roughly correspond to the binary melting temperature
of the two salts i.e. Salt Nos. 1 and 3 remaining solid. Anyhow, Salt
No. 1 seemed present in excess ratios, as its crystalline form – indi-
cated with its characteristic XRD-pattern (Fig. 8e) – has always
been observed in all solids precipitated in the resolution experi-
ments. The assumed binary eutectic temperature of the Salt Nos.
4. Conclusion
1
and 3 has been calculated as low as 135 °C (Fig. 12a). Actually,
It is known that US irradiation may promotes the precipitation
of diastereomeric salt during optical resolution process [30]. We
studied the racemic tetramisole resolution in biphasic solvent mix-
ture, as a model resolution. We examined the composition of crys-
talline phase in respect of duration and power of US.
the experimentally observed temperature values was usually
slightly varying on the achieved composition of the precipitated
ternary solid sample obtained by our resolution methods applying
2
DCM/H O, but they were always significantly lower than any melt-
ing points of pure diastereomeric salts (Salt Nos. 1–4) in the sys-
tem. Note, only Salt No. 1 could be recognised as crystalline
component by XRD phase analysis of these precipitates of resolu-
tion trials, in contrast, superposed XRD patterns of both Salt Nos.
We established that the ultrasound irradiation ensures perma-
nentlyhigherenantiomerexcessoftetramisoleinthediastereomeric
salt after initiation of crystallization. While without ultrasound, the
enantiomer excess value decreases by increasing the crystallization
time (Fig. 13). We achieved the most suitable parameters for enan-
tioseparation with using 4.3 W US irradiation for 15 min.
1
and 3 could be observed during our salt-screening process car-
ried out in EtOH, when racemic tetramisole was mixed with (R,

Z. Szeleczky et al. / Ultrasonics Sonochemistry 32 (2016) 8–17
17
According to our detailed and combined DSC, XRD and FTIR
study, the tartrate salt of (S)-tetramisole with O,O -dibenzoyl-(R,
R)-tartaric acid in molar ratio of base:acid = 2:1 (Salt No. 1) shows
[20] K. Nemák, D. Kozma, E. Fogassy, Study of the mechanism of optical resolutions
via diastereoisomeric salt formation part 4 – the role of the crystallization
temperature in optical resolution of pipecolic acid xylidides, Mol. Cryst. Liq.
Cryst. A 276–277 (1996) 31–36.
0
the highest melting point, thermal stability and the lowest solubil-
ity both in DCM/H O and EtOH solvents among the four salts
2
[21] F.C. Ferreira, N.F. Ghazali, U. Cocchini, A.G. Livingston, Rational approach to the
selection of conditions for diastereomeric resolution of chiral amines by diacid
resolving agents, Tetrahedron Asymmetry 17 (2006) 1337–1348.
occurred in the resolution system. The other three diastereomeric
salts (Salt Nos. 2–4) with a base:acid = 1:1 M ratio seem to be more
closely related to each other, as they show only small but signifi-
cant differences in their IR spectra and melting points. Indeed,
hydrogen-tartrate Salt No 3. can be considered as a ‘racemic’ inter-
molecular lattice compound of diastereomeric bitartrate salts Salt
Nos. 2 and 4, in 1:1 formula ratio (Fig. 12b). Nevertheless all these
three bitartrate salts have lower melting points compared to tar-
trate salt (Salt No. 1), which usually precipitates first and plays a
key role in the resolutions. In EtOH solvent, precipitation of crys-
talline Salt No. 1 is usually escorted with crystals of Salt No. 3,
[
22] M.A. Margulis, Sonoluminescence and sonochemical reactions in cavitation
fields. A review, Ultrasonics 23 (1985) 157–169.
[
23] G. Ruecroft, D. Hipkiss, T. Ly, N. Maxted, P.W. Cains, Sonocrystallization: the
use of ultrasound for improved industrial crystallization, Org. Proc. Res. Dev. 9
(
2005) 923–932.
[24] P.W. Cains, P.D. Martin, C.J. Price, The use of ultrasound in industrial chemical
synthesis and crystallization. 1. Applications to synthetic chemistry, Org. Proc.
Res. Dev. 2 (1998) 34–48.
[
[
[
25] M.D. Luque de Castro, F. Priego-Capote, Ultrasound-assisted crystallization
(sonocrystallization), Ultrason. Sonochem. 14 (2007) 717–724.
26] B. Török, K. Balázsik, K. Felföldi, M. Bartók, Asymmetric reactions in
sonochemistry, Ultrason. Sonochem. 8 (2001) 191–200.
27] S.K. Shingote, A.A. Kelkar, Y.L. Borole, P.D. Joshi, R.V. Chaudhari, Ultrasound
promoted asymmetric transfer hydrogenation of ketones using Ru(II)arene/
amino alcohol catalyst system, Ultrason. Sonochem. 15 (2008) 289–293.
