Ru-catalyzed enantioselective preparation of methyl (R)-o-chloromandelate and its application in the synthesis of (S)-Clopidogrel

Article abstract of DOI:10.1016/j.jorganchem.2009.02.008

The preparation of methyl (R)-o-chloromandelate via Ru-catalyzed asymmetric hydrogenation and transfer hydrogenation was investigated. With Ru-(R,R)-2,4,6-triisopropyl C₆H₂SO₂-DPEN as the catalyst and HCOOH-Et₃N azeotrope as the hydrogen donor, up to 92% ee was obtained in an optional condition. The synthesis of (S)-Clopidogrel was also studied.

Full text of DOI:10.1016/j.jorganchem.2009.02.008

Journal of Organometallic Chemistry 694 (2009) 2092–2095
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Ru-catalyzed enantioselective preparation of methyl (R)-o-chloromandelate and
its application in the synthesis of (S)-Clopidogrel
a,b
Lu Yin a,b, Wenjun Shan a, Xian Jia b, Xingshu Li a, , Albert S.C. Chan
*
a School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510006, China
b School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 January 2009
Received in revised form 9 February 2009
Accepted 10 February 2009
Available online 21 February 2009
The preparation of methyl (R)-o-chloromandelate via Ru-catalyzed asymmetric hydrogenation and trans-
fer hydrogenation was investigated. With Ru-(R,R)-2,4,6-triisopropyl C6H2SO2-DPEN as the catalyst and
HCOOH–Et3N azeotrope as the hydrogen donor, up to 92% ee was obtained in an optional condition.
The synthesis of (S)-Clopidogrel was also studied.
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
Ru-catalyzed
Enantioselective
Transfer hydrogenation
Methyl (R)-o-chloromandelate
(S)-Clopidogrel
1. Introduction
et al. developed an asymmetric reduction of methyl o-chloro-
benzoylformate with recombinant Escherichia coli over producing
(S)-Clopidogrel, commercialized as a brand name, Plavix, is a po-
tent oral antiplatelet agent often used in the treatment of coronary
artery, peripheral vascular and cerebrovascular disease. Plavix
(clopidogrel bisulfate), is the second best-selling drug in the world,
with global sales of $6.4 billion in 2006 and $7.3 billion in 2007
[1,2]. It is marketed by Sanofi-Aventis and Bristol-Myers Squibb.
Many of the early methods proposed for preparing enantiomeri-
cally pure clopidogrel involved separation of the desired enantio-
a versatile carbonyl reductase [13]. Lee et al. used a solvent-free
enzymatic process for methyl (R)-o-chloromandelate through the
CAL-A-catalyzed transesterification reaction using vinyl propionate
as an acyl donor. Under the optimized condition, 41% yield with
more than 99% ee was obtained [14]. On the other hand, the direct
asymmetric reduction of a-keto esters has also been approached in
recent years. Genet et al. developed the Ru-catalyzed asymmetric
hydrogenation of a-keto ester to afford (R)-o-chloromandelate with
50% ee [15]. Zhang et al. reported the asymmetric hydrogenation of
the corresponding ethyl ester with enantioselectivity of up to 78.2%
ee [16,17]. In our previous study, we reported a total synthesis of
(R)-Salmeterol, a selective long-acting b2-adrenoreceptor agonist,
via asymmetric transfer hydrogenation for preparing the chiral sec-
ondary alcohol which is the key intermediate in the synthesis.
Herein, we report our study of ruthenium-catalyzed enantioselec-
tive preparation of methyl (R)-o-chloromandelate and its applica-
tion in the synthesis of (S)-Clopidogrel.
