KR20110080931A - Method for manufacturing crystalline form (i) of clopidogrel hydrogen sulphate - Google Patents

Abstract

PURPOSE: A method for preparing a crystalline form of clopidogrel hydrogen sulphate(I) is provided to prepare a crystal with excellent fluidity and to minimize cracking. CONSTITUTION: A method for preparing a crystalline form of clopidogrel hydrogen sulphate comprises: a step of reacting clopidogrel free base with dark sulfuric acid under the presence of mixture solvent of 2-butanol and water. The use of waer is 5-14 weight% based on a weight of clopidogrel free base. The method additionally comprises a step of seeding the crystalline form(I) of clopidogrel hydrogen sulphate.

Description

Method for manufacturing crystalline form (I) of Clopidogrel hydrogen sulphate}

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

(+)-(S) -α- (2-chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl-5-methyl acetate of Formula 1 Hydrogen sulfate is a drug that has a platelet aggregation inhibitory effect and an antithrombotic effect. Commercially available as PLAVIX ^® tablets.

[Formula 1]

US Patent No. 4529596 describes a racemic compound of Formula 1 and European Patent No. 0281459 describes a technique for separating the optically active agent of a tetrahydro thienopyridine derivative, and the clopidogrel hydrogen sulfate of Formula 1 is disclosed. It is. This European patent discloses racemic clopidogrel with (R)-(-)-10-campa sulfonic acid to form a salt, followed by reflux stirring and recrystallization in acetone to obtain a product having the desired non-photoluminescence value, thereby giving preference to the preferred isomers. It is described that after the formation of precipitate by the formula (1) using concentrated sulfuric acid in acetone solvent.

In addition, European Patent No. 1087976 describes the crystalline forms (I) and (II) of the general formula (1). Preparation by the synthesis method of EP 0281459 specifies that only Clopidogrel Hydrogen Sulfate Crystalline Form (I) can be synthesized, Form (II) has high thermodynamic stability, and Crystal of Form (I) is irregular plate and Form (II) It is described that the crystals are in the form of agglomerates and have lower static electricity than crystalline form (I).

International patent application WO03051362 describes a process for the preparation of novel crystalline forms (III), (IV), (V) and (VI) and amorphous forms of clopidogrel hydrogen sulfate, in particular crystalline form (I) is methyl t-butyl methyl ether or A process for preparing under diethyl ether is disclosed.

International patent application WO2004020443 discloses a crystalline form by reacting clopidogrel and sulfuric acid in the form of a free base or salt in a solvent selected from a series of primary, secondary or tertiary C1 to C5 alcohols or their esters or any mixtures thereof with C1 to C4 carboxylic acids. (I) A method for preparation is disclosed. In particular, precipitation is carried out in a 2-propanol solution at a temperature of −5 to 15 ° C. at low temperature.

International patent application WO2005063708 discloses C6-C12 alcohols such as hexanol, 2-hexanol, 3-hexanol, isohexanol, heptanol, 2-heptanol, 3-heptanol, 4-heptanol, The separation of crystals of crystalline Form (I) by treatment with concentrated sulfuric acid in a mixture of octanol, isooctanol, decanol or mixtures thereof) and water.

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

In addition, the above methods have the problem of having an electrostatic problem due to irregular flat plates or crystal shapes not specified in EP 1087976.

However, none of the methods for preparing crystalline Form (I) disclosed until now has been prepared using a C1-C4 low-carbon carbon alcohol and water mixed solvent to form crystalline Form (I) having a circular crystal shape and excellent fluidity.

Accordingly, the present inventors are to provide a clopidogrel hydrogen sulfate crystalline form (I) having a more easy manufacturing method and high purity and excellent physical properties.

The present invention provides a method for preparing crystalline Form (I) of clopidogrel hydrogen sulfate by reacting clopidogrel free base with concentrated sulfuric acid under 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 preparation method of 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, even more preferably 7.5 to 11% by weight, based on the weight of clopidogrel free base. , 8.6% is most preferred. If the water content exceeds 14%, it is not a crystalline form (I), or even if the crystalline form (I), irregular plate-like crystalline form (I) is produced.If the content is less than 4%, even a crystalline form (I) is an irregular plate-shaped or crystallized. There is a problem that the production is very low yield very low.

In the method for preparing Form (I) of the present invention, seeding of Form (I) of Clopidogrel Hydrogen Sulfate may promote the formation of Form (I).

