KR101616928B1 - Method for manufacturing crystalline form (I) of Clopidogrel hydrogen sulphate - Google Patents

Abstract

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

Description

[0001] The present invention relates to a method for preparing clopidogrel hydrogen sulphate (I) (Clopidogrel hydrogen sulphate)

The present invention relates to a process for preparing crystalline form (I) of clopidogrel hydrogen sulphate.

(S) -? - (2-chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl-5-methyl acetate Hcl is a drug that has anti-platelet aggregation inhibitory effect and antithrombotic effect. It is a useful drug for the treatment of coronary artery disease such as myocardial infarction and angina pectoris such as stroke, thrombus, embolism, etc. It is marketed as PLAVIX ^® tablets.

[Chemical Formula 1]

U.S. Patent No. 4529596 discloses a racemic compound of Formula 1, and European Patent No. 0281459 discloses a technique of separating an optically active substance of a tetrahydrothienopyridine derivative, wherein the clopidogrel hydrogen sulfate of Formula 1 is disclosed . In this European patent, a salt is formed using (R) - (-) - 10-camphorsulfonic acid with racemic clopidogrel and then refluxed and stirred in acetone to obtain a product having a target specific linearity, And then precipitating the compound of formula (1) using concentrated sulfuric acid in an acetone solvent.

European Patent No. 1087976 also describes the crystal forms (I) and (II) of the above formula (1). (II) has a high thermodynamic stability, crystals of crystalline form (I) are irregular plates and crystals (II) have high thermodynamic stability, and crystalline form (II) (II) has a lower electrostatic charge than the crystalline form (I).

International patent application WO03051362 describes a novel crystalline form (III), (IV), (V) and (VI) of clopidogrel hydrogen sulphate and a process for the preparation of an amorphous form, in particular crystalline form (I) Diethyl ether. ≪ / RTI >

International patent application WO2004020443 discloses that clopidogrel in the form of a free base or salt is reacted with sulfuric acid in a solvent selected from a series of primary, secondary or tertiary C1 to C5 alcohols or esters thereof with C1 to C4 carboxylic acids, (I). ≪ / RTI > Especially precipitation, is carried out in a 2-propanol solution at a temperature of from -5 to 15 [deg.] C which is low temperature.

International patent application WO2005063708 discloses a process for the preparation of a pharmaceutical composition comprising a C6-C12 alcohol such as hexanol, 2-hexanol, 3-hexanol, isohexanol, heptanol, 2-heptanol, (I) type crystals are separated by treatment with concentrated sulfuric acid in a mixture of methanol, ethanol, isopropanol, iso-octanol, decanol or mixtures thereof and water.

International patent application WO2006087729 describes a method of forming a crystalline (I) form by adding sulfuric acid on a solvent such as (S) -clopidogrel and a C1 to C5 carboxylic acid.

In addition, the above methods are irregular flat plates as described in European Patent No. 1087976, or have a problem of static electricity because the crystal shape is not round.

However, none of the production methods of the crystal form (I) disclosed so far has produced a crystalline form (I) having a circular crystal shape and excellent flowability by using a low-carbon alcohol and water mixture solvent of C1-C4.

Accordingly, the present inventors intend to provide clopidogrel hydrogen sulphate crystal (I) which is easier to manufacture, has high purity and excellent physical properties.

The present invention provides a process for preparing crystalline form (I) of clopidogrel hydrogen sulphate by reacting clopidogrel free base with concentrated sulfuric acid in a mixed solvent of 2-butanol and water.

Hereinafter, in the present invention, "clopidogrel" means "(+) - (S) -α- (2- chlorophenyl) -4,5,6,7- tetrahydrothieno [3,2- c] pyridinyl- 5-methyl acetate ", and" racemic clopidogrel "means" (±) -α- (2-chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2- c] pyridinyl -5-methyl acetate ".

