Synthetic improvements in the preparation of clopidogrel

Article abstract of DOI:10.1021/op700025d

Synthetic improvements in the preparation of clopidogrel are described. The synthesis was accomplished in four steps or one-pot in above 70% overall yield. The process featured PTC catalyzed alkaline hydrolysis of the key intermediate 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetonitrile and highly effective kinetic resolution of racemic clopidogrel using L-camphorsulphonic acid in toluene and has been successfully used in a 50-kg pilot test.

Full text of DOI:10.1021/op700025d

Organic Process Research & Development 2007, 11, 487−489
Synthetic Improvements in the Preparation of Clopidogrel
Lixin Wang,*,† Jianfen Shen,†,‡ Yi Tang,† Yi Chen,† Wen Wang,† Zegui Cai,† and Zhenjun Du†
Key Laboratory of Asymmetric Synthesis & Chirotechnology of Sichuan ProVince, Union Laboratory of Asymmetric
Synthesis, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P.R. China, and
Graduate School of Chinese Academy of Sciences, Beijing 100039, P.R. China
Abstract:
Synthetic improvements in the preparation of clopidogrel are
described. The synthesis was accomplished in four steps or one-
pot in above 70% overall yield. The process featured PTC
catalyzed alkaline hydrolysis of the key intermediate 2-(2-
chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)ac-
etonitrile and highly effective kinetic resolution of racemic
clopidogrel using -camphorsulphonic acid in toluene and has
been successfully used in a 50-kg pilot test.
Figure 1. (S)-(+)-Clopidogrel bisulfate.
L
industrial inconveniences, including unsatisfactory yield and
efficiency, high raw material cost, and environmental impact.
Results and Discussion
Introduction
Herein we report synthetic improvements in the prepara-
tion of clopidogrel starting from 2-(2-chlorophenyl)-2-(6,7-
dihydrothieno[3,2-c]pyridine-5(4H)-yl)acetonitrile, 4, which
is a key intermediate in our process, that can be cheaply
and effectively prepared from commercially available 3 and
R-bromo-2-chlorophenyl acetonitrile, 2, which is from the
bromination of 2-chlorophenyl acetonitrile 1 (Scheme 1). As
(S)-(+)-Clopidogrel bisulfate (Plavix, Figure 1) is an
orally active inhibitor of platelet aggregation now marketed
as an antithrombotic agent which was licensed by Sanofi in
1986. It is an adenosine diphosphate (ADP) receptor
antagonist indicated for the reduction of atherosclerotic
events including myocardial infarction, ischemic stroke, and
vascular death in patients with atherosclerosis. Clopidogrel
works by helping to prevent harmful blood clots.1 Recent
studies have shown that clopidogrel is more effective in
blocking platelet aggregation than aspirin and ticlopidine
even at much lower dosage.2 A dosage of 75 mg of
clopidogrel has been shown to be more effective than a
Scheme 1a
3
dosage of 325 mg of aspirin, and as a consequence, this
compound has captured the interest of a number of synthetic
groups as a target for commercial total synthesis.4
There were mainly two kinds of syntheses of clopidogrel.
One was from the derivatives of R-halogenphenyl acetate
by alkylation with 4,5,6,7-tetrahydrothieno[3,2-c] pyridine,
3.5 The second was from the derivatives of R-aminophenyl-
acetic acid.6 All of these methods have suffered several
* Corresponding author. Telephone/Fax: (+86)28-85255208. E-mail:
wlxioc@cioc.ac.cn.
† Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences.
‡ Graduate School of Chinese Academy of Sciences.
(1) (a) Gurbel, P. A.; O’Connor, C. M.; Cummings, C. C.; Serebruany, V. L.
Pharmacol. Res. 1999, 40(2), 107-111. (b) Yang, L. H.; Hoppensteadt,
D.; Fareed, J. Thromb. Res. 1998, 92, 83-89.
(2) (a) Coukell, A. J.; Markham, A. Drugs 1997, 54, 745-751. (b) Boneu, B.;
Destelle, G. Thromb. Haemostasis 1996, 76, 939-943.
