WO2011083955A2

WO2011083955A2 - Method for manufacturing crystalline form (i) of clopidogrel hydrogen sulphate

Info

Publication number: WO2011083955A2
Application number: PCT/KR2011/000038
Authority: WO
Inventors: Yoon Seok Oh; Dong Hyuk Shin; Jin Yong Jung
Original assignee: Dong Wha Pharm. Co., Ltd.
Priority date: 2010-01-07
Filing date: 2011-01-05
Publication date: 2011-07-14
Also published as: KR101616928B1; KR20110080931A; WO2011083955A3

Abstract

The present invention provides a method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate(clopidogrel hydrogen sulfate), including reacting a clopidogrel free base with concentrated sulfuric acid in the presence of a mixed solvent containing water in an amount of 4 to 14% by weight based on the weight of the clopidogrel free base and 2-butanol.

Description

[DESCRIPTION]

[Invention Title]

METHOD FOR MANUFACTURING CRYSTALLINE FORM (I) OF CLOPIDOGREL HYDROGEN SULPHATE

[Technical Field]

<i> The present invention relates to a method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate(clopidogrel hydrogen sulfate) .

[Background Art]

<2> Methyl (+)-(S)^~ a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2- c]pyridinyl-5-acetate (hereinafter, referred to as "clopidogrel" ) hydrogen sulphate of the formula 1 below is a drug having a blood platelet aggregation inhibitory effect and an antithrombotic effect. Clopidogrel hydrogen sulphate is a useful drug which is used in treating peripheral arterial diseases such as stroke, thrombosis and embolism, as well as coronary arterial diseases such as myocardial infarction and angina pectoris, and is marketed as PLAVIX ® tablet.

[Formula 1]

( I)

<3>

<4> US Patent No. 4529596 describes a racemic compound of the formula 1, and EP 0281459 describes a technique for separating an optical active form of a tetrahydrothieno pyridine derivative, with the disclosure of clopidogrel hydrogen sulphate of the formula 1 above. This EP 0281459 describes a method of obtaining racemic clopidogrel by forming a salt using (R)-(-)-10- camphorsul fonic acid, and in order to obtain a product having a desired specific optical rotation value, stirring the formed salt in acetone under reflux, followed by recrystal 1 izat ion to form a dextrorotatory isomer, and then precipitating the compound of the formula 1 with concentrated sulfuric acid in the presence of an acetone solvent.

<5> Further, EP 1087976 describes a technique relating to crystalline forms

(I) and (II) of the formula 1. It is specified that the synthetic method of EP 0281459 is capable of synthesizing only the crystalline form (I) of clopidogrel hydrogen sulphate, and it is described that the crystalline form

(II) has high thermodynamic stability, crystals of the crystalline form (I) have an irregular plate-like shape, crystals of the crystalline form (II) have an aggregate shape, and the crystalline form (II) has lower static electricity than the crystalline form (I).

<6> International Patent Application Publication No. W003051362 describes methods for manufacturing novel crystalline forms (III), (IV), (V) and (VI) and amorphous forms of clopidogrel hydrogen sulphate, and particularly discloses a method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate in the presence of methyl t -butyl methyl ether or diethyl ether .

<7> International Patent Application Publication No. W02004020443 discloses a method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate, including reacting clopidogrel in the form of a free base or salt with sulfuric acid in the presence of a solvent selected from the series of the primary, secondary or tertiary C1-C5 alcohols or their esters with C1-C4 carboxylic acids or optionally of mixtures thereof. Particularly, it is disclosed that the precipitation is carried out in a 2-propanol solution at a low temperature of -5 to 15^°C .

<8> International Patent Application Publication No. W02005063708 describes a method of separating crystals of a crystalline form (I) of clopidogrel hydrogen sulphate by treatment with concentrated sulfuric acid in a mixture of a C6-C12 alcohol (for example, hexanol, 2-hexanol, 3-hexanol, isohexanol, heptanol, 2-heptanol , 3-heptanol , 4-heptanol , octanol, isooctanol, decanol or a mixture thereof) and water.

