JP2013241381A - Method for producing clopidogrel sulfate crystal - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrial method for producing crystal polymorphism type I (hereinafter, referred also to as "form I crystal") of clopidogrel sulfate.SOLUTION: There is provided a method for producing a form I crystal in a short time in high crystallization rate and reproducibility by converting free clopidogrel to a sulfate in a solution containing dissolved clopidogrel and, at the same time, adding a specific amount of powdery crystal seed of the form I crystal of clopidogrel sulfate having controlled particle size into the solution containing the converted clopidogrel sulfate. Specifically, the method for producing the form I crystal of clopidogrel sulfate is characterized by addition of concentrated sulfuric acid to 2-butanol solution containing free clopidogrel to convert the free clopidogrel to clopidogrel sulfate in the solution, and addition of a controlled amount of the powdery crystal seed of the form I crystal of clopidogrel sulfate having a controlled particle size to crystallize the sulfate.

Description

  The present invention relates to a method for producing crystals of clopidogrel sulfate, in particular polymorphic Form I (form I crystals).

  Formula (I):

(S)-(+)-(2-chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-ylacetic acid methyl ester sulfate represented by Hereinafter, it may be described as “clopidogrel sulfate”.) Is a platelet aggregation inhibitor clinically used as a therapeutic agent for the prevention of recurrence after ischemic cerebrovascular disorder or ischemic heart disease. is there.

There have been various patent documents relating to clopidogrel sulfate, and Patent Document 1 describes a racemic clopidogrel which is a free base and a pharmaceutically acceptable salt thereof. Patent Document 2 describes dextrorotatory (d-form) clopidogrel and pharmacologically acceptable salts thereof, but does not describe any crystal forms thereof.
Subsequent research has revealed that clopidogrel sulfate has been used clinically, and it has been found that there are several types of crystal polymorphs and pseudopolymorphs such as solvates (patents) References 3, 4).

Regarding the polymorph of clopidogrel sulfate, there are many patent documents (for example, Patent Documents 5 to 7) regarding the production of crystal polymorph Form I (Form I crystal). A method that can be manufactured automatically has not been established. On the other hand, crystalline polymorph II (form II crystal) can be obtained easily and with good reproducibility.
This is difficult to obtain because Form I crystals are thermodynamically unstable compared to Form II crystals. Moreover, even if Form I crystals are obtained, the reproducibility is poor, and these reasons make industrial and stable production difficult.

Japanese Patent Publication No. 64-955 Japanese Examined Patent Publication No. 6-45622 Japanese Patent No. 3641584 JP 2005-514387 A JP-T-2006-502238 Special table 2007-516167 gazette Special table 2007-516934 gazette

Therefore, in view of the above-mentioned present situation, the present invention is to provide an industrial production method for polymorphic form I of clopidogrel sulfate (hereinafter sometimes referred to as “form I crystal”). And
In order to solve such a problem, the present inventors have intensively studied, and as a result, converted to sulfate in a solution in which free clopidogrel was dissolved, and adjusted the particle size in the solution containing the converted clopidogrel sulfate. It was found that by adding a specific amount of clopidogrel sulfate Form I crystal seeds, Form I crystals can be obtained in a short time and with a high crystallization rate with good reproducibility, and the present invention has been completed. It was.

Therefore, the present invention has, as its basic aspect,
(1) Add concentrated sulfuric acid to 2-butanol solution containing clopidogrel free form, convert to clopidogrel sulfate in the solution, then control the powder crystal seeds of form I crystals of clopidogrel sulfate adjusted in particle size And crystallization of the clopidogrel sulfate form I crystal, characterized in that crystallization is carried out by adding the above-mentioned amount.

