Efficient resolution of venlafaxine and mechanism study via X-ray crystallography

Article abstract of DOI:10.1002/chir.22790

Numbers of resolving factors were investigated to improve resolution of venlafaxine 1. An effective resolving agent, O,O′-di-p-toluoyl-(R, R)-tartaric acid 2, was screened using similar method of ‘Dutch resolution’ from tartaric acid derivatives. The resolution efficiency was up to 88.4%, when the ratio of rac-1 and 2 was 1:0.8 in THF with little water (10:1?v/v). Enantiomerically pure venlafaxine was prepared with 99.1% ee in 82.2% yield. The chiral resolution mechanism was first explained through X-ray crystallographic study. One diastereomeric salt with well solubility forms a columnar supramolecular structure as the acidic salt (R)-1·2, while the other diastereomeric salt with less solubility forms a multilayered sandwich supramolecular structure by enantio-differentiation self-assembly as the neutral salt 2(S)-1·2. The water molecules play a key role in the optical resolution, as indicated by the special structures of the diastereomeric salts.

Full text of DOI:10.1002/chir.22790

Received: 12 July 2017
DOI: 10.1002/chir.22790
Revised: 31 October 2017
Accepted: 2 November 2017
R E G U L A R A R T I C L E
Efficient resolution of venlafaxine and mechanism study via
X‐ray crystallography
Zhi‐Jin Liu1 | Han Liu1 | Xuan‐Wen Chen1 | Min Lin1 | Yu Hu1
Zhong‐Yi Yuan1 | Xiao‐Xia Sun2
| Xun Tuo1 |
1 College of Chemistry, Nanchang
Abstract
University, Nanchang, China
Numbers of resolving factors were investigated to improve resolution of
venlafaxine 1. An effective resolving agent, O,O′‐di‐p‐toluoyl‐(R, R)‐tartaric
acid 2, was screened using similar method of ‘Dutch resolution’ from tartaric
acid derivatives. The resolution efficiency was up to 88.4%, when the ratio of
rac‐1 and 2 was 1:0.8 in THF with little water (10:1 v/v). Enantiomerically pure
venlafaxine was prepared with 99.1% ee in 82.2% yield. The chiral resolution
mechanism was first explained through X‐ray crystallographic study. One
diastereomeric salt with well solubility forms a columnar supramolecular
structure as the acidic salt (R)‐1·2, while the other diastereomeric salt with less
solubility forms a multilayered sandwich supramolecular structure by enantio‐
differentiation self‐assembly as the neutral salt 2(S)‐1·2. The water molecules
play a key role in the optical resolution, as indicated by the special structures
of the diastereomeric salts.
2 Jiangxi Key Laboratory of Functional
Organic Molecules, Jiangxi Normal
University of Science and Technology,
Nanchang, China
Correspondence
Yu Hu, College of Chemistry, Nanchang
University, 999 Xuefu Avenue, Nanchang
330031, China.
Email: huyu@ncu.edu.cn
Funding information
Science Fund of the Science and
Technology Department of Jiangxi, China,
Grant/Award Number: 20133BBE50016
KEYWORDS
acidic salt, diastereomeric salt, neutral salt, optical resolution, resolution mechanism, supramolecular
structure, venlafaxine
1 | INTRODUCTION
Currently, the following general methods have been
reported: (1) asymmetric catalytic synthesis;4,5 (2) enzy-
1‐[2(Dimethylamino)‐1‐(4‐methoxyphenyl)ethyl]
matic resolution;6,7 (3) chromatographic resolution;8-10
and (4) diastereomeric salt resolution.11,12 Methods 1 to
3 are limitedly used in large‐scale production, due to com-
plicated operation, low catalyst recovery, high cost, and
the special equipment. Thus, resolution via diastereo-
meric salt is still the major method for preparation of
chiral isomers, especially when the racemate is available.
