Diastereomeric resolution of racemic o-chloromandelic acid

Article abstract of DOI:10.1002/chir.22089

The separation of rac-o-chloromandelic acid 1 with enantiopure aryloxypropylamine via diastereomeric salt formation was investigated. (R)-o-chloromandelic acid (R)-1, a key intermediate for the antithrombotic agent clopidogrel, was obtained in 65% yield a

Full text of DOI:10.1002/chir.22089

CHIRALITY (2012)
Diastereomeric Resolution of Racemic o-Chloromandelic Acid
*
PEI WANG, EN ZHANG, PENG ZHAO, QING-HUA REN, YUAN-YUAN GUAN, AND HONG-MIN LIU
School of Pharmaceutical Sciences and New Drug Research & Development Center, Zhengzhou University, Zhengzhou, People’s Republic of China
ABSTRACT
The separation of rac-o-chloromandelic acid 1 with enantiopure aryloxypropyla-
mine via diastereomeric salt formation was investigated. (R)-o-chloromandelic acid (R)-1, a key
intermediate for the antithrombotic agent clopidogrel, was obtained in 65% yield and 98%
ee by Dutch resolution of rac-1 with (S)-2-hydroxyl-3-(p-chlorophenoxy) propylamine (S)-5
as resolving agent and (S)-2-hydroxyl-3-(o-nitrophenoxy) propylamine (S)-4 as nucleation inhibitor.
Chirality 00:000–000, 2012. © 2012 Wiley Periodicals, Inc.
KEY WORDS: racemic o-chloromandelic acid; diastereomeric resolution; aryloxypropylamine
INTRODUCTION
presented on the diastereomeric resolution of rac-1 with
enantiopure aryloxypropylamine.
The (R)-o-chloromandelic acid (R)-1 is the key chiral inter-
mediate for the industrial synthesis of the antiplatelets aggre-
gation agent clopidogrel1–4 (Fig. 1). Known processes for
producing the chiral acid include (1) asymmetric synthesis
via metal catalysts5–7 or biocatalyst;8,9 (2) racemic resolution
by chromatography;10 (3) racemic resolution from the
racemic acid,11 the corresponding nitrile/ester12–15 or alpha-
keto acids16,17 using microbial methods; (4) alcoholysis
of 1,3-dioxolane-2,4-diones with chiral auxiliary;18 and (5)
diastereomeric salt resolution.19–22
Processes (1)–(4) consist of using metal catalysts, chiral
organic catalysts, whole living cells, and isolated enzymes.
With these methods, (R)-1 could be obtained in high optical
purity. However, these methods are used mainly in laboratory
scale because of the high price of the efficient chiral ligands
and catalysts and also due to the lack of efficient, scalable
processes for industrial purposes. Therefore, diastereomeric
resolution of racemic mixtures remained an economical and
frequently used procedure at chemical and pharmaceutical
industries nowadays.
Because of the practical application, the diastereomeric res-
olution of rac-1 has attracted scholars’s interest. However,
there were a limited number of reports on it. To our knowl-
edge, there were only three kinds of resolving agents for res-
olution of rac-1: enantiopure N-benzyl-a-phenylethanamine
(BPA),19 1-aryl-2-amino-1,3-propane-diol (SA),21,22 and alanine20
(Fig. 2). Using BPA, (R)-1 can be obtained in high yield and
high optical purity, but the price of BPA is high. Enantiopure
SA is not easy to get on account of its two chiral centers,
which can be obtained by optical resolution or asymmetric
synthesis. With optical pure alanine, the diastereomeric salt
needs to be recrystallized once or more, the yield of (R)-1
is low. So, exploring new resolving agent that is cheap and
easy to obtain is necessary.
Enantiopure aryloxypropylamine with a base site, an aro-
matic ring, a hydrogen bond donor, or acceptor, appears to
be a good candidate for chiral discrimination processes.