In the method for producing crystalline form (I) of the present invention, the reaction temperature and the crystal temperature are preferably 15 to 25 ° C. That is, the manufacturing method of the crystalline form (I) of the present invention has the advantage that the crystal temperature does not need to be lowered separately to produce crystals.

In the method for preparing Form (I) of the present invention, it is preferable that the weight ratio of clopidogrel free base and mixed solvent is 1:14 to 25.

In the method for preparing Form (I) of the present invention, the reaction time is preferably 5 to 15 hours.

In the method for preparing 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 the pharmaceutically acceptable salt of clopidogrel, clopidogrel Free base may be unisolated. In addition, the starting material clopidogrel free base may be prepared by a known method, for example, may be prepared by the reaction of clopidogrel camphor sulfonate and potassium carbonate in a dichloromethane solvent.

Here, the clopidogrel camphor sulfonate for preparing the clopidogrel free base, which is a starting material of the present invention, may be prepared by a known method (for example, European Patent No. 0281459), by the following method provided by the present invention. It may be manufactured.

Accordingly, the present invention is to prepare a clopidogrel camphor sulfonate for preparing clopidogrel free base, which is the starting material of the preparation method of crystalline form (I) of the present invention, racemic clopidogrel base and (R)-(-)-10-campa sulfonic acid are dichloromethane. It is prepared by dissolving in a solvent selected from dichloroethane and chloroform, and then adding and reacting an antisolvent selected from primary, secondary and tertiary C1-C5 alkyl acetates. Here, the antisolvent is preferably ethyl acetate. Clopidogrel camphor sulfonate of the present invention as described above has the advantage of providing a high yield and high purity compared to the known method (European Patent No. 0281459) (45% yield, e.e.> 99.5%).

The preparation method of the present invention is an improved preparation method of crystalline Form (I) of clopidogrel hydrogen sulfate, which has a high optical purity even at room temperature, not at low temperature, and has a round crystal (FIG. 3), which allows the preparation of Form (I) having excellent fluidity. There is an advantage. Therefore, the crystalline form (I) prepared by the present invention does not need a pulverization process during tablet tableting, and has an advantage of minimizing cracking or sticking by filling evenly with good fluidity.

1 is X-ray diffraction analysis data of crystalline Form (I) of clopidogrel hydrogen sulfate prepared in Example 5. FIG.
Fig. 2 is a spectrum of FTIR of crystalline Form (I) of clopidogrel hydrogen sulfate prepared in Example 5.
FIG. 3 is a 50 times magnified photograph seen by an optical microscope of crystalline Form (I) of clopidogrel hydrogen sulfate prepared in Example 5. FIG.
FIG. 4 is a 50 times magnified photograph seen by an optical microscope of crystalline Form (I) of Clopidogrel hydrogen sulfate of Comparative Example 1. FIG.
Fig. 5 is a magnified photograph 50 times as seen by an optical microscope of crystalline Form (I) of clopidogrel hydrogen sulfate in Example 6.
FIG. 6 is a 50 times magnified photograph seen by an optical microscope of Form (I) of Clopidogrel hydrogen sulfate of Example 7. FIG.
FIG. 7 is a 50-fold enlarged photograph seen by an optical microscope of crystalline Form (I) of clopidogrel hydrogen sulfate in Example 10; FIG.
FIG. 8 is a 50-fold enlarged photograph seen by an optical microscope of a crystalline form (I), (II) mixture of clopidogrel hydrogen sulfate of Example 11.
9 is a 50 times magnified photograph seen by an optical microscope of crystalline Form (I) of clopidogrel hydrogen sulfate of Comparative Example 2. FIG.

Hereinafter, the present invention will be described in detail with reference to the following examples, but the following examples are only intended to illustrate the present invention and do not limit the scope of the present invention.

X-ray diffraction analysis data, IR data, and purity of Clopidogrel Hydrogen Sulfate Crystalline Form (I) prepared in the following Examples are powder X-ray diffractometer (PXRD, (D8 focus (2.2kw) of Bucker AXS (germany)) And Fourier Transform Infrared Spectroscopy (FTIR, Nicolet 6700 from Thermo Scientific) and HPLC (1200 series from Agilent Technologies, Ultron ES-OVM, 15 cm, 4.6 mm ID, column size particle size 5 μm).

≪ Example 1 > Racemic clopidogrel (racemic methyl α- (2-chlorophenyl) -4,5,6,7-tetrahydrothieno [ 3,2-c] pyridine -5-acetate) free base preparation

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.) were added to 600 ml of methanol. After stirring for an hour, the mixture was cooled to 40 to 45 ° C. 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 20-25 ° C., 200 ml of dichloromethane was added, filtered, and washed with 200 ml of dichloromethane.