merically pure compound from
a
racemic mixture. The
asymmetric synthetic methods of preparing (S)-Clopidogrel with
chiral building blocks were also developed in recent years. Among
them, the most preferred one for industrial synthesis of this useful
compound was with (R)-o-chloromandelic acid as starting material
(Scheme 1). A number of approaches have been reported in the syn-
thesis of (R)-o-chloromandelic acid or its methyl ester. Hyoda and
Balint et al. described the preparation of (R)-o-chloromandelic acid
by diastereomeric crystallization [3,4]. Zhu et al. disclosed their
investigations on the enantioselective insertion reaction of a-diazo-
esters with water catalyzed by Cu/spirobox complexes, however,
only 36% ee was obtained for (R)-(–)-methyl 2-hydroxy-2-(2-chlo-
rophenyl)acetate [5]. Other groups also developed the methods of
enantioselective enzymatic hydrolysis of the corresponding nitrile
compounds [6–8] and ester compounds [9–12]. Recently, Ema
2. Results and discussion
We first investigated the preparation of methyl (R)-o-chloro-
mandelate by asymmetric hydrogenation with Ru-BINAP as the
catalyst (Scheme 2). Nearly quantitative conversion with 41.6%
ee was obtained when the reaction was carried out at 50 °C for
20 h with [Ru(R)-BINAP(p-cymene)Cl]Cl (Cat. 1a) as the catalyst.
Sparked by Zhang group’s work [17], we introduced cerium
* Corresponding author. Tel./fax: +86 20 39943050.
E-mail address: xsli219@yahoo.com (X. Li).
0022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2009.02.008

L. Yin et al. / Journal of Organometallic Chemistry 694 (2009) 2092–2095
2093
O
OCH3
Cl
good enantioselectivity and conversion (Table 2, entry 1, 100% con-
version with 91% ee; the ratio of substrate to catalyst: 200). We
then screened other ligands for the reaction under the same reac-
tion conditions. The results indicated that electronic-drawing
groups on the sulfonyl part of the ligands seemed unfavorable to
the enantioselectivity of the reaction. When (R,R)-o-NO2-
C6H4SO2-DPEN (5b) was chosen as the chiral ligand, only 78% ee
was obtained. On the other hand, ligand (5c), which has three iso-
propyl groups on the sulfonyl part, gave full conversion with 92.6%
ee. The conversions and the enantioselectivities were almost con-
sistent when the S/C ratio was increased to 500, though increasing
reaction time was required (Table 2, entries 4 and 5). Compared
with that of HCOOH–Et3N azeotrope, there was not much differ-
ence in conversion and the reaction time when water was used
as the reaction media (with PEG 2000 or PEG 400 as additive)
and HCOONa as the hydrogen donor. However, the ee values
debased obviously, especially with 5a and 5c as chiral ligands
(Table 2, entries 6–11). The temperature effect was not much sig-
nificant for the reaction; when reaction temperature was droped to
0 °C, the ee values remained nearly the same (Table 2, entries
12–14).
OCH3
Cl
O
N
O
OH
Cl
O
S
O
O
HO
S
O2N
(R)-o-chloromandelic acid
(S)-Clopidogrel
Scheme 1. Asymmetric synthesis of (S)-Clopidogrel.
OMe
N
PPh2
PPh2
MeO
MeO
P(3,5-Me2C6H3)2
P(3,5-Me2C6H3)2
N
OMe
(R)-xyl-P-Phos
(R)-BINAP
Cl
O
Cl
OH
OMe
OMe
Cat., 50 bar of H2
EtOH
The synthesis of (S)-Clopidogrel was also carried out according
to the literature reported procedure [18] with methyl (R)-o-chloro-
mandelate as the starting material (Scheme 4). The ee of the prod-
uct (S)-Clopidogrel free base was almost the same as that of
compound 4, which was determined by HPLC analysis.
O
O
Compound 3
Compound 4
Scheme 2. Ruthenium-catalyzed asymmetric hydrogenation of compound 3.
chloride hydrate as the additive to the reaction system, the ee in-
creased from 41.6% to 58.4% (Table 1, entries 1 and 2). [Ru(R)-BIN-
AP(benzene)Cl]Cl complex (Cat. 1b) as the catalyst seemed slightly
favorable for the enantioselectivity, which gave 64.8% ee at the
same reaction conditions. We then used (R)-xyl-P-Phos as the chi-
ral ligand for the hydrogenation. Comparison experiments, made
between [Ru(R)-xyl-P-Phos(p-cymene)Cl]Cl (Cat. 2a) and [Ru(R)-
xyl-P-Phos(benzene)Cl]Cl (Cat. 2b) with or without additive,
turned out that the addition of cerium chloride hydrate did en-
hance the enantioselectivities. (The ee values increased from
31.1% to 50.4% for Cat. 2a and 29.8–64.8% for Cat. 2b, respectively.
