HU226773B1 - Process for the production of clopidogrel hydrogensulfate polymorph 1 - Google Patents

Abstract

Preparation of the polymorph form 1 of clopidogrel hydrogensulfate (I) comprises dissolving clopidogrel base in an A type solvent, adding sulfuric acid and/or A or B type solvent, the obtained mixture containing clopidogrel hydrogensulfate is added to a mixture of a B type solvent containing clopidogrel hydrogensulfate polymorph form 1 as a suspension and filtering, optionally washing and drying the formed precipitate. Preparation of the polymorph form 1 of methyl (S)-(+)-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridine-5-yl-acetate hydrogensulfate of formula (I) comprises (a) dissolving clopidogrel base in an A type solvent, adding sulfuric acid or a mixture of sulfuric acid and an A or B type solvent to the mixture, the obtained mixture containing clopidogrel hydrogensulfate is added to a mixture of a B type solvent containing clopidogrel hydrogensulfate polymorph form 1 as a suspension; or (b) dissolving clopidogrel base in a mixture of A and B type solvents, clopidogrel hydrogensulfate polymorph form 1 is added to the solution, then adding sulfuric acid or a mixture of sulfuric acid with an A or B type solvent to the obtained mixture; and (c) filtering, optionally washing and drying the formed precipitate. [Image].

Description

The present invention provides clopidogrel hydrogen sulfate [S - (+) - (2-chlorophenyl) -2- (6,7-dihydro-4/7-thieno [3,2-c] pyridine) represented by the formula (I): 5-yl) acetic acid methyl ester bisulfate] by a novel process.

S - (+) - (2-Chloro-phenyl) -2- (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-yl) -acetic acid methyl ester, bisulfate, ) clopidogrel hydrogen sulfate, a known antiplatelet drug and antithrombotic agent.

Clopidogrel hydrogen sulfate was first described in EP 281 459. The Hungarian patent specification HU 197 909 corresponds to this patent. This patent was characterized by a melting point of 182 ° C and an optical rotation of [α] ²⁵ D = -51.61 (c = 2.044 g / 100 ml, methanol). The crystalline form is not mentioned in the patent. Polymorphic modifications of clopidogrel hydrogen sulfate were first described in French patent FR 98/07464. Polymorph Form 1 is described herein as a monoclinic crystalline form characterized by X-ray diffraction and infrared spectra. Polymorph 1 has a melting point of 184 ° C and an optical rotation of [α] ²⁵ D = + 55, r (c = 1.891 / 100 ml, methanol). On this basis, it is claimed that the product described in EP 281 459 is polymorphic form 1 of clopidogrel bisulfate. According to French patent FR 98/07464, clopidogrel bisulfate polymorph 2 has a melting point of 176 ° C and has an orthorhombic crystalline structure.

Polymorphic crystalline Form 1 is prepared according to the above patent by dissolving clopidogrel base in acetone and adding equimolar amounts of 80% sulfuric acid at 20 ° C. A portion of the solvent is then evaporated, the residue is cooled to 0-5 ° C and the product is isolated by filtration.

The crystalline form 2 polymorph was obtained by storing the acetone mother liquor formed during the production of polymorph 1 at a temperature below 40 ° C for 3 to 6 months. The precipitated crystal fraction proved to be polymorphic modification 2.

The preparation of polymorphic crystalline Form 2 can also be carried out according to the above patent by dissolving clopidogrel base in acetone and adding an equimolar amount of 80% sulfuric acid at 20 ° C with or without inoculation. The reaction mixture is then refluxed for two hours and, after evaporation of part of the solvent, the residue is cooled to -5 ° C and filtered, or the inoculated mixture is stirred at 20 ° C and the product isolated by filtration.

According to WO 02/059128, Form 1 of clopidogrel bisulfate polymorph can also be prepared by dissolving clopidogrel base in triple acetone at 0-5 ° C and adding concentrated sulfuric acid to the solution followed by addition of a single amount of acetone. they add to the mixture. After stirring for 4 hours, Form 1 of the polymorph was isolated with a melting point of 185 ° C.