300 ml of purified water was added to the filtered reaction filtrate, the pH of the solution was corrected to 7.0-7.2 with acetic acid, the organic layer was separated, and the water layer was extracted with 200 ml of dichloromethane. The two extracted organic layers were combined and washed with purified water. Distilled washed dichloromethane solution to racemic clopidogrel base (racemic methyl α- (2-chlorophenyl) -4,5,6,7-tetrahydrothieno [3,2-c] pyridine-5-acetate) 183 g was obtained.

< Example  2> Clopidora Kampa  Sulfonates ( methyl  (+)-(S) -α- (2- Chlorophenyl ) -4,5,6,7- rim Trahydrothieno [ 3,2-c] pyridine -5-acetate Kampa Sulfonate  Manufacturing

To 183 g of racemic clopidogrel base prepared in Example 1, 150 ml of dichloromethane and 132.2 g of (R)-(-)-10-campa sulfonic acid were dissolved 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 40-45 ° C., stirred for 1 hour, cooled to 20-25 ° C., and stirred for 3 hours. The resulting crystals were filtered, washed with 100 ml of acetone and dried to give 142 g of clopidogrel camphor sulfonate (yield: 45%). The filtrate obtained at this time was used in Example 3.

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

< Example  3> Clopidora Kampa  Sulfonates ( methyl  (+)-(S) -α- (2- Chlorophenyl ) -4,5,6,7- Tetrahydrothieno [3,2-c] pyridine -5-acetate Kampa Sulfonate  ) Produce

The filtrate filtered in Example 2 was distilled, dissolved in 250 ml of dichloromethane, and then slowly injected with an aqueous sodium hydroxide solution prepared by dissolving 13.4 g of sodium hydroxide in 220 ml of purified water, followed by correction to pH 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, 400 ml of methanol and 7.7 g of sodium methoxide were added thereto, and the mixture was stirred at 60 to 65 ° C. for about 4 hours. The reaction solution was distilled off 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 off to remove the solvent, and dissolved in a concentrated residue with 82 ml of dichloromethane and 72.7 g of (R)-(-)-10-campa sulfonic acid at 20 to 25 ° C. 124 ml of ethyl acetate was added to the reaction solution, and the mixture was stirred at 20 to 25 ° C. for about 2 hours. The reaction solution was heated to 40-45 ° C., stirred for about 1 hour, cooled to 20-25 ° C., and stirred for 3 hours. The resulting crystals were filtered, washed with acetone and dried to give 70 g of clopidogrel camphor sulfonate (yield: 22% from the filtrate of Example 2).

Specific luminance value: 24.8 ^o (c = 1.68, methanol, 23 degrees)

< Example  4> Clopidogrel  Free base manufacturing

100 g of clopidogrel camphor sulfonate prepared in Example 2 was added to 400 ml of dichloromethane, and the mixture was stirred at 10 ° C. or less. Potassium carbonate aqueous solution prepared by dissolving 20 g of potassium carbonate in 300 ml of purified water was slowly injected while maintaining the temperature below 10 ° C., and then stirred for about 40 minutes. The organic layer was separated from the reaction solution and the organic layer separated with 300 ml of purified water was washed. Anhydrous sodium sulfate and activated carbon 0.5g were added to the washed organic layer, stirred at 20-25 ° C., filtered, and washed with 25 ml of dichloromethane. The filtered filtrate was distilled, 50 ml of 2-butanol was added thereto, and further distilled to remove the solvent, thereby obtaining 58 g of pure clopidogrel free base.

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

To 58 g of clopidogrel free base obtained in Example 4, 1100 ml of 2-butanol and 5 ml of purified water were added and stirred at 15 to 20 ° C. 16.8 g of sulfuric acid was slowly added to the reaction solution while stirring and stirred for about 30 minutes, and then 1 g of clopidogrel hydrogen sulfate crystalline form (I) was added, 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 sulfate crystalline form (I).

X-ray diffraction analysis data and IR data values of Crystal Form (I) thus obtained are shown 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 inspection weight: 0.1%

In addition, the obtained crystalline Form (I) was magnified 50 times with an optical microscope (Axiovert 25 manufactured by Zeiss). As a result, it was a round crystal of uniform size.

