2. As a next step, we wished to investigate whether it is bene-
ficial to use resolving agents having high eutectic composi-
tion in order to obtain enantiomeric mixtures with high
purity after resolution, so herein we report the
systematization of our previous studies comparing the eutec-
tic composition of the resolving agents with the enantiomeric
excess values of the enantiomeric mixtures obtained from
corresponding diastereomeric salts.
RESULTS AND DISCUSSION
In this study, we collected and arranged resolutions of dif-
ferent racemic acids13–21
and bases,22–28
which procedures
were elaborated by our research group (18 examples). Most
of these resolutions are used on an industrial scale, thus the
results and conditions are considered optimal. Following the
general procedure of resolutions, the racemic compound
was reacted with a given resolving agent. The diastereomers
obtained were separated by crystallization. The correspond-
ing diastereomer was decomposed to afford the desired enan-
tiomeric mixture whose enantiomeric purity (eeDIA) is now
compared to the eutectic composition of the resolving agent
(eeEUres) used (Fig. 3).
First, we evaluated the examples involving the resolution of
chiral acids (Tables 1 and 2) with the resolving agent having a
basic character. In their statistical analysis, Kozma et al.
evaluated how frequently a given resolving agent is used for
the separation of enantiomers, which study indicated that
the 1-phenyl-ethylamine is the most frequently used basic
resolving agent apart from the extremely poisonous alka-
loids (e.g., brucine, cinchonidine, ephedrine, and morphine)
or psychoactive compounds (e.g., amphetamine). On that list
of basic resolving agents, the 2-amino-1-(4-nitrophenyl)pro-
pane-1,3-diol is in second position and the N-benzyl-2-
aminobutanol is in fifth position.30
The first resolving agent
considered was the 1-phenyl-ethylamine, which has a eutectic
composition of 78% (Table 1). The average enantiomeric
purity of the enantiomeric mixtures of the given chiral acids
( = 81%) showed good agreement with the eutectic compo-
sition of the resolving agent (eeEUres = 78%).
When amino alcohols, such as N-benzyl-2-aminobutanol or
2-amino-1-(4-nitrophenyl)propane-1,3-diol were used for the
resolution of chiral acids, the given enantiomeric purity or
the average enantiomeric purity ( ) also showed correla-
tion with the corresponding eutectic composition values
(Table 2; compare = 87% with eeEures = 90% or eeDIA = 91%
with eeEures = 80%). It is noteworthy that the correlation
between the corresponding eeDIA and eeEUres values was
somewhat better in the case of the N-benzyl-2-aminobutanol
than in the case of the 2-amino-1-(4-nitrophenyl)propane-1,3-
diol (Table 2).
Considering the acidic resolving agents, L-(+)-tartaric acid
and its derivatives were always a popular choice to separate
Fig. 1. Typical binary phase and ee-ee0 diagrams of conglomerate-forming
compounds.
Fig. 2. Typical binary phase and ee-ee0 diagrams of racemate-forming
compounds.
Fig. 3. The general procedure of resolutions.
ROLE OF EUTECTIC COMPOSITION 231
Chirality DOI 10.1002/chir
3. the enantiomers of chiral basic compounds.31,32
According to
Kozma et al.,30
the 34% of the resolution examples for racemic
bases were elaborated using L-(+)-tartaric acid. The L-(+)-
tartaric acid has a eutectic composition (eeEUres) of 95%, which
shows good parity with the average enantiomeric purity
( = 98%) of the enantiomeric mixtures of chiral basic
compounds separated with this resolving agent (Table 3).
Considering Kozma’s book30
and the work with his co-
workers,29
L-(À)-dibenzoyltartaric acid is the second most
common acidic resolving agent.30
It is noteworthy that
the eutectic composition of the structurally related L-(À)-
dibenzoyltartaric acid (eeEUres = 90%) is somewhat lower
than that of the tartaric acid (eeEUres = 95%). However, the
L-(À)-dibenzoyltartaric acid was also a suitable resolving
TABLE 1. Resolution of chiral acids with 1-phenyl-ethylamine
eeEUres 7829
eeDIA 8415
6919
8720
8221
Average enantiomeric purity: = 81%
TABLE 2. Resolution of chiral acids with amino alcohols
eeEUres 9023
8018
eeDIA 8316
9017
9118
Average enantiomeric purity: = 87%
TABLE 3. Resolution of chiral basic compounds with L-(+)-tartaric acid
eeEUres 9531
eeDIA 9922
9526–28
9926–28
Average enantiomeric purity: = 98%
SZELECZKY ET AL.232
Chirality DOI 10.1002/chir
4. agent to prepare the enantiomers of several chiral basic
compounds. In these instances, the average enantiomeric
purity ( ) was 97%, showing good connection with the
eutectic composition of L-(À)-dibenzoyltartaric acid
(Table 4).
Besides the resolving agents having either an acidic or
basic character, the amino acids in the free state are also
applicable resolving agents.33–35
Herein, the resolution of
mandelic acid and its derivatives with pregabalin or phenylal-
anine was considered an example. In the case of the
pregabalin, the average enantiomeric purity of the enantio-
meric mixtures of mandelic acid or 2-chloro-mandelic acid
( = 86%) was in good agreement with the eutectic composi-
tion of the resolving agent (eeEures = 80%). The enantiomeric
purity of the O-acetyl-mandelic acid (eeDIA = 88%) was also
similar to the eutectic composition of the resolving agent,
phenylalanine (eeEures = 78%) (Table 5).
These side-by-side comparisons indicate that the enantio-
meric purity of a given enantiomeric mixture obtained after
resolution is close to the eutectic composition of the
corresponding resolving agent. Although the conditions (e.g.,
solvent, crystallization time, etc.) were not similar in the case
of the individual resolutions included in this study,
considering the large quantity and diversity of the resolutions
detailed above, the conclusions based on this sample size could
be scientifically justified. These individual correlations may also
indicate that resolving agents having high eutectic composition
may presumably lead to good enantiomeric separation of a
given racemic compound. However, kinetic or thermodynamic
factors should always be taken into consideration, as these ef-
fects may also influence the overall efficiency of a given enantio-
meric separation.
CONCLUSION
The selection of the most suitable resolving agent for a
given racemic compound is still based on trial and error.
However, our current statistical study may indicate that
the use of resolving agents with high eutectic composition
could be advantageous, as the eutectic composition of the
racemic compound may be a driving force or a “code”
during the formation of the corresponding diastereomeric
salt.
ACKNOWLEDGMENTS
This project was supported by the Hungarian Scientific and
Research Fund (OTKA K104769). The authors are grateful
for the support of the Richter Gedeon PhD Scholarship.
SUPPORTING INFORMATION
Additional supporting information may be found in the
online version of this article at the publisher’ web site.
TABLE 4. Resolution of chiral basic compounds with L-(À)-dibenzoyltartaric acid
eeEUres 9032
eeDIA 9523
9924
9925
9426–28
9926–28
Average enantiomeric purity: = 97%
TABLE 5. Resolution of chiral acids with amino acids
eeEUres 8014
7813
eeDIA 8014
9214
8813
Average enantiomeric purity: = 86%
ROLE OF EUTECTIC COMPOSITION 233
Chirality DOI 10.1002/chir
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