Table 1, entries 4–7.)
3. Conclusions
In summary, we have developed an asymmetric transfer hydro-
genation process for the preparation of methyl (R)-o-chloromande-
late, which could be carried out in a very mild condition with high
conversion and good ee, and the strategy was successfully applied
to the synthesis of (S)-Clopidogrel.
4. Experimental
It is well known that asymmetric transfer hydrogenation (ATH)
is an alternative to asymmetric hydrogenation (AH) because this
method does not need either pressure vessels or hydrogen gas
and can be carried out in ordinary laboratories, however, to the
best of our knowledge, there are no reports about the preparation
of methyl (R)-o-chloromandelate via asymmetric transfer hydroge-
nation (ATH). For exploring the possibility of ATH as a key strategy
in asymmetric synthesis of (S)-Clopidogrel, we first chose Ts-DPEN
(5a), a widely used chiral ligand in the catalytic asymmetric trans-
fer hydrogenation of ketones, for the Ru-catalyzed ATH of methyl
o-chlorobenzoylformate (compound 3) (Scheme 3). With
HCOOH–Et3N azeotrope as the hydrogen donor, the reaction pro-
ceeded smoothly in a short time and gave the desired product with
4.1. General
1H NMR spectra were recorded with TMS as the internal stan-
dard on a Bruker AV400 in CDCl3. Chiral HPLC analysis was per-
formed on a SHIMADZU LC-20AT chromatography using Daicel
Chiralcel OJ-H column. (R)-BINAP and (R)-xyl-P-Phos were pur-
chased from Alfa Aesar Company. DMF and dichloromethane were
distilled over calcium hydride. Ethanol used for asymmetric hydro-
genation was obtained by distillation from magnesium under
nitrogen.
4.2. Methyl 2-hydroxy-2-(2-chlorophenyl)acetate [18]
To a solution of racemic 2-hydroxy-2-(2-chlorophenyl)acetic
acid (1.2 g, 6.43 mmol) in methanol (4.8 mL) was added 98% sulfu-
ric acid (0.048 g, 0.4894 mmol) with stirring and the mixture was
heated to reflux. After stirring for 2 h, the solvent was removed un-
der reduced pressure. The residue was dissolved in CH2Cl2
(6.5 mL), washed with 10% potassium carbonate and then water.
The solvent was removed in vaccum to afford methyl 2-hydroxy-
2-(2-chlorophenyl)acetate as colorless oil (1.24 g, 94% yield). 1H
NMR (400 MHz, CDCl3): d 7.4–7.2 (m, 4H), 5.58 (s, 1H), 3.66 (s,
3H), 4.22 (brs, 1H).
Table 1
Asymmetric hydrogenation of compound 3.a
b
b
Entry
Catalyst
Additive
Conversion (%)
Ee (%)
1
2
3
4
5
6
7
Cat. 1a
Cat. 1a
Cat. 1b
Cat. 2a
Cat. 2b
Cat. 2a
Cat. 2b
None
100
100
100
100
100
100
100
41.6
58.4
64.8
31.1
29.8
50.4
64.8
CeCl3 Á 7H2O
CeCl3 Á 7H2O
None
None
CeCl3 Á 7H2O
CeCl3 Á 7H2O
4.3. Methyl o-chlorobenzoylformate (compound 3) [19]
a
Reactions were carried out in 1 mmol scale, at 50 °C for 20 h.
The conversion and ee values were determined by HPLC on chiral OJ-H column
b
To a solution of methyl 2-hydroxy-2-(2-chlorophenyl)acetate
(3.73 g, 20 mmol) in CH2Cl2 (20 mL) at room temperature was
(Hexane: i-PrOH = 92:8, 1.0 mL/min); (R)-configuration was assigned by comparing
the retention time with that reported in the literature [5].

