HK1119171A - Method of preparing clopidogrel and intermediates used therein - Google Patents

Description

Process for preparing clopidogrel and intermediates used therein

Technical Field

The present invention relates to a process for preparing optically pure clopidogrel in high yield and a novel intermediate used therein.

Background

Clopidogrel, methyl (S) - (+) - α - (2-chlorophenyl) -6, 7-dihydrothieno [3, 2-a ] pyridine-5 (4H) -acetate of formula (I), is a platelet aggregation inhibitor which is effective in the treatment of peripheral arterial diseases such as stroke, thrombosis and embolism, and coronary arterial diseases such as myocardial infarction and angina pectoris:

various methods for preparing clopidogrel are described in european patents 0,281,459, 0,466,569, 0,971,915, 0,099,802, 1,021,449, 1,404,681 and 1,353,928 and international publication WO 2004/094374. Among these methods, preferred in terms of commercial applicability is a method involving resolution of a racemate consisting of clopidogrel of the formula (I) or an intermediate thereof and a levorotatory isomer thereof using an optical resolution agent.

For example, european patent 0,281,459 discloses a process for the preparation of clopidogrel of formula (I): by reacting a racemic body of clopidogrel with (1R) - (-) -10-camphorsulfonic acid to selectively form a camphorsulfonic acid salt of clopidogrel and removing the camphorsulfonic acid salt portion therefrom (optical resolution process); and the methods disclosed in european patents 0,099,802 and 1,353,928: the intermediate of clopidogrel racemate as described above is optically resolved using (1R) - (-) -10-camphorsulfonic acid, followed by preparation of the desired clopidogrel from the resolved intermediate (see reaction scheme 1).

Reaction scheme 1

European patent 0,281,459

European patent 0,099,802

European patent 1,353,928

However, these methods have problems in that: the salt of clopidogrel or an intermediate thereof formed by selective crystallization from the racemate of clopidogrel or an intermediate thereof and (1R) - (-) -10-camphorsulfonic acid does not have sufficient optical purity and must be further purified, which results in a decrease in yield. In addition, because of the high solubility of (1R) - (-) -10-camphorsulfonic acid in water, it is difficult to recover it from the reaction solution for recycling.

Summary of The Invention

Accordingly, it is a primary object of the present invention to provide a simple, high-yield process for the preparation of optically pure clopidogrel.

It is another object of the present invention to provide novel intermediates useful for the preparation of clopidogrel.

According to one aspect of the present invention, there is provided a process for preparing clopidogrel of formula (I) comprising the steps of:

(a) optically resolving the racemic form of the compound of formula (II) using an optically active amine to form an optically active form of the compound of formula (III) or an acid addition salt thereof; and

(b) methylating the compound of formula (III) formed in step (a) or an acid addition salt thereof:

according to another aspect of the present invention, there is provided a salt of formula (IV) useful as an intermediate in the preparation of clopidogrel:

Detailed Description

The process of the present invention comprises an optical resolution process (step (a) consisting of substeps (a-1) and (a-2)) and an esterification process (step (b)), as shown in scheme 2.

Reaction scheme 2

< step (a) >

The optical resolution process (step (a)) according to the present invention comprises: reacting the racemic form of the compound of formula (II) with an optically active amine to crystallize a salt of formula (IV) (step (a-1)), and removing the optically active amine moiety from the salt to form the optically active form of the compound of formula (III) (step (a-2)).

< step (a-1) >

The crystallization of the salt of formula (IV) in step (a-1) may be carried out as follows: adding a compound of formula (II) and an optically active amine to a suitable solvent, stirring the resulting solution at a temperature in the range from room temperature to the boiling point of said solvent, and allowing the resulting mixture to cool to 0 ℃ to room temperature.

The optically active amine used in the present invention may be one of any conventional optical resolution agents used for optical resolution of racemic carboxylic acids (see [ E.L.Eliel, S.L.Eliel and L.N.Mander, Stereochemistry of Organic Chemistry, 1994, John Wiley & Son, New York, pp 329-337 ]). Such amines are selected from: ephedrine, 2-amino-1, 2-diphenylethanol, α -methylbenzylamine, α - (1-naphthyl) ethylamine, glucosamine, 2-amino-1-phenyl-1, 3-propanediol and derivatives thereof, preferably (1R, 2R) - (-) -2-amino-1- (4-substituted phenyl) -1, 3-propanediol compounds of formula (V):

wherein R is hydrogen, halogen, nitro, methyl or methoxy.

