PAPER
Asymmetric Synthesis of Clopidogrel Hydrogen Sulfate
623
pressure to give a pale oil; yield: 3.78 g (85%, 99% ee); [α]D25 +122
(c 1, MeOH) (Lit.20 +123).
1
The H and 13C spectra were recorded in DMSO-d6 or D2O at 400
MHz with a Varian Gemini 400-MHz FT NMR spectrometer.
Chemical shifts are relative to TMS. The FTIR spectra were record-
ed in the solid state as KBr dispersions by using a PerkinElmer 1650
FT-IR spectrometer. Mass spectra (70 eV) were recorded on an
Agilent 6310 LC-MS spectrometer. Organic solvents were distilled
before use or, if otherwise noted, dried according to the usual pro-
cedures.
IR (neat): 3383, 3061, 2952, 1747, 1593, 1574, 1463, 1169, 751
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 9.25 (s, 3 H), 7.61–7.64 (m, 2
H), 7.46–7.50 (m, 2 H), 5.5 (s, 1 H), 3.72 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 168.5, 133.7, 131.9, 130.9,
130.5, 130.3, 128.5, 53.9, 52.9.
MS: m/z = 199.9 [M + H]+.
(2S)-(2-Chlorophenyl){[(1S)-1-(4-methoxyphenyl)ethyl]ami-
no}acetonitrile Hydrochloride (4)
CAUTION: Cyanide salts can be absorbed through the skin and
are extremely toxic.
(S)-(+)-Clopidogrel Hydrogen Sulfate (1)
2-(2-Bromoethyl)-3-(bromomethyl)thiophene (7; 5.0 g, 18.0 mmol)
was added to a mixture of ester 6 (4.31 g, 21.6 mmol) and MeCN
(50.0 mL), and the resulting mixture was stirred for 15 min at 25–
30 °C. A mixture of DIPEA (3.28 g, 32.0 mmol) and MeCN (5.0
mL) was added, and the mixture was stirred overnight at the reflux.
When the reaction was complete (TLC), the solvents were com-
pletely evaporated under reduced pressure. EtOAc (100.0 mL) was
added to the residue and the mixture was washed with H2O (3 × 75.0
mL). The combined organic layers were washed with sat. aq NaCl
(75.0 mL), dried (Na2SO4), and concentrated under reduced pres-
sure to give clopidogrel as a yellow oil. The oil was mixed with ac-
etone (50.0 mL), carbon (0.25 g), and Hyflo filter aid (0.3 g), and
the mixture was stirred for 10–15 min at 25–30 °C. The solids were
collected by filtration and washed with acetone (5.0 mL). The fil-
trate was mixed with H2O (0.7 mL) and cooled to 0–5 °C. H2SO4
(1.94 g, 19.8 mmol) was added slowly over 1.5 h and the mixture
was stirred for 6.0 h at 0–5 °C. The solid that separated was collect-
ed by filtration, washed with acetone (5.0 mL), and dried under vac-
uum to give (S)-clopidogrel hydrogen sulfate (1) as an off-white
powder; yield: 5.6 g (75%, 99.9% ee); [α]D25 +55 (c 1, MeOH)
(Lit.20 +54.8).
(1S)-1-(4-Methoxyphenyl)ethylamine hydrochloride (3; 6.76 g,
36.0 mmol) and NaCN (1.85 g, 38.0 mmol) were dissolved in a mix-
ture of H2O (5.0 mL) and MeOH (5.0 mL). 2-Chlorobenzaldehyde
(2; 5.0 g, 36.0 mmol) was added, and the soln was stirred for 16 h
at 25–30 °C. When the reaction was complete (TLC), the mixture
was diluted with H2O (12.5 mL) and stirred for 30 min at 25–30 °C.
The solid that separated was collected by filtration, washed with
H2O (5.0 mL), and dried under vacuum at 70 °C to give a cream-
colored powder; yield: 9.0 g (75%, >95% de); mp 112–114 °C;
[α]D25 –129 (c 0.5, MeOH).
IR (KBr): 3312, 3064, 2983, 2226, 1613, 1584, 1243, 1036, 756,
559 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.75–7.76 (m, 1 H), 7.49–7.52
(m, 3 H), 7.31–7.39 (m, 2 H), 6.84–6.94 (m, 2 H), 4.56 (d, 1 H), 3.99
(q, J = 4.0 Hz, 1 H), 3.74 (s, 3 H), 3.61–3.64 (d, J = 2.5 Hz, 1 H),
1.31–1.33 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 159.1, 135.5, 132.5, 131.0,
130.3, 129.7, 128.7, 128.4, 127.9, 119.1, 114.4, 56.2, 55.3, 49.3,
24.8.
