WO2007073095A1 - Process for the preparation of (s)-(+)-clopidogrel on a solid-phase - Google Patents
Process for the preparation of (s)-(+)-clopidogrel on a solid-phase Download PDFInfo
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- WO2007073095A1 WO2007073095A1 PCT/KR2006/005602 KR2006005602W WO2007073095A1 WO 2007073095 A1 WO2007073095 A1 WO 2007073095A1 KR 2006005602 W KR2006005602 W KR 2006005602W WO 2007073095 A1 WO2007073095 A1 WO 2007073095A1
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- represented
- formula
- resin
- following formula
- clopidogrel
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- 0 O[C@@](C(OCc(cc1)ccc1OCCCC1C*CC1)=O)c1ccccc1Cl Chemical compound O[C@@](C(OCc(cc1)ccc1OCCCC1C*CC1)=O)c1ccccc1Cl 0.000 description 2
- OGUWOLDNYOTRBO-UHFFFAOYSA-N C(CNC1)c2c1cc[s]2 Chemical compound C(CNC1)c2c1cc[s]2 OGUWOLDNYOTRBO-UHFFFAOYSA-N 0.000 description 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N COC([C@H](c(cccc1)c1Cl)N(CC1)Cc2c1[s]cc2)=O Chemical compound COC([C@H](c(cccc1)c1Cl)N(CC1)Cc2c1[s]cc2)=O GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present invention relates to a process for preparing S-(+)-clopidogrel using a solid-phase reaction, and more particularly, to a process for preparing S-(+)- clopidogrel represented by the following formula 1 with high optical and chemical purity by carrying out a series of reactions and purifications more simply by a solid- phase synthetic approach using a polymer support.
Description
PROCESS FOR THE PREPARATION OF (S)-(+)-CLOPIDOGREL
ON A SOLID-PHASE
Technical Field
The present invention relates to a process for preparing S-(+)-clopidogrel using
a solid-phase reaction, and more particularly, to a process for preparing S-(+)-
clopidogrel represented by the following formula 1 with high optical and chemical
purity by carrying out a series of reactions and purifications more simply by a solid-
phase synthetic approach using a polymer support.
Background Art
[Formula 1]
The chemical name of the S-(+)-clopidogrel represented by formula 1 is methyl
(+)-(S)-α-(o-chlorophenyl)6,7- dihydrothieno[3,2-a]pyridine-5-(4H)-acetate and has
been known as an effective therapeutic agent for treating vascular system diseases
including peripheral arterial diseases, such as cerebral apoplexy, thrombus, embolus,
etc., and coronary arterial diseases, such as myocardial infarction, angina pectoris, etc.,
as it shows a strong inhibitory activity against platelet aggregation and an
antithrombotic activity.
According to recent research, it has been reported that the S-(+)-clopidogrel is
a very effective agent inhibiting platelet aggregation as it shows a strong effect of
inhibiting the platelet aggregation in with a small dose compared with aspirin and it
minimizes the toxic effects to be given on the gastrointestinal tract.
The S-(+)-clopidogrel is commercially available with the name of "Plavix®"
and the tablet of this product contains approximately 98mg of S-(+)-clopidogrel
hydrogen sulphate and approximately 75mg of S-(+)-clopidogrel base as an active
ingredient.
As general processes for the preparation of clopidogrel, the preparation
processes disclosed in the U.S. Patent Nos. 4,529,596, 4,847,265 and 5,204,469 can be
summarized and expressed by the following scheme 1:
[Scheme 1]
AMPHORSUL
According to the processes of the conventional methods disclosed in scheme 1,
there is required an optical resolution process comprising forming a diastereomeric
salt (h) by reacting a clopidogrel racemate (g) with an optically active acid, obtaining a
pure diastereomeric salt of a dextrorotatory (R) optical isomer containing no
levorotatory (L) optical isomers by recrystallization, and subsequently removing the
optically active acid to prepare S-(+)-clopidogrel as an optically pure dextrorotatory
isomer.
