Efficient Synthesis of (S)-(+)-Clopidogrel Bisulfate-Capped Silver Nanoparticles

Article abstract of DOI:10.1080/15533174.2015.1137028

In this work primarily one-pot synthetic development in the preparation of clopidogrel bisulfate with a polymorphic crystalline form II in 90% yield was developed. This premade antiplatelet drug has been used to protect starch-stabilized silver nanoparticles (AgNPs).

Full text of DOI:10.1080/15533174.2015.1137028

Synthesis and Reactivity in Inorganic, Metal-Organic, and
Nano-Metal Chemistry
ISSN: 1553-3174 (Print) 1553-3182 (Online) Journal homepage: http://www.tandfonline.com/loi/lsrt20
Efficient Synthesis of (S)-(+)-Clopidogrel Bisulfate-
Capped Silver Nanoparticles
Nosrat O. Mahmoodi, Atefeh Ghavidast, Mitra Ashkan, Manouchehr
Mamaghani, Mohammad Ali Zanjanchi, Khalil Tabatabaeian & Armin
Arabanian
To cite this article: Nosrat O. Mahmoodi, Atefeh Ghavidast, Mitra Ashkan, Manouchehr
Mamaghani, Mohammad Ali Zanjanchi, Khalil Tabatabaeian & Armin Arabanian (2016): Efficient
Synthesis of (S)-(+)-Clopidogrel Bisulfate-Capped Silver Nanoparticles, Synthesis and Reactivity
in Inorganic, Metal-Organic, and Nano-Metal Chemistry, DOI: 10.1080/15533174.2015.1137028
To link to this article: http://dx.doi.org/10.1080/15533174.2015.1137028
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ACCEPTED MANUSCRIPT
Efficient Synthesis of (S)-(+)-Clopidogrel Bisulfate-Capped Silver Nanoparticles
*
NOSRAT O. MAHMOODI , ATEFEH GHAVIDAST, MITRA ASHKAN, MANOUCHEHR
MAMAGHANI, MOHAMMAD ALI ZANJANCHI, KHALIL TABATABAEIAN, and ARMIN
ARABANIAN
Department of Chemistry, Faculty of Science, University of Guilan, P. O. Box: 41335-1914,
Rasht, Iran
*
Address correspondence to N. O. Mahmoodi, Department of Chemistry, Faculty of Science,
University of Guilan, P. O. Box: 41335-1914, Rasht, Iran. E-mail: mahmoodi@guilan.ac.ir,
nosmahmoodi@gmail.com.
In this manuscript primarily one-pot synthetic development in the preparation of clopidogrel
bisulfate with a polymorphic crystalline form II in 90% yield was developed. This premade
antiplatelet drug has been used to protect starch-stabilized silver nanoparticles (AgNPs).
Keywords
(S)-(+)-clopidogrel bisulfate, silver nanoparticles, functionalized silver nanoparticles
1
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Introduction
(S)-(+)-Clopidogrel bisulfate 1 (CLP) (Fig. 1), is a thienopyridine derivative as a potent oral
antiplatelet agent often used in the treatment of coronary artery, peripheral vascular and
[
1]
cerebrovascular diseases. This drug is one of the biggest selling drugs in the world. It can
crystallize in various polymorphic crystalline forms and amorphous forms, but only forms I and
[
2,3]
II are used in pharmaceutical products.
Nanoparticles (NPs) are promising as talented candidates for various biomedical applications
such as enhanced resolution magnetic resonance imaging (MRI), drug delivery, tissue repair, cell
[4-20]
and tissue targeting and transfection .
Silver nanoparticles (AgNPs) are a significant class of
nanomaterial for a wide range of industrial and biomedical applications. The unique chemical
properties of AgNPs make it a promising targeted delivery approach for drugs or gene specific
cells. AgNPs also effectively inhibited integrin-mediated platelet functional responses like
aggregation, secretion, adhesion to immobilized fibrinogen or collagen and retraction of fibrin
[
21]
clot in a dose-dependent manner, irrespective of the nature of agonists used.
With increase use of AgNPs as drug carriers and their accepted antiplatelet property, it would be
interesting to investigate its interaction with CLP. Here, synthetic improvement in the
preparation of CLP also is described.