Additionally, it is easy to synthesize.23 In our previous
wok, aryloxypropylamine could be kinetic resolved by C-12
higher carbon sugar without enzymes24 and was used for
the chiral preparation of optically pure b-blockers.25 There
was no report on the enantiopure aryloxypropylamine used
as resolving agent. In order to expand the scope of applica-
tion of enantiopure aryloxypropylamine, we explored the
resolution with it. Herein, the preliminary results were
© 2012 Wiley Periodicals, Inc.
EXPERIMENTAL
General
Racemic o-chloromandelic acid rac-1 was purchased from Sinopharm
Chemical Reagent Co., Ltd (China) and was used without further purifica-
tion. The resolving agents (S)-2, (S)-3, (S)-4, (S)-5, (S)-6, and (S)-7 were
synthesized according to the reported method25 and determined by
NMR, high-performance liquid chromatography (HPLC), or optical rota-
tion. Results implied that they were all enantiopure. 1H NMR and 13C
NMR were recorded at 400 MHz on Bruke Avance II using D2O and
CDCl3 (Tenglong Weibo Technology Co., Ltd, Qingdao, China) as solvent,
and tetramethylsilane was used as the internal reference. The optical
purity of resolving agents were determined by optical rotation on PolAAr
3001 (Optical Activity Limited) or by HPLC using chiral column Lux
Cellulose-1 (4.6 ꢀ 250 mm I.D., 3 mm, Phenomenex). The optical purity of
the acid 1 liberated from salt was determined by HPLC using chiral column
Lux Cellulose-2 (4.6 ꢀ 250 mm I.D., 3 mm, Phenomenex). Infrared (IR)
spectra were measured on a JASCO FT/IR-230 spectrometer in KBr
pellets. Melting points were obtained on Shimadzu DSC-60A.
Preparation of resolving agents (S)-2, (S)-3, (S)-4, (S)-5, (S)-6,
and (S)-7. Resolving agents were synthesized according to reported
method.25 Preparation of (S)-2: 2-chlorophenol was added to (S)-
epichlorohydrin in the presence of K2CO3 with stirring. The mixture
was heated and kept at 110 ꢁC for 2–3 h followed by filtration and con-
centrated under vacuum pressure to recover the (S)-epichlorohydrin.
The residue was added dropwise into excess ammonia water for 24 h
at room temperature. Filtrated the deposition, filter liquor was vapo-
rated under vacuum to remove the water and excess NH3, then dis-
solved the residue with hot ethyl acetate and white deposition
appeared. The precipitate (S)-2 was filtrated. If the optical purity of
(S)-2 was not high, (S)-2 could be recrystallized in ethyl acetate.
Additional Supporting Information may be found in the online version of
this article.
Contract grant sponsor: National Natural Science Foundation of China; Con-
tract grant number: 81172937.
Contract grant sponsor: New Teachers’ Fund for Doctor Stations, Ministry of
Education; Contract grant number: 20114101120013.
Contract grant sponsor: China Postdoctoral Science Foundation; Contract
grant number: 20100480857.
Contract grant sponsor: Special Financial Grant from the China Postdoctoral
Science Foundation; Contract grant number: 201104402.
*Correspondence to: Hong-Min Liu, School of Pharmaceutical Sciences
and New Drug Research & Development Center, Zhengzhou University,
No. 100 of Science Road, Zhengzhou, 450001, People’s Republic of China.
E-mail: liuhm@zzu.edu.cn
Received for publication 29 February 2012; Accepted 29 May 2012
DOI: 10.1002/chir.22089
Published online in Wiley Online Library
(wileyonlinelibrary.com).

WANG ET AL.
7.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) d 163.6, 141.7, 125.9, 114.5,
70.7, 69.8, 43.7. HRMS (ESI) calcd. for C9H12N2O4 [M + H]+: 213.0797,
found 213.0872. ½aꢃD19 = +3.0 (c 1.0, Methanol).