MS: m/z = 301.5 [M + H]+ (free base).
IR (KBr): 3446, 3121, 2956, 1752, 1439, 1188, 750, 569 cm–1.
Anal. Calcd for C17H18Cl2N2O: C, 60.54; H, 5.38; N, 8.31. Found:
C, 60.66; H, 5.55; N, 8.32.
1H NMR (400 MHz, DMSO-d6): δ = 7.68–7.70 (m, 2 H), 7.53–7.57
(m, 2 H), 7.44–7.45 (m, 1 H), 6.88–6.90 (d, J = 5.0 Hz, 1 H), 5.62
(br s, 2 H), 4.93 (br s, 2 H), 4.2 (br s, 2 H), 3.76 (s, 3 H), 3.08 (br s,
2 H).
(2S)-2-(2-Chlorophenyl)glycine Hydrochloride (5)
A mixture of hydrochloride 4 (5.0 g, 15.0 mmol) and 6 M aq HCl
(160.0 mL) was stirred for 4.0 h at 90 °C until the reaction was com-
plete (TLC). The mixture was then cooled to 25–30 °C and extract-
ed with Et2O (2 × 30 mL). The organic extracts were discarded, and
the aqueous layer was concentrated under reduced pressure to give
the crude product, which was stirred with CHCl3 (10.0 mL) for 30
min at 25–30 °C. The solid was collected by filtration, washed with
CHCl3 (2.5 mL), and dried under vacuum to give a white solid;
yield: 2.66 g, (80%, 95.5% ee); mp 200–202 °C; [α]D25 +88.2 (c 1,
1 M aq HCl).
MS: m/z = 322.0 [M + H]+ (free base).
Acknowledgment
We thank the management of Srini Pharmaceuticals Limited for ex-
tending their support to this work. We greatly appreciate the co-ope-
ration of our project colleagues and the analytical department.
IR (KBr) 3415, 3171, 3033, 1679, 1639, 1506, 750 cm–1.
References
1H NMR (400 MHz, D2O): δ = 7.5 (d, 1 H), 7.3–7.4 (m, 3 H), 5.15
(s, 1 H).
13C NMR (100 MHz, D2O): δ = 172.4, 133.7, 131.7, 131.2, 130.3,
130.2, 128.0, 55.6.
(1) Escolar, G.; Heras, M. Drugs Today 2000, 36, 187.
(2) Jarvis, B.; Simpson, K. Drugs 2000, 60, 347.
(3) Chow, G.; Ziegelstein, R. C. Am. J. Cardiovasc. Drugs
2007, 7, 167.
(4) Schwartz, N. E.; Albers, G. W. Curr. Neurol. Neurosci. Rep.
2008, 8, 29.
MS: m/z = 185.9 [M + H]+ (free base).
(5) Gardell, S. J. Perspect. Drug Discovery Des. 1993, 1, 521.
(6) Sajja, E.; Anumala, R. R.; Gilla, G.; Madivada, L. R. US
2007225320, 2007.
Anal. Calcd for C8H9Cl2NO2: C, 43.27; H, 4.08; N, 6.31. Found: C,
43.3; H, 4.12; N, 6.41.
Methyl (2S)-2-(2-Chlorophenyl)glycinate (6)
(7) (a) Badorc, A.; Frehel, D. US 4847265, 1989. (b) Daniel, A.;
Ferrand, C.; Maffrand, J. P. US 4529596, 1985. (c) Bakonyi,
M.; Csatáriné, Nagy. M.; Molnár, L.; Gajáry, A.; Alattyáni,
E. WO 98/051689, 1998. (d) Bousquet, A.; Musolino, A.
WO 99/18110, 1999. (e) Bakonyi, M.; Csatáriné, Nagy. M.;
Molnár, L.; Gajáry, A.; Alattyáni, E. US 6180793, 2001.
(f) Mukarram, M. S. J.; Merwade, Y. A.; Khan, R. A. US
7291735, 2007. (g) Castaldi, G.; Barreca, G.; Bologna, A.
US 7329751, 2008. (h) Lin, S. S.-S.; Chen, C.-C.
H2SO4 (11.27 g, 115.0 mmol) was slowly added to MeOH (30.0
mL) at 0–5 °C. To this soln was added amino acid 5 (5.0 g, 23.0
mmol), and the resulting mixture was stirred and refluxed for 5.0 h.
When the reaction was complete (TLC), the MeOH was completely
removed by distillation, H2O (20.0 mL) was added to the mixture,
and the pH was adjusted to 7.0–8.0 with 20% aq Na2CO3. The prod-
uct was extracted with CH2Cl2 (3 × 10.0 mL) and the organic layers
were combined, dried (Na2SO4), and concentrated under reduced
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 621–624