A scalable synthesis of (±)-2-oxoclopidogrel

Article abstract of DOI:10.1055/s-0029-1219177

As a precondition for detailed pharmacological investigations, an efficient chemical method for the conversion of the antiplatelet drug clopidogrel into its first metabolite 2-oxoclopidogrel was developed. The one-pot procedure, which can easily be performed on a gram scale, exploits the selective borylation of a di-anionic intermediate derived from clopidogrel with subsequent oxidative workup.

Full text of DOI:10.1055/s-0029-1219177

LETTER
467
A Scalable Synthesis of ( )-2-Oxoclopidogrel
Scalable
S
a
ynthesis of
n
(
)-2-Oxoc
ln
opidogrel a Velder,a Christoph Hirschhäuser,a Christopher Waldmann,a Dirk Taubert,b Heleen J. Bouman,c
Hans-Günther Schmalz*a
c
Department für Chemie, Universität zu Köln, Greinstr. 4, 50939 Köln, Germany
Fax +49(221)4703064; E-mail: schmalz@uni-koeln.de
Institut für Pharmakologie, Universitätsklinikum Köln, Gleveler Str. 24, 50931 Köln, Germany
St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands
d
e
Received 29 October 2009
vitro and in vivo quantification and as a precursor for
studying its biotransformation into the active metabolite
3. It should be stressed that the enzymatic production of 2-
oxoclopidogrel (2)4 starting from 1 is not applicable on a
Abstract: As a precondition for detailed pharmacological investi-
gations, an efficient chemical method for the conversion of the an-
tiplatelet drug clopidogrel into its first metabolite 2-oxoclopidogrel
was developed. The one-pot procedure, which can easily be per-
formed on a gram scale, exploits the selective borylation of a di- preparative scale because yields are very low and exten-
anionic intermediate derived from clopidogrel with subsequent ox-
idative workup.
sive purification is required to obtain only tiny amounts of
the product in pure form.
Key words: clopidogrel, drugs, lithiation, oxidation, thiophenes
CO2Me
CO2Me
H
H
N
N
O
Platelet activation is the major factor in the development
of ischemic and thrombotic complications in patients un-
dergoing percutaneous coronary intervention (PCI). Anti-
platelet treatment with the thienopyridine derivative
clopidogrel (1; Plavix®) in addition to aspirin given before
PCI is currently considered the gold standard to prevent
adverse cardiovascular events.1 The main clinical limita-
tion of 1, however, is the high interindividual response
variability. Actually, between 5–54% of PCI patients at-
tain insufficient platelet inhibition2 and thus appear to be
at increased risk for cardiovascular events.3
S
S
Cl
1 (clopidogrel)
Cl
2
CO2Me
H
N
HO2C
HS
Cl
3 (active metabolite)
Scheme 1 Enzymatic conversion of clopidogrel (1) via 2-oxoclopi-
dogrel (2) into the active metabolite 3
The causes of the substantial interpatient differences in re-
sponse to 1 are incompletely understood. Nevertheless, it
has been shown that 1 is actually a prodrug that requires
biotransformation to an active metabolite, that is, the sen-
sitive thiol 3 which then binds covalently by a disulfide
bridge to its pharmacological target.4 Preliminary data in-
dicate that the plasma concentration of the active metabo-
lite is a strong determinant of the antiplatelet activity.5
Based on incubation experiments using liver microsomes,
formation of the active metabolite of 1 was suggested to
proceed through a two-step mechanism via 2-oxoclopi-
dogrel (2) as an intermediate metabolite (Scheme 1).4 Al-
though genetic polymorphisms of cytochrome P450
enzymes have been linked to individual variability in re-
sponsiveness to clopidogrel,6 no direct in vitro or in vivo
assessments of the metabolic pathways leading to clopi-
dogrel activation and the involved enzymes have been
performed.
Against this background a chemical method for the con-
version of 1 into 2 would be highly desirable. Here we dis-
close an operationally simple, non-enzymatic, time-, and
cost-efficient solution for this task, which yields large
quantities of analytical grade 2-oxoclopidogrel (rac-2).
