Calcium(II)-mediated resolution of methyl o-chloromandelate with chiral O,O′-dibenzoyltartaric acid in preparative scale

Article abstract of DOI:10.1515/mgmc-2018-0043

We report here the coordination-mediated resolution of methyl o-chloromandelate, which is a key intermediate for clopidogrel, in preparative scale. The reaction of CaO, optically pure (2R, 3R)-O,O′-dibenzoyltartaric acid, and methyl o-chloromandelate in ethanol solution afforded a mixed-ligands calcium(II) complex that was further purified by stirring of the crystals in hot methanol. Methyl (R)-o-chloromandelate was obtained in good enantiomeric excess value (>99.5%) and yield (71%) by treatment of the complex with acid. At the same time, (2R, 3R)-O,O′-dibenzoyltartaric acid was recovered in 72% yield. In addition, methyl (S)-o-chloromandelate was obtained in good enantiomeric excess value (>99.5%) and yield (73%) by recovery from the mother liquor and resolution with the same procedure for methyl (R)-o-chloromandelate, except that (2S, 3S)-O,O′-dibenzoyltartaric acid was used as the resolving reagent.

Full text of DOI:10.1515/mgmc-2018-0043

Main Group Met. Chem. 2018; aop
Hong-Wu Xu*, Li-Huan Wu, Qiang Ren, Cui-Yu Liu and Guan-Qing Yan
Calcium(II)-mediated resolution of methyl
o-chloromandelate with chiral O,O′-
dibenzoyltartaric acid in preparative scale
https://doi.org/10.1515/mgmc-2018-0043
Methyl (R)-o-chloromandelate, a key intermediate for
clopidogrel (Bousquet and Musolino, 1999), can be pre-
pared using the following three methods. The first one
is the esterification of the corresponding (R)-carboxylic
acid, which can be resolved by some traditional resolution
methods (Hyoda and Nawata, 2001; Noda et al., 2001; Peng
et al., 2012; Yin et al., 2010; Hu et al., 2012; Wang et al., 2012;
Chen and Yang, 2014). The second one is the direct asym-
metric catalysis, in which methyl o-chlorobenzoylformate
or α-diazo-(2-chlorophenyl)acetate can be transformed to
methyl (R)-o-chloromandelate by some chiral metal cata-
lysts (Zhu et al., 2008, 2010; Yin et al., 2009). The last one
is biotransformation, in which o-chlorobenzoylformate
can be transformed to methyl (R)-o-chloromandelate with
some enzymes (Ema et al., 2007, 2008; Uhm et al., 2007;
Jeong et al., 2010; Ma et al., 2012; Ni et al., 2012; Shen
et al., 2012; Xu et al., 2014). However, these methods were
studied mainly in the laboratory because of the high costs.
The optically pure derivatives of tartaric acid can be
used in the coordination-mediated resolution of chiral
Received August 7, 2018; accepted October 23, 2018
Abstract: We report here the coordination-mediated reso-
lution of methyl o-chloromandelate, which is a key inter-
mediate for clopidogrel, in preparative scale. The reaction
of CaO, optically pure (2R, 3R)-O,O′-dibenzoyltartaric
acid, and methyl o-chloromandelate in ethanol solution
afforded a mixed-ligands calcium(II) complex that was
further purified by stirring of the crystals in hot metha-
nol. Methyl (R)-o-chloromandelate was obtained in good
enantiomeric excess value (>99.5%) and yield (71%) by
treatment of the complex with acid. At the same time,
(2R, 3R)-O,O′-dibenzoyltartaric acid was recovered in
72% yield. In addition, methyl (S)-o-chloromandelate was
obtained in good enantiomeric excess value (>99.5%) and
yield (73%) by recovery from the mother liquor and resolu-
tion with the same procedure for methyl (R)-o-chloroman-
delate, except that (2S, 3S)-O,O′-dibenzoyltartaric acid
was used as the resolving reagent.
Keywords: calcium(II); coordination; methyl (R)-o-chlo- acids, alcohols, esters, and P-heterocycles (Mravik et al.,
romandelate; methyl (S)-o-chloromandelate; O,O′- 1996, 1997, 1998; Xu et al., 2005; Ujj et al., 2010, 2015; Bagi
dibenzoyltartaric acid; resolution.
et al., 2014, 2016a,b). The reaction of the corresponding
salt, resolution reagent, and racemate can afford a mixed-
ligands complex, in which the resolution reagent and one
of the enantiomers coordinate to the metal ion. The single
enantiomer can be obtained by treatment of the complex
with acid. Because they are a series of relatively cheap and
nontoxic resolution agents, this method is a promising
one in the pharmaceutical industry.
Herein, we report the coordination-mediated reso-
lution of methyl o-chloromandelate with chiral O,O′-
dibenzoyltartaric acid (DBTA) and CaO in preparative
scale.
Introduction
Chiral drugs play more and more important roles in our eve-
ryday life (Lin et al., 2011). There are three ways to obtain
the enantiomerically enriched substances: natural chiral
compounds or their derivatives, optical resolution of race-
mates, and asymmetric synthesis. Although many asym-
metric catalytic reactions were developed in recent years,
optical resolution is more widely used in the pharmaceuti-
cal industry (Lorenz and Seidel-Morgenstern, 2014).