The optically active amine may be used in an amount ranging from 0.4 to 1.1 molar equivalents based on the amount of the compound of formula (II).

Suitable as solvents for the present invention are organic solvents such as methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, 1, 4-dioxane and N, N-dimethylformamide, or mixtures of one of said organic solvents with water.

The salt of formula (IV) thus obtained has satisfactory optical purity, it does not require further purification, but if necessary, it can be recrystallized from any of the solvents listed above to improve its purity.

< step (a-2) >

In step (a-2), the compound of formula (III) may be prepared as follows: basifying the aqueous solution of the salt of formula (IV) with a base, followed by filtration or extraction to separate the optically active amine from the salt of formula (IV) for further recycling, and acidifying the filtrate, extracting the filtrate with an organic solvent.

The base used in the present invention may be sodium hydroxide or potassium hydroxide, and the amount of the base is preferably in the range of 1 to 3 molar equivalents based on the amount of the compound of formula (IV).

Obtaining the optically active amine released from the salt by filtration; when the optically active amine is a liquid, it can be isolated by extraction using a conventional organic solvent. The optically active amine thus separated can be reused in the crystallization of step (a-1) via a simple purification procedure comprising a recrystallization or distillation step.

After removing the optically active amine moiety, the filtrate is acidified so that its pH becomes 2 to 5, and then extracted with an organic solvent such as ethyl acetate, chloroform and dichloromethane. The resulting extract was concentrated to give the compound of formula (III) as a foam. Preferably, the compound of formula (III) thus obtained is converted into the form of pure acid addition salt crystals (e.g.hydrochloride salt crystals).

The racemic form of the compound of formula (II) can be prepared by conventional methods (see european patent 0,099,802). Preferred for use in the process of the present invention are 4, 5, 6, 7-dihydro-4H-thieno [3, 2-c ] pyridine or its acid addition salt and α -bromo- (2-chlorophenyl) acetic acid, both commercially available, as shown in scheme 3.

Reaction scheme 3

In particular, the compounds of formula (II) may be prepared by reacting α -bromo- (2-chlorophenyl) acetic acid with 4, 5, 6, 7-dihydro-4H-thieno [3, 2-c ] pyridine or an acid addition salt thereof in the presence of a base in a suitable solvent.

Typical examples of the solvent that can be used in the present invention include water, methanol, ethanol, n-propanol, isopropanol, acetone, tetrahydrofuran, 1, 4-dioxane, acetonitrile and a mixture thereof, and typical examples of the base used in the present invention include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and a mixture thereof. The amount of base used is in the range of 1 to 10 molar equivalents, preferably 2 to 4 molar equivalents, and the amount of α -bromo- (2-chlorophenyl) acetic acid is in the range of 0.5 to 2 molar equivalents, preferably 0.9 to 1.1 molar equivalents, based on the amount of 4, 5, 6, 7-dihydro-4H-thieno [3, 2-c ] pyridine or its acid addition salt. The reaction may be carried out at a temperature in the range from 0 ℃ to the boiling point of the solvent, preferably from 5 to 40 ℃.

< step (b) >

The methylation step (b) can be carried out as follows: (i) reacting a compound of formula (III) or an acid addition salt thereof with a chlorinating agent in an inert solvent to form a chlorinated compound of formula (VI) or an acid addition salt thereof, which is treated with methanol; or (ii) reacting a compound of formula (III) or an acid addition salt thereof with an alkyl chloroformate in an inert solvent in the presence of a base to form an anhydride of formula (VII), which is treated with methanol; or (III) reacting the compound of formula (III) or an acid addition salt thereof with methanol in the presence of an acid catalyst;

wherein R is¹Is C_1-4An alkyl group.

In step (b), the reaction of the compound of formula (III) or an acid addition salt thereof with the chlorinating agent may be carried out in an inert solvent such as dichloromethane, chloroform, benzene and toluene at a temperature ranging from-30 to 40 ℃, preferably from-15 ℃ to room temperature, to obtain a chlorinated compound of formula (VI) or an acid addition salt thereof. Typical examples of the chlorinating agent used in the present invention include thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosgene, diphosgene, triphosgene, oxalyl chloride and a mixture thereof, of which oxalyl chloride is preferred. The amount of chlorinating agent used is preferably in the range of 1 to 5 molar equivalents based on the amount of the compound of formula (III) or an acid addition salt thereof.