U.S. Patent No. 4,847,265 discloses an optical resolution method for the
preparation of S-(+)-clopidogrel using a (lR)-(-)-camphorsulfonic acid as an optically
active acid. International Patent Publication No. WO 98/051689 discloses a process
for preparing S-(+)-clopidogrel by performing an optical resolution and subsequent
reactions from a compound of formula (e) in scheme 1, wherein R is a nitrile,
carboxamide, or carboxylic acid. Moreover, International Patent Publication No. WO
02/059128 has disclosed a process for preparing S-(+)-clopidogrel by carrying out an
optical resolution and subsequent reactions of a compound from formula (g) in
scheme 1, wherein R is a nitrile, carboxamide, or carboxylic acid.
As described above, the known processes for the preparation of S-(+)-
clopidogrel may involve out the optical resolution inevitably in a specific step of the
successive preparation processes. However, the optical resolution process of the
clopidogrel racemate and an intermediate thereof is very disadvantageous
environmentally or economically since it is unavoidable that, as for the levorotatory
isomer, at least 50% of the intermediate is wasted. Moreover, in performing the optical
resolution process to obtain an optical isomer with high purity, it is essential to repeat
the purification process such as recrystallization several times, and thus the resulting
yield becomes usually reduced.
International Patent Publication No. WO 98/051689 discloses a method to
overcome the above drawbacks, which can be summarized and expressed by the
following scheme 2:
[Scheme 2]
+ N NaaCCNN
In the conventional process according to scheme 2, 2-(2-thienyl)-ethylamine of
formula (a) in scheme 2 is reacted with o-chlorobenzaldehyde of formula 0 in scheme
2 and sodium cyanide. The resulting nitrile compound of formula (k) in scheme 2 is
converted into an amide compound corresponding to formula (1) in scheme 2 and then
converted into a methyl ester compound of formula (m) in scheme 2. An
intermediate (m) that is an appropriate form used for the synthesis of clopidogrel may
be prepared by reacting with an optically active acid through an optical separation
process of amide (1) or ester (m). Finally, the optical isomer of formula (m) in scheme
2 is subjected to cyclization with formaldehyde in an acidic medium, thus preparing
clopidogrel.
As another conventional process, the process disclosed in European Patent No.
0466569 can be summarized and expressed by the following scheme 3:
[Scheme 3]
wherein X is a halogen or a sulfonate group.
In the conventional process according to scheme 3, methyl 2-amino-(2-
chlorophenyl) acetate of formula (n) in scheme 3 is reacted with 2-(2-thienyl)ethanol
derivative of formula (o) in scheme 3 to prepare an intermediate of formula (m) in
scheme 3 (Process A), or methyl 2-halo-(2-chlorophenyl)acetate of formula (p) in
scheme 3 is reacted with 2-(2-thienyl)-ethylamine of formula (a) in scheme 3 to obtain
an intermediate of formula (m) in scheme 3 (Process B).
Moreover, International Patent Publication No. WO 99/018110 discloses a
process for preparing clopidogrel by a reaction between tetrahydrothienopyridine (r)
and (R)-2-chloromandelic acid ester with a sulfonate leaving group (q) as expressed by
the following scheme 4.
[Scheme 4]
However, the conventional process according to scheme 4 using 4,5,6,7-
tetrahydro[3,2-c]thienopyridine of formula (r) in scheme 4 has a drawback that it is
difficult to be purified by crystallization since it has a low melting point and is readily
dissolved in an organic solvent.
As described above, the conventional processes for the preparation of
clopidogrel have numerous drawbacks to be improved.
Accordingly, the inventors of the present invention has developed a novel
process for the synthesis of clopidogrel, to which a preparation process of a novel
concept significantly different from the organic synthesis process of clopidogrel
known so far, i.e., a solid-phase reaction using a polymer support is introduced, and
completed the present invention.
Accordingly, an object of the present invention is to provide a process for
preparing S-(+)-clopidogrel with high optical and chemical purity by carrying out a
reaction process and a purification process more simply by a solid-phase reaction.
Disclosure
As represented by the following scheme 5, the present invention provides a
process for preparing S-(+)-clopidogrel/ which includes the steps of:
(1) preparing a sulfonylated resin represented by the following formula 3 by
sulf onylating a hydroxy resin represented by the f ollowing formula 2;
(2) preparing a resin compound represented by the following formula 5 by
reacting the sulfonylated resin represented by formula 3 with a ^S/ό/Z-tetrahydroβ^-
c]thienopyridine hydrochloride salt represented by the following formula 4; and
(3) preparing an S-(+)-clopidogrel represented by the following formula 1 by
separating the resin compound represented by formula 5 from a polymer support and
by a methyl esterification reaction.