More specifically, the present invention includes the following aspects.
(2) The powder crystal seed of the form I crystal of clopidogrel sulfate to be added has an average particle diameter of 80 μm to 300 μm, and the powder crystal seed is added from 10 to 25 w / w% as described in (1) above A process for preparing Form I crystals of clopidogrel sulfate
(3) In the above (1), the powder crystal seed of the form I crystal of clopidogrel sulfate to be added has an average particle diameter of 15 μm to 40 μm, and the powder crystal seed is added in an amount of 1 to 25 w / w%. A process for producing Form I crystals of the described clopidogrel sulfate;
(4) The powder crystal seed of the form I crystal of clopidogrel sulfate to be added has an average particle diameter of 1 μm to 10 μm, and the powder crystal seed is added by 0.1 to 5 w / w% of the above (1 ) Method for producing Form I crystals of clopidogrel sulfate according to claim 1;
(5) The clopidogrel sulfate form I crystal according to any one of (1) to (4) above, wherein the crystal seed of the clopidogrel sulfate form I crystal to be added is a pulverized crystal obtained by mechanical pulverization. Production method;
(6) The clopidogrel sulfate Form I crystal obtained by crystallization is solid-liquid separated, dried, and dried again after pulverization to obtain a stable clopidogrel sulfate Form I crystal (1 ) To (5), a method for producing Form I crystals of clopidogrel sulfate according to any one of the above;
(7) The method for producing Form I crystals of clopidogrel sulfate according to (1) above, wherein the clopidogrel free form is a clopidogrel free form obtained by treating clopidogrel (-) camphorsulfonate with an alkali;
It is.

According to the present invention, it has become possible to stably produce clopidogrel sulfate Form I crystals, which have heretofore been difficult to produce industrially, in a high yield.
Usually, a seed crystal is used for crystallization, but there are few examples of adjusting the particle size of the seed crystal used there. In the production of clopidogrel sulfate this time, clopidogrel is not inoculated with 0.5 w / w% as a general seed crystal amount of seed crystals having an average particle diameter of 80 μm to 300 μm without adjusting the particle size. The rate of crystallization of sulfate Form I crystals is extremely slow, it takes about 5 to 6 hours from seed inoculation to the start of crystallization, and the crystallization time also takes 13 to 16 hours in total. This was extremely disadvantageous as an industrial production method. Further, Form I crystals of the obtained clopidogrel sulfate may be mixed with Form II crystals, and could not be produced with good reproducibility.
On the other hand, as a seed crystal, the crystallization time can be greatly shortened by the method of the present invention in which a controlled amount of a powder crystal seed of form I crystal of clopidogrel sulfate adjusted in particle size can be greatly reduced. It became possible to stably obtain the target form I crystal of clopidogrel sulfate with a crystallization rate.

  In particular, by using a small amount of powder crystal seeds of fine form I crystals, clopidogrel sulfate form I crystals can be obtained industrially stably, and the amount of seed crystals can be reduced. The method of the present invention is very specific.

  As described above, the basic aspect of the present invention is that clopidogrel sulfate is prepared by adding concentrated sulfuric acid to a 2-butanol solution containing a free form of clopidogrel, converting it into clopidogrel sulfate in the solution, and then adjusting the particle size. A method for producing Form I crystals of clopidogrel sulfate, characterized in that crystallization is performed by adding a controlled amount of a powder crystal seed of a salt Form I crystal.

  The educt of clopidogrel can be prepared according to the method described in Patent Document 1 or Patent Document 2, for example, according to the following chemical reaction formula.

  That is, in accordance with the above chemical reaction formula, α-chloro- (2-chlorophenyl) acetic acid methyl ester (2) is obtained from α-bromo- (2-chlorophenyl) acetic acid (1), for example, by reaction with thionyl chloride in methanol. Then, the obtained compound of the formula (2) and 4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (3) are combined with potassium carbonate / tetra-n-butyl. Condensation in the presence of ammonium iodide (TBAI) and (±) -2- (2-chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-yl ) Acetic acid methyl ester (4) is obtained.