Although classical resolution has been the most
widely used in laboratory and industry, the selection and
optimization of resolution process are still based on a
large number of experiments. In 1990, enantiomerically
pure 1 was prepared by classical resolution in 68% yield,12
and it was pity that the chiral resolution mechanism and
the optimizing process were not reported. During the last
cyclohexanol (Venlafaxine, 1) is an antidepressant that
inhibits the reuptake of both norepinephrine and seroto-
nin. Because of its unique neuropharmacological activity,
it is used to treat anxiety, panic disorder, and major
depressive disorder, with the name of Effexor. Pharma-
ceutical 1 contains two enantiomers which exhibit differ-
ent pharmacological effects1,2 and metabolic process.3 The
(S)‐1 inhibits primarily the serotonin reuptake, while the
(R)‐1 inhibits both serotonin and norepinephrine
reuptake. So, the efficient and convenient separation of
enantiomers of 1 is important for its medical applications.
Z.J. Liu and H. Liu contributed equally to this work
Chirality. 2017;1–7.
wileyonlinelibrary.com/journal/chir
© 2017 Wiley Periodicals, Inc.
1

2
LIU ET AL.
1
decade, it has been proved that the resolution was greatly
influenced by many factors, such as resolution agent and
solvent.13-15 Notably, the efficient ratio between the chiral
host and guest compounds is different in using tartaric
acid acyl derivatives as resolving agent.16 It is known that
the classical resolution depends on the different solubility
of diastereomeric salt pairs and the solubility is
determined by the supramolecular structures of respective
diastereomeric salts.17 With the development of crystal-
lography, the crystal structures of diastereomeric salts
are convictive proof in the mechanism research of chiral
resolution.13,18-21
In this work, the optimized yield of enantiomerically
pure 1 was increased from 68% to 82.2%, and the resolu-
tion mechanism was first explained via the diastereomeric
crystal structures. Each factor was discussed during the
resolution of 1 (Scheme 1) with the analogues of tartaric
acid 2 to 4, and single factor experiments were carried
out to determine the most effective resolving condition.
directly without further purification. H NMR and 13C
NMR spectra were recorded on a Bruker 400 MHz spec-
trometer. 1H NMR and 13C NMR chemical shifts are
expressed in ppm with the residual signal of DMSO‐d6
or D2O as an internal standard. Melting points were deter-
mined with a digital melting point apparatus and are
uncorrected. IR spectra were recorded on a Nicolet MX‐
1 spectrometer by the KBr method. Optical rotations were
measured on Rudolph AUTOPOL IV automatic polarime-
ter. The enantiomeric excess value of 1 was determined by
HPLC analysis using an Agilent‐1100 instrument
equipped with Chiralpak AD‐H column (4.6 × 250 mm).
The mobile phase was hexane/ethanol (90:10) with 0.2%
triethylamine, and flow rate was 0.7 mL/min under detec-
tion wavelength of 274 nm. Retention time: (R)‐1
7.2 minutes, (S)‐1 10.3 minutes.
2.2 | Resolution of 1
The venlafaxine hydrochloride (31.292 g, 100 mmol) was
added to the solution of NaOH (120 mL, 1 mol/L). The
solution was stirred in several minutes and then extracted
with ethyl acetate (150 mL×4). The organic layer was
combined and washed with water (100 mL×2). The organic
phase was dried over anhydrous MgSO4, filtered, and the
solvent evaporated. The free base of venlafaxine (27.435 g,
2 | MATERIALS AND METHODS
2.1 | General
Racemic venlafaxine hydrochloride was purchased from
commercial resource and used without further purifica-
tion. The resolving agents O,O′‐di‐p‐toluoyl‐(R, R)‐tartaric
acid 2 ((R,R)‐DTTA), O,O′‐dibenzoyl‐(R,R)‐tartaric acid 3,
and O,O′‐di‐p‐anisoyl‐(R,R)‐tartaric acid 4 were commer-
cially available or prepared in our laboratory. All
chemicals and solvents were analytically pure and used
1
98.9%) was obtained as a white solid. Mp: 74–76°C; H
NMR (400 MHz, DMSO‐d6, δ):7.09 (d, J = 8.6 Hz, 2H),
6.79 (d, J =8.6 Hz, 2H), 5.21 (s, 1H), 3.71 (s, 3H),
2.95–2.92 (m, 1H), 2.77–2.74 (m, 1H), 2.43–2.38 (m, 1H),
2.12 (s, 6H), 1.57–1.29 (m, 7H), 1.15–0.88 (m, 3H) ppm.