<9> International Patent Application Publication No. W02006087729 describes a method for forming a crystalline form (I) of clopidogrel hydrogen sulphate, from (S)-clopidogrel with the addition of sulfuric acid in the presence of a solvent such as C1-C5 carboxylic acid.

<io> The above-mentioned methods have the problems stated by EP 1087976, such as irregular plate-like shape of crystals, and occurrence of static electricity due to non-spherical crystal shape.

<ii> However, among manufacturing methods of a crystalline form (I) of clopidogrel hydrogen sulphate published hitherto, there was no report showing a method of manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate having a spherical crystal shape and excellent fluidity by using a mixed solvent of C1-C4 lower alcohol and water.

[Disclosure]

[Technical Problem]

<12> Therefore, the present inventors provide a crystalline form (I) of clopidogrel hydrogen sulphate which is prepared by a more convenient manufacturing method and has high purity and excellent physical properties. [Technical Solution]

<!3> The present invention provides a method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate, including reacting a clopidogrel free base with concentrated sulfuric acid in the presence of a mixed solvent of 2-butanol and water.

<^]4> Hereinafter, the term "clopidogrel" as used herein refers to "methyl

(+)-(S)- a -(2-chlorophenyl )-4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl-5- acetate" , and the term "racemic clopidogrel" refers to "methyl (±)-a- (2-chlorophenyl )-4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl-5-acetate" .

<i5> In the method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate in accordance with the present invention, the volume of water used is preferably in the range of 4 to 14% by weight based on the weight of the clopidogrel free base, more preferably 5 to 14% by weight, still more preferably 7.5 to 11%, and most preferably 8.6%. When the water content is higher than 14%, the resulting product is not a crystalline form (I), or even if the resulting product is a crystalline form (I), an irregular plate-like crystalline form (I) is manufactured. When the water content is lower than 4%, an irregular plate-like crystalline form is manufactured even if the resulting product is a crystalline form (I), or crystallization is very sluggish thereby resulting in production with a very low yield.

<16> In the method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate in accordance with the present invention, the formation of the crystalline form (I) may be promoted by seeding a crystalline form (I) of clopidogrel hydrogen sulphate.

<17> In the method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate in accordance with the present invention, the reaction temperature and the crystallization temperature are preferably in the range of 15 to 25 ^°C . That is, the method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate in accordance with the present invention has an advantage of no need to additionally set the crystallization temperature at a low temperature for the formation of crystals.

<18> In the method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate in accordance with the present invention, the weight ratio of clopidogrel free base to mixed solvent is preferably in the range of 1:14 to 25.

<i9> In the method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate in accordance with the present invention, the reaction time is preferably in the range of 5 to 15 hours.

<20> In the method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate in accordance with the present invention, the clopidogrel free base which is a starting material may be one isolated from other compounds, or otherwise may be a state where a clopidogrel free base is not isolated in the process for manufacturing the clopidogrel free base from a pharmaceutically acceptable salt of clopidogrel. Further, the clopidogrel free base which is a starting material may be manufactured by a known method, and for example, may be one manufactured by the reaction between clopidogrel camphor sul fonate and potassium carbonate in the presence of a dichloromethane solvent.

<2i> Here, clopidogrel camphor sul fonate for use in manufacture of the clopidogrel free base which is a starting material of the present invention may be manufactured by a known method (for example, see EP 0281459) or may be one manufactured by the following method given in the present invention.

<22> Therefore, the present invention provides a method for manufacturing clopidogrel camphor su 1 fonate for use in manufacture of the clopidogrel free base which is a starting material in the method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate in accordance with the present invention, which includes dissolving a racemic clopidogrel base and an (R)-(-)-10-camphorsul fonic acid in a solvent selected from dichloromethane, dichloroethane and chloroform, and adding thereto an antisolvent selected from primary, secondary and tertiary C1-C5 alkyl acetates, followed by reaction. Here, the antisolvent is preferably ethyl acetate. The clopidogrel camphor sulfonate of the present invention as described above is advantageously provided with high yield and high purity, as compared to the known method (EP 0281459) (45% yield, e.e.>99.5%).