Initially, we considered it necessary to first convert the es-
ter function of 1 into a protected alcohol 4, which could
then be selectively oxidized to a thiobutenolide of type 5
prior to the final re-establishment of the ester moiety in 2
(Scheme 2).
O-PG
O-PG
H
H
N
N
1
2
O
S
S
Cl
Cl
To elucidate these pathways and the variability of clopi-
dogrel metabolism, substantial amounts of 2-oxoclopi-
dogrel (2) are needed both as an analytical standard for in
4
5
Scheme 2 Initial concept for the conversion of 1 into 2
Following this plan, clopidogrel (1) was reduced with
LiAlH4 in diethyl ether, and the resulting alcohol 6 was
converted into the silylether 7 by treatment with TBSCl
and Et3N (88% overall yield). The key thiophene oxida-
SYNLETT 2010, No. 3, pp 0467–0469
Advanced online publication: 07.01.2010
DOI: 10.1055/s-0029-1219177; Art ID: G38009ST
© Georg Thieme Verlag Stuttgart · New York
1
2.
0
2.
2
0
1
0

468
J. Velder et al.
LETTER
tion was then initiated by lithiation of the thiophene ring
using n-BuLi in THF in the presence of tetramethylurea
(TMU, instead of HMPT7) as a co-solvent. After addition
of B(OMe)3 the resulting boronate was directly oxidized
with H2O2 to afford compound 8 in good yield as a mix-
ture of diastereomers (Scheme 3). To our surprise, the
cleavage of the silyl protecting group then proved to be
difficult under various established conditions,8 and the al-
cohol 9 was isolated in only 34% yield in the best case.
Moreover, the planned oxidation of 9 using either the
Dess–Martin periodinane9 or Jones reagent10 failed. Nev-
ertheless, compounds 8 and 9 proved of value as referenc-
es for further structural assignments.
Li-O
N
OMe
CO2Me
H
LDA
THF
N
S
S
Cl
Cl
1
10
n-BuLi, TMU
Li-O
OMe
CO2Me
B(OMe)3
H2O2
N
N
Li
O
41%
S
S
Cl
rac-2
Cl
11
OTBS
OR
H
H
Scheme 4 Synthesis of 2-oxoclopidogrel (rac-2) in a one-pot proce-
dure.
a
N
N
c
1
O
80%
92%
S
b
S
Cl
Cl
Starting from (inexpensive) clopidogrel (1) the transfor-
mation is achieved in a one-pot procedure and proceeds
with an overall yield of 40% even on a gram scale. While
the absolute stereochemical information is lost during this
process and the product is formed as a mixture of diaste-
reomers, the method represents the first and sole synthetic
entrance to a key metabolite (precursor of the active spe-
cies) of the important antiplatelet drug clopidogrel. Also
the synthetic material proved to be perfectly suited as an
analytical standard for detailed pharmacological investi-
gations, the results of which will be separately reported in
due course.
6 (R = H)
8
96%
d
34%
7 (R = TBS)
OH
H
N
O
2
S
Cl
9
Scheme 3 Initial approach for the conversion of 1 into 2. Reaction
conditions: (a) LiAlH4, Et2O, 20 h, r.t.; (b) TBSCl, Et3N, CH2Cl2.
–10 °C to r.t., 24 h; (c) n-BuLi, THF, TMU, –78 °C, 17 min, then
B(OMe)3, –60 °C to 0 °C, 3 h, then H2O2–H2O, 0 °C, 45 min; (d)
THF–H2O–AcOH (1:1:2.5), r.t., 30 min, 30 °C, 20 h concept for the
conversion of 1 into 2.