SCHEME 1 Resolution pathway of
racemic 1

LIU ET AL.
3
The racemic venlafaxine (5.548 g, 20 mmol) was added
158.2, 143.8, 130.8, 130.5, 129.3, 129.2, 126.8, 113.5, 79.2,
72.0, 71.7, 58.2, 54.9, 50.3, 43.2, 36.2, 33.1, 25.3, 21.3, 21.2,
21.0 ppm; IR (KBr): γ = 3571.7, 3413.7, 3067.3, 2928.4,
2860.1, 2842.8, 1704.6, 1611.0, 1514.4, 1470.9, 1409.2,
1339.5, 1273.2, 1176.0, 1109.0, 903.3, 846.0, 816.4, 773.5,
to a solution of 2 (6.182 g, 16 mmol) in THF (34 mL). The
mixture was stirred and refluxed for 30 minutes. A little
water (3.4 mL) was added dropwise into the mixture. The
solution was refluxed for another 30 minutes and then
cooled to room temperature slowly. The resulting colorless
crystals were afforded by filtration and recrystallized twice
in hydrous THF. The enantiomeric pure neutral salt
750.3, 695.4, 579.6, 543.9, 514.0, 470.3, 440.8, 417.2 cm−1
.
2.4 | Growth of single crystals and
crystallographic analysis
2(S)‐1·2 was obtained as a colorless solid (4.458 g).
1
Mp:125–127 °C; [α]25 = −44.4 (c = 1.07 in EtOH); H
D
NMR (400 MHz, DMSO‐d6, δ):7.83 (d, J = 7.9 Hz, 4H),
7.31 (d, J = 7.9 Hz, 4H), 7.12 (d, J = 8.3 Hz, 4H), 6.82 (d,
J = 8.3 Hz, 4H), 5.61 (s, 2H), 3.72 (s, 6H), 3.60 (bs, 2H),
3.32–3.29 (m, 2H), 2.96–2.93 (m, 2H), 2.86–2.83 (m, 2H),
2.35 (s, 15H), 1.75 (bs, 3H), 1.55–1.22 (m, 14H), 1.11–0.89
(m, 6H) ppm; 13C NMR (100 MHz, DMSO‐d6, δ):168.4,
164.9, 157.9, 143.6, 132.0, 130.3, 129.3, 129.2, 127.1, 113.2,
79.2, 72.1, 67.0, 59.0, 54.9, 50.8, 43.9, 36.5, 33.0, 25.4, 25.1,
21.3, 21.2, 21.1 ppm; IR (KBr): γ = 3868.6, 3749.3, 3429.8,
2922.2, 1905.6, 1713.2, 1631.6, 1512.7, 1384.1, 1278.2,
1109.3, 908.4, 843.8, 760.7, 677.3, 634.2, 547.7, 517.5,
Using (R)‐1·2 salt 5 in Section 2.3 and the enantiomeric
pure neutral salt 2(S)‐1·2 6 in Section 2.2 as raw material,
single crystal of 5 was obtained in isopropyl alcohol, and
single crystal of 6 was obtained in aqueous THF. The
powder X‐ray diffraction pattern of 5 obtained in aqueous
i
THF is similar with that obtained in PrOH. It showed
that the precipitated salts of (R)‐1·2 in aqueous THF or
iPrOH possess the same formation of supramolecular
structure.17 Powder X‐ray diffraction was performed on a
Siemens D5005 diffractometer with filtered Cu‐Kα
radiation (λ = 1.5418 Å) at 40 kV and 30 mA. Diffraction
patterns were collected from 3° to 45° with a step size of
2° min−1. Single‐crystal X‐ray diffraction data of 5 and 6
were collected on a Bruker Smart 1000 CCD diffractometer
equipped with a graphite‐monochromatic MoKα radiation
(λ = 0.71073 Å) at room temperature. The empirical
absorption corrections were applied using the SADABS
program.22 All calculations were performed using the
SHELXTL‐97 system of computer programs.23 The crystal
data of 5 and 6 have been uploaded to Cambridge
Crystallographic Data Centre and the Cambridge
Crystallographic Data Centre reference numbers are
1542851 and 1580285, respectively.
487.1, 455.6, 436.5, 419.0 cm−1
.