[Scheme 5]
wherein O represents a polymer support for solid-phase reaction.
Hereinafter, the present invention will be described in more detail.
The present invention is directed to a process for preparing (S)-(+)-clopidogrel
represented by formula 1 efficiently by carrying out a solid-phase reaction.
The process for preparing (S)-(+)-clopidogrel in accordance with the present
invention is carried out by the solid-phase reaction using a polymer support. The
conventional solid-phase reaction has advantages that (1) the purification process is
simplified as residual reactants and reaction by-products can be readily removed by
resin washing; (2) the preparation process can be automated as multi-step reaction
processes can be made easily and successive reactions are available; (3) it can deal with
the compounds, not causing damage to the environment, as toxic or harmful
compounds are bonded to resin.
The solid-phase support used in the solid-phase reaction in accordance with
the present invention is the one generally used in solid-phase combinatorial chemistry
synthesis techniques. Polymer supports having a skeleton structure such as
poly sty rene-divinylbenzene, methacrylic acid- dimethylacrylamide, hydroxy 1
methacrylic acid, etc. may be used; however, the present invention does not impose
restrictions on the selection of the polymer supports. The polymer supports used in
the solid-phase reaction of the present invention may be exemplified by Merrifield
resin, Wang resin or a derivative thereof.
Any organic solvent swelling the polymer supports may be applicable to the
solid-phase reaction in accordance with the present invention. For example,
dimethylsulfoxide (DMSO)x tetrahydrofuran (THF), dimethylformamide (DMF),
methanol (MeOH), dichloromethane (CH2CI2), etc. may be used as the reaction solvent.
It was possible to readily obtain a target compound with high purity even if
the purification of the solid-phase reaction in accordance with the present invention
was carried out by a simple method such as filtration and washing. Water and
organic solvents might be available as the solvent used in the filtration, and the by¬
products and the residual reactants produced should be removed as much as possible.
The preparation process in accordance with the present invention will be
described in more detail by the respective steps.
Step (1) is directed to a process of sulfonylating the hydroxy resin represented
by formula 2. The sulfonylation reaction is carried out by using a conventional
sulfonylation agent. More specifically, a benzenesulfonyl chloride may be used as
the sulfonylation agent and the sulfonylation reaction may be carried out under the
condition of using a base catalyst such as dimethylaminopyridine (DMAP) or
triethylamine. Moreover, the above sulfonylation reaction may be performed at a
temperature range of -20 to 30°C and preferably at room temperature.
Step (2) is directed to a process of bonding the sulf onylated resin represented by
formula 3 to the 4,5,6,7-tetrahydro[3,2-c]thienopyridine hydrochloride salt represented
by formula 4. The present invention is characterized by using the compound
represented by formula 4 in the form of a hydrochloride salt. Accordingly, the present
invention provides a method of solving the drawbacks of having difficulty in
purification associated with the same thienopyridine in the form of a free base since its
melting point is low and the poor crystalline property. The bonding reaction may be
performed at a temperature range of -20 to 3O0C and preferably at room temperature.
Moreover, the bonding reaction may be carried out under the condition of using a base
catalyst such as dimethylaminopyridine (DMAP) or triethylamine, if necessary.
Step (3) is directed to a process of preparing an S-(+)-clopidogrel represented by
formula 1 in accordance with the present invention by separating the compound
represented by formula 5 from the polymer support through a methyl esterification
reaction.
In carrying out the preparation process in accordance with the present
invention, step (3) may be carried out in a two-step process for preparing the (S)-(+)-
clopidogrel represented by formula 1 as depicted in the following scheme 6. That is,
it is possible to prepare the (S)-(+)-clopidogrel represented by the following formula 1
by separating a compound represented by the following formula 5 from the polymer
support to obtain a compound represented by the following formula 6 and then
performing the methyl esterification reaction.
[Scheme 6]
5 6 1
wherein Q represents a polymer support for solid-phase reaction.
The separation process from the polymer support can be readily performed by
using an organic acid such as trifluoroacetic acid (TFA) and the like at a temperature
range of -20 to 300C and preferably at room temperature. Besides, the compound
represented by formula 6 can be readily separated from the polymer support by various
methods well-known in the art.