Experimental
Material and Measurements
AgNO (99.9%), paraformaldehyde (PFA, 99%), L-camphorsulfonic acid (L-CSA), soluble
3
starch and NaBH (99%) were purchased from Merck. The FT-IR spectra for the samples were
4
obtained using Shimadzu FT-IR-8900 spectrophotometer by using KBr pellets. All NMR data
2
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were recorded in DMSO-d using Bruker Avance 500 MHz spectrometer. Chemical shifts are
6
reported in ppm (δ) using deuterated solvents as internal references. Elemental analyses were
made by a Carlo-Erba EA1110 CNNO-S analyzer and agreed with the calculated values. UV-Vis
absorption spectra in the range 200-500 nm in EtOH were measured with a Shimadzu UV-2100
spectrophotometer. Melting points are uncorrected and determined by electrothermal 9100
melting point apparatus. The X-ray diffraction (XRD) patterns were recorded in a wide angle
range (2θ = 10-70) by Phillips (pw-1840) X-ray diffractometer with Cu-Kα radiation. The
morphology and particle sizes of synthesized powder were characterized by transmission
electron microscope (TEM) images on a Phillips CM-10 instrument with an accelerating voltage
of 100 kV.
One-pot procedure for the synthesis of racemic clopidogrel bisulfate (2)
To a vessel equipped with Dean-Stark assembly, 2-(thiophen-2-yl)ethanamine 5 (0.48 g, 4
mmol), PFA (0.13 g, 4.3 mmol ) and toluene (6 mL) were added and the reaction mixture was
refluxed for 2 h to obtain a yellow solution contain imine. After cooling to 20 °C, a solution of
o
6
1
1
N HCl (0.7 mL) in DMF was added into the reaction mixture and continued to heat at 50 C for
h to produce 4 as a white precipitate. The reaction was cooled to 25 °C and aqueous solution of
0 % Na CO was added and stirred for 30 min. Then a solution of methyl-2-bromo-2-(2-
2
3
chlorophenyl)acetate 3 (1.04 g, 4 mmol) in toluene (7 mL) was added to the reaction mixture.
The reaction mixture stirred at r.t for 12 h. The aqueous layer is discarded and the organic layer
was washed with water. The organic phase was evaporated, to afford viscose oil. To this oil,
conc. H SO (0.42 mL) and EtOAc (8 mL) was added. The mixture was stirred for 1 h. The
2
4
precipitated crystals filtered off and washed with cool acetone. The pure racemic clopidogrel
3
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bisulfate 2 was dried in oven at 50 °C (1.35 g, 90% yield). White powder; mp 220-222 ºC; IR: v
-1
(
KBr, cm ) 3434 (OH stretch), 3100, 2989, 2953, 1755 (C=O stretch), 1239, 1222 (C-O stretch),
1
063.
Preparation of (S)-(+)-clopidogrel camphorsulfonate salt
The racemic clopidogrel bisulfate 2 (1.5 g, 3.75 mmol) and L-CSA (0.88 g, 3.75 mmol) were
dissolved in acetone and stirred at r.t for 12 h. The formed precipitate was filtered, washed and
dried to give a white solid as a (S)-clopidogrel camphor sulfonate salt (0.96 g, 75% yield), [α] =
D
-1
+
25 (c = 1.68 % in CH OH); IR: v (KBr, cm ) 3454 (N-H stretch), 2975, 1756 (C=O stretch),
3
1
735, (C=O stretch), 1630, 1506, 1473, 1439, 1263, 1234, 1157, 1030, 753, 724, 701.
Preparation of (S)-(+)-clopidogrel bisulfate (1, CLP)
The (S)-(+)-clopidogrel camphorsulfonate salt obtained (0.96 g, 4.8 mmol) was suspended in
o
EtOAc and stirred vigorously at 10 C. Subsequently, H SO (0.3 g, 3 mmol) was added
2
4
dropwise into mixture and stirred for 4 h and (S)-(+)-clopidogrel bisulfate 1 was obtained by the
usual filtering, washing and drying (0.78 g, 85% yield); mp 176-178 ºC; [α] = +55.10 (c = 1.68
D
-1
%
in CH OH); IR: v (KBr, cm ) 3435 (O-H stretch), 3121, 2956, 2550, 2552, 1753, 1591, 1439,
3
1
1
4
7
2
188, 1154, 1029; H NMR (500 MHz, DMSO-d ): δ 3.10 (s, 2H), 3.49 (s, 2H), 3.76 (s, 3H),
6
.24 (s, 2H), 5.67 (s, 1H), 6.89 (d, 1H, J = 4.7 Hz), 7.44 (d, 1H, J = 5.1 Hz), 7.52-7.58 (m, 2H),
13
.66 (dd, 1H, J = 1.5, 7.8 Hz), 7.72 (dd, 1H, J = 1.5, 7.4 Hz); C NMR (125 MHz, DMSO-d ): δ
6
3.3, 54.5, 66.4, 125.9, 126.3, 129.4, 131.1, 131.5, 132.5, 133.1, 135.1, 168.3; Anal. Calcd for
C H ClNO S : C, 45.77; H, 4.32; N, 3.34. Found: C, 45.61; H, 4.39; N, 3.48.