  Then, this compound (4) is abbreviated as (R)-(−)-10-camphorsulfonic acid [hereinafter referred to as (−)-CSA. To form the corresponding (+)-(S)-(2-chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-yl acetate methyl Derived to a crude crystal of ester • (−)-CSA salt, ie, clopidogrel • (−)-CSA salt [(5) -1].

  At this stage, the obtained crude crystals of clopidogrel • (−)-CSA salt [(5) -1] were recrystallized with a mixed solution of methanol / isopropyl acetate, and purified clopidogrel • (−)-CSA salt [(5) -2] and the purified clopidogrel • (−)-CSA salt [(5) -2] can be treated with alkali to obtain the desired free clopidogrel (6) (details are described below) See example).

  In the present invention, in particular, clopidogrel · (−)-CSA salt (5) is treated with an alkali to dissolve free clopidogrel (6) in a 2-butanol solution, and concentrated sulfuric acid is added to the solution. And then converting to clopidogrel sulfate, followed by crystallization by adding a controlled amount of powdered crystal seeds of form I crystals of clopidogrel sulfate adjusted in particle size.

  Hereinafter, conversion from clopidogrel · (−)-CSA salt [(5) -2] to free clopidogrel (6) by alkali treatment in the above chemical reaction formula, which is a basic production method of the present invention, and further release The production of clopidogrel sulfate Form I crystal (I) from clopidogrel (6) is described in detail.

  The purified clopidogrel • (−)-CSA salt [(5) -2] produced according to the known production method described above (see the production example described later) is suspended in a suitable organic solvent, preferably ethyl acetate. After adding an aqueous alkali solution, preferably an aqueous potassium carbonate solution and stirring to confirm the dissolution of crystals, the aqueous layer is removed, the organic layer is washed with water, dried over anhydrous magnesium sulfate, and the desiccant is filtered off. 2-Butanol is added to the mixture, and the solvent is distilled off under reduced pressure to distill off ethyl acetate.

  At this stage, free clopidogrel (6) is present dissolved in the 2-butanol solution. An amount of concentrated sulfuric acid corresponding to the free clopidogrel (6) is added to the 2-butanol solution of the clopidogrel free form at a temperature of 20 to 40 ° C., preferably 25 to 30 ° C., to obtain a uniform solution. By adding powder crystals of clopidogrel sulfate form I crystals with adjusted particle size as seed crystals, stirring the solution at the same temperature, and cooling the solution as necessary, the desired clopidogrel sulfate form I crystals were obtained. Precipitate.

  The production method of the present invention is characterized in that, for the clopidogrel sulfate Form I crystal added as a seed crystal, a powder crystal whose particle size is adjusted is used, and the addition amount of the crystal seed is adjusted according to the particle size. .

Adjustment of the particle size of the Form I crystal of clopidogrel sulfate added as a seed crystal was adjusted by the average particle diameter (median diameter), and it was found that the amount of seed crystal added varies depending on the size of the particle size.
For example, when the powder crystal seed of the form I crystal of clopidogrel sulfate to be added has an average particle diameter of 80 μm to 300 μm, it is preferable to add 10 to 25 w / w% of the crystal seed, and the average particle diameter is In the case of 15 μm to 40 μm, it is preferable to add 1 to 25 w / w% of the powder crystal seed. Further, in the case where the average particle diameter is 1 μm to 10 μm, the powder crystal seed is 0.1 to 10 μm. It has been found that it is good to add 5 w / w%.
That is, it was found that the amount of clopidogrel sulfate Form I crystals added as crystal seeds can be reduced as the particle diameter becomes finer.

It has been found that the amount of seed crystals added depending on the degree of the particle size also affects the crystallization time of clopidogrel sulfate Form I crystals and the crystallization rate based thereon.
For example, when the powder crystal seed of the clopidogrel sulfate form I crystal to be added has an average particle diameter of 80 μm to 300 μm, the target clopidogrel sulfate form I crystal is about 6 hours. Can be obtained stably.