28] C.-Z. Zang, S.-C. Kan, C.-W. Yeh, C.-C. Lin, C.-J. Shieh, Y.-C. Liu, Ultrasound-
assisted (R)-phenylephrine whole-cell bioconversion by S. marcescens
N10612, Ultrason. Sonochem. 26 (2015) 415–421.
2
while in DCM/H O solvent system, the application of ultrasound
prevented the co-precipitation of Salt No. 3 in crystalline form.
[
Acknowledgements
[29] D.D. Medina, A. Gedanken, Y. Mastai, Chiral amplification in crystallization
under ultrasound radiation, Chem. Eur. J. 17 (2011) 11139–11142.
[
30] I.J. Barve, L.-H. Chen, P.C.P. Wei, J.-T. Hung, C.-M. Sun, Enantioselective
synthesis of (ꢂ)-(R) Silodosin by ultrasound-assisted diastereomeric
crystallization, Tetrahedron 69 (2013) 2834–2843.
The above project was supported by the Hungarian Scientific
and Research Fund (OTKA K104769). Zs.Sz. is grateful for the sup-
port of Richter Gedeon PhD Scholarship.
[31] M. Ács, E. Fogassy, F. Faigl, A convenient method for optical resolutions via
diastereoisomeric salt formation, Tetrahedron 41 (1985) 2465–2470.
[32] A Process for the resolution of DL-6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-6]
thiazole, British Pantent No. 1169310, Chem. Abstr. 72, 1969, 55453
[33] S. Nii, S. Takayanagi, Growth and size control in anti-solvent crystallization of
glycine with high frequency ultrasound, Ultrason. Sonochem. 21 (2014) 1182–
References
[
1] S.W. Smith, Chiral toxicology: it’s the same thing...only different, Toxicol. Sci.
10 (2009) 4–30.
1186.
1
[
34] L. Peng, S. Jayapalan, B. Chankvetadze, T. Farkas, Reversed-phase chiral HPLC
and LC/MS analysis with tris(chloromethylphenylcarbamate) derivatives of
cellulose and amylose as chiral stationary phases, J. Chromatogr. A 1217
[
2] H. Murakami, From racemates to single enantiomers – chiral synthetic drugs
over the last 20 years, in: K. Sakai, N. Hirayama, R. Tamura (Eds.), Novel
Optical Resolution Technologies, Springer, Berlin, Heidelberg, 2007, pp. 273–
(
2010) 6942–6955.
2
99.
[
35] C. Röben, J.A. Souto, Y. González, A. Lishchynskyi, K. Muñiz, Enantioselective
metal-free diamination of styrenes, Angew. Chem. Int. Ed. 50 (2011) 9478–
[
[
3] T.E. Beesley, R.P.W. Scott, Chiral Chromatography, Wiley, 1998.
4] H.B. Kagan, J.C. Fiaud, Kinetic resolution, in: Topics in Stereochemistry, John
Wiley & Sons Inc, 2007, pp. 249–330.
9482.
[
36] A.L. Spek, 2,3,5,6-Tetrahydro-6-phenylimidazo [2,1-b] thiazole,
Cryst. Struct. Commun. 1 (1972) 309.
11 12 2
C H N S,
[
5] M.T. Reetz, Combinatorial and evolution-based methods in the creation of
enantioselective catalysts, Angew. Chem. Int. Ed. 40 (2001) 284–310.
6] L. Pasteur, CR Acad. Sci. 26 (1853) 162.
[
37] M. Ács, E. Fogassy, F. Faigl, K. Tomor, K. Simon, K. Marsó, V. Fülöp, M.-J. Brienne,
J. Jacques, Evidence of polymorphism in the case of a substituted imidazolo-
thiazole, Mol. Cryst. Liq. Cryst. (Discontinued) 156 (1988) 193–203.
38] K. Simon, M. Ács, S. Larsen, V. Fülöp, E. Gács-Baitz, Comparison of the
structures of the enantiomeric and racemic forms of an imidazo[2,1-b]thiazole
anthelmintic agent and their hydrochlorides, Acta Crystallogr. Sect. B: Struct.
Sci. 48 (1992) 88–95.
[
[
7] E.L. Eliel, S.H. Wilen, L.N. Mander, Stereochemistry of Organic Compounds,
Wiley-Interscience, New York, 1994.
[
[
[
8] D. Kozma, CRC Handbook of Optical Resolutions via Diastereomeric Salt
Formation, CRC Press, London, 2002.
9] J.C. Jacques, A. Collet, S.H. Willen, Enantiomers, Racemates, and Resolutions,
John Wiley, New York, 1981.
[
39] F.H. Allen, The Cambridge structural database: a quarter of a million crystal
structures and rising, Acta Cryst. B 58 (2002) 380–388.
[
[
[
10] R. Siedlecka, Recent developments in optical resolution, Tetrahedron 69 (2013)
6
331–6363.
[
40] C.F. Macrae, I.J. Bruno, J.A. Chisholm, P.R. Edgington, P. McCabe, E. Pidcock, L.