International Patent Publication No. WO 03/051362 discloses that clopidogrel hydrogen sulfate can be crystallized from various solvents or precipitated from solution with certain solvents into a number of different crystalline forms. The various polymorphic modifications herein are designated by Roman numerals, of which I. in the present application is polymorph 1 and II. corresponds to polymorph 2.

According to the description, thermodynamically controlled, more stable polymorph II is recrystallized from various solvents. modification occurs. The only solvent excepted is isopropanol, from which recrystallized polymorph IV. modification occurs.

It is quite different when clopidogrel bisulfate is taken up in various solvents and evaporated and then rubbed with another solvent, or a solvent is added to the clopidogrel bisulfate solution which reduces the solubility of the product, such as clopidogrel hydrogen sulfate. precipitates out of solution. The use of different types of solvents and solubilizers results in quite different polymorphic modifications. In said application, polymorph II. is formed when the acetonitrile solution of clopidogrel hydrogen sulfate is mixed with diethyl ether. Separated from methanol or acetone in a similar process gives amorphous or polymorphic product I. For the preparation of Polymorph I, each of the processes described in the literature uses an ether-type solvent as a solubility reducing agent or a triturated clopidogrel hydrogen sulfate.

From the examples above, it cannot be predicted which polymorphic modification or conversion will occur when clopidogrel hydrogen sulphate is interacted with various solvents when a given solvent is used.

Nowadays, there is a great demand for the preparation of high purity and morphologically uniform active pharmaceutical ingredients. On the one hand, this is encouraged by the stricter drug registration requirements and, on the other hand, there may be significant differences in the absorption properties of formulations containing different polymorphs. The tablet produced by the originator contained the Form 1 polymorph of clopidogrel bisulfate during the initial period. Each of the polymorphs may also have different drug technology properties. Morphologically homogeneous products have a constant filtration and transport properties, and it is easier to maintain the required high quality characteristics when formulating the product. From the economic point of view, there is an advantage in the control of technological processes both in the manufacture of the active ingredient and in the preparation.

There is a need for the preparation of clopidogrel hydrogen sulfate, which is morphologically uniform and of sufficient purity, to meet the requirements of the active compounds used in pharmaceutical formulations.

Our experience has shown that neither French patent FR 98/07464 nor WO 02/059128

By repeating the process described in U.S. Pat. No. 1,71,731, the preparation of clopidogrel bisulfate polymorphic crystalline modification 1 is not well reproducible. Although the methods described in WO 03/051362 for the preparation of polymorph 1 are described, the killing provides a very narrow framework for the solvents that can be used. The reaction may optionally be carried out in a mixture of polymorph 1 and amorphous form. This, however, is undesirable because, from a pharmaceutical technology point of view, uniform morphology substances are generally easier to handle.

It is an object of the present invention to provide a process that allows the use of different types of solvents to produce a uniform polymorphic Form 1.

The present invention relates to a process for preparing clopidogrel hydrogen sulfate [S - (+) - (2-chlorophenyl) -2- (6,7-dihydro-4 H- thieno [3,2-c] pyridine-5 il) -acetic acid methyl ester hydrogen sulfate] type 1 polymorph by dissolving clopidogrel base in a halogenated solvent, an aliphatic ketone type solvent or 2-propanol, sulfuric acid, or optionally a sulfuric acid halide solvent, an aliphatic ketone solvent, A mixture of 2-propanol, an ethereal solvent, a saturated hydrocarbon solvent, or an ester solvent is added, and the resulting solution containing clopidogrel hydrogen sulfate is suspended in an ether solvent containing clopidogrel bisulfate polymorph Form 1 as a suspension. , with a saturated hydrocarbon type solvent or an ester type solvent, with the proviso that when clopidogrel base is aliphatic ton, or 2-propanol, the mixture is mixed with an ethereal solvent and the resulting mass is separated from the mother liquor 35, optionally washed and dried.

The present invention is based on the discovery that when the polarity of a solution of clopidogrel bisulfate in a suitable organic solvent is appropriately changed by the addition of another organic solvent in the presence of a polymorph of Form 1, it is surprisingly unlikely that the amorphous form or the thermodynamically stable polymorphic form 2 is formed, but polymorph 1.