In the crystalline form (I) of the present invention, the amount of water used is preferably 4 to 14% by weight, more preferably 5 to 14% by weight, more preferably 7.5 to 11% by weight based on the weight of clopidogrel free base , And 8.6%. When the content of water is more than 14%, irregular flat plate-like crystalline form (I) is produced even if it is not crystalline form (I) or crystalline form (I) Is very slow and the yield is very low.

In the crystal form (I) production method of the present invention, the crystal form (I) of clopidogrel hydrogen sulphate can be seeded to promote the generation of crystalline form (I).

In the crystalline form (I) of the present invention, the reaction temperature and the crystal temperature are preferably 15 to 25 ° C. That is, the crystal form (I) production method of the present invention has an advantage that it is not necessary to separately set the crystal temperature to low to generate crystals.

In the crystalline form (I) of the present invention, the weight ratio of the clopidogrel free base and the mixed solvent is preferably 1: 14 to 25.

In the process for producing a crystalline form (I) of the present invention, the reaction time is preferably 5 to 15 hours.

In the crystalline form (I) of the present invention, the starting material, clopidogrel free base, may be isolated from other compounds, and in the process for preparing clopidogrel free base from a pharmaceutically acceptable salt of clopidogrel, The free base may be in a non-isolated state. The clopidogrel free base, which is a starting material, can also be prepared by a known method, for example, by reaction of clopidogrel camphorsulfonate and potassium carbonate in a dichloromethane solvent.

Herein, the clopidogrel camphorsulfonate salt for producing clopidogrel free base, which is a starting material of the present invention, can be prepared by a known method (for example, European Patent No. 0281459), and the following method May be manufactured.

Therefore, the present invention relates to a method for producing clopidogrel free base, which is a starting material of the crystalline form (I) of the present invention, comprising reacting clopidogrel camphorsulfonate with a racemic clopidogrel base and (R) - (-) - 10-camphorsulfonic acid in dichloromethane , Dichloroethane and chloroform, followed by addition of an antisolvent selected from primary, secondary, and tertiary C 1 -C 5 alkyl acetates, followed by reaction. Here, it is preferable that the semi-solvent is ethyl acetate. The clopidogrel camphorsulfonate salt of the present invention as described above has the advantage of providing a high yield and a high purity (45% yield, e.e. > 99.5%) as compared to the known method (European Patent No. 0281459).

The process of the present invention is an improved process for preparing crystalline clopidogrel hydrogen sulphate (I), which is known to have high optical purity even at room temperature, not at low temperatures, and which allows crystals to be rounded (Fig. 3) There is an advantage. Therefore, the crystalline form (I) prepared according to the present invention has an advantage of being able to minimize cracking or sticking by filling the tablets without needing a pulverizing process, filling the tablets evenly with good fluidity.

1 is X-ray diffraction analysis data of crystal form (I) of clopidogrel hydrogen sulphate prepared in Example 5. Fig.
2 is a spectrum of the FTIR of the crystalline form (I) of clopidogrel hydrogen sulphate prepared in Example 5. Fig.
Fig. 3 is an enlarged photograph of the crystal form (I) of clopidogrel hydrogen sulphate prepared in Example 5 at 50 times magnified by an optical microscope.
4 is an enlarged photograph of the crystal form (I) of clopidogrel hydrogen sulphate of Comparative Example 1, which is 50 times magnified by an optical microscope.
5 is an enlarged photograph of the crystal form (I) of clopidogrel hydrogen sulphate of Example 6 by 50 times magnified by an optical microscope.
6 is an enlarged photograph of the crystal form (I) of clopidogrel hydrogen sulphate of Example 7 by 50 times magnified by an optical microscope.
FIG. 7 is an enlarged photograph of the crystal form (I) of clopidogrel hydrogen sulphate of Example 10 by 50 times magnified by an optical microscope.
FIG. 8 is an enlarged photograph of a mixture of the crystalline forms (I) and (II) of clopidogrel hydrogen sulphate of Example 11, which is 50 times magnified by an optical microscope.
9 is an enlarged photograph of the crystal form (I) of clopidogrel hydrogen sulphate of Comparative Example 2, which is 50 times magnified by an optical microscope.