The compound represented by formula 6 separated from the polymer support is
subjected to the methyl esterification reaction to obtain the (S)-(+)-clopidogrel in
accordance with the present invention. That is, the methyl esterification reaction may
be carried out by reacting the compound represented by formula 6 with methanol
under an acidic condition, where an organic acid such as thionyl chloride and the like is
used 1.0 to 2.0 equivalents, at a temperature range of 40 to 80°C, preferably, at a reflux
temperature.
Moreover, in carrying out the preparation process in accordance with the
present invention, step (3) may be carried out in a one-step process, where the
separation from the polymer support and the methyl esterification reaction are
simultaneously performed by reacting the compound represented by formula 5 with
an alkali metal alkoxide, thus preparing the (S)-(+)-clopidogrel represented by formula
1 in accordance with the present invention.
That is, the (S)-(+)-clopidogrel represented by formula 1 can be prepared by
heating and stirring the compound represented by formula 5 with the alkali metal
alkoxide of 0.1 to 1 equivalent at reflux. Here, the reaction solvent used in the present
invention may be a general organic solvent and preferably a mixed solvent of
methanol and tetrahydrofuran mixed in a volume ratio of 1:5 to 5:1. In case of a
reaction in which the alkali metal alkoxide is used, the separation and the methyl
esterification can be achieved by a single reaction. Accordingly, it may be a very
useful process in terms of process simplification and an industrial point of view as it
can prevent the corrosion of the reactor caused by using acidic materials such as
trifluoroacetic acid or thionyl chloride.
Moreover, the polymer supports exhausted in the separation process can be
recovered and recycled by an appropriate treatment.
Meanwhile, the compound represented by formula 2 used as a starting material
in the preparation process in accordance with the present invention may be prepared by
a conventional method.
For example, as depicted in the following scheme 7, in case of using a Wang
resin as a polymer support, the compound represented by the following formula 2 used
as a starting material can be prepared by brominating a hydroxyl group of a Wang resin
end represented by the following formula 7 to form a brominated resin represented by
the following formula 8 and then bonding the brominated resin with a (R)-2-
chloromandelic acid represented by the following formula 9.
[Scheme 7]
wherein O represents a polymer support for solid-phase reaction.
Moreover, in case of using a Merrifield resin, the compound represented by
formula 2 can be prepared by bonding the (R)-2-chloromandelic acid represented by
formula 9 directly to the resin represented by formula 8.
Furthermore, in performing the preparation process by the solid-phase
reaction in accordance with the present invention, the respective polymer reactions
can be confirmed by FT-IR readily and qualitatively. In addition, the chemical
structure of the compound can be analyzed and confirmed by NMR and mass
spectrum after the compound is separated from the polymer support and then
purified and separated by column chromatography.
The (S)-(+)-clopidogrel represented by formula 1 prepared by the solid-phase
reaction as described above may be prepared as a pharmaceutically acceptable salt by a
general method. That is, it is possible to form pharmaceutically acceptable salts along
with organic or inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid,
phosphoric acid, acetic acid, citric acid, fumaric acid, lactic acid, maleic acid, succinic
acid, tartaric acid and the like, or prepare pharmaceutically acceptable salts by reacting
with alkali metal ions, such as sodium, potassium, etc., or with ammonium ions.
Best Mode
The present invention as described above will be described in more detail based
on the following examples; however, the present invention is not limited thereto.
Examples: Synthesis of (S)-(+)-clopidogrel by successive solid-phase reactions
Example 1: Synthesis of (S)-(+)-clopidogrel by successive reactions including four
steps
(1) Synthesis of hydroxy resin of formula 2
Wang resin (7; 0.87 mmol/g, 1 g, 0.87 mmol) and triphenylphosphine (0.684 g,
2.7 mmol) were placed into a 50 mL flask, dichloromethane (20 mL) was added and
then shaken for 10 minutes. Then, bromine (Br2; 0.134 mL, 2.61 mmol) was slowly
added thereto. After reaction at room temperature for 5 hours, the resin was washed
with each 50 mL of water, water:DMF (1:1), DMF, MeOH, MeOH:CH2Cl2 (1:1) and
CH2Cb (two times) in the sequential order and then dried under vacuum at room
temperature to obtain a brominated resin (8).
The brominated resin (8) obtained as above, (R)-2-chloromandelic acid (9; 647.3
mg, 3.48 mmol) and cesium carbonate (1.28 g, 3.92 mmol) were placed into a 50 mL
flask, diluted with DMF (40 mL) and then shaken at room temperature for 4 hours.