2094
L. Yin et al. / Journal of Organometallic Chemistry 694 (2009) 2092–2095
Scheme 3. Ruthenium-catalyzed asymmetric transfer hydrogenation of compound 3.
Table 2
Asymmetric transfer hydrogenation of compound 3.a
b
Entry
Ligand
Hydrogen source
S/C
Time (h)
Conversion (%)
Eeb (%)
1
2
3
4
5a
5b
5c
5b
5c
5a
5b
5c
5a
5b
5c
5a
5b
5c
HCOOH/Et3N(5:2)
HCOOH/Et3N(5:2)
HCOOH/Et3N(5:2)
HCOOH/Et3N(5:2)
HCOOH/Et3N(5:2)
HCOONa/H2O
HCOONa/H2O
HCOONa/H2O
HCOONa/H2O
HCOONa/H2O
200
200
200
500
500
200
200
200
200
200
200
200
200
200
40 (min)
40 (min)
40 (min)
20
1.5
1
1
1
1
1
1
5
5
5
100
100
100
100
100
100
100
100
100
100
100
100
100
100
91.4
77.5
92.6
78.9
92.1
78.4
76.4
72.1
75.8
74.6
77.5
89.2
80.7
90.3
5
6c
7c
8c
9d
10d
11d
12e
13e
14e
HCOONa/H2O
HCOOH/Et3N(5:2)
HCOOH/Et3N(5:2)
HCOOH/Et3N(5:2)
a
Reactions were carried out in 1 mmol scale; for reaction details, see Section 4.
The conversion and ee values were determined by HPLC on chiral OJ-H column (Hexane: i-PrOH = 92:8, 1.0 mL/min); (R)-configuration was assigned by comparing the
b
retention time with that reported in the literature [5].
c
PEG 2000 (PEG 2000/H2O = 3:1, v/v) was added.
PEG 400 (PEG 400/H2O = 3:1, v/v) was added.
Reactions were carried out at 0 °C.
d
e
hydrogen before the pressure was set to 50 bar. The autoclave
was stirred at 50 °C for 20 h and cooled, and then hydrogen was re-
leased carefully. The solvent was removed under reduced pressure
and the residue was purified by chromatography on silica gel to
give the desired product.
4.5. General procedure for the preparation of ligands [20]
Scheme 4. Synthesis of (S)-Clopidogrel from compound 4.
4.5.1. (R,R)-Ts-DPEN (5a)
To
a
solution of (R,R)-diphenylethylene-diamine (0.5 g,
added KMnO4 (3.17 g, 20 mmol) followed by Al2(SO4)3 Á 18H2O
(4.84 g, 20 mmol). The resulting mixture was stirred vigorously
for 2 h. After this time the reaction mixture was filtered and the fil-
trate was concentrated under reduced pressure to provide methyl
o-chlorobenzoylformate (compound 3) as light yellow oil (3.53 g,
88% yield). 1H NMR (400 MHz, CDCl3): d 7.7–7.4 (m, 4H), 3.95 (s,
3H).
2.36 mmol) in CH2Cl2 (4 mL) was added 1 M NaOH solution
(4 mL) at 0 °C, followed by a cold solution of p-toluenesulphonyl
chloride (0.45 g, 2.36 mmol) in CH2Cl2 (8 mL) at the same temper-
ature in 10 min. After stirring for 1 h, the reaction mixture was
washed with brine and water. The organic phase was concentrated
under reduced pressure and the residue was purified by
crystallization (toluene:hexane; v/v 3:1) to afford (R,R)-Ts-DPEN
as a white crystal solid (0.27 g, 31% yield). 1H NMR (400 MHz,
CDCl3): d 7.30 (d, J = 8 Hz, 2H), 7.15 (m, 10H), 6.96 (d, J = 7.6 Hz,
2H), 4.38 (d, J = 5.2 Hz, 1H), 4.13 (d, J = 5.2 Hz, 1H), 2.31 (s, 3H),
1.42 (brs, 2H).