Rodriguez-Monge, R. Taylor, J. van de Streek, P.A. Wood, Mercury CSD 2.0 -
new features for the visualization and investigation of crystal structures, J.
Appl. Cryst. 41 (2008) 466–470.
11] F. Faigl, E. Fogassy, M. Nógrádi, E. Pálovics, J. Schindler, Strategies in optical
resolution: a practical guide, Tetrahedron Asymmetry 19 (2008) 519–536.
12] F. Faigl, E. Fogassy, M. Nógrádi, E. Pálovics, J. Schindler, Separation of non-
racemic mixtures of enantiomers: an essential part of optical resolution, Org.
Biomol. Chem. 8 (2010) 947–959.
[
41] M.J. Brienne, J. Jacques, K. Marsó, M. Ács, Sur les propriétés physiques du
tétramisole, du lévamisole at de leurs mélanges (About the physical properties
of tetramisole, levamisol and their mixtures), Bull. Soc. Chim. France 5 (1985)
[
13] J. Bálint, G. Egri, V. Kiss, A. Gajáry, Z. Juvancz, E. Fogassy, Unusual phenomena
during the resolution of 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline
876–880.
(
3
FTHQ): thermodynamic-kinetic control, Tetrahedron Asymmetry 12 (2002)
435–3439.
[
[
[
42] R. Illés, C. Kassai, G. Pokol, J. Madarász, E. Fogassy, D. Kozma, Thermoanalytical
study of O,O’-dibenzoyl-(2R,3R)-tartaric acid supramolecular compounds. Part.
[
14] E. Pálovics, J. Schindler, F. Faigl, E. Fogassy, The influence of molecular
structure and crystallization time on the efficiency of diastereoisomeric salt
forming resolutions, Tetrahedron Asymmetry 21 (2010) 2429–2434.
1, J. Therm. Anal. Calorim. 61 (2000) 745–755.
43] D. Kozma, G. Pokol, M. Ács, Calculation of the efficiency of optical resolutions
on the basis of the binary phase diagram for diastereomeric salts, J. Chem Soc.
Perkin Trans. 2 (1992) 435–439. Table 2, row 3.
44] D. Kozma, M. Ács, E. Fogassy, Predictions of which diastereoisomeric salt
precipitates during an optical resolution via diastereoisomeric salt formation,
Tetrahedron 50 (1994) 6907–6912. Table 1, row 12.
[
15] F. Faigl, B. Mátravölgyi, T. Holczbauer, M. Czugler, J. Madarász, Resolution of 1-
[
2-carboxy-6-(trifluoromethyl)phenyl]-1H-pyrrole-2-carboxylic acid with
methyl (R)-2-phenylglycinate, reciprocal resolution and second order
asymmetric transformation, Tetrahedron Asymmetry 22 (2011) 1879–1884.
16] F. Faigl, A. Thurner, F. Farkas, Á. Proszenyák, M. Valacchi, A. Mordini, Time
[
[
[
0
[45] J. Madarász, D. Kozma, G. Pokol, M. Ács, E. Fogassy, Merit of estimation from
DSC measurements for the efficiency of optical resolutions, J. Therm. Anal.
Calorim. 42 (1994) 877–894.
dependent efficiency of optical resolution of aminooxiranes with O,O -
dibenzoyl-(R,R)-tartaric acid, Arkivoc 2004 (2004) 53–59.
17] Z. Szeleczky, P. Bagi, E. Pálovics, E. Fogassy, The effect of SDE on the separation
of diastereomeric salts: a case study for the resolution of mandelic acid
derivatives with Pregabalin, Tetrahedron Asymmetry 25 (2014) 1095–1099.
18] Z. Szeleczky, P. Bagi, E. Pálovics, E. Fogassy, The effect of the eutectic
composition on the outcome of kinetically and thermodynamically
controlled resolutions that are based on the formation of diastereomers,
Tetrahedron Asymmetry 26 (2015) 377–384.
[
46] A.A. Smith, Calculation of the efficiency of purification by crystallization of
ideal multicomponent stereoisomeric mixtures, Tetrahedron Asymmetry 9
(
1998) 2925–2937.
[
47] P. Thorey, P. Bombicz, I.M. Szilágyi, P. Molnár, G. Bánsághi, E. Székely, B.
Simándi, L. Párkányi, G. Pokol, J. Madarász, Co-crystal of (R,R)-1,2-
cyclohexanediol with (R,R)-tartaric acid, a key structure in resolution of the
(
±)-trans-diol by supercritical extraction, and the related ternary phase
[
19] L. Ge, Q. Zhao, K. Yang, S. Liu, F. Xia, Optical resolution and optimization of (R,
S)-propranolol using dehydroabietic acid via diastereomeric crystallization,
Chirality 27 (2015) 131–136.
system, Thermochim. Acta 497 (2010) 129–136. and refs therein.