  Further, when the powder crystal seed of the clopidogrel sulfate form I crystal to be added has an average particle diameter of 15 μm to 40 μm, the target clopidogrel sulfate form I crystal is about 5 hours. Can be obtained stably.

  Further, when the powder crystal seed of the clopidogrel sulfate Form I crystal to be added has an average particle diameter of 1 μm to 10 μm, the target clopidogrel sulfate Form I can be obtained in about 2 to 5 hours as a crystal crystallization time. Crystals can be obtained stably.

In order to obtain a powder crystal of Form I crystal of clopidogrel sulfate as a seed crystal to be added, it is preferable to use a powder crystal obtained by mechanical pulverization. Such mechanical pulverization can be performed by, for example, jet mill pulverization, bandham mill pulverization, or the like.
Even in the case of powder crystals obtained by this mechanical pulverization, the particle size of the powder crystals obtained by the pulverization means is different, which affects the precipitation rate, crystallization rate, etc. of the target clopidogrel sulfate form I crystal. As a result of the study by the present inventors, as an industrially most excellent method, 1 to 25 w / w% of a crystal seed having an average particle diameter of 15 μm to 40 μm obtained by pulverizing a bandam mill is added for about 5 hours. In this crystallization time, the crystallization rate is preferably about 50 to 90%.

  The present invention is characterized in that the particle size and amount of crystal seeds to be added are appropriately controlled. In the production of the desired clopidogrel sulfate Form I crystal, these elements are appropriately combined. Industrial production conditions can be optimized.

  In the crystallization of the conventional crystal, a crystallization time of 13 to 16 hours is required, and considering that Form I crystal and Form II crystal are mixed, the manufacturing method of the present invention shortens time and manufactures. As a result, it is proved that it is exceptionally excellent.

  Hereinafter, the present invention will be described in more detail with reference to specific examples. However, the present invention is not limited to these examples, and needless to say, modifications can be made as appropriate.

Production example: (+)-(S) -2- (2-chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-yl) acetic acid methyl ester (- ) -Camphorsulfonate [clopidogrel (-)-CSA salt (5)]

(1) Synthesis of α -chloro- (2-chlorophenyl) acetic acid methyl ester (2 ) 2.0 kg of α-bromo- (2-chlorophenyl) acetic acid (1) was dissolved in 6.0 L of methanol, and thionyl chloride 1 was dissolved at room temperature. .2 L was added and reacted at 65 ° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, toluene (8.0 L) was added, and the pH was adjusted to 7 with 2N aqueous sodium hydroxide solution. The aqueous layer was separated, and the toluene layer was washed with purified water (4.0 L) to obtain a toluene solution of the title compound.

(2) Synthesis of (±) -2- (2-chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-yl) acetic acid methyl ester (4) To a toluene solution of α-chloro-2- (2-chlorophenyl) acetic acid methyl ester (2) obtained in (1), 4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride (3 1.4 kg of tetra-n-butylammonium iodide (TBAI) and an aqueous potassium carbonate solution were added and reacted at 85 ° C. for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, methanol (2.0 L) was added and stirred, and then the aqueous layer was separated. The obtained organic layer was adjusted to pH 3 with 1N hydrochloric acid, and the aqueous layer was separated. Subsequently, the organic layer was washed with an aqueous sodium carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate to obtain a toluene solution of the title compound (4).

(3) (+)-(S) -2- (2-Chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-yl) acetic acid methyl ester (- ) -CSA salt (5) synthesis (±) -2- (2-chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c] pyridine- obtained in (2) above To a toluene solution of 5-yl) acetic acid methyl ester (4), toluene (2.9 L), acetone (2.0 L) and (R)-(−)-10-camphorsulfonic acid [(−)-CSA] 1 .2 kg was added. The seed crystals were inoculated, and the obtained crystals were filtered off and dried to obtain 1.6 kg of the title compound crude crystals [(5) -1] as a known crystal form.
The total yield was 36.6% in the three steps (1) to (3).