4.4. Typical procedure for asymmetric hydrogenation [17]
A solution of [Ru(benzene)Cl2]2 (2.5 mg, 0.005 mmol) and (R)-
xyl-P-Phos (8.51 mg, 0.011 mmol) was heated at 50 °C in degassed
EtOH and CH2Cl2 (0.75 mL/0.75 mL) for 1 h under argon atmo-
sphere. After the mixture was cooled to ambient temperature
and vacuumed to give the catalyst, CeCl3 Á 7H2O (18.75 mg,
0.05 mmol) in degassed EtOH (2 mL) and compound 3 (0.198 g,
1.0 mmol) were added. The reactor was purged three times with
4.5.2. (R,R)-o-NO2-C6H4SO2-DPEN (5b) and (R,R)-2, 4, 6-iPr3-C6H2SO2-
DPEN (5c)
To
a
solution of (R,R)-diphenylethylene-diamine (0.5 g,
2.36 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride

L. Yin et al. / Journal of Organometallic Chemistry 694 (2009) 2092–2095
2095
(0.713 g, 2.36 mmol) in CH2Cl2 (8 mL) was added 1 M NaOH solu-
tion (4 mL) at 0 °C. With the same procedure as that of (R,R)-Ts-
DPEN, crude (R,R)-2,4,6-iPr3-C6H2SO2-DPEN was obtained, which
was purified by flash column chromatography on silica gel to give
an off-white powder (1.0 g, 89% yield); Similarly, (R,R)-o-NO2-
C6H4SO2-DPEN as a yellow powder (0.83 g, 88% yield) was obtained
by reaction of (R,R)-diphenylethylene-diamine (0.5 g, 2.36 mmol)
with 2-nitro-benzenesulfonyl chloride (0.523 g, 2.36 mmol) in
CH2Cl2 (8 mL).
solution of 4-nitrobenzenesulfonyl chloride (1.33 g, 6.0 mmol) in
CH2Cl2 (3 mL). After stirring for 3 h at the same temperature, the
mixture was quenched with water. The organic layer was
separated, dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The residue was purified by flash column
chromatography to afford the title compound as a light yellow
solid (1.8 g, 78% yield). 1H NMR (400 MHz, CDCl3): d 8.31 (d,
J = 8.8 Hz, 2H), 8.08 (d, J = 8.8 Hz, 2H), 7.39–7.24 (m, 4H), 6.39 (s,
1H), 7.35 (s, 3H).
(R,R)-2,4,6-iPr3-C6H2SO2-DPEN. 1H NMR (400 MHz, CDCl3): d
7.15-6.98 (m, 10H), 6.82 (d, J = 7.2 Hz, 2H), 4.51 (d, J = 7.6 Hz,
1H), 4.06 (d, J = 7.6 Hz, 1H), 3.98 (m, 2H), 2.82 (m, 1H), 1.21 (d,
J = 7.2 Hz, 6H), 1.17 (d, J = 6.8 Hz, 6H), 1.09 (d, J = 6.4 Hz, 6H).
(R,R)-o-NO2-C6H4SO2-DPEN. 1H NMR (400 MHz, CDCl3): d 7.63
(d, J = 7.6 Hz, 1H), 7.45 (t, J = 8.4 Hz, 2H), 7.30 (m, 1H), 7.25–6.98
(m, 10H), 4.69 (d, J = 3.6 Hz, 1H), 4.30 (d, J = 3.6 Hz, 1H).
