Synthesis and characterization of impurity B of S-(+)-clopidogrel bisulfate: An antiplatelet

Article abstract of DOI:10.1080/00397911.2011.635393

S-(+)-Clopidogrel bisulfate [(S-(+)-methyl 2-(2-chlorophenyl)-2-(6, 7-dihydrothieno[3, 2-c]pyridin-5(4H)-yl)acetate bisulfate)] is a platelet aggregation inhibitor drug. S-(+)-Clopidogrel bisulfate is prepared by different synthetic approaches in the literature. In almost all the approaches the major impurities known in the literature (A, B, and C) are also listed in the U.S. pharmacopoeia. The control of these pharmaceutical impurities is currently a critical issue to the pharmaceutical industry. In this article, a description of these impurities and their origins in the S-(+)-clopidogrel bisulfate process are presented along with the preparation of impurity B.

Full text of DOI:10.1080/00397911.2011.635393

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Synthesis and Characterization of
Impurity B of S-(+)-Clopidogrel Bisulfate:
An Antiplatelet
K. Tatendra Reddy a , K. Suneel Kumar a , G. Omprakash a & P. K.
Dubey b
a PharmaZell R&D, Visakhapatnam, India
b J. N. T. University, Kukatpally, Hyderabad, India
Accepted author version posted online: 14 Mar 2012.Version of
record first published: 05 Mar 2013.
To cite this article: K. Tatendra Reddy , K. Suneel Kumar , G. Omprakash & P. K. Dubey (2013):
Synthesis and Characterization of Impurity B of S-(+)-Clopidogrel Bisulfate: An Antiplatelet, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:10, 1387-1396
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Synthetic Communications1, 43: 1387–1396, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.635393
SYNTHESIS AND CHARACTERIZATION OF IMPURITY B
OF S-(þ)-CLOPIDOGREL BISULFATE: AN
ANTIPLATELET
K. Tatendra Reddy,1 K. Suneel Kumar,1 G. Omprakash,1 and
P. K. Dubey2
1PharmaZell R&D, Visakhapatnam, India
2J. N. T. University, Kukatpally, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract S-(þ)-Clopidogrel bisulfate [(S-(þ)-methyl 2-(2-chlorophenyl)-2-(6,
7-dihydrothieno[3, 2-c]pyridin-5(4H)-yl)acetate bisulfate)] is a platelet aggregation
inhibitor drug. S-(þ)-Clopidogrel bisulfate is prepared by different synthetic approaches
in the literature. In almost all the approaches the major impurities known in the literature
(A, B, and C) are also listed in the U.S. pharmacopoeia. The control of these pharmaceu-
tical impurities is currently a critical issue to the pharmaceutical industry. In this article, a
description of these impurities and their origins in the S-(þ)-clopidogrel bisulfate process
are presented along with the preparation of impurity B.
Keyword Antiplatelet; impurity B; S-(þ)-clopidogrel bisulfate
INTRODUCTION
Clopidogrel bisulfate [S-(þ)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno-
[3,2-c]pyridin-5(4H)-yl)acetate bisulfate] 1, is an oral, thienopyridine-class antiplate-
let agent used to inhibit blood clots caused by coronary artery disease, peripheral
vascular disease and cerebrovascular disease.[1,2] The drug works by irreversibly inhi-
biting a receptor called P2Y12, an adenosine diphosphate ADP chemoreceptor.[3,4]
Adverse effects include hemorrhage, severe neutropenia, and thrombotic thrombo-
cytopenic purpura (TTP).
Clopidogrel bisulfate is a prodrug whose action may be related to an adenosine
diphosphate (ADP) receptor on platelet cell membranes. The drug specifically and
irreversibly inhibits the P2Y12 subtype of the ADP receptor, which is important in
Received August 1, 2011.