The reaction of the chlorinated compound of formula (VI) or its acid addition salt with methanol may then be carried out at a temperature ranging from-15 ℃ to room temperature. The amount of methanol used is preferably in the range of 1 to 10 molar equivalents based on the amount of the compound of formula (III) or an acid addition salt thereof.

The reaction of the compound of formula (III) or an acid addition salt thereof with an alkyl chloroformate may be carried out in an inert solvent such as dichloromethane, chloroform, tetrahydrofuran, acetonitrile, benzene and toluene in the presence of a base at a temperature ranging from-30 to 40 ℃, preferably from-15 ℃ to room temperature, to obtain an anhydride of formula (VII). Suitable for this step are alkyl chloroformates such as methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, isopropyl chloroformate and isobutyl chloroformate. Typical examples of the base used in the step include triethylamine, diisopropylethylamine, tributylamine, pyridine, picoline, rutidine, dimethylaminopyridine and a mixture thereof. The amounts of alkyl chloroformate and base are preferably in the range of 1 to 3 molar equivalents and 1 to 4 molar equivalents, respectively, based on the amount of compound of formula (III) or acid addition salt thereof.

The reaction of the acid anhydride of the formula (VII) with methanol may be carried out by adding methanol to the mixture obtained in the above step and stirring the resulting mixture at a temperature ranging from-15 ℃ to room temperature. The amount of methanol used is preferably in the range of 1 to 10 molar equivalents based on the amount of the compound of formula (III) or an acid addition salt thereof.

The reaction of the compound of formula (III) or an acid addition salt thereof with methanol may be carried out in methanol in the presence of an acid catalyst such as anhydrous hydrochloric acid, sulfuric acid, methanesulfonic acid and p-toluenesulfonic acid. The amount of the acid catalyst used is preferably in the range of 1 to 4 molar equivalents based on the amount of the compound of formula (III) or an acid addition salt thereof.

The methyl ester of optically active clopidogrel of formula (I) thus obtained is practically free of the levorotatory isomer and can be converted into its acid addition salt form by conventional methods (see European patent 0,281,459 and International application patent No. PCT/KR 2004/002665). Such salts of clopidogrel include hydrochloride, hydrobromide, bisulfate, benzenesulfonate, 2-naphthalenesulfonate and 1, 5-naphthalenedisulfonate.

Clopidogrel or an acid addition salt thereof obtained according to the process of the present invention has a high optical purity of at least 98% ee, which meets the minimum pharmaceutical purity required by the united states pharmacopeia.

In addition, the salt of formula (IV) used as an intermediate in the preparation of clopidogrel according to the present invention is a novel compound comprising an optically active amine such as ephedrine, 2-amino-1, 2-diphenylethanol, α -methylbenzylamine, α - (1-naphthyl) ethylamine, glucosamine, 2-amino-1-phenyl-1, 3-propanediol and derivatives thereof, preferably (1R, 2R) - (-) -2-amino-1- (4-substituted phenyl) -1, 3-propanediol of formula (V).

The following examples are given for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1: (±) -alpha- (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c]-5-acetic acid (preparation of formula (II)) Prepare for

50.0g of 4, 5, 6, 7-tetrahydrothieno [3, 2-c ] pyridine hydrochloride and 74.6g of α -bromo- (2-chlorophenyl) acetic acid are successively added to a mixture of 275ml of water and 75ml of methanol, and the resulting solution is cooled to below 10 ℃ with stirring. 63.9g of 85.0% KOH dissolved in 142ml of water were slowly added to the above solution while keeping the temperature below 15 ℃. The resulting clear solution was heated to 40 ℃ and stirred at this temperature for 3 hr. The pH of the reaction solution was adjusted to 3.5 with 6N-HCl, cooled to room temperature and stirred for 2 hr. The reaction mixture was then cooled to below 5 ℃ and stirred for 2 hr. The precipitated crystals were filtered, washed successively with 150ml of water and 100ml of n-hexane, and dried at 40 ℃ to obtain 81.7g of the title compound (yield: 88%) as a white-yellow monohydrate.