The salt was added to 1 N NaOH and stirred in several
minutes. The free base was extracted with ethyl acetate
(40 mL×4). The organic layer was combined, washed with
water, dried over anhydrous MgSO4, and evaporated to a
crystalline residue (S)‐1 (2.279 g, 82.2% yield and 99.1%
ee). Mp:103–104 °C; [α]25 = +30.9 (c = 1.07 in EtOH).
D
The (S)‐1 was treated with 1 N HCl/ethyl acetate and then
concentrated. The precipitated solid (S)‐1·HCl was
obtained as a white solid (2.547 g). Mp: 243–244 °C;
1
[α]25 = −23.5 (c = 0.98 in H2O); H NMR (400 MHz,
D
D2O, δ):7.32 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.6 Hz,
2H), 3.80 (s, 3H), 3.72 (t, J = 12.6 Hz, 1H), 3.57 (dd,
J = 13.1 Hz and 3.8 Hz, 1H), 3.07 (dd, J = 12.0 Hz and
3.8 Hz, 1H), 2.80 (s, 3H), 2.76 (s, 3H), 1.68–1.65 (m, 1H),
1.48–1.21 (m, 9H) ppm.
3 | RESULTS AND DISCUSSION
3.1 | Resolution of venlafaxine
It was reported that the rac‐1 could be resolved with (R,
2.3 | Preparation of (R)‐1·2 salt
R)‐DTTA
2
in ethyl acetate, through which
In the method described above, (R)‐1 (>99.0%ee) was
obtained from rac‐1 as a colorless solid by using (S, S)‐
DTTA. Equimolar quantities of (R)‐1 and 2 dissolved in
THF. After the organic solvent concentrated in vacuum,
the resulting crystals were collected by filtration, and the
enantiomerically pure 1 was prepared in 68% overall
yield.12 To improve the resolution efficiency, solvents of
methanol, ethanol, isopropanol, acetone, dichlorometh-
ane, tetrahydrofuran, and ethyl acetate were first
screened. The results show that acetone, tetrahydrofuran,
and ethyl acetate lead to excellent resolution efficiency.
The resolution efficiency is 76.8% in tetrahydrofuran (ace-
tone 71.5%; ethyl acetate 62.8%). Further research
revealed that small amount of water could greatly affect
the efficiency. The better result for the resolution of 1
could be obtained in the solution of 90% tetrahydrofuran
and 10% water, and the resolution efficiency can be up
to 83.3%. (Table 1, entry 1)
enantiomeric pure salt of (R)‐1 and 2 was obtained.
1
Mp:122–123 °C; [α]25 = −67.4 (c = 1.01 in EtOH); H
D
NMR (400 MHz, DMSO‐d6, δ):7.83 (d, J = 8.0 Hz, 4H),
7.32 (d, J = 8.0 Hz, 4H), 7.17 (d, J = 8.5 Hz, 2H), 6.87 (d,
J = 8.5 Hz, 2H), 5.64 (s, 2H), 3.74 (s, 3H), 3.53–3.49 (m,
1H), 3.35–3.29 (m, 1H), 2.94–2.91 (m, 1H), 2.52 (s, 6H),
2.50 (s, 1H), 2.33 (s, 6H), 1.54–1.23 (m, 6H), 1.19–0.91 (m,
4H) ppm; 13C NMR (100 MHz, DMSO‐d6, δ):168.1, 164.8,

4
LIU ET AL.
TABLE 1 Results of resolution of rac‐1 in hydrous THF
7). One half molar equivalent of 2 was used in
literature,12 which is different from this work. To explore
the reason of the host‐guest ratio, two optical pure diaste-
Entry 1:2:3:4a
ee, %b Yield, %c
Eff., %d
1
2
3
4
5
6
7
8
1:1:0:0
83.1
80.9
91.9
‐
100.2
83.3
1
reomeric salts were obtained and analyzed by H NMR,
3:1:1:1
73.0
59.1 (5:2:3)e
respectively. According to the 1H NMR records, the
more‐soluble salt 5 contains equal numbers of (R)‐1 and
2, while the less‐soluble salt 6 consists of (S)‐1 and 2 in a
ratio of 2:1. Therefore, it can exactly explain why the ratio
of 1:0.8 is the best. And it is derived that the salification is
faster and more stable than the crystallization of
diasteromeric salts during the resolution of 1. Thus, with
0.8 equimolar 2 as a resolving agent, enantiomerically
pure 1 was prepared from the racemate in 82.2% yield,
the typical resolution procedure is described in Section 2.2.