Hereinafter, the present invention will be described in detail by way of examples, but the following examples are intended to illustrate the present invention and not limit the scope of the present invention.

X-ray diffraction analysis data, IR data, and purity of the clopidogrel hydrogen sulphite salt crystal form (I) prepared in the following examples were analyzed by X-ray diffractometer (PXRD, D8 focus (2.2 kw) of Buker AXS (germany) , Fourier Transform Infrared Spectroscopy (FTIR, Nicolet 6700 from Thermo Scientific) and HPLC (1200 series, Ultron ES-OVM from Agilent Technologies, 15 cm, 4.6 mm ID, particle size 5 μm).

≪ Example 1 > Racemic clopidogrel (racemic methyl? - (2-chlorophenyl) -4,5,6,7-tetrahydrothieno [ 3,2-c] pyridine Acetate) < / RTI >

90.5 g of anhydrous sodium carbonate and 100 g of 4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (manufacturer: Zhejiang Liaoyuan Pharm Co.) were added to 600 ml of methanol. After stirring for a time, the mixture was cooled to 40 to 45 ° C. To this solution, 165 g of bromo (2-chlorophenyl) -acetic acid methyl ester (manufacturer: Jiacheng-Chem Enter. Ltd.) and 100 ml of methanol were added and stirred at 60 to 65 ° C for 24 hours. The reaction solution was cooled to 20 to 25 ° C, and 200 ml of dichloromethane was added thereto, followed by filtration and washing with 200 ml of dichloromethane.

300 ml of purified water was added to the filtered filtrate, and the pH of the solution was adjusted to 7.0 to 7.2 with acetic acid. The organic layer was separated and the aqueous layer was extracted once more with 200 ml of dichloromethane. The extracted two organic layers were combined and washed with purified water. The washed dichloromethane solution was distilled to obtain a racemic clopidogrel base (racemic methyl? - (2-chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine- Was obtained.

< Example  2> Clofidoreal Campa  Sulfonate ( methyl  (+) - (S) - &amp;alpha;-( 2- Chlorophenyl ) -4,5,6,7- rim Trihydrothieno [ 3,2-c] pyridine -5-acetate Campa Sulfonate  )

150 ml of dichloromethane and 132.2 g of (R) - (-) - 10-camphorsulfonic acid were added and dissolved in 183 g of the racemic clopidogrel base prepared in Example 1 at 20 to 25 ° C. 225 ml of ethyl acetate was added to the reaction solution, and the mixture was stirred at 20 to 25 ° C for 2 hours. The reaction solution was heated to 40 to 45 占 폚, stirred for 1 hour, cooled to 20 to 25 占 폚, and stirred for 3 hours. The resulting crystals were filtered, washed with 100 ml of acetone and dried to obtain 142 g of clopidogrel camphorsulfonate (yield: 45%). The filtrate thus obtained was used in Example 3.

specific OR: 25.5 ^o (c = 1.68, methanol, 25 ° C) ee> 99.5%

< Example  3> Clofidoreal Campa  Sulfonate ( methyl  (+) - (S) - &amp;alpha;-( 2- Chlorophenyl ) -4,5,6,7- Tetrahydrothieno [3,2-c] pyridine -5-acetate Campa Sulfonate  ) Produce

The filtrate filtered in Example 2 was distilled, 250 ml of dichloromethane was added and dissolved, and then an aqueous sodium hydroxide solution prepared by dissolving 13.4 g of sodium hydroxide in 220 ml of purified water was slowly injected to adjust the pH to 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 60 to 65 ° C for about 4 hours. The reaction solution was distilled to remove the solvent, 200 ml of dichloromethane and 200 ml of purified water were added at 20 to 25 ° C, and the pH was adjusted to 7.0 to 7.2 with acetic acid. 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-camphorsulfonic acid were dissolved in the concentrated residue at 20 to 25 ° C. To the reaction solution was added 124 ml of ethyl acetate and the mixture was stirred at 20 to 25 캜 for about 2 hours. The reaction solution was heated to 40 to 45 DEG C, stirred for about 1 hour, cooled to 20 to 25 DEG C, and stirred for about 3 hours. The resulting crystals were filtered, washed with acetone, and dried to obtain 70 g of clopidogrel camphorsulfonate (yield: 22% from the filtrate of Example 2).