(3) Valeriano, M.; Daverio, P.; Bianchi. S. U.S. Patent 2004/0024012A1, 2004.
(4) (a) Pandey, B.; Lohray, V. B.; Lorhray. B. B. U.S. Patent 2002/0177712A1,
2002. (b) Kumar, A.; Vyas, K. D.; Barve, S. G. WO Patent 2005/104663A2,
2005. (c) Castaldi, G.; Barreca, G.; Bologna. A. U.S. Patent 2005/
0143414A1, 2005. (d) Valeriano, M.; Daverio, P.; Bianchi. S. U.S. Patent
6737411B2, 2004.
(5) (a) Bousquet, A.; Calet, S.; Heymes, A. U.S. Patent 5,132,435, 1992. (b)
Bousquet, A.; Musolino, A. U.S. Patent 6,573,381 B1, 2003. (c) Bouisset,
M.; Radisson, J. U.S. Patent 5,036,156, 1991.
a Reagents and conditions: (a) Br2, 100-110 °C, 6 h, 86%; (b) NaHCO3,
methanol, reflux, 3 h, 85%; (c) TEBA, 10-20% NaOH (aq), methanol, reflux,
12 h, 96%; (d) TEBA, 40-50% NaOH (aq), methanol, reflux, 12 h, 95%; (e)
TEBA, 40-50% NaOH (aq), methanol, reflux, 12 h, 95%; (f) TEBA, methanol,
NaOH, dimethyl sulfate, 40 °C, 12 h; 87%; TEBA ) triethylbenzylammonium
chloride.
far as we know, our synthetic route and the whole process
are effective, facile, and economical.
In contrast to our syntheses, Pandey and his co-workers
reported a Strecker synthesis of nitrile 4 by reacting amine
3 with sodium cyanide and 2-chlorobenzaldehyde in high
(6) (a) Castro, B.; Dormoy, J; Previero, A. U.S. Patent 6,080,875, 2000. (b)
Descamps, M.; Radisson, J. U.S. Patent 5,204,469, 1993.
10.1021/op700025d CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/31/2007
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Scheme 2a
yield.7 Acid 6 and clopidogrel were prepared from amide 5
by methanolysis in large excess of concentrated sulfuric acid,
and the amide 5 was prepared from nitrile 4 by alkaline
hydrolysis in alcohol. They also reported that clopidogrel
could be synthesized from nitrile 4 in one step, but they did
not offer the details or related descriptions of direct ester-
fication of nitrile 4 in their patents. In fact, we could only
obtain 5 or a small amount of 6 according to the methods
they offered, and the direct acid hydrolysis of 4 to clopidogrel
had few real applications in commercial production for the
reported low yield (38%). Herbert also reported the conver-
sion of nitrile 4 to the final product 7 through methanolysis
of 5 in 28% yield.8 It seems that the direct alkaline hydrolysis
of nitrile 4 to acid 6 is difficult under general circumstances.
To our delight, we have found that direct alkaline
hydrolysis of nitrile 4 to acid 6 could be accomplished almost
quantitatively in the mixed solvent and high concentration
of inorganic strong base in the presence of phase transfer
catalyst, whereas by controlling the concentration of base
(<20%), amide 5 may also be obtained selectively. To the
best of our knowledge, there are no successful analogous
reports for this direct alkaline hydrolysis of nitrile 4 to acid
6.
a Reagents and conditions: (a) L-CSA. H2O, toluene, 48 h, 93%, ee > 99.5%;
(b) NaHCO3, acetone, reflux, 6 h; (c) H2SO4, 0 °C, 12 h, 95% (two steps).
separation and purification. After simple washing off of HBr,
amine 3 and NaHCO3 were added directly to the brominated
intermediate 2 to form nitrile 4. The reactants were alkaline
hydrolyzed to form the salt of 6; after cooling, a highly pure
(>98%) salt of 6 was obtained in above 75% yield.