Results and discussion
*Corresponding author: Hong-Wu Xu, Department of Environmental
and Chemical Engineering, Zhaoqing University, Zhaoqing, 526061,
Guangdong, China, e-mail: xuhongwu@zqu.edu.cn
Li-Huan Wu, Qiang Ren, Cui-Yu Liu and Guan-Qing Yan: Department
of Environmental and Chemical Engineering, Zhaoqing University,
Zhaoqing, 526061, Guangdong, China
Preparation of Ca(L-HL0)2((R)-1)2
The resolving agent Ca(L-HL0)2 was prepared by the
reaction of a solution of L-DBTA (L-H2L0) and CaO in hot
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ꢀꢀꢀꢁ
2ꢀ ꢀH.-W. Xu et al.: Resolution of methyl o-chloromandelate
ethanol for approximately 2 h (Mravik et al., 1996). Then, that the reaction can be performed very well in kilograms
racemic methyl o-chloromandelate (Rac-1) in ethanol was grade. Therefore, this method is promising for the prepa-
added. After stirring for about 30 min at 80°C, a white ration of methyl (R)-o-chloromandelate and clopidogrel in
precipitate formed, and the suspension was stirred for an the pharmaceutical industry.
additional 5 hours at the same temperature (Figure 1). The
white precipitate was collected by filtration and character-
ized as Ca(L-HL0)2((R)-1)2 by elemental and ICP analyses. Recovery and resolution of methyl (S)-o-
The coordinative complex was further purified by stirring
of the crystals in hot methanol. The complete dissolution
chloromandelate from the mother liquor
of the crystals was not necessary because the procedure Although methyl (S)-o-chloromandelate ((S)-1) cannot be
was sufficient enough to obtain the diastereomerically used in the synthesis of clopidogrel, it is still a potential
pure complex (Ujj et al., 2015). In the complex, there are chiral reagent. Therefore, the crude methyl (S)-o-chlo-
−
two L-HL0 ions and two methyl (R)-o-chloromandelate romandelate was recovered by treatment of the mother
molecules that coordinate to a calcium(II) ion. The reason liquor, which was obtained from the preparation of Ca(L-
is that calcium(II) has a large coordinating capacity for HL0)2((R)-1)2, and resolved by the same procedure for
oxygen-containing ligands (Mravik et al., 1996; Ujj et al., methyl (R)-o-chloromandelate, except that D-DBTA was
2010, 2015; Bagi et al., 2014, 2016a,b).
used as the resolving reagent. Optically active methyl
(S)-o-chloromandelate was obtained in good enantiomer
selectivity (>99.5% ee) and yield (73%).
Decomposition of the complex
The (R)-(ꢀ−)-form of methyl o-chloromandelate was Conclusions
obtained in good enantiomer selectivity [>99.5% enan-
tiomeric excess (ee)] and yield (71%) by treatment of the We have described a successful example of coordination-
complex with 2 mol/L hydrogen chloride. At the same mediated resolution of methyl o-chloromandelate in pre-
time, L-DBTA was recovered in 72% yield. The results show parative scale using chiral O,O′-dibenzoyltartaric acid
Figure 1:ꢀCoordination-mediated resolution of methyl o-chloromandelate with chiral O,O′-dibenzoyltartaric acid.
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ꢂ3
H.-W. Xu et al.: Resolution of methyl o-chloromandelateꢂ
The complex was taken up in 1700 mL of methanol. The suspen-
sion was stirred at 60°C for 4 h and then cooled to room temperature.
The crystals were filtered off, washed with methanol, and air-dried
overnight at room temperature to give 1098 g of Ca(L-HL0)2((R)-1)2.
Yield: 76% (based on the half of racemic methyl o-chloromandelate).
De: >99.5%.
and CaO as resolving reagents. Methyl (R)-o-chloroman-
delate can be obtained in high enantiomeric excess value
(>99.5%) and yield (71%). Moreover, methyl (S)-o-chloro-
mandelate in the mother liquor can also be resolved in
high enantiomeric excess value (>99.5%) and yield (73%)
by the same way after recovery.
Decomposition of the complex:ꢁThe complex was suspended in
1000 mL of 2 mol/L hydrochloric acid and 1000 mL of toluene. The
mixture was warmed to 60°C for 3 h with vigorous stirring, cooled
to room temperature, and seeded with 2 g of L-DBTAꢀ·ꢀH2O. The pre-
cipitate (L-DBTAꢀ·ꢀH2O, 746 g) was filtered and washed with 500 mL
of toluene. The toluene layer was separated, and the aqueous layer
was extracted with toluene (3ꢀ×ꢀ100 mL). The organic phases were
combined, washed with 0.5 mol/L NaHCO3 solution (3ꢀ×ꢀ100 mL),
and dried over sodium sulfate. The filtrate was concentrated to
give optically active methyl (R)-o-chloromandelate (355 g). Yield:
71.0% (based on the half of racemic methyl o-chloromandelate). ee:
Experimental
Material and reagents
All the other reagents were purchased from commercial sources and
were used without purification.