[Advantageous Effects]

<23> The manufacturing method in accordance with the present invention is an improved method for manufacturing a crystalline form (I) of known clopidogrel hydrogen sulphate(clopidogrel hydrogen sulfate), which has an advantage of enabling the manufacture of a crystalline form (I) of clopidogrel hydrogen sulphate which has high optical purity even at room temperature which is not a low temperature, a spherical crystal shape (FIG. 3), and excellent fluidity. Accordingly, the crystalline form (I) of clopidogrel hydrogen sulphate manufactured according to the present invention has advantages such as no need of a grinding process upon tablet compression, uniform filling due to having favorable fluidity and therefore minimized cracking or sticking. [Description of Drawings]

<24> FIG. 1 shows the X-ray diffraction analysis data for a crystalline form

(I) of clopidogrel hydrogen sulphate prepared in Example 5.

<25> FIG. 2 shows the FTIR spectrum for a crystalline form (I) of clopidogrel hydrogen sulphate prepared in Example 5.

<26> FIG. 3 shows the photomicrograph (x50) of a crystalline form (I) of clopidogrel hydrogen sulphate prepared in Example 5.

<27> FIG. 4 shows the photomicrograph (x50) of a crystalline form (I) of clopidogrel hydrogen sulphate of Comparative Example 1.

<28> FIG. 5 shows the photomicrograph (x50) of a crystalline form (I) of clopidogrel hydrogen sulphate of Example 6.

<29> FIG. 6 shows the photomicrograph (x50) of a crystalline form (I) of clopidogrel hydrogen sulphate of Example 7.

<30> FIG. 7 shows the photomicrograph (x50) of a crystalline form (I) of clopidogrel hydrogen sulphate of Example 10.

<3 i> FIG. 8 shows the photomicrograph (x50) of a mixture of crystalline forms (I) and (II) of clopidogrel hydrogen sulphate of Example 11.

<32> FIG. 9 shows the photomicrograph (x50) of a crystalline form (I) of clopidogrel hydrogen sulphate of Comparative Example 2.

[Mode for Invention!

<33> Now, the present invention will be described in more detail with reference to the following Examples. These examples are provided only for illustrating the present invention and should not be construed as limiting the scope and spirit of the present invention.

<34> X-ray diffraction analysis data, IR data, and purity for the crystalline form (I) of clopidogrel hydrogen sulphate prepared in the following Examples were determined using a powder X-ray dif fractometer (PXRD, D8 Focus (2.2 kw) manufactured by Buker AXS, Germany), Fourier transform infrared spectroscopy (FTIR, Nicolet 6700 manufactured by Thermo Scientific) and HPLC (1200 series manufactured by Agilent Technologies, Column: Ultron ES-0VM, 15 cm, 4.6 mm I.D, particle size 5 jean) .

<35>

<36> Example 1·^' Preparation of racemic clopidogrel (racemic methyl q-(2- ch1orophenyl)-4,5,6.7-tetrahydrothieno[3 , 2^~c1 yr idine^~5-acetate) free base

<37> To 600 ml of methanol were added 90.5 g of anhydrous sodium carbonate and 100 g of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (manufactured by Zhejiang Liaoyuan Pharm. Co., Ltd.), and the mixture was stirred at a temperature of 60 to 65^°C for 1 hour, followed by cooling to a temperature of 40 to 45^°C . To the solution were added 165 g of methyl bromo- (2-chlorophenyl )-acetate (manufactured by J i acheng-Chem Enterprises Ltd.) and 100 ml of methanol, followed by stirring at a temperature of 60 to 65^°C for 24 hours. The reaction liquid was cooled to a temperature of 20 to 25^°C , and 200 ml of dichloromethane was added thereto, followed by filtration and washing with 200 ml of dichloromethane.

<38> 300 ml of purified water was added to the reaction filtrate, and pH of the solution was adjusted to a value of 7.0 to 7.2 by adding acetic acid. Then, the organic layer was separated, and the aqueous layer was extracted once more with 200 ml of dichloromethane. Two extracted organic layers were combined and washed with purified water. The washed dichloromethane solution was distilled to afford 183 g of a racemic clopidogrel base (racemic methyl a-(2-chlorophenyl )-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-5-acetate) .