m.p.：114-116℃

Water content: 5.6% (Karl-Fischer method)

¹H-NMR(CDCl₃，ppm)：δ3.00(brs，2H)，3.16-3.56(m，2H)，4.05-4.28(m，2H)，5.14(d，1H，J＝4.4Hz)，6.04(brs，H)，6.55-6.68(m，1H)，7.04-7.31(m，1H)，7.31-7.41(m，1H)，7.85-7.98(m，1H)

¹³C-NMR(CDCl₃，ppm)：δ22.64，48.47，50.43，67.13，124.72，125.58，128.00，129.35，130.36，130.57，130.72，132.01，132.06，135.63，170.34

IR(KBr，cm^-1)：3394，3079，1668，1638

MS(ESI，M/Z)：308.2(M+H)

Example 2: (S) - (+) -alpha- (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c]Pyridine-5-acetic acid Preparation of (1R, 2R) - (-) -2-amino-1- (4-nitrophenyl) -, 3-propanediol salt (formula (, IV))

167.0g of (. + -.) - α - (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c ] pyridine-5-acetic acid monohydrate obtained in example 1 and 55.0g of (1R, 2R) - (-) -2-amino-1- (4-nitrophenyl) -1, 3-propanediol (formula (V): R is nitro) were added to a mixture of 1000ml of water and 1500ml of methanol, and the resulting solution was refluxed for 12 hours. The resulting reaction mixture was slowly cooled to below 5 ℃ and stirred for 2 hr. The precipitated crystals were filtered, washed with 200ml of methanol and dried at 40 ℃ to obtain 113g of the title compound (yield: 85% of calculated value) as a white-yellow powder.

m.p.：199-201℃

Optical rotation: [ alpha ] to]_D ²⁰+9.53°(c＝1％，DMF)

Optical purity: 99.0% ee (HPLC, on compound of formula (III))

¹H-NMR(DMSO-d⁶，ppm)：δ2.61-2.91(m，4H)，2.92-3.07(m，1H)，3.12-3.28(m，1H)，3.35-3.45(m，1H)，3.52(d，1H，J＝14.5Hz)，3.68(d，1H，J＝14.5Hz)，4.50(s，1H)，4.79(d，1H，J＝7.0Hz)，6.74(d，1H，J＝5.1Hz)，7.10-7.35(m，3H)，7.39(d，1H，J＝7.4Hz)，7.63(d，2H，J＝8.6Hz)，7.74(d，1H，J＝7.4Hz)，8.21(d，2H，J＝8.6Hz)

¹³C-NMR(DMSO-d⁶，ppm)：δ25.29，47.95，50.34，58.19，59.38，70.13，70.57，122.75，123.27，125.50，126.74，128.09，128.34，128.91，130.41，132.78，133.76，134.33，137.45，146.89，150.15，173.77

IR(KBr，cm^-1)3419，1920，1606，1556，1518，1350

40.0g of the compound thus obtained was recrystallized from 280ml of 90% isopropanol to obtain 35.0g of the title compound with higher purity.

m.p.：207-208℃

Optical rotation: [ alpha ] to]_D ²⁰+9.56°(c＝1％，DMF)

Optical purity: 99.9% ee (HPLC, based on the compound of formula (III))

Example 3: (S) - (+) -alpha- (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c]Pyridine-5-acetic acid Preparation of (1R, 2R) - (-) -2-methyl-1- (4-nitrophenyl) -1, 3-propanediol salt (formula (IV))

130.0g of (. + -.) - α - (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c ] pyridine-5-acetic acid monohydrate obtained in example 1 and 42.4g of (1R, 2R) - (-) -2-amino-1- (4-nitrophenyl) -1, 3-propanediol (formula (V): R is nitro) were added to a mixture of 800ml of water and 3200ml of isopropanol. The resulting suspension was then refluxed until it became a homogeneous solution. The resulting solution was cooled to below 5 ℃ and stirred for 2 hr. The precipitated crystals were filtered, washed with 200ml of isopropyl alcohol and dried at 40 ℃ to obtain 78.0g of the title compound as a white yellow solid (yield: 75% of calculated value). The solid was the same as that obtained in example 2.