Address correspondence to K. Tatendra Reddy, PharmaZell R&D (India) Private Limited,
Visakhapatnam 531 162, India. E-mail: talk2tatendra@yahoo.com
1387

1388
K. T. REDDY ET AL.
aggregation of platelets and cross-linking by the protein fibrin.[3] The blockade of
this receptor inhibits platelet aggregation by blocking activation of the glycoprotein
IIb=IIIa pathway. The IIb=IIIa complex functions as a receptor mainly for fibrino-
gen and vitronectin but also for fibronectin and von Willebrand factor. Activation of
this receptor complex is the ‘‘final common pathway’’ for platelet aggregation and is
important in the cross-linking of platelets by fibrin. Platelet inhibition can be demon-
strated 2 h after a single dose of oral clopidogrel bisulfate, but the onset of action is
slow, so that a loading dose of 300–600 mg is usually administered.
Impurities in pharmaceuticals are the unwanted chemicals that remain with the
active pharmaceutical ingredients (APIs) or develop during formulation. The presence
of these unwanted chemicals, even in small amounts, may influence the efficacy and
safety of the pharmaceutical products. Impurity profiling (identification and quantifi-
cation) is now receiving important critical attention from regulatory authorities. The
different pharmacopoeias, such as the European Pharmacopoeia (EP), British Phar-
macopoeia (BP), and the United States Pharmacopoeia (USP), are slowly incorporat-
ing limits to allowable levels of impurities present in the APIs or formulations.
The International Conference on Harmonization (ICH) has published guide-
lines on impurities in new drug substances,[5] products,[6] and residual solvents.[7]
Impurity and API reference standards are in good demand for both regulatory
authorities and pharmaceutical companies. A number of recent articles[8–10] have
described a designed approach and guidance for isolating and identifying process-
related impurities and degradation products using spectral and analytical techniques.
The important step in impurity profiling is the synthesis of the material
(impurity standard) with the proposed structure. The synthesized material with the
proposed structure is useful for analytical method development and validation.
There are many synthetic methods known in the literature for the synthesis of
clopidogrel bisulfate.[11,12] Innovator route for the preparation of clopidogrel bisul-
fate[12] involves the formation of impurities A, B, and C.
Impurities A and C are process impurities and were well controlled by main-
taining proper reaction conditions. The main source for impurity B was a key raw
material, that is, 2-substituted thiophene, along with traces amount of 3-substituted
thiophene. The impurity B formation was controlled by controlling the impurity
levels in that key raw material.
SOURCES OF IMPURITIES
Impurity A
During the synthesis of compound 1 [reaction of S-(þ)-clopidogrel base with
concentrated sulfuric acid], the ester group in the S-(þ)-clopidogrel base hydrolyzed
and afforded the formation of impurity A [S-(þ)-2-(2-chlorophenyl)-2-(6,7-
dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetic acid hydrochloride], 2.
Impurity B
According to the literature,[13] compound 1 was prepared by using 2-substitued
thiophene as one of the key raw materials. It is well known that 3-substitued

S-(þ)-CLOPIDOGREL BISULFATE
1389
thiophene was a major impurity during the synthesis of 2-substitued thiophene.[14]
Commercially available 2-substitued thiophene contains about 0.5–1.0% of 3-substi-
tued thiophene as an impurity. This 3-substituted thiophene also participates in the
reaction during the synthesis of compound 1 and leads the formation of methyl
2-(2-chlorophenyl)-2-(4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl) acetate hydrochlor-
ide, 3. Detailed synthesis of impurity B is discussed in the experimental section.
Impurity C
During the synthesis of compound 1, concentrated sulfuric acid was used for
bisulfate salt formation. Because of the high concentration of sulfuric acid, com-
pound 1 undergoes racemization. Unwanted R-(ꢀ)-clopidogrel bisulfate remained
as impurity C, 4, in the S-(þ)-clopidogrel bisulfate 1.
There is no synthetic approach available for impurity B in the literature. Out of
these three impurities, synthesis of impurity B is critical. This impurity standard is
not easily available to pharmaceutical industries. In the European pharmacopeia,
impurity B was specified as racemic hydrochloride salt. In high-performance liquid
chromatography (HPLC) analysis of clopidogrel bisulfate, 1 impurity B shows two
peaks for both the isomers at different retention times. Sometimes this leads to
confusion during interpretation of impurity B levels. To avoid such problems we pre-
pared S-(þ)-isomer of impurity B (3a) also. This made us provide a feasible synthetic
approach for the synthesis of impurity B to cater the needs of the pharmaceutical
industry as well as pharmacopeias.