f
‐
72.1g
Trace
66.8
‐ (12:2:5)e
1:0:1:0
1:0:0:1
‐
53.7
35.9
85.1
88.4
‐
1:0.9:0:0 85.3
99.8
1:0.8:0:0 88.9
99.4
h
g
‐
99.1
82.7
(82.2 overall yield)
9
1:0.7:0:0 90.1
1:0.6:0:0 88.8
1:0.5:0:0 80.6
97.8
92.8
89.4
88.1
82.4
72.1
10
11
3.2 | Crystal structures of diastereomeric
salts
aThe initial molar ratio of rac‐1, 2, 3, and 4.
bIn all experiments, (S)‐1 was obtained, and the enantiomeric purity was
Different diastereomeric salts have different supramolecu-
lar structures and intermolecular interactions, which
could discover the resolution mechanism effectively. As
can be seen from the crystal structures of diastereomeric
salts (Table 2), the more‐soluble salt 5 forms a columnar
supramolecular structure (Figure 1A,B), while the less‐
soluble salt 6 has multilayered sandwich supramolecular
structure which is formed by the superimposition of
venlafaxine molecular layer and DTTA molecular layer
each other (Figure 2A,B).
determined by HPLC.
cThe yield of (S)‐1 based on half the initial amount of rac‐1.
dResolving efficiency, defined as a product of the yield and the ee of the
liberated 1.
eMolar ratio of 2, 3, and 4 in the precipitated salts.
fRecrystallization from the mixed salt of entry 2.
gThe yield of recrystallization.
hRecrystallization from the salt of entry 7.
Resolving agent is another important factor affecting
the resolution efficiency. Because 2, 3, and 4 are used
widely for the resolution of racemic amines,15,24 we
choose these acids as resolving agents in this work.
In the multilayered sandwich structure, 1 DTTA
molecule connects with four (S)‐1 molecules, and one
(S)‐1 molecule directly links with two DTTA molecules
(Figure 2B,C). So, the molar ratio of venlafaxine and
DTTA is 2:1 in the less‐soluble salt 6, compared with
the equal numbers of venlafaxine molecule and DTTA
molecule in the more‐soluble salt 5 (Figure 1A,B). As
discussed in the previous sections, (S)‐1 forms neutral
salt with half‐quantity of 2, and (R)‐1 unites with equal
numbers of 2 to be acidic salt. Therefore, rac‐1 and 2
can react to form salt in the ratio of 4:3. It is reasonable
that the mixture of rac‐1 and 2 consisting in the ratio of
1:0.8 is the most efficient in the chiral resolution
(Table 1, entry 7).
In both sandwich and columnar supramolecules, the
carboxylate groups of DTTA are point to the opposite
directions (Figures 1C and 2C). In the more‐soluble salt
5, the carboxylate groups are interlinked by hydrogen
bonds to self‐assemble into ribbon structure along the b
axis (Figure 1C), which is similar to another acidic salt
of tartaric acid acyl derivatives.13,17,26 In addition, the
water molecules are found to be embedded into the rib-
bon structure and linked with upper and lower DTTA
molecules as hydrogen bond donor. Meanwhile, the water
molecules act as hydrogen bond acceptors to link with
In order to effectively screen the appropriate resolving
agent, a ‘family’ approach similar to Dutch resolution25
was developed involving a mixture of resolving agents.
During the resolution with the mixture of resolving
agents, the less soluble diastereomeric salt tends to con-
tain more effective resolving agent.13,17 So, the equimolar
mixture of 2, 3, and 4 was added to a solution of rac‐1 in
aqueous tetrahydrofuran. As a result, (S)‐1 was obtained
with 73% yield and 80.9% enantiomeric excess (Table 1,
entry 2). After recrystallization of the salt, 2 became the
major component in the complex, in which the molar
ratio of 2, 3, and 4 changed from 5:2:3 to 12:2:5 (Table 1,
entry 2 and 3). The resolution was also studied with 2, 3,
or 4 alone. The resolving efficiencies of 3 and 4 were lower
than 2 (Table 1, entry 1, 4–5). It is difficult to precipitate
out with 3 as resolving agent. So, compound 2 was proved
to be the best resolving agent in the tartaric acid ‘family’.