<39>

<40> Example 2: Preparation of clopidogrel camphorsulfonate (methyl (+)-(S)^~ α -(2-chlorophenyl)-4.5.6.7-tetrahvdrothieno[3.2-clpyr idine-5-acetate camphorsu1 fonate)

<4i> 150 ml of dichloromethane and 132.2 g of (R)-(-)-10-camphorsul fonic acid were added and dissolved in 183 g of the racemic clopidogrel base prepared in Example 1 at a temperature of 20 to 25^°C . To the reaction liquid was added 225 ml of ethyl acetate, followed by stirring at a temperature of 20 to 25^°C for 2 hours. The reaction liquid was heated to a temperature of 40 to 45^°C, stirred for 1 hour, cooled to a temperature of 20 to 25^°C , and then stirred for 3 hours. The resulting crystals were filtered, washed with 100 ml of acetone, and then dried to afford 142 g (yield: 45%) of clopidogrel camphorsul fonate. The resulting filtrate was used in Example 3.

<42> Specific O.R. : 25.5° (c=1.68, methanol, 25^°C) e.e.>99.5%

<43>

<44> Example 3: Preparation of clopidogrel camphorsul fonate (methyl (+)-(S)- α -(2-ch1oropheny1 )-4.5.6.7-1etrahydrothienoΓ3.2-c] yr idine-5-acetate camphorsul fonate)

<45> The filtrate obtained in Example 2 was distilled, to which 250 ml of di chl or ome thane was then added and dissolved, and an aqueous sodium hydroxide solution prepared by dissolving 13.4 g of sodium hydroxide in 220 ml of purified water was gradually added thereto to make a pH of 7.0 to 7.2, followed by layer separation. The separated organic layer was washed with purified water. The washed organic layer was distilled to remove the solvent, and 400 ml of methanol and 7.7 g of sodium methoxide were added thereto, followed by stirring at a temperature of 60 to 65 ^"C for about 4 hours. The reaction liquid was distilled to remove the solvent, and 200 ml of dichloromethane and 200 ml of purified water were added thereto at a temperature of 20 to 25^°C . The pH of the mixture was adjusted to a value of 7.0 to 7.2 by adding acetic acid, and the organic layer was separated and washed with purified water. The washed organic layer was distilled to remove the solvent, and 82 ml of dichloromethane and 72.7 g of (R)-(-)-10- camphor sulfonic acid were added and dissolved in the concentrated residue at a temperature of 20 to 25^°C. To the reaction liquid was added 124 ml of ethyl acetate, followed by stirring at a temperature of 20 to 25 ^°C for about 2 hours. The reaction liquid was heated to a temperature of 40 to 45^°C, stirred for about 1 hour, cooled to a temperature of 20 to 25^°C, and then stirred for about 3 hours. The resulting crystals were filtered, washed with acetone, and then dried to afford 70 g (yield: 22% from the filtrate of Example 2) of clopidogrel camphor su 1 fonate.

<46> Specific O.R. : 24.8° (c=1.68, methanol, 23^°C)

<47>

<48> Example 4: Preparation of clopidogrel free base

<49> To 400 ml of dichloromethane was added 100 g of clopidogrel camphor sulfonate prepared in Example 2, followed by stirring at a temperature of less than 10^°C . To the reaction liquid was gradually added an aqueous potassium carbonate solution prepared by dissolving 20 g of potassium carbonate in 300 ml of purified water while maintaining a temperature of less than 10^°C, followed by stirring for about 40 minutes. The organic layer was separated from the reaction liquid, and the separated organic layer was washed with 300 ml of purified water. To the washed organic layer were added anhydrous sodium sulphate and 0.5 g of activated carbon, and the mixture was stirred at a temperature of 20 to 25^°C, filtered, and washed with 25 ml of dichloromethane. The filtrate was distilled, and 50 ml of 2-butanol was added thereto, followed by further distillation to remove the solvent. 58 g of quantitatively pure clopidogrel free base was obtained.