16
18
6 2
4
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Preparation of (S)-(+)-clopidogrel bisulfate-coated silver nanopaticles (Ag@CLP)
A solution of AgNO (0.082 g, 0.48 mmol) in ultrapure H O (10 mL) was prepared. To this
3
2
solution were added 0.03 g soluble starch in 5.0 mL ultrapure H O and then the mixture was
2
stirred heavily for 30 min in an ice bath. A solution of NaBH (0.018 g, 0.48 mmol) in ultrapure
4
H O (6 mL) was added dropwise to the aqueous solution, the color of solution suddenly turned to
2
bright yellow, attributed to the formation of AgNPs. Then, the color of solution turned to black.
On complete addition of NaBH , the resulting mixture was further stirred for 30 min at r.t. Then,
4
a solution of CLP (0.403 g, 0.96 mmol) in EtOH (10 mL) was added to the reaction vessel, and
then the mixture was stirred for further 4 h at this stage the color of solution was turned to dark
brown. The suspension obtained was then centrifuged at 10,000 rpm for 15 min and the
precipitate washed three times with double distilled H O to remove any water soluble impurity.
2
After that, the precipitate was washed 3 times by dispersion and centrifugation using EtOH to
remove excess CLP and excess reducing agent. The precipitate was then dried in an oven at 60
°
C for 10 h and the pale gray powder was obtained.
Results and Discussion
In continuation to our interest in the design and synthesis of chemically and biologically
[
22-27]
medicinal heterocycles,
in this paper, we attempts to functionalized AgNPs covalently with
[
28-32]
the CLP (Ag@CLP). There are many routes to synthesis of CLP.
Herein; first we report an
efficient modified synthesis of CLP with excellent yield and in high optical purity resolution.
The one-pot synthesis of CLP 1 is depicted in Scheme 1. In this effort 2-(thiophen-2-
yl)ethanamine 5 upon reaction with paraformaldehyde (PFA) and HCl (6 N) in toluene followed
by electrophilic cyclization afforded tetrahydrothieno pyridine 4. Subsequently, this intermediate
5
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undergoes reaction with methyl-2-bromo-2-(2-chlorophenyl)acetate 3 and acetone/conc. H SO
2
4
to obtain a pure racemic 2, which was resolved using L-camphorsulfonic acid (L-CSA) in
acetone to afford (S)-(+)-clopidogrel bisulfate 1.
1
13
The mp, IR, H NMR, C NMR, XRD, [α] and elemental analysis confirm that a polymorphic
D
[
3]
crystalline form II of 1 was produced.
The synthesis of tetrahydrothieno pyridine 4 was optimized and the results are shown in Table 1.
When this reaction was carried out in the presence of DMF.HCl and toluene, the yield of 4 was
increased up to 90% (Table 1, Entry 2).
In other efforts, we examined several other bases and solvents to optimize the reaction conditions
for preparation of 1. The results are listed in Table 2. It was found that using toluene along with
Na CO led to higher yields in shorter reaction times (Table 2, Entry 5).
2
3
The kinetic resolution of prepared racemic clopidogrel bisulfate 1 was completed by using L-
CSA. An optimization of the reaction parameter such as utilized L-CSA (in mmol), solvent and
yield with respect to the final product concentration were performed. It was found that using
0
.012 mmol L-CSA in acetone led to higher yields (Table 3, Entry 3). Subsequently, the obtained
(
S)-clopidogrel camphor sulfonate salt, was converted to (S)-(+)-clopidogrel bisulfate 1 in H SO
2
4
/
EtOAc condition (Table 4, Entry 5).
For preparation of Ag@CLP, solution of AgNO in ultrapure H O and starch as a capping agent
3
2
under vigorous stirring was added to the round bottom flask. Subsequently, a modified Brust
[
33]
reaction was carried out by addition of excess amount of NaBH as reducing agent. In order to
4
+
reduce all of the Ag ions to metallic silver, the molar ratio of metal to the reducing agent was
selected as 1:2 respectively. Then, EtOH solution of CLP (molar ratio CLP/Ag = 2:1) was added
6
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[
25,34-
to the reaction vessel. The sulfur of CLP bind strongly to AgNPs surface by self-assembly.
3
5]
Formation of Ag@CLP was monitored by IR, X-ray diffraction, UV-Vis and TEM. To
[
36]
achieve a fine nanosized particle the amylose was used as a green capping agent.
The interaction between CLP and AgNPs was recognized by IR spectra of CLP and Ag@CLP
-
+
(
Figure S3 and S4). In both spectra the C=O, O-H of the HSO , N -H and aromatic C-H
4
-1
stretching vibration bands at 1753, 3435, 2552 and 3121 cm were observed respectively. The
C=Csym and C=Casym bands of thiophene for CLP and Ag@CLP were observed at 1439, 1591
-1
-1
[34]
cm and 1444, 1590 cm respectively, indicating that sulfur is attached to the AgNPs surface.