[α]2D0 = −179.0
Physical measurements
>99.5%;
(cꢀ=ꢀ1.0, CHCl3), {lit. (Ema et al., 2008) for
[α]1D9 :–178.3
1
the (R) isomer:
(cꢀ=ꢀ1.3, CHCl3)}. H NMR (600 MHz,
CDCl3), δ: 7.38–7.40 (m, 2H, Ar-H), 7.26–7.28 (m, 2H, Ar-H), 5.57 (s, 1H,
Optical rotations were measured on a Perkin-Elmer 341 polarimeter
(Perkin-Elmer, Waltham, MA, USA). IR spectra were recorded on a
SHIMADZU IRTracer-100 spectrophotometer (Shimadzu (China),
Shanghai, China) over the range 4000–400 cm−1 using KBr pellets.
1H NMR spectra were measured on a Bruker (600 MHz) spectrometer
(Bruker, Germany). The elemental (C, H, N) analyses of the powdered
samples were performed on a Perkin-Elmer model 240C automatic
instrument. The concentration of Ca2+ in the complex was deter-
mined using an IRIS Advantage (Thermo-Fisher Scientific, Carlsbad,
CA, USA) ICP spectrophotometer after heating to 400°C and treat-
ment with acid. The enantiomeric excess value of methyl o-chloro-
mandelate was determined by HPLC analyses using an Shimadzu
LC20AT instrument (Shimadzu (China), Shanghai, China) equipped
with Daicel Chiralpak AD-H column (4.6ꢀ×ꢀ250 mm) [hexane/2-pro-
panol (95:5); flow rate, 1.0 mL/min; detection wavelength, 254 nm;
retention time, 14.1 min for (S)-form, 15.4 min for (R)-form].
CH), 3.76 (s, 3H, CH3), 3.68 (brs, 1H, OH) ppm.
Recovery and resolution of methyl (S)-o-chloromandelate from the
mother liquor:ꢁThe mother liquor, which was obtained from the
preparation of Ca(L-HL0)2((R)-1)2, was concentrated by the evapora-
tion of the solvent. The residue was suspended in 1000 mL of 1 mol/L
hydrochloric acid and 1000 mL ethyl acetate. The mixture was
warmed to 60°C for 2 h with vigorous stirring and then cooled to room
temperature. The organic layer was separated and the aqueous layer
was extracted with ethyl acetate (3ꢀ×ꢀ100 mL). The organic phases were
combined, washed with 0.5 mol/L NaHCO3 solution (3ꢀ×ꢀ200 mL), and
dried over sodium sulfate. The filtrate was concentrated to give crude
methyl (S)-o-chloromandelate (565 g, 63.5% ee), which was resolved
with D-DBTAꢀ·ꢀH2O (1036 g) and CaO (77 g) in 2200 mL of ethanol by the
same procedures described above for methyl (R)-o-chloromandelate.
Optically active methyl (S)-o-chloromandelate (365 g) was obtained.
Yield: 73.0% (based on the half of racemic methyl o-chloromande-
[α]2D0 = +179.1
1
late). ee: >99.5%;
(cꢀ=ꢀ1.0, CHCl3). H NMR (600 MHz,
Resolution of methyl o-chloromandelate
CDCl3), δ: 7.38–7.40 (m, 2H, Ar-H), 7.26–7.28 (m, 2H, Ar-H), 5.57 (s, 1H,
CH), 3.76 (s, 3H, CH3), 3.68 (brs, 1H, OH) ppm.
Preparation of Ca(L-HL0)2((R)-1)2:ꢁCaO (77 g, 1.375 mol) was added
to a solution of L-DBTAꢀ·ꢀH2O (1036 g, 2.75 mol) in 1700 mL of etha-
nol at 80°C. After stirring for approximately 2 h, CaO was dissolved
and the mixture became clear. Racemic methyl o-chloromandelate
(1000 g, 5 mol) in 500 mL of ethanol was added. After stirring for
about 30 min at 80°C, a white precipitate formed, and the mix-
ture was stirred for an additional 5 h at the same temperature. The
crystals were filtered off and washed with ethanol to give 1185 g of
Ca(L-HL0)2((R)-1)2. Yield: 82% (based on the half of racemic methyl
o-chloromandelate). Anal. (C54H44O22Cl2Ca) C, H, Ca: calcd., 56.11%,
3.84%, 3.47%; found, 56.18%, 3.89%, 3.5%. IR absorption bands
(cm−1): 3360 (s), 3068 (w), 2950 (w), 1732 (s), 1688 (s), 1665 (s), 1452
(m), 1277 (w), 1128 (w), 1097 (w), 1030 (w), 764 (w), 706 (m). De:
93.8% (the diastereomeric excess of the complex was determined
by the enantiomeric excess of methyl o-chloromandelate described
Acknowledgements: The authors would like to acknowl-
edge financial support provided by the Zhaoqing Univer-
sity (2016ZXBS09) for carrying out this research.
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