Our synthetic route and the whole process for racemic
clopidogrel were simple, easily controlled, industrially
economical, and environmental friendly in excellent total
yield, and the starting materials were commercially available
and cheap. Furthermore, all these conversions or reaction
steps could be taken in one-pot just by the simple filtration
of the potassium salt of 6.
Bromination of 2-(2-chlorophenyl) acetonitrile (1) without
solvent at 100-110 °C afforded 2-bromo-2-(2-chlorophenyl)-
acetonitrile 2 in 86% separated yield (above 95% conver-
9,10
sion).
To reduce dibromination, it was better to add
The process described above has been used in a 50-kg
pilot scale, wherein high-quality racemic clopidogrel bisulfate
was obtained in four steps from commercially inexpensive
available materials in over 70% overall separated yield.
For the manufacture of (S)-clopidogrel,currently, there
were mainly three known processes. Each of these processes
relies on classical resolution, enzymatic techniques, or
asymmetric synthesis to introduce the sole chiral center into
the molecule. While the classical resolution of clopidogrel
is still the main method in industry and shows advantages
in cost and method flexibility, the reported methods of
classical resolution of clopidogrel using L-CSA (10-L-
camphorsulphonic acid) were all in acetone,14 methyl tert-
butyl ether,15 or in the cosolvent of DMF.16 The reported
resolution yield in acetone was 67.8% or lower, but we could
not repeat these procedures, and almost no desired chiral
isomer was obtained; in the cosolvent, the resolution, yield,
and efficiency were unsatisfactory, the recovery of the
solvents was rather difficult, and no exact results were
reported. To our surprise, when only 0.45-0.55 equiv of
L-CSA was used and only in toluene, we found a highly
selective and effective kinetic resolution method of racemic
clopidogrel in above 98.3% ee and 88% total yield (Scheme
2). Qualified clopidogrel was obtained in above 99.5% ee
just by washing with cold isopropanol. From the scope of
literature searched and to the best of our knowledge, our
resolution method is the most effective and economical one
until now.
bromine dropwise in a period of more than 2 h and in a
little excess quantity, such as 1.1 equiv. 3 is commercially
available or can be synthesized from 2-(2-thienyl)ethylamine
in two steps in 90% overall yield.11
2 was alkylated with 3 to give nitrile 4 in above 85%
separated yield in the presence of at least one equivalent of
base in polar solvent. The resulting nitrile 4 was directly
hydrolyzed to acid 6 in high concentration (>35%) of strong
bases (e.g., KOH, NaOH) in water and alcohols, e.g., BuOH
in the presence of phase transfer catalysts (PTC) almost
quantitatively (>95% yield).12 The concentration of base and
PTC are crucial for this direct conversion, at lower base
concentration, amide 5 was the main product, while without
PTC, almost no acid 6 could be obtained. The final product
was obtained by esterification of acid 6 in refluxing methanol
and at least 2 equiv of concentrated sulfuric acid in more
than 70% yield or esterification with dimethyl sulfate in the
presence of sodium hydroxide in 75% yield. Unreacted acid
6 was easily recycled by forming salt.13
Our experiments also show that the whole process of the
synthesis of 6 could be taken in one-pot or without strict
(7) Pandey, B.; Lohray, V. B.; Lorhray, B. B. CN Patent 1487943A, 2004.
(8) Burgos, A.; Herbert, J. M.; Simpson, I. J. Labelled Cmpd. Radiopharm
2000, 43, 891-898.
(9) Robb, C. M.; Schultz, E. M. Org. Synth. 1948, 28, 55-58.
(10) Lodewijk, E.; Khatri, H. N. EP Patent 0342118A1, 1989.
(11) (a) Venkatesan, A. M.; Agarwal, A.; Abe, T. J. Med. Chem. 2006, 49,
4623-4637. (b) El Ashry, E. S. H.; Ramadan, E. S.; Abdel Hamid, H. M.
Synlett 2004, 4, 723-725.
(12) (a) Hasegawa, T.; Kawanaka, Y.; Kasamatsu, E. Org. Process Res. DeV.