To further improve the resolving efficiency of 2,
resolving host‐guest ratios were tested during the resolu-
tion of rac‐1. We screened the ratio from 1:1 to 1:0.5, and
the ratio of 1:0.8 was found to be the best (Table 1, entry

LIU ET AL.
5
TABLE 2 Crystallographic data collection and structural refine-
ment information
In the neutral salt 6, there is no obvious hydrogen
bonding interactions between DTTA molecules. In fact,
each DTTA molecule is connected to another nearby
DTTA molecules via (S)‐1 molecules, which can form
intermolecular hydrogen bonds with the carboxylate
groups of DTTA (Figure 2C). The ammonium ion of
(S)‐1 holds only one DTTA molecule by salt‐bridge hydro-
gen bond, and the hydroxyl group of (S)‐1 forms the other
hydrogen bond with the carboxylate group of another
DTTA molecule. So, they form the multilayered sandwich
supramolecular structure. The interlayer space of the
sandwich supramolecule is 9.143 Å.
It is noted that the molecules of solvent are also found
in the supramolecular structure of the less‐soluble salt 6.
Although water does not work between (S)‐1 and 2, it
forms hydrogen bonds with two carboxylate groups on
the same DTTA. The effect can influence spatial arrange-
ment of DTTA to enhance the stability of the multilayered
sandwich supramolecule. In the more‐soluble salt 5, there
are 2 water molecules linked with upper and lower DTTA
molecules to form ribbon structure (Figure 1C). So, water
plays different roles in the formations of the diastereoiso-
meric supramolecular structure 5 and 6, which explain its
effect on improving the resolution efficiency of 1. On the
other hand, it is hinted that the amount of water
participating in the formation of supramolecular struc-
tures influence on the tightness of 1 and 2 connection
structure. Therefore, the acidic diastereomeric salt
(R)‐1·2·2H2O reflects better solubility than the neutral
diastereomeric salt 2(S)‐1·2·H2O. Besides, another water
and tetrahydrofuran molecules, which are found between
the supramolecular assemblies respectively (Table 2),
have little contribution to the supramolecular structure.
To the best of our knowledge, it was the first report
that the diastereomeric complexes respectively exist in
form of acidic salt and neutral salt. In classical resolution,
the difference of diastereomeric complexes depends on
the supramolecular structures, and a more tightness
diastereomeric complex formation is conducive to be
Crystal No.
More‐Soluble Salt 5 Less‐Soluble Salt 6
Configuration
(R)‐1
(S)‐1
Formula
2(C17H28NO2)+
2(C20H17O8)−
4.5(H2O)a
4(C17H28NO2)+
2(C20H16O8)2−
2(H2O) (C4H8O)
Formula weight
1408.55
1
1990.41
1
Z
Crystal system
Space group
a/Å
Monoclinic
p21
Monoclinic
C2
14.296(2)
7.9189(12)
17.427(3)
90
18.285(2)
9.1147(10)
17.2500(19)
90
b/Å
c/Å
α (°)
β (°)
107.708(4)
90
97.9120(10)
90
γ (°)
V/Å3
1879.4(5)
1.245
2847.6(5)
1.161
ρ
calcd/Mg m−3
μ/mm−1
0.093
0.082
Total reflections
Wavelength/Å
15545
11488
0.71073
0.71073
Unique
8849 [R(int) = 0.0228] 5592 [R(int) = 0.0179]
reflections
F(000)
753
1072
θmax
29.42
27.66
aIn the structural final refinement, the position is occupied by the disordered
H2O molecule with 25% occupancy.
ammonium or hydroxyl of venlafaxine. So, (R)‐1 mole-
cules connect with water at the joints of the DTTA ribbon.
They are incorporated in a vertical way between the two
opposite DTTA ribbons to construct the columnar
supramolecules (Figure 1A,B).