Determination of diastereomeric excess of 1 in the salt. The
diastereomeric excess (% de) of the salt (=enantiomeric excess (% ee)
of 1) was determined by HPLC with Lux Cellulose-2 column
(4.6 ꢀ 250 mm I.D., 3 mm, Phenomenex). The salt was treated with
HCl aq. The liberated acid was extracted by ethyl acetate and dried with
anhydrous Na2SO4. After removal of solvent under reduced pressure,
the enantiopurity of the liberated 1 was determined by HPLC analysis
on chiral column Lux Cellulose-2. The mobile phase was hexane/ethanol
(93/7) with 0.15% trifluoroacetic acid (TFA), and flow rate was 1.0 ml/min
under detection wavelength of 210nm. Retention time: (S)-1 15.47min,
(R)-1 18.16 min.
Fig. 1. The structure of Clopidogrel.
Preparation of (S)-3, (S)-4, (S)-5, (S)-6, and (S)-7 was the same as that of
(S)-2, just replacing the 2-chlorophenol with 2-methoxylphenol, 2-nitrophenol,
4-choloro phenol, 3-nitrophenol, and 4-nitrophenol, respectively.
(S)-2. Yield: 82%; mp: 102–106 ꢁC; IR (KBr): 3381, 3140, 3069, 2935,
2869, 1589, 1577, 1487, 1455, 1298, 1283, 1252, 1102, 1073,1062, 1002,
958, 749, 692 cmꢂ1 1H NMR (400 MHz, CDCl3) d 7.38 (dd, J = 7.9,
;
Resolution of rac-1. Traditional resolution procedure is as follows.
To a 5 ml flask were added 186 mg of rac-1 (1 mmol), 1 mmol of
resolving agent, and 1 ml of resolving solvent followed by heating under
stirring to obtain a clear solution at 70 ꢁC. The solution was gradually
cooled to 25 ꢁC and kept for about 7 days,1 and the precipitated diastereo-
meric salt was filtered off and washed with cooled resolving solvent to
yield salt crystals, followed by drying at 45 ꢁC under vacuum.
Dutch resolution procedure was the same as traditional resolution
procedure, just replacing 0.1 mmol of resolving agent with additive. In
other words, 0.9 mmol resolving agent and 0.1 mmol additive were added
to the resolution system.
1.6 Hz, 1H), 7.23 (td, J= 8.3, 1.6 Hz, 1H), 6.94 (ddd, J= 15.1, 7.8, 1.3 Hz, 2H),
4.13–3.97 (m, 3H), 3.02 (dd, J= 12.9, 4.1 Hz, 1H), 2.98–2.89 (m, 1H). 13C
NMR (101 MHz, CDCl3) d 154.1, 130.2, 127.8, 122.9, 121.8, 113.6, 71.5,
70.0, 44.0. High-resolution mass spectrometry (HRMS) (electrospray
ionization, ESI) calcd. for C9H12ClNO2 [M + H]+: 202.0557, found 202.0634.
The optical purity of (S)-2 was determined by HPLC with Lux Cellulose-1
column (4.6 ꢀ 250 mm I.D., 3 mm, Phenomenex). The mobile phase was
hexane/isopropanol (50/50) with 0.2% diethylamine and flow rate
was 0.8 ml/min under detection wavelength of 224 nm. Retention
time: (S)-2 5.82 min, (R)-2 6.95 min. ½aꢃ1D9 = +9.5 (c 1.0, Methanol).
Analytical data of the less soluble salt (R)-1ꢄ(S)-5 by the Dutch resolu-
(S)-3. Yield: 87%; mp: 97–101 ꢁC; IR (KBr): 3417, 3007, 2935, 2841,
tion are shown as follows. (R)-1ꢄ(S)-5: ½aꢃ2D1 = ꢂ78 (c 1.0, Ethanol); mp:
126–130 ꢁC; IR (KBr) cmꢂ1 : 3394, 3101, 2921, 1583, 1492, 1473, 1438,
1367, 1285, 1245, 1088, 821, 749; 1H NMR (400 MHz, D2O) d 7.33–7.27
(m, 1H), 7.27–7.21 (m, 1H), 7.18 (dd, J = 9.1, 3.3 Hz, 4H), 6.81 (d,
J = 8.9 Hz, 2H), 5.17 (s, 1H), 4.09 (dt, J = 8.4, 4.1 Hz, 1H), 3.92 (qd,
J = 10.3, 4.6 Hz, 2H), 3.11 (dd, J = 13.2, 3.3 Hz, 1H), 3.00 (dd, J = 13.2,
9.1 Hz, 1H).; 13C NMR (101 MHz, D2O): 178.6, 156.5, 137.6, 133.2,
129.7, 129.6, 129.4, 129.3, 127.3, 125.7, 125.7, 116.0, 72.0, 69.6, 65.9, 41.6.