This is very surprising because our own experiments 45 show that the formation of polymorphic form 2 is such a favorable process that polymorphic form 2 is formed in the presence of sulfuric acid to form clopidogrel base in the presence of seed crystal of polymorph.

It is also known that, when the polarity of a solution of clopidogrel bisulfate is changed, different polymorphic forms are formed depending on the solvents used. However, it is surprising that a technical solution has been found which allows the reproducible production of polymorph Form 1 using several different types of solvent.

In the process of the present invention, the solvent used to dissolve the clopidogrel base is halogenated solvents, ketones, 2-propanol. The halogenated solvent is preferably an aliphatic halogenated hydrocarbon, more preferably dichloromethane. Preferably, ketones are lower aliphatic ketones, most preferably acetone.

Solvents containing clopidogrel hydrogen sulfate polymorph Form 1 as a suspension are ether, saturated hydrocarbon type solvents or lower aliphatic esters. Of the ether types, diethyl ether, tetrahydrofuran, diisopropyl ether, most preferably diisopropyl ether, most preferably of the hydrocarbon type, cyclohexane, hexane or heptane are used. Most preferably the lower aliphatic ester is ethyl acetate.

It has been found that the preparation of polymorph Form 1 using the known methods is difficult. For those skilled in the art, examples of WO 99/65915 show that it is convenient to assist in the preparation of polymorphic Form 2 by the addition of seed crystals, otherwise the Form 1 polymorph is formed. Based on these, it is believed that polymorph Form 1 can be readily prepared, and no further results are expected with the addition of a suitable polymorphic seed crystal 1.

However, our experiments show that the use of acetone and many other solvents or solvent mixtures does not produce the desired polymorph

Form 1, whether or not a polymorph Form 1 seed crystal is used.

The examples in the table below illustrate that the formation of the thermodynamically more stable polymorph 2 is expected when the clopidogrel hydrogen sulfate is separated from the base solution in an organic solvent by salt formation. In the following examples, the salt was obtained by the addition of an almost equimolar amount of 96 wt% sulfuric acid.

Experiment sign clopidogrel The amount Solvent (quantity) T _s Crystal vaccines (quantity) Product polymorphism CLP-142 38.6 g acetone (119 mL) 20 ° C - polymorph 2. CLP-144 38.6 g acetone (119 mL) 20 ° C polymorph 1. (0.87 g) polymorph 2. CLP-130 38g acetone (330 mL) 5 ° C polymorph 1. (0.15 g) polymorph 2.

HU 226 773 Β1

Table (continued)

Experiment sign clopidogrel The amount Solvent (quantity) T _s Crystal vaccines (quantity) Product polymorphism CLP-188 27.8 g dichloromethane (300 mL) 15 ° C polymorph 1. (0.15 g) polymorph 2. CLP-196 28.55 g ethyl acetate (78 mL) -acetone (172 mL) 15 ° C polymorph 1. (0.15 g) polymorph 2. CLP-201 28 yrs dichloromethane (200 mL) -acetone (119 mL) 15 ° C polymorph 1. (0.15 g) polymorph 2. CLP-208 36.9 methyl ethyl ketone (300 mL) -acetone (119 mL) 15 ° C polymorph 1. (0.15 g) polymorph 2.

T _s : temperature of the reaction mixture during salt formation.

One of the examples in the table is described in more detail by way of reference (Comparative Example A).

The kinetically controlled polymorphic variant 1 can be obtained according to WO 03/051362 by altering the polarity of a solution of clopidogrel bisulfate in an organic solvent by reducing the solubility of clopidogrel bisulfate. However, our experimental results show that even with the addition of the proposed ether-type polarity reducing solvent "B", the desired polymorphic polymorph 1 product is not amorphous.

In the following examples, the salt was obtained by the addition of an almost equimolar amount of 96 wt% sulfuric acid.