The powder XRD patterns of the CLP and Ag@CLP are shown in Fig. 2. The peaks position of
the CLP were observed at 2θ = 8.87°, 13.04°, 17.76°, 18.59°, 20.24°, 21.69°, 23.04°, 23.86°,
2
4.79°, 26.61°, 27.72°, 29.44°, 34.30°, 35.76°, 41.15° and 48.68° (Figure 2a). This pattern
3
correlated well with the crystalline structure of form II. In Figure 2b, the characteristic peaks of
AgNPs were at 2θ = 38.24°, 44.43° and 64.56° respectively, assigned as (111), (200) and (220)
reflection lines of the face centered cubic (fcc) structure of metallic silver. The average
crystallite size, D, was calculated from Scherrer's equation to be 29 nm while D = Kλ/(βcosθ) and
λ is the wavelength of Cu-Kα radiation used (λ = 1.54 ˚A), β is the full width at half-maximum
(FWHM) intensity (0.31) of the diffraction line, θ is the Bragg angle for the measured hkl peak,
and K is a constant equal to 0.94. This value is in good agreement with the TEM image. The
intensity of peaks reflected the high degree of crystallinity of the AgNPs.
UV-Vis Absorption Spectra
Fig. 3, illustrates the UV-Vis absorption spectra of CLP and Ag@CLP in EtOH solution. The
pure CLP, shows a λmax at 243 nm corresponds to the -* transition of the chlorobenzene and
7
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thiophene moiety while, solution of Ag@CLP shows absorption peaks at 243 and 412 nm
corresponds to CLP and surface plasmon resonance absorption band (SPRAB) of AgNPs,
respectively. The weaker absorption band of Ag@CLP, compared to absorption band of free
CLP at 243 nm, confirms a lower concentration of CLP on AgNPs. The appearance of two new
peaks at 297 and 346 nm probably are related to the formation of Ag-CLP complex.
TEM Imaging
The TEM of Ag@CLP image reveals that particles are spherical shape with approximate size of
<
40 nm; Scherrer's calc. = 29 nm (Fig. 4).
Conclusions
We have developed one-pot process for the synthesis of polymorphic crystalline form II CLP and
utilizing a novel method for adsorption of premade CLP molecule on AgNPs surface. The sulfur
of CLP bind strongly to AgNPs surface by self-assembly as confirmed by IR and UV-Vis. This
Ag@CLP system may provide an advantage model system for the development of new effective
antiplatelet drug.
Acknowledgements
The authors are grateful to the Research Council of University of Guilan & Iranian
Nanotechnology Initiative Council (INIC) for the financial support of this research work.
8
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Table 1. Reaction conditions for the synthesis of tetrahydrothieno pyridine 4.
Entry
Utilized Acid
DMF.HCl
Solvent
Cl
Toluene
Cl
Yield (%)
1
2
C
2
H
4
2
80
90
DMF.HCl
3
4
5
i-Pr.HCl
i-Pr.HCl
p-TSA
C
2
H
4
2
75
80
65
Toluene
Toluene
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Table 2. Reaction conditions for the synthesis of racemic-CLP.
Entry
Solvent
Base
NEt
Na CO
CO
Time (h)
Yield (%)
1
2
C
C
2
2
H
4
Cl
2
2
3
6
80
85
H
4
Cl
10
2
3
3
4
5
6
DMF
K
2
3
5
5
2
4
80
85
90
88
Toluene
Toluene
NEt
3
Na
CO
2
2
3
CH
OH
Na
CO
3
3
15
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Table 3. Reaction conditions for the kinetic resolution.
Optical
rotation
Entry
L-CSA (mmol)
Solvent
Time (h)
Yield (%)
1
2
0.015
0.012
acetone
acetone
4
4
+23
72
66
+24
3
4
5
6
0.012
0.015
0.012
0.009
acetone
Toluene
Toluene
Toluene
12
4
+25
+22
75
70
75
74
4
+23
12
+24.5
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Table 4. Variation of solvent for resolution of (S)-(+)-clopidogrel bisulfate.
Entry
Solvent
Time (h)
Yield (%)
*
1
2
MIPK
8
8
80
75
THF
3
4
5
i-PrOH
acetone
EtOAc
12
5
80
80
85
4
*
Methyl isopropyl ketone
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Fig.1. Chemical structure of (S)-(+)-clopidogrel bisulfate (CLP).
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Fig. 2. X-ray diffraction patterns of the (a) CLP and (b) Ag@CLP.
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-4
Fig. 3 UV-Vis absorption spectra of CLP and Ag@CLP (EtOH, c = 1.0 × 10 M, 293 K).
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Fig. 4. TEM image of the Ag@CLP.
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Scheme 1. Preparation of Ag@CLP.
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