<50>

<5 i > Example 5: Preparation of crystalline form (I) of clopidogrel hydrogen sulphate (Formula 1)

<52> To 58 g of the clopidogrel free base obtained in Example 4 were added

1100 ml of 2-butanol and 5 ml of purified water, followed by stirring at a temperature of 15 to 20^°C . To the reaction liquid was gradually added 16.8 g of sulfuric acid while maintaining a temperature of 20 to 25^°C , followed by stirring for about 30 minutes, and 1 g of a crystalline form (I) of clopidogrel hydrogen sulphate was added thereto, followed by stirring at a temperature of 20 to 25^°C for 12 hours. The resulting crystals were filtered, washed with acetone, and then dried to afford 40 g (yield: 53%) of a crystalline form (I) of clopidogrel hydrogen sulphate.

<53> The X-ray diffraction analysis data and IR data values of the resulting crystalline form (I) are shown in FIGS. 1 and 2.

<54> Specific O.R.: 56.3° (c=1.891, methanol, 24^°C) e.e. > 99.9%

<55> Impurity A: 0.015%, Impurity B: 0.03%, Impurity C: 0.025%, Dried weight: 0.1%

<56> According to the examination of the obtained crystalline form (I) under a light microscope (Axiovert 25 manufactured by Zeiss, x50), crystals were observed to have a spherical crystal shape of a uniform size (FIG. 3).

<57>

<58> Examples 6 to 11 and Comparative Example 1:

<59> In order to confirm changes in clopidogrel hydrogen sulphate crystals in response to changes in the content of water (purified water) based on the weight of the clopidogrel free base, clopidogrel hydrogen sulphates were manufactured with varying contents of purified water as described below Table 1 under the same conditions as in Example 5. <60> [Table 1]

X: irregular crystal shape, ο,Δ: spherical crystals are predominant over irregular crystals

Crystal shapes of Comparative Example 1 and Examples 6 to 11 given in Table 1 above were measured using the same light microscope as in Example 5, at the same magnification (x50).

In the method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate in accordance with the present invention, the volume of water used is preferably in the range of 4 to 14% by weight based on the weight of the clopidogrel free base. When the water content is higher than 14%, the resulting product is not a crystalline form (I), or even if the resulting product is a crystalline form (I), an irregular plate-like crystalline form (I) is manufactured. When the water content is lower than 4%, an irregular plate-like crystalline form is manufactured even if the resulting product is a crystalline form (I), or crystallization is very sluggish thereby resulting in production with very low yield.

<64>

<65> Example 12: Preparation of crystalline form (I) of clopidogrel hydrogen sulphate (Formula 1)

<66> To 46 g of clopidogrel free base were added 800 ml of 2-butanol and 5 ml of purified water, followed by stirring at a temperature of 15 to 20^°C. 14.1 g of sulfuric acid was gradually added to the reaction liquid while maintaining a temperature of 20 to 25^°C , followed by stirring at a temperature of 20 to 25 ^°C for 7 hours. The resulting crystals were filtered, washed with acetone, and then dried to afford 31.3 g (yield: 52%) of a crystalline form (I) of clopidogrel hydrogen sulphate.

<67>

<68> Example 13: Preparation of crystalline form (I) of clopidogrel hydrogen sulphate (Formula 1)

<69> To 50 g of clopidogrel free base (available from J i acheng-Chem

Enterprises Limited) were added 1000 ml of 2-butanol and 4.3 ml of purified water, followed by stirring at a temperature of 15 to 20^°C. 15.2 g of sulfuric acid was gradually added to the reaction liquid while maintaining a temperature of 20 to 25^°C , followed by stirring for about 30 minutes, and 0.9 g of a crystalline form (I) of clopidogrel hydrogen sulphate was added thereto, followed by stirring at a temperature of 20 to 25^°C for 14 hours. The resulting crystals were filtered, washed with acetone, and then dried to afford 33.5 g (yield: 51.3%) of a crystalline form (I) of clopidogrel hydrogen sulphate.