Example sign clopidogrel “The solvent Temperature used for salt formation “Solvent B polymorphism Amorphous 1 * 32.2 g acetone 10-15'C diisopropyl ether amorphous Amorphous 2 * 32.2 g dichloromethane 10-15'C diisopropyl ether amorphous Amorph 3 32.2 g a mixture of isopropyl alcohol and diisopropyl ether 10-15'C diisopropyl ether amorphous

* The salt formation is carried out in a solution of the base in solvent A.

** A solution of the base in solvent A is mixed with solvent B containing sulfuric acid.

One of the examples in the table is described in more detail by way of reference (Comparative Example B).

However, if the seed crystal contains solvent B, clopidogrel bisulfate polymorph is formed in Form 1. The method reliably yields polymorph Form 1 from a solution of different types of solvents using different types of precipitants. According to the present process, starting from clopidogrel base or clopidogrel hydrogen sulfate of other morphology, the polymorphic Form 1 product is obtained using the present process.

The structure of Form 1 polymorph of clopidogrel hydrogen sulfate according to the invention (Example 1) was confirmed by the following X-ray powder diffraction test: Apparatus: Bruker D8 Advanced Powder Diffractometer Radiation: CuKo ^ (λ = 1.54060), CuKa ₂ (λ = 1, 54439) Voltage: 40 kV

Anode current: 30 mA

Accessories: Round mirror Soller slot

Standard reference material used: SRM 675

Mica Powder (synthetic fluorophlogopite), serial number: 981307

The measurement is continuous Θ / Θ scan: 5 ° -35.00 ° 2Θ Step size: 0.04 °

Sample: flat surface, inaccurate, measured and stored at room temperature.

The X-ray powder diffraction pattern of clopidogrel bisulfate crystalline Form 1 is shown below.

Position of diffraction lines and relative intensities (> 5%)

Peak 2 * th D (hkl) l (abs) l (rel) Woman. [Deg] [L] [Cps] [%] First 9.19 9.6216 241 22.6 Second 10.87 8.1339 224 21.0 Third 11.49 7.6969 152 14.2

HU 226 773 Β1

Table (continued)

Peak 2 * th D (hkl) l (abs) l (rel) Woman. [Deg] [L] [Cps] [%] 4th 13.80 6.4143 71 6.6 5th 14.38 6.1532 137 12.8 6th 14.81 5.9772 198 18.5 7th 15.24 5.8083 156 14.6 8th 15.49 5.7169 193 18.1 9th 16.32 5.4285 53 5.0 10th 17.95 4.9386 121 11.3 11th 18.28 4.8498 103 9.7 12th 18.49 4.7940 133 12.5 13th 18.97 4.6758 170 15.9 14th 19.65 4.5136 119 11.1 15th 20.54 4.3203 315 29.5 16th 21.59 4.1127 130 12.2 17th 21.87 4.0614 143 13.4 18th 22.60 3.9308 93 8.7 19th 23,17 3.8357 1068 100 20th 23.43 3.7937 173 16.2 21st 23.84 3.7294 196 18.4 22nd 24.41 3.6434 73 6.9 23rd 25.52 3.4875 356 33.3 24th 25.95 3.4314 100 9.3 25th 26.54 3.3553 96 9.0 26th 27.35 3.2587 95 8.9 27th 28.47 3.1323 83 7.8 28th 28.92 3.0849 165 15.4 29th 30.76 2.9043 131 12.3 30th 32.64 2.7412 57 5.3 31st 32.94 2.7172 73 6.9

One of the great advantages of the process is that it is possible to select from a broader range of prior art the most suitable solvent for the given technology line and the product will be a reliably pure polymorph 1.

By way of example, the use of dichloromethane as a type A solvent is very advantageous since clopidogrel base can be extracted with dichloromethane by cleavage of the camphorsulfonic acid salt formed at resolution and the present process can be used to obtain . This also reduces technology time and chemical costs.

The following examples are intended to illustrate the process of the present invention, but are not intended to limit the scope thereof.