1594, 1509, 1465, 1450, 1258, 1230, 1125, 1025, 913, 860, 747 cmꢂ1 1H
;
NMR (400 MHz, CDCl3) d 7.03–6.85(m, 4H), 4.12–4.03 (m, 1H), 3.99
(dq, J = 12.6, 6.3 Hz, 2H), 3.90–3.83 (m, 3H), 2.96 (d, J = 12.7 Hz, 1H),
2.88 (t, J = 8.7 Hz, 1H), 2.48–1.76 (m, 3H). 13C NMR (101 MHz, CDCl3) d
149.8, 148.1, 122.0, 121.0, 114.8, 111.8, 72.4, 70.3, 55.8, 44.0. HRMS
(ESI) calcd. for C10H15NO3 [M + H]+: 198.1127, found 198.1127. The
optical purity of (S)-3 was determined as the same as (S)-2. Retention
time: (S)-3 7.75 min, (R)-3 22.98 min. ½aꢃ2D0 = +5.5 (c 1.0, Methanol).
(S)-4. Yield: 83%; mp: 91–95 ꢁC; IR (KBr): 3378, 3301, 3190, 2921,
2881, 1610, 1583, 1524, 1347, 1278, 1169, 1151, 1089, 1201, 860,
RESULTS AND DISCUSSION
Traditional Resolution of Rac-1 with Resolving Agents
743 cmꢂ1 1H NMR (400 MHz, CDCl3) d 7.87 (d, J = 8.1 Hz, 1H), 7.55
;
(t, J = 7.9 Hz, 1H), 7.24–6.91 (m, 2H), 4.63–4.08 (m, 2H), 4.01 (dt,
J = 10.1, 5.0 Hz, 1H), 2.96 (ddd, J = 19.3, 12.8, 5.4 Hz, 2H). 13C NMR
(101 MHz, CDCl3) d 151.7, 138.6, 135.5, 125.9, 121.1, 115.0, 71.2, 67.9,
42.3. HRMS (ESI) calcd. for C9H12N2O4 [M + H]+: 213.0797, found
Optical active (R)-phenylethylamine (PEA) is well known to
be a good resolving agent for mandelic acid derivatives.26–28
The m-chloromandelic acid and p-chloro mandelic acid can
be resolved by enantiopure PEA, but rac-1 could not.29
Maybe, the o-chlorine disturbs the aromatic interactions of
PEA and o-chloromandelic acid. In order to find the suitable
resolving agent for rac-1, enantiopure aryloxypropylamines
with heteroatom Cl or hetero groups OCH3 and NO2 on ben-
zene ring were chosen as resolving agents.30,31 Halogen
bonding interactions may occur between chlorine of rac-1
and heteroatoms (Fig. 3). A series of aryloxypropylamines
were synthesized according to the reported method.25
213.0878. ½aꢃ2D0 = +7.0 (c 1.0, Methanol).