The present article describes a simple and facile synthesis for impurity B. This
may serve as a standard for impurity profiling in drug development.
RESULTS AND DISCUSSION
The overall synthesis of impurity B proceeded through two routes. One was
condensation of methyl 2-bromo-2-(2-chlorophenyl)acetate 6 with 2-(thiophen-3-
yl)ethanamine 7 to afford compound 11, which again underwent cyclization with for-
maldehyde, and resolution with a chiral agent followed by bisulfate formation
afforded impurity B. In another way, direct condensation of methyl 2-bromo-2-
(2-chlorophenyl)acetate 6 with 4,5,6,7-tetrahydrothieno[2,3-c]pyridine 10 followed
by bisulfate formation afforded impurity B.
Condensation of methyl 2-bromo-2-(2-chlorophenyl)acetate 6 with 2-(thio-
phen-3-yl)ethanamine 7 in the presence of a base afforded methyl 2-(2-(thiophen-
3-yl)ethyl amino)-2-(2-chlorophenyl) acetate 11. Compound 11 was also prepared
by the condensation of methyl 2-amino-2-(2-chlorophenyl)acetate 8 with 3-(2-
iodoethyl) thiophene 9. The same synthesis was conducted with the S-(þ)-isomer
of methyl 2-bromo-2-(2-chlorophenyl)acetate 6a and methyl 2-amino-2-(2-chloro-
phenyl)acetate 8a for compound S-(þ)-methyl 2-(2-(thiophen-3-yl)ethyl amino)-2-
-(2-chlorophenyl)acetate 11a (Scheme 1).
Condensation of methyl 2-bromo-2-(2-chlorophenyl)acetate 6 with 4,5,6,7-
tetrahydrothieno[2,3-c]pyridine 10 in the presence of a base afforded methyl 2-(2-
chlorophenyl)-2-(4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl)acetate 12. The same
synthesis was conducted with S-(þ)-methyl 2-bromo-2-(2-chlorophenyl) acetate 6a.

1390
K. T. REDDY ET AL.
Scheme 1.
4,5,6,7-Tetrahydrothieno[2,3-c]pyridine 10 was prepared by the cyclization of
2-(thiophen-3-yl)ethanamine 7 with formaldehyde (Scheme 2).
Compound 3 was prepared by cyclization of 10 with 37% formaldehyde
solution followed by hydrochloride salt formation. Compound 3a was prepared in
different methods. In one method compound 11a was prepared from 11 by treatment
with 1S-(þ)-10-camphorsulfonic acid in acetone, which then proceeded to 12a by
cyclization in 37% formaldehyde solution. In another method compound 12 was pre-
pared by the cyclzation in 37% formaldehyde solution, which then proceeded to 12a
by treatment with 1R-(ꢀ)-10-camphorsulfonic acid in acetone. Compound 12a was
converted to 3 in acetone with hydrochloric acid (Scheme 3).
In Schemes 1 and 2, condensation was attempted with methyl a-halo (2-chlor-
ophenyl) acetate (halo ¼ fluoro, chloro, bromo, iodo). The reaction proceeded well
Scheme 2.

S-(þ)-CLOPIDOGREL BISULFATE
1391
Scheme 3.
with bromo moiety. In Scheme 3, resolution was attempted with S-(þ) and R-(ꢀ)
isomers of camphor sulfonic acid, tartaric acid and mandelic acid. Resolution of
racemic mixture was achieved with S-(þ)-camphor sulfonic acid. Methyl 2-bromo-2-
(2-chlorophenyl) acetate 6 was prepared from a-bromo(2-chloro phenyl)acetic acid
by the reported method.[13]
EXPERIMENTAL
Melting points were determined on a Buchi 540 melting-point apparatus and
were uncorrected. Fourier transform–infrared (FT-IR) spectra were recorded as
KBr pellet on a Nicolet 380 FT-IR instrument (model Thermo Electron Corporation
Spectrum One). 1H NMR spectra were recorded on a Varian 300-MHz spectrometer
using CDCl3 or dimethylsulfoxide (DMSO-d6) as solvents and tetramethylsilane
(TMS) as internal standard. Mass spectra were recorded on an Agilent triple quad-
rupole mass spectrometer equipped with turboion spray interface at 375 ꢁC. All the
organic extracts were dried over sodium sulfate after workup. Unless otherwise
mentioned, all the solvents and reagents used were of commercial grade.