Clopidogrel hydrogen sulfate was prepared by variously changing the content of purified water under the same conditions as in Example 5 to confirm the change of clopidogrel hydrogen sulfate crystals according to the change in the content of reference water (purified water) based on the weight of clopidogrel free base.

TABLE 1

In the preparation method of Form (I) of the present invention, it is preferable that the amount of water used is 4 to 14% by weight based on the weight of clopidogrel free base, and if the content of water exceeds 14%, it is not Form (I) or Form (I). Irregular plate-like crystalline form (I) is prepared even if less than 4%, even if the crystalline form (I) is irregular plate-shaped, or the crystallization is very slow, there is a problem that the yield is very low.

Example 12 Preparation of Form (I) of Clopidogrel Hydrogen Sulfate (Formula 1)

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

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

1000 g 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 stirred at 15 to 20 ° C. 15.2 g of sulfuric acid was slowly added to the reaction solution while stirring and stirred for about 30 minutes, and 0.9 g of clopidogrel hydrogen sulfate 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 sulfate crystalline form (I).

< Comparative example  2> Clopidogrel Hydrogen sulfate  Form (I) Preparation WO2005063708 of Example  12)

86.1 g of clopidogrel camphor sulfonate 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 separated with 180 ml of purified water were washed. The washed organic layer was dried over anhydrous sodium sulfate and distilled to obtain a clopidogrel free base.

250 ml of n-hexanol and 1 ml of water were added to the clopidogrel free base, and the mixture was stirred at 25 to 30 ° C. Concentrated sulfuric acid was added at 10 to 15 ° C, and inoculated with crystalline form (I), followed by stirring at 20 to 25 ° C for 10 hours. Stirred rapidly at 22-25 ° C. for 2 hours and slowly for 6 hours. The reaction was filtered, washed with 150 ml of methyl tert-butyl ester and dried to give 11 g (yield: 17%) of Clopidogrel Hydrogen Sulfate Crystalline Form (I). {Reference, WO2005063708, when manufactured in the same manner as described above, yields of 85.95%, but the results of direct experiments yielded 17%}

In addition, the obtained crystalline Form (I) was magnified 50 times with an optical microscope (Axiovert 25 manufactured by Zeiss), and found to be a powdered crystalline form (FIG. 9).

Claims (11)

A method for preparing crystalline form (I) of clopidogrel hydrogen sulfate by reacting clopidogrel free base with concentrated sulfuric acid in a mixed solvent of water having 4 to 14% by weight based on the weight of 2-butanol and clopidogrel free base. The method for preparing crystalline form (I) of clopidogrel hydrogen sulfate according to claim 1, wherein the amount of water used is 5 to 14% by weight based on the weight of clopidogrel free base. The method for preparing crystalline Form (I) of clopidogrel hydrogen sulfate according to claim 2, wherein the amount of water used is 7.5 to 11% by weight based on the weight of clopidogrel free base. The method for preparing crystalline Form (I) of clopidogrel hydrogen sulfate according to claim 3, wherein the amount of water used is 8.6% by weight based on the weight of clopidogrel free base. The method for preparing crystalline form (I) of clopidogrel hydrogen sulfate according to claim 1, further comprising seeding crystalline form (I) of clopidogrel hydrogen sulfate. The method for preparing crystalline form (I) of clopidogrel hydrogen sulfate according to claim 1, wherein the reaction temperature and the crystal temperature are 15 to 25 ° C. The method for preparing crystalline form (I) of clopidogrel hydrogen sulfate according to claim 1, wherein the weight ratio of clopidogrel free base and mixed solvent is 1:14 to 25. The method for preparing crystalline form (I) of clopidogrel hydrogen sulfate according to claim 1, wherein the reaction time is 5 to 15 hours. The method for preparing crystalline form (I) of clopidogrel hydrogen sulfate according to any one of claims 1 to 8, wherein the clopidogrel free base is prepared by the reaction of clopidogrel camphor sulfonate and potassium carbonate in a dichloromethane solvent. 10. The method according to claim 9, wherein the clopidogrel camphor sulfonate is dissolved in racemic clopidogrel base and (R)-(-)-10-campa sulfonic acid in a solvent selected from dichloromethane, dichloroethane, chloroform, followed by primary, secondary, 3 A process for preparing crystalline form (I) of clopidogrel hydrogen sulfate, which is prepared by addition and reaction of a selected antisolvent in C1-C5 alkyl acetate of tea. The method for preparing crystalline form (I) of clopidogrel hydrogen sulfate according to claim 10, wherein the antisolvent is ethyl acetate.

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