(S)-5. Yield: 91%; mp: 115–119 ꢁC; IR (KBr): 3345, 3276, 3066, 2962,
2923, 2870, 2750, 1596, 1581, 1492, 1466, 1317, 1289, 1248, 1219, 1170,
1118, 1102, 1028, 999, 823, 673 cmꢂ1 1H NMR (400 MHz, CDCl3) d
;
7.28–7.21 (m, 2H), 6.91–6.81 (m, 2H), 4.01–3.91 (m, 3H), 3.03–2.94 (m,
1H), 2.86 (ddd, J = 12.7, 7.3, 3.6 Hz, 1H). 13C NMR (101 MHz, CDCl3) d
157.2, 129.3, 125.9, 115.7, 70.4, 70.2, 43.9. HRMS (ESI) calcd. for
C9H12ClNO2 [M + H]+: 202.0557, found 202.0633. The optical purity of
(S)-5 was determined as the same as (S)-2. Retention time: (S)-5
5.53 min, (R)-5 6.35 min. ½aꢃ1D9 = +4.5 (c 1.0, Methanol).
(S)-6. Yield: 83%; mp: 105–109 ꢁC; IR (KBr): 3336, 3290, 3100, 2950,
2927, 2862, 2789, 1615, 1581, 1514,1481, 1461,1355, 1321,1253, 1139,
1In the resolution of rac-1 with (S)-5 and (S)-4, in order to obtain the less
soluble salt in a short time, three types of experiments were performed:
(a) stay the solution containing the less soluble salt at 0ꢁC, (b) stir the
solution containing the less soluble salt at room temperature, (c) stir the
solution containing the less soluble salt at 0 ꢁC. As a result, the salt precip-
itated at moment with the conditions (a) and (c). However, the salt turned
sticky immediately once it was put at room temperature. So, it is too difficult
to filter the salt. With condition (b), the salt precipitated in half to 1 h and
the salt was powdered; the yield of the salt was 82%. However, the enantio-
purity of the salt was poor, and the de value was 23%. When the solution was
stayed at room temperature for 7 days, the precipitation was spherical,
which was easy to filter, and the enantiopurity of the salt was high, the ee
value was 98%. So, it was the best choice for obtaining the best salt when
staying the solution for 7 days at room temperature.
1003, 990, 906, 863, 815, 791, 737 cmꢂ1 1H NMR (400 MHz, CDCl3) d
;
7.90–7.81 (m, 1H), 7.77 (t, J = 2.1 Hz, 1H), 7.45 (t, J = 8.2 Hz, 1H), 7.27
(dd, J = 8.6, 2.7 Hz, 1H), 4.12–4.05 (m, 2H), 4.01 (ddd, J = 11.9, 9.1,
4.4 Hz, 1H), 3.02 (dd, J = 12.8, 3.9 Hz, 1H), 2.88 (dd, J = 12.8, 7.1 Hz, 1H).
13C NMR (101 MHz, CDCl3) d 159.2, 149.1, 130.0, 121.6, 116.1, 108.9,
70.8, 70.0, 43.7. HRMS (ESI) calcd. for C9H12N2O4 [M + H]+: 213.0797,
found 213.0870. ½aꢃD20 = +2.5 (c 1.0, Methanol).
(S)-7. Yield: 86%; mp: 125–129 ꢁC; IR (KBr): 3354, 3298, 3076, 2933,
2883, 2831, 2717, 1622, 1606, 1593, 1498, 1451, 1344, 1270, 1179, 1112,
1090, 982, 939, 861, 824, 752, 683 cmꢂ1 1H NMR (400 MHz, CDCl3) d
;
8.32–8.17 (m, 2H), 7.08–6.93 (m, 2H), 4.14–4.05 (m, 2H), 4.01 (ddd,
J = 9.3, 7.2, 5.1 Hz, 1H), 3.03 (dd, J = 12.8, 4.0 Hz, 1H), 2.87 (dd, J = 12.8,
Chirality DOI 10.1002/chir

DIASTEREOMERIC RESOLUTION OF RACEMIC O-CHLOROMANDELIC ACID
Fig. 2. Structures of enantiopure N-benzyl-a-phenylethanamine (BPA), 1-aryl-2-amino-1,3-propane-diol (SA), and Alanine.
Fig. 3. Resolving agents (S)-2, (S)-3, (S)-4, and (S)-5.