Non-linearity value: 24.8 ^o (c = 1.68, methanol, 23 degrees)

< Example  4> Clopidogrel  Free base preparation

100 g of clopidogrel camphorsulfonate prepared in Example 2 was added to 400 ml of dichloromethane, and the mixture was stirred at 10 ° C or lower. An aqueous potassium carbonate solution obtained by dissolving 20 g of potassium carbonate in 300 ml of purified water was slowly added to the reaction solution while keeping the temperature at 10 ° C or lower, and then stirred for about 40 minutes. The organic layer was separated from the reaction solution and the separated organic layer was washed with 300 ml of purified water. To the washed organic layer was added anhydrous sodium sulfate and 0.5 g of activated carbon, stirred at 20 to 25 ° C, and then 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 to obtain 58 g of clopidogrel free base quantitatively pure.

< Example  5> Clopidogrel Hydrogen sulphate  Preparation of Crystalline Form (I) (Formula 1)

To 58 g of the clopidogrel free base obtained in Example 4 was added 1100 ml of 2-butanol and 5 ml of purified water, and the mixture was stirred at 15 to 20 ° C. 16.8 g of sulfuric acid was slowly added to the reaction solution at 20 to 25 ° C, stirred for 30 minutes, and 1 g of clopidogrel hydrogen sulfide crystal form (I) was added thereto, followed by stirring at 20 to 25 ° C for 12 hours. The resulting crystals were filtered, washed with acetone, and dried to obtain 40 g (yield: 53%) of clopidogrel hydrogen sulfide crystal form (I).

The X-ray diffraction analysis data and the IR data values of the crystalline form (I) obtained at this time are the same as in FIGS. 1 and 2.

specific OR: 56.3 ^o (c = 1.891, methanol, 24 degrees) ee> 99.9%

impurity A: 0.015%, impurity B: 0.03%, impurity C: 0.025%, dry calibration: 0.1%

Further, the obtained crystalline form (I) was enlarged by 50 times with an optical microscope (Axiovert 25 from Zeiss), and as a result, it was in the form of a round crystal having a uniform size (Fig. 3).

Clopidogrel hydrogen peroxide was prepared by varying the content of purified water under the same conditions as in Example 5 in order to confirm the change of clopidogrel hydrogen sulphate crystals according to the change of the content of the free base of clopidogrel (purified water).

[Table 1]

In the crystalline form (I) of the present invention, the amount of water used is preferably 4 to 14% by weight based on the weight of clopidogrel free base, and when the content of water is more than 14% ), Irregular flat plate-like crystal form I is produced. If it is less than 4%, there is irregular flat plate shape even if crystal form I, or crystallization is very slow and yield is very low.

Example 12 Preparation of Crystalline Form (I) of Clopidogrel Hexasulphite (Formula 1)

To 46 g of clopidogrel free base, 800 ml of 2-butanol and 5 ml of purified water were added and the mixture was stirred at 15 to 20 ° C. 14.1 g of sulfuric acid was slowly added to the reaction solution while maintaining the temperature at 20 to 25 캜, and the mixture was stirred at 20 to 25 캜 for 7 hours. The resulting crystals were filtered, washed with acetone, and dried to obtain 31.3 g (yield: 52%) of clopidogrel hydrogen sulfite crystal form (I).