Methyl 2-Bromo-2-(2-chlorophenyl)acetate (6)
Concentrated sulfuric acid (2.76 g, 28.14 mmol) was slowly added to a stirring
solution of 2-bromo-2-(2-chlorophenyl) acetic acid 5 (50.0 g, 200.4 mmol) in meth-
anol (250 mL) at room temperature. Reaction mass was refluxed for 3 h and then
cooled to 45 ꢁC. Methanol was completely distilled off under vacuum and the residue
was dissolved in dichloromethane (200 mL) and washed with 10% sodium bicarbon-
ate solution (50 mL) and water (2 ꢂ 100 mL). Dichloromethane was vacuum distilled
to yield 6 as a yellowish oily residue. This residue was carried to the next stage as
1
such (50.2 g, 95.07%); IR (KBr, cmꢀ1) 3009, 1758, 1572, 1439, 760, 684; H NMR
(DMSO-d6, 300 MHz): d 3.6 (s, 3H), 5.0 (s, 1H), 7.3–7.6 (m, 4H); MS (ESI, m=z):
264.42 [M þ H]þ. Anal. calcd. for C9H8BrClO2 (263.52): C, 41.02; H, 3.06; O,
12.14%. Found: C, 41.12; H, 3.05; O, 12.15%.
S-(þ) Methyl 2-Bromo-2-(2-chlorophenyl)acetate (6a)
This compound was prepared in a similar way to 6, using S-(þ)-2-bromo-2-
(2-chlorophenyl) acetic acid (25.0 g, 100.2 mmol), as a light yellowish oily residue.
This residue was carried to the next stage as such (24.3 g, 92.04%); MS (ESI, m=z):
264.62 [M þ H]þ. Anal. calcd. for C9H8BrClO2 (263.52): C, 41.02; H, 3.06; O,
12.14%. Found: C, 41.08; H, 3.09; O, 12.10%.

1392
K. T. REDDY ET AL.
Methyl 2-(2-(Thiophen-3-yl)ethyl amino)-2-(2-chlorophenyl)acetate
(11) from 6 and 7
Sodium bicarbonate (8.0 g, 94.85 mmol) and 2-(thiophen-3-yl) ethanamine 7
(24.13 g, 189.7 mmol) were added slowly to a stirring solution of methyl 2-bromo-2-
(2-chlorophenyl) acetate 6 (50.0 g, 189.7 mmol) in methanol (180.0 mL) at below
10 ꢁC. Mass was heated to reflux temperature for 2 h. After reaction completion,
methanol was distilled off completely under vacuum, and water (200 mL) and
dichloromethane (200 mL) were added. The dichloromethane layer was separated
and washed with saturated sodium chloride solution (50 mL) and then with water
(100 mL). Dichloromethane was distilled completely under vacuum to yield 11 as
an off-white color oily residue (54.3 g, 92.4%); purity 99.48% (by HPLC); IR
(KBr, cmꢀ1) 3463, 3071, 2912, 1741, 1485, 1462, 1232, 765; 1H NMR (CDCl3,
300 MHz): d 3.0 (t, J ¼ 7.8 Hz, 2H), 3.1 (t, J ¼ 14.7 Hz, 2H), 3.7 (s, 3H), 5.6 (s,
1H), 7.0 (d, J ¼ 6.3 Hz, 1H), 7.3 (s, 1H), 7.5–7.7 (m, 4H); MS (ESI, m=z): 310.1
[M þ H]þ. Anal. calcd. for C15H16ClNO2S (309.81): C, 58.15; H, 5.21; N, 4.52; S,
10.35; O, 10.33%. Found: C, 58.20; H, 5.25; N, 4.48; S, 10.31; O, 10.29%.