An equimolar resolving agent was used with rac-1 (186 mg,
1 mmol), the resolving solvent was chosen from ethanol and
isopropanol, and the volume was 1 ml. Experimental results
are summarized in Table 1.
widening the width of the metastable zone of supersaturation
(the temperature of the zone between dissolution and the
lower temperature at which precipitation begins) to a greater
extent for the more soluble salt than the less soluble salt.36,37
Therefore, to increase the optical purity of the less soluble
salt, Dutch resolution of rac-1 was carried out with (R)-4 or
(S)-4 as additive. 0.9 equimolar resolving agent and 0.1 equi-
molar (R)-4 or (S)-4 were used with rac-1 (186 mg, 1 mmol),
the resolution solvent was isopropanol, and the volume was
1 ml. Experimental results are summarized in Table 2.
To our excitement, three aryloxypropylamines gave good
to excellent yield of salt although the chiral purity was poor
(0–26% de, E = 0–35%) (Table 1, entries 2–4 and 7–8). (S)-2,
(S)-3, and (S)-5 were benefits to the precipitation of salt
except (S)-4. From comparison, para-chloro aryloxypropyla-
mine (S)-5 was better in chiral recognition. Maybe, para-
substituted group affected the CH/p interaction slightly while
ortho-substituted group seriously.32 To clarify the resolving
agents with different substituted groups on phenyl ring show-
ing different chiral recognition abilities, a more in-depth anal-
ysis is necessary. Weak molecular forces, the crystal packing,
the state of hydration, and the ion-pair interactions in the sol-
vent may give rise to differences in solubility and resolution.
The salt of (S)-4 and rac-1 had difficulty in precipitation;
therefore, to improve the optical purity of the diastereomeric
salt, Dutch resolution was carried out with enantiopure 4.
TABLE 2. Dutch resolution of rac-1 with resolving agents in
the presence of enantiopure 4
Entry Resolving agenta Additiveb Yield(%)c de(%)d E(%)e
1
2
3
4
5
6
(S)-2
(S)-3
(S)-5
(R)-4
(S)-4
(R)-4
(S)-4
(R)-4
(S)-4
18
36
60
100
16
65
3
5
8
10
80
98
1
2
5
10
13
64
Dutch Resolution of Rac-1 with Resolving Agents
Dutch resolution is the use of structurally related resolving
agents. A mixture of these resolving agents could result in
high diastereomeric excesses of the less soluble salt.33–35
Further investigations revealed that certain family members
of resolving agents were efficient nucleation inhibitors, which
did not incorporate into the less soluble salt. Inhibitor acts by
aMolar ratio of resolving agent to rac-1 was 0.9/1.0, concentration of rac-1 was
186 mg/ml.
bMolar ratio of additive to rac-1 was 0.1/1.0.
cBased on a half amount of the rac-1 used.
dde of the salt was based on the ee of the acid 1 liberated from the salt.
eResolution efficiency E(%) = Yield(%) ꢀ de(%).
TABLE 1. Traditional resolution of rac-1 with resolving agents in ethanol and isopropanol
Entry
Resolving agenta
Solvent
Absolute configuration
Yield(%)b
de(%)c
E(%)d
1
2
3
4
5
6
7
8
(S)-2
Ethanol
Isoprapanol
Ethanol
Isoprapanol
Ethanol
Isoprapanol
Ethanol
R
R
R
R
R
R
R
R
26
93
110
157
0
3
5
6
0
3
6
9
(S)-3
(S)-4
(S)-5
No salts precipitate
No salts precipitate
98
134
16
26
16
35
Isoprapanol
aMolar ratio of resolving agent to rac-1 was 1.0/1.0, concentration of rac-1 was 186 mg/ml.
bBased on a half amount of the rac-1 used.
cde of the salt was based on the ee of the acid 1 liberated from the salt.
dResolution efficiency E(%) = Yield(%) ꢀ de(%).
Chirality DOI 10.1002/chir

WANG ET AL.