Example 13 Preparation of Crystalline Form (I) of Clopidogrel Hydrogen Sulfate (Formula 1)

1000 ml of 2-butanol and 4.3 ml of purified water were added to 50 g of clopidogrel free base (source: Jiacheng-Chem Enterprises Limited) and the mixture was stirred at 15 to 20 캜. 15.2 g of sulfuric acid was slowly added to the reaction solution while stirring, and 0.9 g of clopidogrel hydrogen sulfide crystal form (I) was added thereto, followed by stirring at 20 to 25 ° C for 14 hours. The resulting crystals were filtered, washed with acetone, and dried to obtain 33.5 g (yield: 51.3%) of clopidogrel hydrogen sulfide crystal form (I).

< Comparative Example  2> Clopidogrel Hydrogen sulphate  Preparation of Crystalline Form (I) WO2005063708 of Example  12)

86.1 g of clopidogrel camphorsulfonate was added to 450 ml of dichloromethane, and an aqueous sodium bicarbonate solution (10%, 650 ml) was added at 25 to 30 ° C, followed by stirring for 10 minutes. The organic layer was separated from the reaction solution and the aqueous layer was extracted again with 90 ml of dichloromethane. Two organic layers were washed with 180 ml of purified water. The washed organic layer was dried over anhydrous sodium sulfate and distilled to obtain clopidogrel free base.

The clopidogrel free base was added with 250 ml of n-hexanol and 1 ml of water, and the mixture was stirred at 25 to 30 ° C. Concentrated sulfuric acid was added at 10 to 15 DEG C, and the crystalline (I) form was inoculated, followed by stirring at 20 to 25 DEG C for 10 hours. The mixture was rapidly stirred at 22 to 25 DEG C for about 2 hours, and then slowly stirred for about 6 hours. The reaction product was filtered, washed with 150 ml of methyl tert-butyl ester and dried to obtain 11 g (yield: 17%) of clopidogrel hydrogen sulfide crystal form (I). (For reference, the patent WO2005063708 states that the yield is 85.95% when manufactured by the above-mentioned method, but the yield was 17% as a result of direct examination)

Further, the obtained crystalline form (I) was enlarged 50 times by an optical microscope (Axiovert 25 from Zeiss) and was found to be a crystalline form of powder form (Fig. 9).

Claims (11)

(I) of clopidogrel hydrogen sulfate by reacting clopidogrel free base with concentrated sulfuric acid in a mixed solvent of 2-butanol and water having a weight of 4-14% by weight based on the weight of clopidogrel free base. The process according to claim 1, wherein the amount of water used is from 5 to 14% by weight, based on the weight of clopidogrel free base, of crystalline form (I) of clopidogrel hydrogen sulphate. 3. The process according to claim 2, wherein the amount of water used is from 7.5 to 11% by weight, based on the weight of clopidogrel free base, of crystalline form (I) of clopidogrel hydrogen sulphate. 4. The process according to claim 3, wherein the amount of water used is 8.6% by weight based on the weight of clopidogrel free base. The process according to claim 1, further comprising seeding a crystalline form (I) of clopidogrel hydrogen sulphate. The process for producing clopidogrel hydrogen sulphate according to claim 1, wherein the reaction temperature and the crystallization temperature are 15 to 25 占 폚. The process according to claim 1, wherein the weight ratio of clopidogrel free base and mixed solvent is 1: 14 to 25. The process for preparing clopidogrel hydrogen sulphate according to claim 1, wherein the reaction time is 5 to 15 hours. 9. The process according to any one of claims 1 to 8, wherein the clopidogrel free base is prepared by the reaction of clopidogrel camphorsulfonate and potassium carbonate in dichloromethane solvent. 10. The method according to claim 9, wherein the clopidogrel camphorsulfonate is obtained by dissolving the racemic clopidogrel base and (R) - (-) - 10-camphorsulfonic acid in a solvent selected from dichloromethane, dichloroethane and chloroform, (I) of the present invention is prepared by adding an antisolvent selected from the group consisting of C1-C5 alkyl acetates. 11. The process according to claim 10, wherein the antisolvent is ethyl acetate.

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