(2-Chlorophenyl)-{2-oxo-2,6,7,7a-tetrahydro-4H-thieno[3,2-
c]pyridin-5-yl}acetic Acid Methyl Ester (rac-2)
To a solution of clopidogrel (1, 3.8 g, 11.84 mmol) in THF (80 mL)
was added dropwise at –78 °C a 1.8 M solution of LDA (7.2 mL,
13.02 mmol) in THF. After 45 min at –78 °C TMU (2.8 mL, 26.05
mmol) was added, followed by a 1.58 M solution of n-BuLi in hex-
ane (16.5 mL, 26.05 mmol). The mixture was stirred for 10 min be-
fore B(OMe)3 (2.9 mL, 26.05 mmol) was added at –60 °C. The
stirred solution was allowed to slowly warm to 0 °C (4.5 h) before
a solution (35% w/w) of H2O2 in H2O (1.2 mL, 14.21 mmol, 1.2
equiv) was added and stirring was continued for 45 min at 0 °C. The
mixture was then partitioned between H2O (20 mL) and MTBE (50
mL), and the aqueous layer was re-extracted with MTBE. The com-
bined organic layers were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. Purification by flash chroma-
tography (cyclohexane–EtOAc = 3:1) afforded the rac-2 as a solid
(1.58 g, 4.8 mmol, 41%). Rf = 0.32 (cyclohexane–EtOAc = 10:1).
IR (ATR, CHCl3): 2928 (m), 2857 (m), 1758 (s), 1685 (s), 1469 (m),
In order to circumvent the above-mentioned problems as-
sociated to functional-group transformations in the pres-
ence of the sensitive thiobutenolide moiety we envisioned
that the borylation step (to prepare for the thiophene oxi-
dation) could possibly be achieved employing a dilithiat-
ed intermediate of type 11 (Scheme 4). In this case, the
ester functionality would be in situ protected as the eno-
late 10. And indeed: When clopidogrel (1) was first depro-
tonated with LDA (1 equiv) and subsequently treated with
n-BuLi/TMU, trimethylborate, and H2O2, the desired
product, that is, 2-oxoclopidogrel (rac-2), was obtained as
a mixture of diastereomers (Scheme 3).
The constitution of rac-2 was unambiguously established
through the spectroscopic data, also in comparison to
compounds 8 and 9. Particular characteristic features of
the thiobutenolide substructure are the carbonyl proton
signal at d = ca. 5.95 ppm and a 13C signal at d = 198.5
ppm corresponding to the carbonyl group. The doubling
of most 13C and some 1H signals indicated the presence of
two diastereomers in a ratio of ca. 1:1.
1
1255 (m), 1094 (s), 835 (s) cm–1. H NMR (300 MHz, CDCl3):
d = 1.72–1.86 (m, 1 H), 2.25–2.35 (m, 1 H), 2.48–2.64 (m, 1 H),
2.94–3.10 (m, 1 H), 3.09–3.23 (m, 1 H), 3.64/3.65 (s, 3 H, OCH3),
3.74–3.87 (m, 1 H), 4.05 (m, 1 H, H-C7a), 4.82/4.84 (s, 1 H, CHN),
5.93 (s, 1 H, HC3), 7.23 (m, 2 Har), 7.35 (m, 1 Har), 7.45 (m, 1 Har).
13C NMR (75 MHz, CDCl3): d = 33.7/33.9 (C7), 48.9/45.5 (C4),
51.0 (C7a), 52.3 (OCH3), 51.5/52.3 (C6), 67.1 (CH-N), 126.4/126.6
(C-3), 127.0/127.1 (Car4), 129.6/129.7 (Car5), 129.9/130.0 (Car3),
129.5/129.6 (Car6), 132.6/132.8 (C3), 134.5/134.7 (Car1), 167.2/
In conclusion, we have found an astonishingly simple so-
lution for the preparation of 2-oxoclopidogrel (rac-2). 167.4 (C3a), 170.6/170.7 (CO2Me), 198.5 (C=O). ESI-HRMS: m/z
[M + H]+ calcd for C16H16ClNO3S: 337.0539; found: 337.0538.