4.7.3. (S)-Clopidogrel free base [18]
To a stirred mixture of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine
(0.168 g, 1.2 mmol) and 30% aqueous solution of potassium car-
bonate (0.57 g) in CH2Cl2 (1.5 mL) was added a solution of com-
pound 6 (0.385 g, 1.0 mmol) in CH2Cl2 (0.5 mL). The two-phase
mixture was refluxed for 2.5 h. The mixture was cooled to room
temperature and filtered under vaccum then washed with a small
amount of CH2Cl2 to give the (S)-Clopidogrel or methyl (S)-2-(2-
chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridyl)acetate
(0.23 g, 70% yield, 90% ee, determined by HPLC analysis). 1H NMR
(400 MHz, CDCl3): d 7.70 (m, 1H), 7.41 (m, 1H), 7.33–7.22 (m,
2H), 7.06 (d, J = 5.2 Hz, 1H), 6.67 (d, J = 5.2 Hz, 1H), 4.92 (s, 1H),
3.74 (s, 2H), 3.73 (s, 3H), 2.88 (s, 4H).
4.6. General procedure for asymmetric transfer hydrogenation
4.6.1. HCOOH/Et3N (5:2) as hydrogen source [21]
To a Schlenk tube were added [Ru(p-cymene)Cl2]2 (1.53 mg,
0.005 mmol) and the chiral ligand (1.2 equiv., to the metal atom)
under argon atmosphere, followed by the addition of DMF
(0.5 mL). The system was allowed to stir at 80 °C for 20 min before
cooling to room temperature. Methyl o-chlorobenzoylformate
(0.198 g, 1.0 mmol) and HCOOH/Et3N azeotrope (0.44 g, 5 mmol
HCOOH) were subsequently added. The resulting mixture was stir-
red at 25 °C for the time shown in Table 2 and then concentrated in
vacuum. The residue was purified by silica gel chromatography to
give pure methyl (R)-o-chloromandelate (compound 4).
Acknowledgements
We thank the Science and Technology Foundation of Guangz-
hou (07A8206031), National Science Foundation of China
(20472116) for financial support of this study.
4.6.2. HCOONa as hydrogen source [22]
A mixture of [Ru(p-cymene)Cl2]2 (1.53 mg, 0.005 mmol), (R,R)-
Ts-DPEN (2.2 mg, 0.006 mmol) in water (0.5 mL) was heated at
40 °C for 1 h under argon atmosphere. After cooling to room tem-
perature, a mixture of methyl o-chlorobenzoylformate (0.198 g,
1.0 mmol), 2.5 M HCOONa (2 mL, 5.0 mmol) and PEG 2000 (or
PEG 400) (1.5 mL) was introduced. The resulting solution was stir-
red at 40 °C for a certain period of time. Then the mixture was ex-
tracted with n-hexane, dried over anhydrous sodium sulfate,
filtered and concentrated in vacuum to give the crude product
which was purified by silica gel chromatography.
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4.7. Preparation of (S)-Clopidogrel from compound 4
4.7.1. 4,5,6,7-Tetrahydrothieno[3,2-c]pyridine hydrochloride [23]
A solution of 2-thienylethylamine (5 g, 39.3 mmol) in dichloro-
ethane (30 mL) was stirred for 5 min in a vessel equipped with a
dean stark assembly for azeotropic removal of water formed in
the reaction. Paraformaldehyde (1.32 g) was added and the result-
ing mixture was heated to reflux for 4 h. After this period the reac-
tion mixture was cooled to ambient temperature, 6.6 N
hydrochloric acid solution (6.65 mL) in dimethylformamide was
added. The reaction mass was heated to 70 °C for 4 h. After cooling
to room temperature, the mixture was filtered under vacuum and
washed with dichloroethane. The filter cake was dried in oven at
50 °C to provide the title compound as a white solid (4.8 g, 70%
yield).
5 (2007) 1175–
4.7.2. (R)-4-nitrobenzenesulfonyloxy-2-(2-chlorophenyl)acetate
(compound 6) [18]
To a stirred mixture of DMAP (0.073 g, 0.6 mmol), (R)-2-hydro-
xy-2-(2-chlorophenyl)acetate (1.2 g, 6.0 mmol) and Et3N (0.78 g,
7.8 mmol) in CH2Cl2 (2 mL) at 0 °C was slowly added an ice-cold
[23] A. Kumar, K.D. Vyas, S.G. Barve, P.J. Bhayani, S. Nandavadekar, C.H. Shah, S.M.
Burudkar, L.D. Kushwaha, WO 2005104663, 2005.