(4) (+)-(S) -2- (2-Chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-yl) acetic acid methyl ester (- ) -CSA Salt (5) Recrystallization The crude crystal [(5) -1] obtained in (3) above was suspended in isopropyl acetate (4.9 L) and methanol (2.1 L) at 45 ° C. Dissolved.
After adding 11.4 L of isopropyl acetate to the obtained solution and stirring for 2 hours, the reaction mixture was cooled to 0 ° C. The produced crystals are filtered off and dried to obtain (+)-(S) -2- (2-chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c] pyridine. -5-yl) acetic acid methyl ester (-)-CSA salt, ie, clopidogrel (-)-CSA salt [(5) -2] (1.2 kg) was obtained.
The recrystallization yield was 76.1%.

Hereinafter, specific production of Form I crystals of clopidogrel sulfate from the clopidogrel (−)-CSA salt [(5) -2] obtained above will be described in detail in Comparative Examples and Examples.
In addition, the particle size distribution measurement by the following Examples and the measurement conditions of XRD (X-ray diffraction) are as follows.

Particle size distribution measurement conditions:
Equipment used: Microtrac MT3000 II (manufactured by Nikkiso Co., Ltd.)
Measurement method: Laser diffraction scattering method Solvent: Diisopropyl ether

Measurement conditions of XRD (X-ray diffraction, X-ray Diffraction) Equipment used: Ultima IV (manufactured by Rigaku Corporation)
X-ray light source: Cu
Monochromator tube voltage: 40kV
Tube current: 30 mA
Divergent slit: 1/2 deg
Scattering slit: 1/2 deg
Receiving slit: 0.15mm
Scanning range: 2-40 °
Scanning axis: 2θ / θ
Step width: 0.02 °
Scanning speed: 2 ° / min

Comparative Example: Production of Form I Crystal of Clopidogrel Sulfate by Difference in Addition of Seed Crystal 90.0 g (0.16 mol) of Clopidogrel (-)-CSA Salt [(5) -2] Obtained in the Production Example Was suspended in 360 mL of ethyl acetate, and an aqueous potassium carbonate solution was added thereto and stirred. After confirming the dissolution of crystals, the aqueous layer was discarded. The obtained organic layer was washed with purified water (180 mL) and dried over anhydrous magnesium sulfate. After filtering off the desiccant, 2-butanol was added and distilled off under reduced pressure to remove ethyl acetate.
Concentrated sulfuric acid 16.1g (0.16mol) was dripped at 25-30 degreeC to the 2-butanol solution of the obtained clopidogrel free body. To the obtained uniform solution, 0.05 g of clopidogrel sulfate Form I crystals (0.5 w / w% of free form, average particle size of 100 to 200 μm) as seed crystals was added, and 6.25 to 30 ° C. After stirring for 5 hours, the product was collected by filtration. The obtained crystals were dried at 30 ° C. under reduced pressure to obtain 44.8 g (yield: 65.7%) of clopidogrel sulfate.
The obtained clopidogrel sulfate was found to be a mixture of Form I crystals and Form II crystals by XRD.