m.p.：201-202℃

Optical rotation: [ alpha ] to]_D ²⁰+9.50°(c＝1％，DMF)

Optical purity: 99.4% ee (HPLC, based on the compound of formula (III))

Example 4: (S) - (+) -alpha- (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c]Pyridine-5-acetic acid Preparation of (-, 1R, 2R) - (-) -2-amino-1-phenyl-1, 3-propanediol salt (formula (IV))

10.0g of (. + -.) - α - (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c ] pyridine-5-acetic acid monohydrate obtained in example 1 and 2.8g of (1R, 2R) - (-) -2-amino-1-phenyl-1, 3-propanediol (formula (V): R is hydrogen) were added to 100ml of 95% isopropanol. Then, the resulting solution was refluxed until it became a uniform solution. The resulting solution was cooled to below 5 ℃ and stirred for 2 hr. The precipitated crystals were filtered, washed with 10ml of isopropyl alcohol and dried at 40 ℃ to obtain 4.2g of the title compound as a white yellow solid (yield: 57% of calculated value).

m.p.：181-183℃

Optical purity: 99.0% ee (HPLC, on compound of formula (III))

¹H-NMR(DMSO-d⁶，ppm)：δ2.72-2.84(4H，m)，2.99-3.03(1H，m)，3.18(1H，dd，J＝11.51，5.76Hz.)，3.34(1H，dd，J＝11.63，3.47Hz.)，3.60(2H，dd，J＝49.87，14.40Hz.)，4.48(1H，s)，4.58(1H，d，J＝8.37Hz.)，6.74(1H，d，J＝5.09Hz.)，7.22-7.41(9H，m)，7.75(1H，dd，J＝7.54，1.89Hz.)

¹³C-NMR(DMSO-d⁶，ppm)：δ25.32，47.96，50.35，58.57，59.01，70.83，70.91，122.70，125.49，126.67，126.81，127.57，128.17，128.83，130.45，132.77，133.74，134.42，137.74，142.18，173.90

IR(KBr，cm^-1)：3455，3069，1561

Example 5: (S) - (+) -alpha- (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c]Pyridine-5-acetic acid (formula) (III)) preparation of

113.0g of the salt obtained in example 2 or 3 are added to 250ml of water and cooled to below 5 ℃. 17.4g of sodium hydroxide dissolved in 125ml of distilled water were added thereto and stirred at this temperature for 30 minutes. The precipitated crystals were filtered and washed with 125ml of distilled water. 43.0g of (1R, 2R) - (-) -2-amino-1- (4-nitrophenyl) -1, 3-propanediol (formula (V): R is nitro) was isolated and recovered therefrom (recovery: 93%). On the other hand, 113g of sodium chloride and 340ml of chloroform were added to the filtrate, the pH of the resulting mixture was adjusted to 3.5 with 6N-HCl, and the organic layer was separated. The aqueous layer was extracted with 340ml of chloroform. The chloroform layers were combined and concentrated under reduced pressure to give 68g of the title compound as a foam.

Optical purity: 99.0% ee (HPLC)

Example 6: (S) - (+) -alpha- (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c]Pyridine-5-acetic acid salt Preparation of acid salt (hydrochloride of formula (III))

61g of (S) - (+) - α - (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c ] pyridine-5-acetic acid obtained in example 5 were added to a mixture of 300ml of acetone and 15ml of methanol, followed by heating to 40 ℃. 16.4ml of concentrated hydrochloric acid was added thereto, and the resulting mixture was stirred at room temperature for 2hr and then at 5 ℃ or lower for at least 2 hr. The precipitated crystals were filtered, washed with 100ml of acetone and dried under reduced pressure at 40 ℃ to give 61g of the title compound as a pale yellow solid (yield: 90%).

m.p.：200-201℃

Optical rotation: [ alpha ] to]_D ²⁰+64.87°(c＝1％，MeOH)

Optical purity: 99.5% ee (HPLC)

¹H-NMR(DMSO-d⁶，ppm)：δ3.10(s，3H)，3.47(s，2H)，4.30(s，2H)，5.54(s，1H)，6.91(d，1H，J＝4.8Hz)，7.44(d，1H，J＝4.8Hz)，7.46-7.58(m，2H)，7.65(d，1H，7.4Hz)，7.97(d，1H，J＝7.1Hz)