Synlett 2010, No. 3, 467–469 © Thieme Stuttgart · New York

LETTER
Scalable Synthesis of ( )-2-Oxoclopidogrel
469
(S)-5-[2-(tert-Butyldimethylsilanyloxy)-1-(2-chlorophenyl)eth-
yl]-5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one (8)
(2) (a) Wang, T. H.; Bhatt, D. L.; Topol, E. J. Eur. Heart J.
2006, 27, 647. (b) Gurbel, P. A.; Bliden, K. P.; Hiatt, B. L.;
O’Connor, C. M. Circulation 2003, 107, 2908.
To a solution of silyl ether 7 (2.0 g, 4.93 mmol) in THF (50 mL) was
added dropwise at –78 °C TMU (2.8 mL, 5.91 mmol, 1.2 equiv) fol-
lowed by addition of a 2.41 M solution of n-BuLi in hexane (2.45
mL, 5.91 mmol, 1.2 equiv) over a period of 7 min. Stirring was con-
tinued for 10 min under warming to –60 °C before B(OMe)3 (0.6
mL, 5.42 mmol, 1.1 equiv) were added. The mixture was then al-
lowed to warm to 0 °C over a period of 3 h and stirred for 30 min at
0 °C before aq H2O2 (35% w/w, 0.5 mL, 5.91 mmol, 1.2 equiv) were
added. After 45 min at 0 °C the mixture was allowed to warm to r.t.
and H2O (20 mL) and MTBE (50 mL) were added. The layers were
separated, and the aqueous layer was re-extracted with MTBE. The
combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. Purification by flash
chromatography (cyclohexane–EtOAc = 10:1) afforded the product
8 as yellow oil (1.67 g, 3.93 mmol, 80%). Rf = 0.29 (cyclohexane–
EtOAc = 10:1). IR (CHCl3): 3061 (w), 2950 (m), 2925 (m), 2854
(m), 1569 (w), 1469 (m), 1254 (m), 1099 (s), 834 (s), 775 (m), 699
(3) (a) Matetzky, S.; Shenkman, B.; Guetta, V.; Shechter, M.;
Bienart, R.; Goldenberg, I.; Novikov, I.; Pres, H.; Savion,
N.; Varon, D.; Hod, H. Circulation 2004, 109, 3171.
(b) Gurbel, P. A.; Bliden, K. P.; Samara, W.; Yoho, J. A.;
Hayes, K.; Fissha, M. Z.; Tantry, U. S. J. Am. Coll. Cardiol.
2005, 46, 1827. (c) Hochholzer, W.; Trenk, D.; Bestehorn,
H. P.; Fischer, B.; Valina, C. M.; Ferenc, M.; Gick, M.;
Caputo, A.; Buttner, H. J.; Neumann, F. J. J. Am. Coll.
Cardiol. 2006, 48, 1742.
(4) (a) Savi, P.; Pereillo, J. M.; Uzabiaga, M. F.; Combalbert, J.;
Picard, C.; Maffrand, J. P.; Pascal, M.; Herbert, J. M.
Thromb. Haemost. 2000, 84, 891. (b) Pereillo, J. M.;
Maftouh, M.; Andrieu, A.; Uzabiaga, M. F.; Fedeli, O.; Savi,
P.; Pascal, M.; Herbert, J. M.; Maffrand, J. P.; Picard, C.
Drug Metab. Dispos. 2002, 30, 1288. (c) Clarke, T.;
Waskell, L. A. Drug Metab. Dispos. 2003, 31, 53.
(5) (a) Von Beckerath, N.; Taubert, D.; Pogatsa-Murray, G.;
Schomig, E.; Kastrati, A.; Schomig, A. Circulation 2005,
112, 2946. (b) Wallentin, L.; Varenhorst, C.; James, S.;
Erlinge, D.; Braun, O. O.; Jakubowski, J. A.; Sugidachi, A.;
Winters, K. J.; Siegbahn, A. Eur. Heart J. 2008, 29, 21.