S-(þ)-Methyl 2-(2-(Thiophen-3-yl)ethylamino)-2-
(2-chlorophenyl)acetate (11a) from 6a and 7
This compound was prepared in a similar way to 11, using S-(þ)-methyl
2-bromo-2-(2-chlorophenyl) acetate, 6a (25.0 g, 94.85 mmol), and 2-(thiophen-3-yl)
ethanamine 7 (12.07 g, 94.85 mmol) as an off-white oily residue (27.0 g, 91.86%);
purity 99.39% (by HPLC); SOR [a]D20 þ 109.5 (c 1.61, CH3OH); MS (ESI, m=z):
310.28 [M þ H]þ. Anal. calcd. for C15H16ClNO2S (309.81): C, 58.15; H, 5.21; N,
4.52; S, 10.35; O, 10.33%. Found: C, 58.18; H, 5.25; N, 4.55; S, 10.32; O, 10.30%.
Methyl 2-(2-(Thiophen-3-yl)ethyl amino)-2-(2-chlorophenyl)acetate
(11) from 8 and 9
Triethyl amine (38.0 g, 375.69 mmol) and 3-(2-iodoethyl) thiophene 9 (71.55 g,
300.55 mmol) were added to a stirring solution of methyl 2-amino-2-(2-chlorophe-
nyl) acetate 7 (50.0 g, 250.46 mmol) in acetonitrile (200.0 mL) at 25–30 ꢁC and the
mass was refluxed for 10–12 h. The reaction mass was completely distilled off under
vacuum and the residue was dissolved in dichloromethane (100 mL). The dichloro-
methane layer was washed with water (100 mL) and distilled off under vacuum to
yield 11 as an off-white oily residue (64.3 g, 82.86%); purity 99.56% (by HPLC);
IR (KBr, cmꢀ1) 3463, 3071, 2912, 1745, 1521, 1452, 1232, 765; MS (ESI, m=z):
310.12 [M þ H]þ. Anal. calcd. for C15H16ClNO2S (309.81): C, 58.15; H, 5.21; N,
4.52; S, 10.35; O, 10.33%. Found: C, 58.18; H, 5.22; N, 4.55; S, 10.34; O, 10.35%.
S-(þ)-Methyl 2-(2-(Thiophen-3-yl)ethyl amino)-2-(2-
chlorophenyl)acetate (11a) from 8a and 9
This compound was prepared in a similar way to 11, using S-(þ)-methyl
2-amino-2-(2-chlorophenyl)acetate 8a (22.0 g, 110.20 mmol) and 3-(2-iodoethyl)thio-
phene 9 (31.48 g, 132.23 mmol) as an off-white oily residue (27.5 g, 80.68%); SOR

S-(þ)-CLOPIDOGREL BISULFATE
1393
[a]D20 þ 108.9 (c 1.61, CH3OH); IR (KBr, cmꢀ1) 3463, 3071, 2912, 1741, 1581, 1585,
1232, 765; MS (ESI, m=z): 310.22 [M þ H]þ. Anal. calcd. for C15H16ClNO2S
(309.81): C, 58.15; H, 5.21; N, 4.52; S, 10.35; O, 10.33%. Found: C, 58.10; H,
5.28; N, 4.59; S, 10.31; O, 10.39%.
4,5,6,7-Tetrahydrothieno[2,3-c]pyridine (10)
Concentrated hydrochloric acid (5 mL) added slowly to a solution of
2-(thiophen-3-yl) ethanamine 7 (100.0 g, 786.1 mmol) in 37% formaldehyde solution
(500 mL) at 25–30 ꢁC and the mass was heated at 80–85 ꢁC for 30 min. The mass was
cooled to room temperature, neutralized with sodium bicarbonate (24.5 gs), and
extracted with dichloromethane (300 mL). The dichloromethane was washed
with saturated sodium chloride solution (50 mL) and then with water (2ꢂ 100 mL).