¹³C-NMR(DMSO-d⁶，ppm)：δ21.78，48.81，50.17，65.43，125.04，125.54，127.99，128.29，128.36，130.37，130.46，131.49，132.02，134.43，167.53

IR(KBr，cm^-1)：3435，3114，1728

Example 7: (S) - (+) -alpha- (2-chlorophenyl) -6, 7-dihydrothieno [3, 2-a]Pyridine-5 (4H) -acetic acid methyl ester Preparation of the ester (formula (I))

8.9g of (S) - (+) - α - (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c ] pyridine-5 (4H) -acetic acid obtained in example 5 was dissolved in 150ml of anhydrous methanol, and 6.4ml of anhydrous sulfuric acid was added thereto. The resulting mixture was refluxed for 24 hr. The resulting mixture was then subjected to reduced pressure to remove methanol therefrom. To the resulting residue were added 200ml of ethyl acetate and 150ml of water, and the pH was adjusted to 8 using saturated sodium bicarbonate to facilitate separation of the aqueous phase and the organic phase. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 7.2g of the title compound as a yellow oil (yield: 77%).

Optical purity: 98.5% ee (HPLC)

¹H-NMR(DMSO-d⁶，ppm)：δ2.89(s，4H)，3.60-3.78(m，2H)，3.73(s，3H)，4.93(s，1H)，6.67(d，1H，J＝5.1Hz)，7.06(d，1H，J＝5.1Hz)，7.26-7.30(m，2H)，7.37-7.45(m，1H)，7.68-7.77(m，1H)

Example 8: (S) - (+) -alpha- (2-chlorophenyl) -6, 7-dihydrothieno [3, 2-a]Pyridine-5(4H) -methyl acetate Preparation of the ester (formula (I))

8.9g of (S) - (+) - α - (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c ] pyridine-5 (4H) -acetic acid obtained in example 5 was dissolved in 150ml of anhydrous methanol, and 7.5ml of methanesulfonic acid was added thereto. The resulting mixture was then refluxed for 24hr, and reduced pressure was applied to remove methanol therefrom. To the resulting residue were added 200ml of ethyl acetate and 150ml of water, and the pH was adjusted to 8 with saturated sodium bicarbonate to facilitate separation of the aqueous phase and the organic phase. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 6.1g of the title compound as a yellow oil (yield: 65%) in the same manner as obtained in example 7.

Optical purity: 98.5% ee (HPLC)

Example 9: (S) - (+) -alpha- (2-chlorophenyl) -6, 7-dihydrothieno [3, 2-a]Pyridine-5 (4H) -acetic acid methyl ester Preparation of the ester (formula (I))

8.9g of (S) - (+) - α - (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c ] pyridine-5 (4H) -acetic acid obtained in example 5 were dissolved in 60ml of dichloromethane, 0.2ml of dimethylformamide was added thereto and the resulting mixture was cooled to-20 ℃. A mixture of 4.7ml of oxalyl chloride and 20ml of dichloromethane was slowly added thereto at-10 ℃ or lower over a period of 30 minutes, followed by stirring at-10 to 0 ℃ for 2 hr. Then, a mixture of 5.4ml of methanol and 20ml of methylene chloride was added to the above mixture over a period of 30 minutes, slowly warmed to room temperature, and then stirred at the same temperature for 2 hours. To the resulting solution was slowly added 70ml of water, and the pH was adjusted to 7.5 with saturated sodium bicarbonate to facilitate separation of the aqueous and organic phases. The organic layer was separated, washed with 150ml of saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 8.9g of the title compound as a yellow oil (yield: 96%) in the same manner as obtained in example 7.