The resin was washed with each 50 mL of water, water :DMF (1:1), DMF, MeOH,
MeOKCH2Cl2 (1:1) and CH2Cl2 (two times) in the sequential order and then dried
under vacuum at room temperature to obtain hydroxy resin (2). The hydroxy resin
(2) was used in the following reaction without any purification process and the
formation of the compound was confirmed by FT-IR (FT-IR: 3514, 1736 cm-1).
(2) Synthesis of sulf onylated resin of formula 3
2 3
The hydroxy resin (2) obtained in the above step was placed into a 50 mL flask
and diluted with CH2Ch (30 mL). Then, benzenesulfonyl chloride (0.23 mL, 1.74
mmol), triethylamine (0.36 mL, 2.61 mmol), dimethylaminopyridine (DMAP; 53 mg)
were added and shaken at room temperature for 12 hours. The resin was washed
with each 50 mL of water, water:DMF (1:1), DMF, MeOH, MeOH:CH2Cl2 (1:1) and
CH2CI2 (two times) in the sequential order and then dried under vacuum at room
temperature to obtain sulfonylated resin (3). The sulfonylated resin (3) was used in
the following reaction without any purification process and the formation of the
compound was confirmed by FT-IR (FT-IR: 1439, 1375 cm-1).
3) Synthesis of resin compound of formula 5
4,5,6,7-tetrahydrothieno(3,2-c)pyridine hydrogen chloride (4; 454 mL, 2.61
mmol) was placed into a 50 mL flask, CH2Cl2 solvent (30 mL) and triethylamine (0.73
mL, 5.22 mmol) were added and then shaken for 30 minutes. The sulfonylated resin
(3) obtained in the above step was added thereto and shaken at room temperature for 12
hours. The resin was washed with each 50 mL of water, water :DMF (1:1), DMF,
MeOH, MeOH:CH2Cl2 (1:1) and CH2Cl2 (2 times) in the sequential order and then
dried under vacuum at room temperature to obtain resin compound (5). The resin
compound (5) was used in the following reaction without any purification process and
the formation of the compound was confirmed by FT-IR (FT-IR: 1095, 1016 cm4).
(4) Synthesis of (S)-(+)-clopidogrel of formula 1
20 mL of a mixed solution of THF:MeOH (4:1) was placed into a 50 mL flask,
the resin compound (5) obtained in the above step and 20 mg of sodium methoxide
were added and then heated at reflux for 6 hours. The resulting solution was cooled
to room temperature and 10 mL of ammonium chloride solution was added thereto.
The resulting solution was extracted with CH2CI2 (20 mL X 2 times) and then dried
with Na2SO4. After filtered and concentrated under reduced pressure, the resultant
was passed through a small amount of silica gel column and washed with ethyl
acetate:n-hexane (1:6). Then, the resultant was dried under vacuum at room
temperature to obtain 162 mg of (S)-(+)-clopidogrel (1) as a pale yellow oil.
Yield of the successive reactions (1) to (4) of example 1 58%; optical purity 98 %e.e.
(HPLC); 1H NMR (300 MHz, CDCl3) δ 7.68-7.70 (m, IH), 7.38-7.44 (m, IH), 7.27-7.30 (m,
2H), 7.06 (d, IH, / = 5.1 Hz), 6.67 (d, IH, / = 5.1 Hz), 4.92 (s, IH), 3.72(s, 3H), 3.61-3.79 (m,
2H), 2.88 (brs, 4H).
The optical purity of the (S)-(+)-clopidogrel synthesized in the above step Was
measured by chiral HPLC and the HPLC conditions applied to the separation are as
follows:
- Column: Ultron ES-OVM (Ovomucoid product), 150 X 4.6 mm, 5.0 mm
- Flow rate: 1 mL/min.
- Detection wavelength: 220 nm
- Eluate: dibasic sodium phosphate buffer solution (20 nM, pH 7)/acetonitrile
(80/20, v/v)
- Sample: dissolved in a mixed solution of 0.1 mg/mL of the dibasic sodium
phosphate buffer solution (20 nM, pH 7)/acetonitrile (80/20, v/v)
Example 2: Synthesis of (S)-(+)-clopidogrel by successive reactions including five
steps
(5) Synthesis of compound of formula 6
5 6
The reaction was continuously carried out following the successive reactions
(1) to (3) of example 1.