2005, 9, 774-781. (b) Watson, T. J. N.; Horgan, S. W.; Shah, R. S. Org.
Process Res. DeV. 2000, 4, 477-487. (c) Katagiri, T.; Irie, M.; Uneyama,
K. Org. Lett. 2000, 2(16), 2423-2425.
(13) The sodium/potassium salt of 6 is hardly soluble in cold water and most
organic solvents.
(14) (a) Badorc, A.; Frehel, D. U.S. Patent 4,847,265, 1989. (b) Bakonyi, M.;
Nagy, M. C.; Bako, E. M. U.S. Patent 6,258,961 B1, 2001.
(15) Tarur, V. R.; Sathe, D. G.; Sawant, K. D. WO Patent 2006/087729A1,
2006.
(16) Valeriano, M.; Daverio, P.; Bianchi, S. U.S. Patent 2005/0049275A1, 2005.
488
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Conclusion
In summary, an effective synthetic pathway beyond the
TEBA (1.0 g), NaOH (aq 360 g, 40-50%), and butanol (100
mL) was refluxed for 12 h. After cooling to room temper-
ature, the solution was neutralized with HCl (aq 35-37%)
to pH 8 and then acidified with acetic acid to pH 4-5. The
suspension was filtered, washed, and dried to give 6 (61 g,
95%). IR (cm-1): 3439.5, 2849.1, 1691.3, 1628.3, 1474.4,
1351.3, 1329.3, 1035.6, 890.0, 847.6, 756.5, 748.4; 1HNMR
(300 MHz, DMSO): δ 10.3-14.3 (1 H, br ), 7.35-7.64 (4
H, m), 7.26 (1 H, d, J ) 5.1), 6.8 (1 H, d, J ) 5.1), 4.7 (1
H, s), 3.61-3.65 (2 H, dd, J ) 10.8), 2.78-2.85 (4 H, m).
Methyl(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyri-
dine-5(4H)-acetate (7). The mixture of acid 6 (60 g, 0.198
mol), TEBA (1.2 g), methanol (250 mL), and NaOH (aq
20%, 60 g) was refluxed for 30 min. After cooling to about
10 °C, Me2SO4 (40 g, 0.317 mol) was added dropwise. The
solution was reacted at 40 °C for 12 h. After removal of
methanol, butyl acetate (150 mL) was added. The organic
layer was washed with water and brine and dried over
anhydrous sodium sulfate. After removal of solvent by
vacuum, brown oil was obtained (54.7 g, 87%). IR (cm-1):
3452, 2554.5, 1752.3, 1630.5, 1591.0, 1437.8, 1187.6, 882.0,
coverage of the present patents for the commercial prepara-
tion of clopidogrel bisulfate starting from commercially
available materials has been accomplished in four separated
steps or in a one-pot procedure in above 70% overall yield.
Highly effective and selective kinetic resolution of clopi-
dogrel using L-CSA in toluene is presented. The whole
process and all of the procedures are environmental friendly,
economical, industrially reliable, and easily scaled up.
Experimental Section
Materials and Instruments. All solvents and reagents
were purchased from the suppliers and used without further
purification. The IR spectra were performed on a NICOLET
1
MX-1E FT-IR instrument. H and 13C NMR spectra were
recorded on a Bruker DPX 300 MHz spectrometer in CDCl3,
DMSO-d6, or D2O with Me4Si (TMS) as internal standard
at room temperature. Mass spectra were obtained with a
Bruker Daltonics Data Analysis 3.2.
HPLC analyses were performed on Schimadzu LC-
12ATVP according to the following conditions: (1) column,
Shimpack VP-ODS (150 mm × 4.6 mm, 5 µm); eluent, 80:
20 methanol/water; flow rate 1 mL/min; temperature, 30 °C;
wavelength 240 nm. (2) Column, Chiral-AGP (150 mm ×
4.0 mm + 10 mm × 4.0 mm, 5 µm); eluent, 83:17 sodium
acetate (aq, pH 6.2)/acetonitrile; flow rate 0.8 mL/min;
temperature, 30 °C; wavelength 225 nm.