Dichloromethane was distilled off completely under vacuum to yield 10 as a light yel-
low residue (101.6g, 92.8%); purity 99.74% (by HPLC); IR (KBr, cmꢀ1) 2924, 2829,
1
1595, 1490, 1446, 1340; H NMR (CDCl3, 300 MHz): d 2.0 (s, 1H), 2.7–2.9 (m,
4H), 3.8 (s, 2H), 6.5 (s, 1H), 6.8 (s, 1H); MS (ESI, m=z): 139.48 [M]þ. Anal. calcd.
for C7H9NS (139.22): C, 60.39; H, 6.52; N, 10.06; S, 23.03%. Found: C, 60.42; H,
6.55; N, 10.00; S, 23.01%.
Methyl 2-(2-Chlorophenyl)-2-(4,5-dihydrothieno[2,3-c]pyridin-6(7H)-
yl)acetate (12) from 6 and 10
Water (150.0 mL) and potassium carbonate (72.37 g, 523.65 mmol) were added
to a suspension of methyl 2-bromo-2-(2-chlorophenyl) acetate 6 (46.0 g, 174.55 mmol)
in methanol (100.0 mL) and stirred for 10 min at 25 ꢁC. 4,5,6,7-Tetrahydro-
thieno[2,3-c]pyridine 10 (24.3 g, 174.55 mmol) was added under stirring. Mass was
maintained at 60–65 ꢁC for 6 h and then water (150 mL) and dichloromethane
(200 mL) were added at 25 ꢁC. The dichloromethane layer was separated and
washed with water. Dichloromethane was distilled off completely under reduced
pressure to yield 11 as an off-white oily residue (46.17 g, 87.2%); purity 99.37%
(by HPLC); IR (KBr, cmꢀ1) 3060, 2951, 1752, 1604, 1588, 1406, 1224, 771; MS
(ESI, m=z): 322.33 [M þ H]þ. Anal. calcd. for C16H16ClNO2S (321.82): C, 59.71;
H, 5.01; N, 4.35; S, 9.96; O, 9.94%. Found: C, 59.69; H, 5.06; N, 4.32; S, 9.91; O,
9.98%.
S-(þ)-Methyl 2-(2-Chlorophenyl)-2-(4,5-dihydrothieno[2,3-c]pyridin-
6(7H)-yl)acetate (12a) from 6a and 10
This compound was prepared in a similar way to 11, using S-(þ)-methyl
2-bromo-2-(2-chlorophenyl) acetate 6a (23.0 g, 87.27 mmol) and 4,5,6,7-tetrahydro-
thieno[2,3-c]pyridine 10 (12.1 g, 86.91 mmol) as an off-white oily residue (23.9 g,
85.2%). Purity 99.55% (by HPLC); SOR [a]D20 þ 52.58 (c 1.61, CH3OH); IR
(KBr, cmꢀ1) 3060, 2951, 1752, 1604, 1588, 1406, 1224, 771; MS (ESI, m=z): 322.48
[M þ H]þ. Anal. calcd. for C16H16ClNO2S (321.82): C, 59.71; H, 5.01; N, 4.35; S,
9.96; O, 9.94%. Found: C, 59.74; H, 5.04; N, 4.32; S, 9.90; O, 9.97%.