That is, the resin compound (5) obtained in step (3) of example 1 was placed
into a 50 mL flask, 20 mL of trifluoroacetic acid (TFA) :CH2C12 (1:4) was added and then
shaken at room temperature at 6 hours. The resin was filtered under reduced pressure
and washed with MeOH (10 mL X 2 times) and CH2Cl2 (10 mL x 2 times). The filtrate
was concentrated under reduced pressure, passed through a small amount of silica gel
column and then washed with MeOH:CH2Cl2 (1:19) several times. The resulting
filtrate was concentrated under reduced pressure, crystallized by adding diethyl ether
and n-hexane and then dried under vacuum to obtain 165 mg of compound (6) as a
white solid.
5 Yield of the continuous reactions (1) to (4) of example 1, 62%; optical purity, 98 %e.e.
(HPl-Q1H NMR (300 MHz, CDCl3) δ 10.61 (brs, IH), 7.81-7.84 (m, IH), 7.37-7.40 (m, IH),
7.20-7.31 (m, 2H), 7.16 (d, IH, / = 5.1 Hz), 6.66 (d, IH, / - 5.1 Hz), 5.29 (s, IH), 4.17-4.30(m,
2H), 3.44-3.64 (m, 2H), 3.06 (brs, 2H).
The optical purity of the compound of formula 6 synthesized as above was
o measured by chiral HPLC and the HPLC conditions applied to the separation are as
follows:
- Column: Ultron ES-OVM (Ovomucoid product), 150 x 4.6 mm, 5.0 mm
- Flow rate: 1 mL/min
- Detection wavelength: 220 ran
s - Eluate: methanol/ dibasic sodium phosphate buffer solution (2 nM, pH 7.5)
(5/95, v/ v)
- Sample: dissolved in a mixed solution of 0.1 mg/mL of the methanol/ dibasic
sodium phosphate buffer solution (2 nM, pH 7.5) (5/95, v/v) and added 1OmL thereto.
o (6) Synthesis of (S)-(+)-clopidogrel of formula 1
The compound (6; 40 mg, 0.13 mmol) obtained in the above step was dissolved
in 2 mL of MeOH. Thionyl chloride (0.013 mL, 0.16 mmol) was added to the
resulting solution and then stirred at 7O0C for 6 hours. After cooled to room
temperature, the resulting solution was concentrated under reduced pressure and
then 20 mL of water was added thereto. After adding 5% NaHCO3 (4 mL), the
resulting solution was extracted with CH2CI2 (20 mL) and then dried using Na2SO4.
After filtered and concentrated under reduced pressure, the resultant was passed
through a small amount of silica gel column and washed with ethyl acetate:n-hexane
(1:6). Then, the resultant was dried under vacuum at room temperature to obtain 35
mg of (S)-(+)-clopidogrel (1) as a pale yellow oil.
Yield 84%; optical purity 98 %e.e. (HLPC); 1H NMR (300 MHz, CDCl3) δ 7.66-7.70
(m, IH), 7.37-7.44 (m, IH), 7.27-7.31 (m, 2H), 7.07 (d, IH, / = 5.1 Hz), 6.66 (d, IH, / = 5.1
Hz), 4.92 (s, IH), 3.73(s, 3H), 3.60-3.80 (m, 2H), 2.89 (brs, 4H).
The optical purity of the (S)-(+)-clopidogrel synthesized as above was
measured by chiral HPLC and the HPLC conditions applied to the separation are the
same as step (4) of example 1.
Industrial Applicability
As described in detail above, the preparation process by the solid-phase
reaction in accordance with the present invention is very useful as the purification
process is conveniently carried out and the (S)-(+)-clopidogrel can be prepared with
high optical and chemical purity.
Claims
1. A process for preparing (S)-(+)-clopidogrel comprising the steps of:
(1) preparing a sulfonylated resin represented by the following formula 3 by
sulf onylating a hydroxy resin represented by the f ollowing formula 2;
5 (2) preparing a resin compound represented by the following formula 5 by
reacting the sulfonylated resin represented by formula 3 with a ^δ^y-tetrahydroP^-
cjthienopyridine hydrochloride salt represented by the following formula 4; and
(3) preparing an S-(+)-clopidogrel represented by the following formula 1 by
separating the resin compound represented by formula 5 from a polymer support
i o through a methyl esterif ication reaction.