Example 1 Production of Form I Crystals of Clopidogrel Sulfate (Part 1)
1037.1 g (1.87 mol) of clopidogrel (−)-CSA salt [(5) -2] obtained in the above production example was suspended in 4.2 L of ethyl acetate, and an aqueous potassium carbonate solution (potassium carbonate 258) was suspended therein. 0.7 g was obtained by dissolving in 5.2 L of purified water) and stirred. After confirming the dissolution of crystals, the aqueous layer was discarded. The obtained organic layer was washed with purified water (2.1 L) and dried over anhydrous magnesium sulfate. After filtering off the desiccant, 2-butanol was added and distilled off under reduced pressure to remove ethyl acetate.
Concentrated sulfuric acid 174.1 g (1.75 mol) was added dropwise at 25 to 30 ° C. to the resulting 2-butanol solution of clopidogrel free.
To the obtained uniform solution, 112.7 g of clopidogrel sulfate Form I crystals (20 w / w% of free form, average particle size of 100 to 200 μm) was added as a seed crystal and stirred at 25 to 30 ° C. for 6 hours. did. The crystallization rate was confirmed by HPLC, and the product was centrifuged at a crystallization rate of 56.8%. The obtained crystal was dried under reduced pressure at 30 ° C., pulverized, and dried under reduced pressure at 60 to 80 ° C. to obtain clopidogrel sulfate.
The obtained clopidogrel sulfate was confirmed to be Form I crystal by XRD.

Example 2 Production of Form I Crystals of Clopidogrel Sulfate (Part 2)
1000.3 g (1.81 mol) of clopidogrel (−)-CSA salt [(5) -2] obtained in the above production example was suspended in 4.0 L of ethyl acetate, and an aqueous potassium carbonate solution (potassium carbonate 249) was suspended therein. 0.5 g was obtained by dissolving in 5.0 L of purified water) and stirred. After confirming the dissolution of crystals, the aqueous layer was discarded. The obtained organic layer was washed with purified water (2.0 L) and dried over anhydrous magnesium sulfate. After filtering off the desiccant, 2-butanol was added and distilled off under reduced pressure to remove ethyl acetate.
Concentrated sulfuric acid 180.7g (1.81mol) was dripped at 25-30 degreeC to the 2-butanol solution of the free body of the obtained clopidogrel.
To the obtained uniform solution, 14.5 g of clopidogrel sulfate Form I crystals (2.5 w / w% of free form, average particle size 30 μm) was added as seed crystals, and 4.5 to 25 ° C. to 25 ° C. Stir for hours. The crystallization rate was confirmed by HPLC, and the product was centrifuged at a crystallization rate of 60.0%. The obtained crystal was dried under reduced pressure at 30 ° C. and then dried under reduced pressure at 60 to 80 ° C. to obtain clopidogrel sulfate.
The obtained clopidogrel sulfate was confirmed to be Form I crystal by XRD.

Example 3 Production of Form I Crystals of Clopidogrel Sulfate (Part 3)
17.2 g (31.04 mmol) of clopidogrel (−)-CSA salt [(5) -2] obtained in the above production example was suspended in 69 mL of ethyl acetate, and an aqueous potassium carbonate solution was added thereto and stirred. After confirming the dissolution of crystals, the aqueous layer was discarded. The obtained organic layer was washed with purified water (34 mL) and dried over anhydrous magnesium sulfate. After filtering off the desiccant, 2-butanol was added and distilled off under reduced pressure to remove ethyl acetate.
Concentrated sulfuric acid 3.1g (31.07 mmol) was dripped at 25-30 degreeC to the 2-butanol solution of the obtained free body of clopidogrel.
To the obtained uniform solution, 0.50 g of clopidogrel sulfate Form I crystals (5.0 w / w% of free form, average particle size 30 μm) was added as a seed crystal and stirred at 25 to 30 ° C. for 4 hours. Then, the solution was cooled to 10 ° C. or lower and stirred for a total of 9 hours. The crystallization rate was confirmed by HPLC, and the product was centrifuged at a crystallization rate of 86.3%. The obtained crystal was dried under reduced pressure at 30 ° C. and then dried under reduced pressure at 60 to 80 ° C. to obtain clopidogrel sulfate.
The obtained clopidogrel sulfate was confirmed to be Form I crystal by XRD.