1394
K. T. REDDY ET AL.
Methyl 2-(2-Chlorophenyl)-2-(4,5-dihydrothieno[2,3-c]pyridin-6(7H)-
yl)acetate (12) from 11
Concentrated hydrochloric acid (0.85 g, 23.24 mmol) was added slowly to a
suspension of methyl 2-(2-(thiophen-3-yl)ethyl amino)-2-(2-chlorophenyl)acetate 11
(36.0 g, 116.2 mmol) in 37% formaldehyde solution (288.0 mL) at 25 ꢁC. The reaction
mass was maintained at 50–55 ꢁC for 3–4 h. Dichloromethane (100 mL) was added
and the mass pH was adjusted to 7.0–7.5 with 10% sodium bicarbonate solution
(64 mL). The dichloromethane layer was separated, washed with water (2 ꢂ 100 mL),
and distilled off under reduced pressure to yield 11 as an off-white oily residue
(34.7 g, 92.8%). Purity 99.72% (by HPLC); IR (KBr, cmꢀ1) 3060, 2951, 1750, 1604,
1588, 1406, 1224, 771; MS (ESI, m=z): 322.21 [M]þ. Anal. calcd. for C16H16ClNO2S
(321.82): C, 59.71; H, 5.01; N, 4.35; S, 9.96; O, 9.94%. Found: C, 59.70; H, 5.06; N,
4.39; S, 9.92; O, 9.91%.
S-(þ)-Methyl 2-(2-Chlorophenyl)-2-(4,5-dihydrothieno[2,3-c]pyridin-
6(7H)-yl)acetate (12a) from 11a
This compound was prepared in a similar way to 11, using S-(þ)-methyl
2-(2-(thiophen-3-yl)ethyl amino)-2-(2-chlorophenyl)acetate 11a (46.0 g, 148.47 mmol)
as an off-white oily residue (44.6 g, 93.4%). Purity 99.88% (by HPLC); SOR
[a]D20 þ 53.01 (c 1.61, CH3OH); IR (KBr, cmꢀ1) 3060, 2951, 1752, 1604, 1588,
1452, 1224, 771; MS (ESI, m=z): 320.38 [M-H]þ. Anal. calcd. for C16H16ClNO2S
(321.82): C, 59.71; H, 5.01; N, 4.35; S, 9.96; O, 9.94%. Found: C, 59.790; H, 5.02;
N, 4.30; S, 10.01; O, 9.99%.
S-(þ)-Methyl 2-(2-(Thiophen-3-yl)ethyl amino)-2-
(2-chlorophenyl)acetate (11a) from 11
1S-(þ)-10-Camphorsulfonic acid (24.0 g, 103.29 mmol) was added at room tem-
perature to a solution of methyl 2-(2-(thiophen-3-yl)ethyl amino)-2-(2-chlorophenyl)
acetate 11 (32.0 g, 103.29 mmol) in acetone (50.0 mL). The mass was maintained
under stirring at 25–30 ꢁC for 5 h, filtered, and washed with acetone (10 mL). Wet
material was refluxed three times in a mixture of acetone (84.0 mL) and methyl ethyl
ketone (52.0 mL). The resulting wet material was charged to a stirring solution of
dichloromethane (50 mL) and water (30 mL) and the mass pH was adjusted to
8–8.5 with 10% sodium bicarbonate solution (35 mL). The dichloromethane layer
was separated and washed with water (2 ꢂ 50 mL). The dichloromethane was distilled
off completely at reduced pressure to yield 11a as an almost white residue (12.4 g,
38.7%); purity 99.57% (by HPLC); SOR [a]D20 þ 110.42 (c 1.61, CH3OH); IR
(KBr, cmꢀ1) 3463, 3071, 2912, 1741, 1485, 1462, 1232, 765; MS (ESI, m=z): 310.34
[M þ H]þ. Anal. calcd. for C15H16ClNO2S (309.81): C, 58.15; H, 5.21; N, 4.52; S,
10.35; O, 10.33%; Found: C, 58.12; H, 5.26; N, 4.59; S, 10.38; O, 10.35%.