The addition of (R)-4 or (S)-4 indeed lead to a decrease in
It is noteworthy that rac-1 could be well resolved by using
(S)-5 as resolving agent in the presence of m- and p-nitro-
phenoxypropylamines (S)-6 and (S)-7. (S)-6 and (S)-7 also
worked as well as o-nitrophenoxypropylamine (S)-4 in
improving the resolution of rac-1 (Table 3 entries 5 and
6, Table 2 entry 6). However, (S)-4 was better in the salt
yield and optical purity (Table 2entry 6 vs Table 3 entries
5 and 6). As a result, (R)-1 could be obtained in 65% yield
with 98% ee. So, the nitro-aryl aromatics may be potential
nucleation inhibitors.
the yield of salt (Table 2 entries 2 and 3 vs Table 1 entry 2;
Table 2 entries 4 and 5 vs Table 1 entry 4; Table 2 entries 5
and 6 vs Table 1 entry 8). In the case of (S)-2 and (S)-3 as
resolving agents, (R)-4 or (S)-4 did not improve the optical
purity of the less soluble salt. However, it was found that
the use of (R)-4 or (S)-4 as additive cooperated with (S)-5
could improve the purity of salt significantly (Table 2 entries
5 and 6 vs entries 1–4). The best salt was obtained in 65%
yield with 98% de (Table 2 entry 6). The composition of the
salt precipitated from the solution of rac-1, (S)-5, and (S)-4
was checked by NMR. From the NMR data, it was found that
the salt contained only (S)-5 and o-chloromandelic acid; there
was no detectable amount of (S)-4 or (R)-4.
CONCLUSION
With this new kind of resolving agent, racemic o-chloromandelic
acid rac-1 was successfully resolved by Dutch resolution. Using
(S)-5 as resolving agent and (S)-4 as nucleation inhibitor, (R)-1
could be obtained in 65% yield with 98% ee. Structurally related
resolving agents were potential nucleation inhibitors, especially
the nitro-aryl aromatics. Further investigations on resolving
other acids with this new agent and the synthetic applications
of resolved acid are currently in progress.
Both (S)-4 and (R)-4 worked as efficient nucleation inhi-
bitors. Moreover, (S)-4, which has the same chiral sense
with the resolving agent (S)-5, is better compared with
(R)-4 (Table 2 entry 5 vs 6). Therefore, more exploration
on the inhibitors was carried out, especially the additives
enantiopure aryloxypropylamines (S)-6 and (S)-7 with nitro
group on benzene ring (Fig. 4). 0.9 equimolar resolving agent
and 0.1 equimolar additive were used with rac-1 (186 mg,
1 mmol), the resolving solvent was isopropanol, and the volume
was 1 ml. Experimental results are summarized in Table 3.
The additions of (S)-6 and (S)-7 also gave decreased yields
(Table 3 entries 1 and 2 vs Table 1 entry 4; Table 3 entries 3
and 4 vs Table 1 entry 2; Table 3 entries 5 and 6 vs Table 1
entry 8). In the case of (S)-3 as resolving agent, additives
(S)-6 and (S)-7 did not improve the optical purity (Table 3
entries 1 and 2). Cooperating with (S)-2, (S)-6, and (S)-7
resulted in no salt (Table 3 entries 3 and 4). However, in
the presence of (S)-5, good resolution was obtained with
the salt in moderate yield and excellent de value (Table 3
entries 5 and 6).
ACKNOWLEDGMENT
We are indebted to Mr. Bing Zhao for the NMR.
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Entry Resolving agenta Additiveb Yield(%)c de(%)d E(%)e
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1
2
3
4
5
6
(S)-3
(S)-2
(S)-5
(S)-6
(S)-7
(S)-6
(S)-7
(S)-6
(S)-7
100
144
2
1
2
1
No salts precipitate
No salts precipitate
52
50
98
96
51
48
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bMolar ratio of additive to rac-1 was 0.1/1.0.
cBased on a half amount of the rac-1 used.
dde of the salt was based on the ee of the acid 1 liberated from the salt.
eResolution efficiency E(%) = Yield(%) ꢀ ee(%).
Chirality DOI 10.1002/chir

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