2-Bromo-2-(2-chlorophenyl)acetonitrile (2). Bromine
(176 g, 1.1 mol) was added over a period of 3 h to 2-(2-
chlorophenyl)acetonitrile (151.5 g, 1 mol) with stirring at
105-110 °C and was reacted for another 3 h. Then butyl
acetate (250 mL) and sodium bisulfate (11.4 g, 0.11 mol)
were added at 30 °C. After 15 min stirring, the mixture was
filtered, washed with water, and dried over anhydrous sodium
sulfate. Removal of the solvent was done in vacuum to afford
2 (200 g, 86%): mp: 110 °C /15 mmHg; IR (cm-1): 2969,
2253, 1589.0, 1472, 1445, 1194, 1051, 765, 725, 646;
1HNMR (300 MHz, CDCl3): δ 7.83 (1 H, m), 7.38-7.45
(4 H, m), 5.87 (1 H, s).
1
867.2, 847.7, 772.4; HNMR (300 MHz, D2O): δ 7.65 (1
H, d, J ) 8.0), 7.5-7.6 (3 H, m), 7.3 (1 H, d, J ) 5.2), 6.7
(1 H, d, J ) 4.7), 5.9 (1 H, s), 4.2-4.4 (2 H, m), 3.8 (3 H,
s), 3.7-3.8 (2 H, m), 3.2 (2 H, s).
Kinetic Resolution of Racemic Clopidogrel. L-CSA‚
1H2O (13.3 g, 0.053 mol) was added batchwise into the
solution of racemic 7 (32 g, 0.10 mol) and toluene (140 mL)
at room temperature. After stirring at 50 °C for 1 h, the
mixture was cooled to room temperature, stirred, and seeded
for another 48 h. It was then filtered, washed, and dried to
give a white solid (25.7 g, ee ) 99.6%). Then a mixture of
the white solid (25.7 g, 0.046 mol), NaHCO3 (3.9 g, 0.046
mol), and acetone (100 mL) was refluxed for 6 h. After the
mixture was cooled to -5 °C, filtered, and washed with cold
acetone, then H2SO4 (98%, 4.6 g, 0.046 mol) was added
dropwise into the filtrate, stirring continuously at 0 °C for
12 h. (S)-(+)-Clopidogrel bisulfate (18.4 g, 88%, ee )
99.5%) was obtained by the usual filtering, washing, and
drying.
2-(2-Chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridine-
5(4H)-yl)acetonitrile (4). 3 (98.7 g, 0.43 mol), 2 (70.2 g,
0.4 mol), sodium hydrogen carbonate (84 g, 1.0 mol), and
methanol (300 mL) were combined and refluxed for 3 h.
Then the mixture was stirred at 5 °C for more than 30 min,
filtered, washed with water and cold methanol, and dried to
Acknowledgment
This project was financially supported by Huahai Phar-
maceuticals Co., Ltd, Zhejiang, China.
1
give 4 (98 g, 85%). HNMR (300 MHz, CDCl3): δ 7.35-
Supporting Information Available
7.72 (4 H, m), 7.08 (1 H, d, J ) 5.1), 6.69 (1 H, d, J ) 5.1),
5.32 (1 H, s), 3.78 (1 H, d, J ) 13.7), 3.65 (1 H, d, J )
13.7), 2.8-3.0 (4 H, m); 13CNMR (300 MHz, CDCl3): δ
136.46, 132.78, 132.38, 130.69, 130.46, 130.38, 129.90,
126.73, 124.96, 123.01, 115.09, 59.12, 49.30, 47.66, 25.47.
2-(2-Chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridine-
5(4H)-yl)acetic Acid (6). The mixture of 4 (60 g, 0.22 mol),
Spectrograms. This material is available free of charge
via the Internet at http://pubs.acs.org.
Received for review January 31, 2007.
OP700025D
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