Optical purity: 98.1% ee (HPLC)

Practice ofExample 10: (S) - (+) -alpha- (2-chlorophenyl) -6, 7-dihydrothieno [3, 2-a]Pyridine-5 (4H) -acetic acid Preparation of the methyl ester (formula (I))

41.8g of the (S) - (+) - α - (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c ] pyridine-5 (4H) -acetic acid hydrochloride obtained in example 6 were suspended in 252ml of dichloromethane, 0.94ml of dimethylformamide was added thereto and cooled to-20 ℃. A mixture of 12.8ml of oxalyl chloride and 84ml of dichloromethane was slowly added thereto at-10 ℃ or lower over a period of 30 minutes, followed by stirring at a temperature in the range of-10 to 0 ℃ for 2 hr. Over a period of 30 minutes, a mixture of 24.6ml of methanol and 84ml of methylene chloride was added thereto, and the resulting mixture was warmed to room temperature and then stirred at the same temperature for 2 hr. To the resulting solution was slowly added 170ml of water, and the pH was adjusted to 7.5 with saturated sodium bicarbonate to facilitate the separation of the aqueous and organic phases. The obtained organic layer was separated, washed with 150ml of saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 37.1g of the title compound as a yellow oil (yield: 95%) which was the same as that obtained in example 7.

Optical purity: 98.5% ee (HPLC)

Example 11: (S) - (+) -alpha-o-chlorophenyl-6, 7-dihydrothieno [3, 2-a]Pyridine-5 (4H) -acetic acid methyl ester Preparation of the ester (formula (I))

7.9g of (S) - (+) - α - (2-chlorophenyl) -6, 7-dihydro-4H-thieno [3, 2-c ] pyridine-5 (4H) -acetic acid obtained in example 5 were dissolved in 80ml of dichloromethane, 5ml of triethylamine was added thereto and the resulting mixture was cooled to-10 ℃ or below. 2.6ml of methyl chloroformate were added thereto and stirred at 0 ℃ for 2 hr. Then, 4ml of methanol was added to the resultant mixture, 1.6g of 4-dimethylaminopyridine was added thereto and the resultant mixture was stirred at that temperature for 1hr and further at room temperature for 1 hr. The reaction mixture was then washed successively with saturated ammonium chloride and sodium bicarbonate. The obtained organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 6.0g of the title compound as a yellow oil (yield: 73%), which was the same as that obtained in example 7.

Optical purity: 98.0% ee (HPLC)

The reference ratio is 1: preparation of clopidogrel hydrogensulfate (hydrogensulfate of formula (I))

According to the method disclosed in european patent 0,281,459, 35.0g of clopidogrel obtained in example 9 is dissolved in 150ml of acetone and 12.5g of concentrated sulfuric acid is added thereto. The resulting mixture was cooled to below 10 ℃ and stirred overnight. The precipitated crystals were filtered, washed with acetone and dried to obtain 39.7g of the title compound (yield: 87%).

Optical purity: 98.5% ee (HPLC)

And 2, reference ratio: preparation of clopidogrel-1, 5-naphthalenedisulfonate (1, 5-naphthalenedisulfonate of formula (I))

35.0g of clopidogrel obtained in example 9 was dissolved in 200ml of acetone according to the method disclosed in international application PCT/KR 2004/002665. 20.2g of 1, 5-naphthalenedisulfonic acid tetrahydrate dissolved in a mixture of 140ml of acetone and 10ml of water was added to the clopidogrel solution over a period of 30 minutes, and the resulting mixture was stirred at room temperature for 12 hours and then at 0 to 5 ℃ for 4 hours. The precipitated crystals were filtered, washed with 100ml of cold acetone and dried at 50 ℃ to give 46.7g of the title compound as a white powder (yield: 90%).

m.p.：223-225℃

Water content: 1.91% (Karl-Fischer method)

Optical purity: 99.8% ee (HPLC)

As shown above, the process of the present invention gives optically pure clopidogrel in high yield.

While the invention has been described with respect to the above specific embodiments, it will be appreciated that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims (26)

1. A process for preparing clopidogrel of formula (I) comprising the steps of:

(a) optically resolving the racemic form of the compound of formula (II) using an optically active amine to form an optically active form of the compound of formula (III) or an acid addition salt thereof; and

(b) methylating the compound of formula (III) formed in step (a) or an acid addition salt thereof:

2. the process according to claim 1, wherein the optical resolution in step (a) comprises: reacting a racemic form of a compound of formula (II) with the optically active amine to crystallize a salt of formula (IV), and recovering the optically active amine therefrom to obtain an optically active form of a compound of formula (III):

3. the process of claim 2, wherein the optically active amine is selected from the group consisting of: ephedrine, 2-amino-1, 2-diphenylethanol, alpha-methylbenzylamine, alpha- (1-naphthyl) ethylamine, glucosamine, 2-amino-1-phenyl-1, 3-propanediol derivatives and derivatives thereof.