Example 4 Production of Form I Crystals of Clopidogrel Sulfate (Part 4)
17.0 g (30.68 mmol) of clopidogrel (−)-CSA salt [(5) -2] obtained in the above production example was suspended in 68 mL of ethyl acetate, and an aqueous potassium carbonate solution was added thereto and stirred. After confirming the dissolution of crystals, the aqueous layer was discarded. The obtained organic layer was washed with purified water (34 mL) and dried over anhydrous magnesium sulfate. After filtering off the desiccant, 2-butanol was added and distilled off under reduced pressure to remove ethyl acetate.
Concentrated sulfuric acid 3.0g (29.97mmol) was dripped at 25-30 degreeC to the 2-butanol solution of the obtained clopidogrel free body.
To the obtained uniform solution, 0.19 g of clopidogrel sulfate Form I crystals (2.0 w / w% of free form, average particle size of 3 to 8 μm) was added as a seed crystal, and 4 at 25 to 30 ° C. Stir for 5 hours. The crystallization rate was confirmed by HPLC, and clopidogrel sulfate Form I crystals were obtained at a crystallization rate of 85.6%.

As can be seen from the above examples, in the preparation of clopidogrel sulfate from clopidogrel (−)-CSA salt, by using a large amount of seed crystals, industrial production by greatly shortening the crystallization time of Form I crystals A method was established, and an industrial production method could be established by using a finely pulverized product as a seed crystal to be used, and by greatly reducing the crystallization time of Form I crystals.
Such a point is extremely specific, which is not described at all in the conventional method for producing clopidogrel sulfate Form I crystals.

As described above, clopidogrel sulfate Form I crystals can be produced on an industrial scale according to the present invention.
The present invention can greatly shorten the crystallization time of Form I crystals of clopidogrel sulfate, which has heretofore been difficult to produce industrially, and can provide the desired clopidogrel sulfate with a high crystallization rate. Form I
Crystals can be obtained stably, and their industrial applicability is enormous.

Claims (7)

(+)-(S) -2- (2-Chlorophenyl) -2- (4,5,6,7-tetrahydrothieno [3,2-c] pyridin-5-yl) acetic acid methyl ester (hereinafter “clopidogrel”) Concentrated sulfuric acid is added to the 2-butanol solution containing the free form of) and converted to clopidogrel sulfate in the solution, and then the powder seed of the form I crystal of clopidogrel sulfate adjusted in particle size is controlled. The following formula (I):

A process for producing Form I crystals of clopidogrel sulfate represented by the formula:   The clopidogrel sulfate salt according to claim 1, wherein the powder crystal seed of the form I crystal of clopidogrel sulfate to be added has an average particle diameter of 80 µm to 300 µm, and the powder crystal seed is added in an amount of 10 to 25 w / w%. A process for producing Form I crystals.   The clopidogrel sulfate according to claim 1, wherein the powder crystal seed of the form I crystal of clopidogrel sulfate to be added has an average particle size of 15 to 40 µm, and the powder crystal seed is added in an amount of 1 to 25 w / w%. A process for producing Form I crystals.   The clopidogrel sulfate according to claim 1, wherein the powder crystal seed of the form I crystal of clopidogrel sulfate to be added has an average particle diameter of 1 µm to 10 µm, and the powder crystal seed is added in an amount of 0.1 to 5 w / w%. Process for the production of sulfate Form I crystals.   The method for producing Form I crystals of clopidogrel sulfate according to any one of Claims 1 to 4, wherein the crystal seed of the Form I crystals of clopidogrel sulfate to be added is ground crystals subjected to mechanical grinding.   The clopidogrel sulfate Form I crystal obtained by crystallization is solid-liquid separated, dried, and dried again after pulverization to obtain a stable clopidogrel sulfate Form I crystal. A process for producing Form I crystals of clopidogrel sulfate according to any one of the above.   The process for producing Form I crystals of clopidogrel sulfate according to claim 1, wherein the clopidogrel free form is a clopidogrel free form obtained by treating clopidogrel (-) camphorsulfonate with an alkali.