S-(þ)-Methyl 2-(2-Chlorophenyl)-2-(4,5-dihydrothieno[2,3-c]pyridin-
6(7H)-yl)acetate (12a) from 12
To a stirring solution of methyl 2-(2-chlorophenyl)-2-(4,5-dihydrothieno-
[2,3-c]pyridin-6(7H)-yl) acetate 12 (40.0 g, 124.29 mmol) in acetone (140.0 mL),

S-(þ)-CLOPIDOGREL BISULFATE
1395
1R-(ꢀ)-10-camphorsulfonic acid (23.1 g, 99.43 mmol) was added, and the mixture
was stirred at 30–35 ꢁC for 20–24 h. The separated material was filtered and washed
with acetone (10 mL). The wet material was charged into a dichloromethane
(100 mL) and water (100 mL) mixture and the mass pH was adjusted to 7.5–8.0 with
10% sodium bicarbonate solution (46 mL). The dichloromethane layer was separated
and washed with water (2 ꢂ 60 mL). Dichloromethane was distilled off completely at
reduced pressure to yield 12a as an almost white residue (12.4 g, 38.7%); purity
99.90% (by HPLC); SOR [a]D20 þ 52.58 (c 1.61, CH3OH); IR (KBr, cmꢀ1) 3060,
2912, 1740, 1604, 1480, 1224, 771; MS (ESI, m=z): 322.34 [M þ H]þ. Anal. calcd.
for C15H16ClNO2S (321.82): C, 59.71; H, 5.01; N, 4.35; S, 9.96; O, 9.94%. Found:
C, 59.78; H, 5.02; N, 4.34; S, 9.98; O, 9.95%.
Methyl 2-(2-Chlorophenyl)-2-(4,5-dihydrothieno[2,3-c]pyridine-
6(7H)-yl)acetate Hydrochloride (3) from 12
Concentrated hydrochloric acid (13.4 g) was added slowly to a stirring solution
of methyl 2-(2-chlorophenyl)-2-(4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl) acetate 12
(40.0 g, 124.29 mmol) in acetone (200.0 mL) at 25 ꢁC and stirred for 10–12 h. It was
filtered, washed with chilled acetone (10 mL), and dried at 40–45 ꢁC under reduced
pressure to yield 3 (32.8 g, 73.7%) as an off-white crystalline solid; purity 99.90%
(by HPLC); assay 99.50% (by HPLC); IR (KBr, cmꢀ1) 3060, 2963, 1752, 1604,
1
1588, 1480, 1326, 1224, 771; H NMR (300 MHz, DMSO-d6) d 2.9 (t, J ¼ 3.3 Hz,
2H), 3.3 (t, J ¼ 2.9 Hz, 2H), 3.7 (s, 3H), 4.3 (s, 2H), 5.4 (s, 1H), 6.9 (d, J ¼ 5.1 Hz,
1H), 7.4–7.6 (m, 4H), 7.8 (d, J ¼ 3.2 Hz, 1H); 13CNMR (300 MHz, DMSO-d6): d
22.7, 48.1, 49.2, 53.3, 64.20, 65.2, 125.0, 126.7, 127.3, 128.1, 128.8, 130.3, 131.7,
132.0, 134.18, 167.4; MS (ESI, m=z): 322.2 [M þ H]þ. Anal. calcd. for
C16H17Cl2NO2S (358.28): C, 53.64; H, 4.78; N, 3.91; S, 8.95; O, 8.93%. Found: C,
53.60; H, 4.76; N, 3.98; S, 8.92; O, 8.92%.
S-(þ)-Methyl 2-(2-Chlorophenyl)-2-(4,5-dihydrothieno[2,3-c]pyridine-
6(7H)-yl)acetate Hydrochloride (3a) from 12a
This compound was prepared in a similar way to 3, using S-(þ)-methyl
2-(2-chlorophenyl)-2-(4,5-dihydrothieno[2,3-c]pyridin-6(7H)-yl) acetate 12a (20.0 g,
62.14 mmol) as an off-white crystalline solid (16.6 g, 74.6%). Purity 99.94% (by
HPLC); SOR [a]D20 þ 50.06 (c 1.61, CH3OH); purity 99.94% (by HPLC); assay
99.64% (by HPLC); IR (KBr, cmꢀ1) 3060, 2951, 1752, 1604, 1588, 1461, 1326,
1224, 771; MS (ESI, m=z): 321.38 [M]þ. Anal. calcd. for C16H17Cl2NO2S
Figure 1.

1396
K. T. REDDY ET AL.
Figure 2.
(358.28): C, 53.64; H, 4.78; N, 3.91; S, 8.95; O, 8.93%. Found: C, 53.69; H, 4.71; N,
3.95; S, 8.90; O, 8.99%.
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