4. The process of claim 2, wherein the optically active amine is a compound of formula (V):

wherein R is hydrogen, halogen, nitro, methyl or methoxy.

5. The method of claim 4, wherein R is hydrogen or nitro.

6. The process of claim 2, wherein the crystallization of the salt of formula (IV) is carried out as follows: adding the compound of formula (II) and the optically active amine to a solvent, stirring the resulting solution at a temperature in the range from room temperature to the boiling point of the solvent, and cooling the resulting mixture to a temperature in the range from 0 ℃ to room temperature.

7. The process of claim 6, wherein the optically active amine is used in an amount ranging from 0.4 to 1.1 molar equivalents based on the amount of the compound of formula (II).

8. The process of claim 6, wherein the solvent is an organic solvent selected from the group consisting of: methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, and mixtures thereof, or a mixture of one of the organic solvents and water.

9. The process of claim 2, wherein the recovery of the optically active amine is performed by basifying an aqueous solution of the salt of formula (IV) with a base.

10. The process of claim 9, wherein the base is used in an amount ranging from 1 to 3 molar equivalents based on the amount of the compound of formula (IV).

11. The process of claim 9, wherein the base is sodium hydroxide or potassium hydroxide.

12. The process according to claim 1, wherein the racemic form of the compound of formula (II) is prepared by carrying out a substitution reaction of α -bromo- (2-chlorophenyl) acetic acid with 4, 5, 6, 7-dihydro-4H-thieno [3, 2-c ] pyridine or an acid addition salt thereof.

13. The method of claim 12, wherein the substitution reaction is carried out in the presence of a base.

14. The process of claim 13, wherein the base is selected from the group consisting of: sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and mixtures thereof.

15. The process of claim 13, wherein the base is used in an amount ranging from 2 to 4 molar equivalents based on the amount of 4, 5, 6, 7-dihydro-4H-thieno [3, 2-c ] pyridine or its acid addition salt.

16. The process of claim 1, wherein the methylation step (b) is carried out as follows: (i) reacting a compound of formula (III) or an acid addition salt thereof with a chlorinating agent in an inert solvent to form a chlorinated compound of formula (VI) or an acid addition salt thereof, which is treated with methanol; or (ii) reacting a compound of formula (III) or an acid addition salt thereof with an alkyl chloroformate in an inert solvent in the presence of a base to form an anhydride of formula (VII), which is treated with methanol; or (III) reacting the compound of formula (III) or an acid addition salt thereof with methanol in the presence of an acid catalyst;

wherein R is¹Is C_1-4An alkyl group.

17. The process of claim 16, wherein the chlorinating agent is selected from the group consisting of: thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosgene, diphosgene, triphosgene, oxalyl chloride, and mixtures thereof.

18. The process of claim 16, wherein the chlorinating agent is oxalyl chloride.

19. The process of claim 16, wherein the chlorinating agent is used in an amount ranging from 1 to 5 molar equivalents based on the amount of the compound of formula (III) or an acid addition salt thereof.

20. The method of claim 16, wherein said alkyl chloroformate is selected from the group consisting of: methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, isopropyl chloroformate, isobutyl chloroformate, and mixtures thereof.

21. The process of claim 16, wherein the base is selected from the group consisting of: triethylamine, diisopropylethylamine, tributylamine, pyridine, picoline, rutidine, dimethylaminopyridine, and mixtures thereof.

22. The process of claim 16, wherein the acid catalyst is selected from the group consisting of: anhydrous hydrochloric acid, anhydrous sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and mixtures thereof.

23. A salt of formula (IV) for use as an intermediate in a process according to claim 1 or 2:

24. the salt of claim 23, wherein the optically active amine is selected from the group consisting of: ephedrine, 2-amino-1, 2-diphenylethanol, alpha-methylbenzylamine, alpha- (1-naphthyl) ethylamine, glucosamine, 2-amino-1-phenyl-1, 3-propanediol and derivatives thereof.

25. The salt of claim 23, wherein the optically active amine is a compound of formula (V):

wherein R is hydrogen, halogen, nitro, methyl or methoxy.

26. The salt of claim 25, wherein R is hydrogen or nitro.