1
wherein O represents a polymer support for solid-phase reaction.
2. In claim 1, the polymer support for solid-phase reaction has a polymer
skeleton structure selected from the group consisting of polystyrene-divinylbenzene,
15 methacrylic acid- dimethylacrylamide and hydroxy 1 methacrylic acid.
3. In claim I1 the polymer support for solid-phase reaction is Wang resin,
Merrif ield resin or a derivative thereof.
4. In claim 1, in step (3), the (S)-(+)-clopidogrel represented by the following
formula 1 is prepared by separating a compound represented by the following
formula 5 from a polymer support to obtain a compound represented by the following
formula 6 and then by carrying out a methyl esterif ication reaction:
wherein O represents a polymer support for solid-phase reaction.
5. In claim 4, the separation is carried out using an organic acid.
6. In claim 5, the organic acid is a trifluoroacetic acid.
7. In claim 4, the methyl esterification reaction is carried out by reacting the
compound represented by formula 6 with methanol under an acidic condition.
8. In claim l,in step (3), the (S)-(+)-clopidogrel represented by the following formula 1 is directly prepared by carrying out separation and methyl esterification
reactions simultaneously by refluxing a compound represented by the following
formula 5 with an alkali metal alkoxide:
wherein O represents a polymer support for solid-phase reaction.
9. In claim 8, the alkali metal alkoxide is a sodium methoxide.
10. In claim 1, the hydroxy resin represented by formula 2 is prepared by
brominating a hydroxyl group of a Wang resin end represented by the following
formula 7 to form a brominated resin represented by the following formula 8 and then
subjected to a bonding reaction with a (R)-2-chloromandelic acid represented by the
following formula 9:
11. In claim 1, the hydroxy resin represented by formula 2 is prepared by bonding the (R)-2-chloromandelic acid represented by formula 9 directly to the resin
represented by formula 8.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2005-0127800 | 2005-12-22 | ||
| KR1020050127800A KR20070066518A (en) | 2005-12-22 | 2005-12-22 | Process for the preparation of (s)-(+)-clopidogrel on the solid-phase |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2007073095A1 true WO2007073095A1 (en) | 2007-06-28 |
Family
ID=38188806
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2006/005602 WO2007073095A1 (en) | 2005-12-22 | 2006-12-20 | Process for the preparation of (s)-(+)-clopidogrel on a solid-phase |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR20070066518A (en) |
| WO (1) | WO2007073095A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020177712A1 (en) * | 2001-01-24 | 2002-11-28 | Cadila Healthcare Limited | Process to prepare clopidogrel |
| WO2003066637A1 (en) * | 2002-02-06 | 2003-08-14 | EGIS Gyógyszergyár Rt. | Polymorphs of clopidogrel hydrochloride and their use as antithrombic compounds |
| US6800759B2 (en) * | 2002-08-02 | 2004-10-05 | Teva Pharmaceutical Industries Ltd. | Racemization and enantiomer separation of clopidogrel |
| WO2005063708A2 (en) * | 2003-11-03 | 2005-07-14 | Cadila Healthcare Limited | Processes for preparing different forms of (s)-(+)- clopidogrel bisulfate |
-
2005
- 2005-12-22 KR KR1020050127800A patent/KR20070066518A/en not_active Application Discontinuation
-
2006
- 2006-12-20 WO PCT/KR2006/005602 patent/WO2007073095A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020177712A1 (en) * | 2001-01-24 | 2002-11-28 | Cadila Healthcare Limited | Process to prepare clopidogrel |
| WO2003066637A1 (en) * | 2002-02-06 | 2003-08-14 | EGIS Gyógyszergyár Rt. | Polymorphs of clopidogrel hydrochloride and their use as antithrombic compounds |
| US6800759B2 (en) * | 2002-08-02 | 2004-10-05 | Teva Pharmaceutical Industries Ltd. | Racemization and enantiomer separation of clopidogrel |
| WO2005063708A2 (en) * | 2003-11-03 | 2005-07-14 | Cadila Healthcare Limited | Processes for preparing different forms of (s)-(+)- clopidogrel bisulfate |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20070066518A (en) | 2007-06-27 |
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