<70>

<7i> Comparative Example 2: Preparation of crystal 1 ine form (I) of clopidogrel hydrogen sulphate (according to Example 12 of W02005063708)

<72> 86.1 g of clopidogrel camphor su 1 fonate was added to 450 ml of dichloromethane, and an aqueous sodium bicarbonate solution (10%, 650 ml) was added thereto at a temperature of 25 to 30 ^°C, followed by stirring for 10 minutes. The organic layer was separated from the reaction liquid, and the aqueous layer was extracted again with 90ml of dichloromethane. Two separated organic layers were washed with 180 ml of purified water. The washed organic layer was dried over anhydrous sodium sulphate and then distilled to afford a clopidogrel free base. 1

<73> To the clopidogrel free base were added 250ml of n-hexanol and 1ml of water, followed by stirring at a temperature of 25 to 30^°C. Concentrated sulfuric acid was added thereto at a temperature of 10 to 15^°C , and a crystalline form (I) of clopidogrel hydrogen sulphate was seeded thereto, followed by stirring at a temperature of 20 to 25^°C for 10 hours. High-speed stirring was carried out at a temperature of 22 to 25^°C for about 2 hours, and low-speed stirring was carried out for about 6 hours. The reactants were filtered, washed with 150 ml of methyl tert-butyl ester, and then dried to afford 11 g (yield: 17%) of a crystalline form (I) of clopidogrel hydrogen sulphate. {For reference, W02005063708 describes that when manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate according to the above- mentioned method, a yield of 85.95% is achieved, but the practical application by the present inventors showed a yield of only 17%}

<74> Further, when the obtained crystalline form (I) was examined under a light microscope (Axiovert 25 manufactured by Zeiss, x50), it was a powder^¬ like crystalline form (FIG. 9).

[Industrial Applicability]

<75> The manufacturing method in accordance with the present invention is an improved method for manufacturing a crystalline form (I) of known clopidogrel hydrogen sulphate(clopidogrel hydrogen sulfate), which has an advantage of enabling the manufacture of a crystalline form (I) of clopidogrel hydrogen sulphate which has high optical purity even at room temperature which is not a low temperature, a spherical crystal shape (FIG. 3), and excellent fluidity. Accordingly, the crystalline form (I) of clopidogrel hydrogen sulphate manufactured according to the present invention has advantages such as no need of a grinding process upon tablet compression, uniform filling due to having favorable fluidity and therefore minimized cracking or sticking.

Claims

[CLAIMS]

[Claim 1]

<77> A method for manufacturing a crystalline form (I) of clopidogrel hydrogen sulphate, comprising:

<78> reacting a clopidogrel free base with concentrated sulfuric acid in the presence of a mixed solvent of water in an amount of 4 to 14% by weight based on the weight of the clopidogrel free base and 2-butanol .

[Claim 2]

<79> The method according to claim 1, wherein the volume of water used is in the range of 5 to 14% by weight based on the weight of the clopidogrel free base.

[Claim 3]

<80> The method according to claim 2, wherein the volume of water used is in the range of 7.5 to 11% by weight based on the weight of the clopidogrel free base.

[Claim 4]

<8i > The method according to claim 3, wherein the volume of water used is

8.6% by weight based on the weight of the clopidogrel free base.

[Claim 5]

<82> The method according to claim 1, further comprising seeding a crystalline form (I) of clopidogrel hydrogen sulphate.

[Claim 6]

<83> The method according to claim 1, wherein the reaction temperature and the crystallization temperature are in the range of 15 to 25^°C .

[Claim 7]

<84> The method according to claim 1, wherein the weight ratio of clopidogrel free base to mixed solvent is in the range of 1:14 to 25.

[Claim 8]

<85> The method according to claim 1, wherein the reaction time is in the range of 5 to 15 hours.

[Claim 9]

<86> The method according to any one of claims 1 to 8, wherein the clopidogrel free base is manufactured by reacting clopidogrel camphor sulfonate and potassium carbonate in the presence of a dichloromethane solvent.

[Claim 10]

<87> The method according to claim 9, wherein the clopidogrel camphor sulfonate is manufactured by dissolving a racemic clopidogrel base and an (R)-(-)-10-camphorsulfonic acid in a solvent selected from dichloromethane, dichloroethane and chloroform, and adding thereto an antisolvent selected from primary, secondary and tertiary C -C5 alkyl acetates, followed by reaction.

[Claim 11]

<88> The method according to claim 10, wherein the antisolvent is ethyl acetate.