FIGURE 1 Supramolecular columnar structure in crystal structure of (R)‐1·2. A, Top view and B, side view down the b axis; C, ribbon
structure of (R,R)‐DTTA molecules in the more soluble salt 5

6
LIU ET AL.
FIGURE 2 Supramolecular multilayered sandwich structure in crystal structure of 2(S)‐1·2. A, Top view and B, side view down the a axis;
C, the connection of (S)‐1 and (R,R)‐DTTA molecules in the less‐soluble salt 6
precipitated out. After the structure of resolving agent was
found to impact on the diastereomeric supramolecular
structures via X‐ray crystallography,13 the solvent effect
and amount of resolving agent are also confirmed to be
vital factors by analyzing crystal structures of 5 and 6.
So, the comprehensive influence of the factors
contributes to the chiral discrimination in resolving
host‐guest chemistry and the resolution efficiency.
Chen and Prof. Zhen‐Hong Wei in Nanchang University
for their assistance in the crystallographic analysis work.
ORCID
Yu Hu http://orcid.org/0000-0002-7987-6878
REFERENCES
1. Holliday SM, Benfield P. Venlafaxine:
a review of its
pharmacology and therapeutic potential in depression. Drugs.
1995;49:280‐294.
4 | CONCLUSION
2. Rudaz S, Stella C, Balant‐Gorgia AE, Fanali S, Veuthey JL.
Simultaneous stereoselecive analysis of venlafaxine and O‐
desmethylvenlafaxine enantiomers in clinical samples by
capillary electrophoresis using charged cyclodextrins. J Pharm
Biomed Anal. 2000;23:107‐115.
The direct resolution of venlafaxine 1 was investigated.
The effective resolving agent 2 was confirmed by the
‘family’ approach from the tartaric acid derivates 2 to 4,
and resolution efficiency was best when the ratio of rac‐
1 and 2 was 1:0.8 in THF with little water (10:1 v/v). These
influent factors were substantiated in X‐ray crystallo-
graphic studies, and the diastereomeric complexes were
first found to be acidic salt and neutral salt respectively.
The studies demonstrate that the acidic diastereomeric
salt (R)‐1·2 with well solubility forms a columnar
supramolecular structure, in which water molecule is a
connection between (R)‐1 and 2, while the neutral
diastereomeric salt 2(S)‐1·2 with less solubility forms a
multilayered sandwich supramolecular structure by direct
interactions of (S)‐1 and 2. In less‐soluble supramolecular
structure, water contributes to tighten the supramolecular
structure by influencing spatial arrangement of 2. These
factors can greatly affect diastereomeric supramolecular
structures and thus the resolution efficiency. Conse-
quently, a slight change in these factors can make a big
difference in chiral resolution.
3. Klamerus KJ, Maloney K, Rudolph RL, Sisenwine SF, Jusko WJ,
Chiang ST. Introduction of a composite parameter to the
pharmacokinetics of Venalfaxine and its active O‐desmethyl
metabolite. J Clin Pharmacol. 1992;32:716‐724.
4. Davies HML, Ni A. Enantioselective synthesis of β‐amino esters
and its application to the synthesis of the enantiomers of the
antidepressant venlafaxine. Chem Commun. 2006;37:3110‐3112.
5. Chavan SP, Garai S, Pawar KP. Asymmetric total synthesis of
(−)‐venlafaxine using an organocatalyst. Tetrahedron Lett.
2013;54:2137‐2139.
6. Kochetkov KA, Galkina MA, Galkin OM. Enzymatic resolution
of ( )‐venlafaxine. Mendeleev Commun. 2010;20:314‐315.
7. Bhuniya R, Nanda S. Asymmetric synthesis of both the
enantiomers of antidepressant venlafaxine and its analogues.
Tetrahedron Lett. 2012;53:1990‐1992.
8. Caccamese S, Bianca S, Carter JT. Direct high‐performance
liquid chromatographic separation of the enantiomers of
venlafaxine and 11 analogs using amylose‐derived chiral
stationary phases. Chirality. 2009;21:569‐577.
9. Fanali S, Cotichini V, Porra R. Analysis of venlafaxine by capil-
lary zone electrophoresis. J Capillary Electrophor. 1997;4:21‐26.
