Scheme 3. Synthesis of clopidogrela
a Reagents and conditions: a) HCl/acetone (95%); b) H2SO4/MeOH (94%); c) 6/MeCN (95%, ee > 99%).
1H NMR (DMSO-d6) δ 9.36 (2H, b), 7.67(1H, m), 7.57 (1H,
m), 7.45 (2H, m), 5.44 (1H, s) 3.76 (3H, s); 13C NMR (DMSO-
d6) δ 168.7, 134.0, 132.1, 131.1, 130.7, 130.5, 128.7, 54.1, 53.0;
[M + 1] (TOF/ESI) calculated for C9 H10NO2Cl: 200.05, found:
200.1.
(+/-)-2-Chlorophenylglycinamide (3). To ester 2·HCl
(100 g, 424 mmol) was added concentrated aqueous ammonia
(315 mL), and the resulting mixture was stirred overnight at
room temperature. The mixture was cooled with ice, and the
solids were collected by filtration, washed with water, and
stripped 3× with toluene to give 57.2 g of amide 3. The mother
liquor was extracted with dichloromethane (2 × 300 mL), dried
over Na2SO4, combined with the solid amide, and concentrated
to give amide 3 (63.6 g, 344 mmol, 81%) as a white solid.
1H NMR (DMSO-d6) δ 7.22-7.46 (5H, m), 7.18 (1H, b),
4.61 (1H, s), 2.31 (2H, b); 13C NMR (DMSO-d6) δ 175.3, 141.3,
133.3, 129.8, 129.5, 129.2, 127.8, 56.8; [M + 1] (TOF/ESI)
calculated: 185.05, found: 185.1.
(+/-)-2-(Benzylideneamino)-2-(2-chlorophenyl)aceta-
mide (4a). To amide 3 (58.7 g, 318 mmol) in dichloromethane
(DCM, 480 mL) was added benzaldehyde (35.3 mL, 350 mmol,
1.1 equiv) and Na2SO4 (73.4 g, 517 mmol, 1.63 equiv), and
the mixture was stirred overnight at room temperature. The
mixture was then heated with a hot water bath, and the solids
were removed by filtration. The residue was washed with warm
dichloromethane, and the combined mother liquors were
concentrated to give 88.3 g, 324 mmol crude imine 4a, which
was recrystallized from CH3CN (500 mL) to give 4a (77.9 g,
286 mmol, 90%) as a white solid.
to give (S)-4a (115.6 g, including glass beads, 28.1 g, 103 mmol,
corrected, 80%) as a white solid.
Deracemization Following Isothermal Protocol of ref 1c.
(S)-(E)-2-(Benzylideneamino)-2-(2-chlorophenyl)aceta-
mide (4a). A scintillisation vial was charged with 2 mm glass
beads (10 g), Schiff-base 3a (389 mg, 1.43 mmol) and MeCN
(3.5 mL). The flask was placed in an ultrasonic bath, fitted with
a thermostat (keeping the temperature at 20 °C), and was
sonicated for 5 min. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU,
0.10 g, 0.76 mmol, 0.53 equiv) was added, and the mixture
was sonicated at 20 °C overnight. After 1 night, ee was >80%,
after 2 nights ee was 91-98%. This experiment was carried
out as described above five times, and each time similar results
were obtained; in all cases the (S)-enantiomer of 4a was
obtained.
(S)-2-Chlorophenylglycinamide Hydrochloride (4 ·HCl).
To (S)-4a (28.0 g, 103 mmol) was added a mixture of
concentrated aqueous HCl (10.1 mL) and acetone (1.8 L), and
the resulting mixture was stirred for 1 h at room temperature.
The suspension was decanted from the glass beads from the
previous step, and the solids were collected by filtration, washed
with acetone, and dried to give (S)-3·HCl (21.6 g, 97 mmol,
95%) as a white solid.
1H NMR (DMSO-d6) δ 8.60 (3H, b), 7.75 (2H, d),
7.46-7.62 (m, 4H), 5.14 (1H, s); 13C NMR (DMSO-d6) δ
168.6, 134.2, 132.4, 131.7, 130.5, 130.2, 128.4, 53.0; [M + 1]
(TOF/ESI) calculated C8H9ON2Cl: 185.05, found: 185.0.
(S)-2-Chlorophenylglycine Methyl Ester (2). H2SO4 (26.0
mL, 487 mmol, 5 equiv) was added dropwise under ice cooling
to MeOH, and the resulting mixture was heated at reflux for
30 min. Amide (S)-3·HCl (21.6 g, 97 mmol) was added, and
the resulting mixture was stirred for 4 h. at reflux and then
overnight at room temperature. After NMR analysis revealed
complete conversion, MeOH was evaporated, and water (175
mL) was added. The aqueous layer was basified with 1 M
NaOH and extracted with DCE (3 × 50 mL). The combined
organic layers were washed with water (50 mL), dried over
Na2SO4, and concentrated to give (S)-2 (16.9 g, 85 mmol, 94%)
as a pale oil.
1H NMR (DMSO-d6) δ 8.45 (1H, s), 7.87 (2H, dd), 7.63,
(1H, dd), 7.44-7.51 (6H, m), 7.32-7.38 (2H, m), 5.43 (1H,
s); 13C NMR (DMSO-d6) δ 172.1, 164.17, 138.1, 136.3, 133.4,
132.0, 130.9, 130.0, 129.8, 129.4, 129.2, 128.0, 73.6; [M + 1]
(TOF/ESI) calculated: 273.08, found: 273.2. The imines 3b-i
were prepared in a similar manner.
Deracemization Following Protocol of ref 10. (S)-(E)-2-
(Benzylideneamino)-2-(2-chlorophenyl)acetamide (4a). In a
1 L round-bottom flask with a 5 × 2 cm stirring egg was loaded
racemic-imine 4a (35 g, 128 mmol). MeCN (315 mL) and the
mixture were stirred at 1050 rpm. Glass beads (borosilicate,
0.2 mm, 87.5 g) were added, followed by the addition of DBU
(5.1 mL, 38.5 mmol, 0.3 equiv). The mixture was heated to 70
°C to form a homogeneous solution and subsequently cooled
to 20 °C with a rate of 0.1 °C/min using a thermostat (Huber
ministat cc). To the mixture were added a few milligram-sized
crystals of enantiopure imine 4a, obtained in a previous
experiment, at 68, 67, 66, and 64 °C. After stirring overnight
at 20 °C, chiral HPLC analysis revealed an ee > 99.5%, and
the solids were collected by filtration and washed with TBME
1H NMR (DMSO-d6) δ 7.48 (1H, dd), 7.42 (1H, dd),
7.26-7.7.36 (2H, m), 4.84 (1H, s), 3.58 (3H, s); 13C NMR
(DMSO-d6) δ 174.4, 139.3, 133.0, 130.0, 129.8, 129.6, 128.1,
56.2, 52.7; [M + 1] (TOF/ESI) calculated: 200.05, found: 200.1.
(S)-Clopidogrel (1). To 2-(2-bromoethyl)-3-(bromometh-
yl)thiophene, prepared by a literature procedure,14 (4.3 g, 15.1
mmol) in MeCN (45 mL) was added a mixture of ester (S)-2
(3.3 g, 17.8 mmol, 1.18 equiv) and di-isopropylethyl amine
(14) (Patent Hanmi Pharm. Co.). WO2005/87779, 2005.
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