(6) (a) Angiolillo, D. J.; Fernandez-Ortiz, A.; Bernardo, E.;
Ramirez, C.; Cavallari, U.; Trabetti, E.; Sabate, M.;
Hernandez, R.; Moreno, R.; Escaned, J.; Alfonso, F.;
Banuelos, C.; Costa, M. A.; Bass, T. A.; Pignattim, P. F.;
Macaya, C. Arterioscler., Thromb., Vasc. Biol. 2006, 26,
1895. (b) Brandt, J. T.; Close, S. L.; Iturria, S. J.; Payne,
C. D.; Farid, N. A.; Ernest, C. S.; Lachno, D. R.; Salazar, D.;
Winters, K. J. J. Thromb. Haemost. 2007, 5, 2429.
(c) Mega, J. L.; Close, S. L.; Wiviott, S. D.; Shen, L.;
Hockett, R. D.; Brandt, J. T.; Walker, J. R.; Antman, E. M.;
Macias, W.; Braunwald, E.; Sabatine, M. S. New Engl. J.
Med. 2009, 360, 354.
1
(m) cm–1. H NMR (300 MHz, CDCl3): d = –0.10/–0.05 (s, 3 H,
SiMe2), 0.82 [s, 9 H, SiC(CH3)3], 1.71–1.92 (m, 1 H,), 2.22–2.28
(m, 1 H, H-C7), 2.35–2.44 (m, 1 H, HC4), 2.50–2.60 (m, 1 H, HC4),
2.90–2.97 (m, 1 H, HC6), 3.72 (d, J = 11.7 Hz, 1 H, HC6), 3.78–
3.98 (m, 2 H, H2COTBS), 4.11–4.21 (m, 2 H, HCN and HC7a),
5.87/6.04 (s, 1 H, HC3), 7.17–7.21 (m, 2 H, Ar), 7.32–107.37 (m, 1
Har), 7.47–7.53 (m, 1 Har). 13C NMR (75 MHz, CDCl3): d = –5.6
(SiMe2), 25.7 [SiC(CH3)3], 34.2/34.7 (C7), 49.4/50.6 (C4), 51.5
(C7a), 52.7/53.5 (C6), 64.6 (CHOTBS), 65.5/66.0 (CHN), 125.8
(C-3), 126.5/126.8 (Car2), 128.4/128.5 (Car4), 129.3/129.4 (Car5),
129.5/129.6 (Car3), 133.8 (Car6), 137.5 (Car1), 168.6/168.9 (C3a),
198.7/198.8 (C=O). MS (EI, 70 eV): m/z (%) = 425 (23) [M+], 278
(100).
Acknowledgment
This work was supported by Cimex Development AG and the Uni-
versity of Cologne. The authors also thank the Chemetall GmbH for
generous gifts of butyllithium.
(7) Boigegrain, R.; Maffrand, J.-P.; Suzuki, N.; Matsubayashi,
K.; Ashida, S. US 4,515,951, 1985.
(8) (a) Prakash, C.; Saleh, S.; Blair, I. A. Tetrahedron Lett.
1989, 30, 19. (b) Ikawa, T.; Hattori, K.; Sajiki, H.; Hirota, K.
Tetrahedron 2004, 60, 6901. (c) Paquette, L. A.; Collado, I.;
Purdie, M. J. Am. Chem. Soc. 1998, 120, 2553.
References
(1) (a) Yusuf, S.; Zhao, F.; Mehta, S. R.; Chrolavicius, S.;
Tognoni, G.; Fox, K. K. New Engl. J. Med. 2001, 345, 494.
(b) Mehta, S. R.; Yusuf, S.; Peters, R. J.; Bertrand, M. E.;
Lewis, B. S.; Natarajan, M. K.; Malmberg, K.; Rupprecht,
H.; Zhao, F.; Chrolavicius, S.; Copland, I.; Fox, K. A. Lancet
2001, 358, 527.
(d) Fürstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120,
2817. (e) Batten, R. J.; Dixon, A. J.; Taylor, R. K. Synthesis
1980, 234.
(9) Dess, D. B.; Martin, J. C. J Am. Chem. Soc. 1991, 113, 7277.
(10) Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C.
L. J. Chem. Soc. 1946, 39.
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