ACKNOWLEDGMENTS
This work was supported by the Science Fund of the
Science and Technology Department of Jiangxi, China
(20133BBE50016). We would like to thank Prof. Chao
10. Fanali S, Rudaz S, Veuthey JL, Desiderio C. Use of vancomycin
silica stationary phase in packed electrochromatography. II.
Enantiomer
separation
of
venlafaxine
and
O‐

LIU ET AL.
7
desmethylvenlafaxine in human plasma.
2001;919:195‐203.
J
Chromatogr A.
19. Pallavicini M, Valoti E, Villa L, Piccolo O, Marchetti F.
Isopropylidene glycerol hydrogen phthalate as a resolving agent:
a study of its diastereomeric salts with (S)‐ and (R)‐1‐phenyleth-
ylamine. Tetrahedron: Asymmetry. 2000;11:1957‐1964.
11. Rameshchandra SB, Patel MS, Patel GB, et al. Manufacture of
venlafaxine hydrochloride and crystalline polymorphs thereof
WO 03050074; 2003.
20. Bialonska A, Ciunik Z. Dielectrically controlled priority of
interactions in molecular recognition. Cryst Growth Des.
2015;15:358‐365.
12. Yardley JP, Husbans GEM, Stack G, et al. 2‐Phenyl‐2‐(1‐
hydroxycycloalkyl)ethylamine derivatives: synthesis and anti-
depressant activity. J Med Chem. 1990;33:2899‐2905.
21. Wang YL, Chen A. Crystallization‐based Separation of
Enantiomers. New York: John Wiley & Sons; 2013:1663‐1682.
13. Hu Y, Yuan JJ, Sun XX, et al. Resolutions of sibutramine with
enantiopure tartaric acid derivatives: chiral discrimination
mechanism. Tetrahedron: Asymmetry. 2015;26:791‐796.
22. Sheldrick GM. SADABS, Program for Empirical Absorption
Correction of Area Detector Data. Göttingen: University of
Göttingen; 1996.
14. Hu Y, Wu C, Wu XY, Li SL, Sun XX, Tang ZB. Efficient prepara-
tion of (R)‐2‐chloromandelic acid via a recycle process of
resolution. Chirality. 2015;27:281‐285.
23. Sheldrick GM. SHELXTL‐97, Program for Crystal Structure Solu-
tion and Refinement. Göttingen: University of Göttingen; 1997.
24. Jacques J, Collet A, Wilen SH. Enantiomers, Racemates and
Resolution. New York: John Wiley & Sons; 1981:259‐260.
15. Ludwik S, Urszula B, Pawel R. Tartatic acid and its O‐acyl
derivatives. Part 2. Application of tartaric acid and of O‐acyl
tartaric acids and anhydrides. Resolution of racemates. Org Prep
Proced Int. 2008;40:163‐200.
25. Vries T, Wynberg H, van Echten E, et al. The family approach
to the resolution of racemates. Angew Chem Int Ed.
1998;37:2349‐2354.
16. Ferreira FC, Ghazali NF, Cocchini U, Livingstone AG. Rational
approach to the selection of conditions for diastereomeric resolu-
tion of chiral amines by diacid resolving agents. Tetrahedron:
Asymmetry. 2006;17:1337‐1348.
26. Tomori H, Yoshihara H, Ogura K. Facile optical resolution of a
dibenzopyrazinoazepine derivative and the nature of molecular
recognition of amines by chiral 2,3‐di‐O‐(arylcarbonyl)tartaric
acids. Bull Chem Soc Jpn. 1996;69:3581‐3590.
17. Liao J, Peng XH, Zhang JH, et al. Facile resolution of racemic
terbutaline and a study of molecular recognition through chiral
supramolecules based on enantiodifferentiating self‐assembly.
Org Biomol Chem. 2003;1:1080‐1085.
How to cite this article: Liu Z‐J, Liu H, Chen
X‐W, et al. Efficient resolution of venlafaxine
and mechanism study via X‐ray crystallography.
Chirality. 2017;1–7. https://doi.org/10.1002/
chir.22790
18. Valente EJ, Williams‐Knight PM, Moore MC. Discrimination in
resolving systems. III: pseudoephedrine‐mandelic acid. Chirality.
1998;10:325‐337.