Example 1

Preparation of Clopidogrel Hydrogen Sulphate Polymorph Form 1

32.2 g of clopidogrel base are dissolved in 130 ml of acetone, the solution is cooled to 10-15 ° C with stirring, and 10.2 g of 96% sulfuric acid is added. This mixture was added dropwise to a suspension of 1000 ml of diisopropyl ether and 10 g of polymorph Form 1 clopidogrel hydrogen sulfate at 0 ° C with stirring for 15-20 minutes. After the addition, the reaction mixture was stirred for an additional hour at 0 ° C, filtered, washed with cold 100 ml of cold diisopropyl ether and dried at 50 ° C for 5 days. 48 g (90.5%) of the title compound are obtained, m.p. 184 ° C. ¹ H-NMR (DMSO-d 6, 00 400): 7.88 (d, J = 6.5 Hz, 1H), 7.64 (dd, J 1 = 1.8 Hz, J 1 = 7.9 Hz, 1H). , 7.52 (m, 2H), 7.42 (d, J = 5.1 Hz, 1H), 6.87 (d, J = 5.1 Hz, 1H), 5.57 (b,

1H), 4.20 (b, 4H), 3.74 (s, 3H), 3.08 (b, 2H). ¹³ C NMR: 167.65, 134.38, 132.07, 131.89, 130.74,

128.46, 125.67, 124.92, 65.77, 53.57, 50.27, 48.86,

22.61.

Example 2

Preparation of Clopidogrel Hydrogen Sulphate Polymorph Form 1

32.2 g of clopidogrel base are dissolved in 200 ml of dichloromethane, the solution is cooled to 0 ° C with stirring, and 9.7 g of 96% sulfuric acid are added. This mixture was added dropwise to a suspension of 850 ml of diisopropyl ether and 10 g of polymorph Form 1 clopidogrel bisulfate at 0 ° C with stirring for 15-20 minutes. After addition, the reaction mixture was stirred for an additional hour at 0 ° C, filtered, washed with cold diisopropyl ether (2 x 100 mL) and dried at room temperature for 5 days. 47 g (88.1%) of the title compound are obtained, m.p. 184 ° C.

¹ H-NMR (DMSO-d ₆ , 00 400): 7.88 (d, J = 6.5 Hz, 1H), 7.64 (dd, J 1 = 1.8 Hz, J 1 = 7.9 Hz, 1H ), 7.52 (m, 2H), 7.42 (d, J = 5.1 Hz, 1H), 6.87 (d, J = 5.1 Hz, 1H), 5.57 (b,

1H), 4.20 (b, 4H), 3.74 (s, 3H), 3.08 (b, 2H). ¹³ C NMR: 167.65, 134.38, 132.07, 131.89, 130.74,

128.46, 125.67, 124.92, 65.77, 53.57, 50.27, 48.86,

22.61.

Example 3

Preparation of Clopidogrel Hydrogen Sulphate Polymorph Form 1

32.2 g of clopidogrel base are dissolved in 140 ml of 2-propanol, the solution is cooled to 10-15 ° C with stirring, and then 10.2 g of 96% sulfuric acid is added. This mixture was added dropwise to a suspension of 850 ml of diisopropyl ether and 10 g of polymorph Form 1 clopidogrel bisulfate at 0 ° C with stirring for 15-20 minutes. After addition, the reaction mixture was stirred for an additional hour at 0 ° C, filtered, washed with cold diisopropyl ether (2 x 100 mL) and dried at room temperature for 5 days. 49 g (92.8%) of the title compound are obtained, m.p. 184 ° C.

¹ H-NMR (DMSO-d 6, 00 400): 7.88 (d, J = 6.5 Hz, 1H), 7.64 (dd, J 1 = 1.8 Hz, J 1 = 7.9 Hz, 1H). , 7.52 (m, 2H), 7.42

HU 226,773 Β1 (d, J = 5.1 Hz, 1H), 6.87 (d, J = 5.1 Hz, 1H), 5.57 (b,

1H), 4.20 (b, 4H), 3.74 (s, 3H), 3.08 (b, 2H). ¹³ C NMR: 167.65, 134.38, 132.07, 131.89, 130.74,

128.46, 125.67, 124.92, 65.77, 53.57, 50.27, 48.86,

22.61.

Example 4

Preparation of Clopidogrel Hydrogen Sulphate Polymorph Form 1

32.2 g of clopidogrel base are dissolved in a mixture of 860 ml of diisopropyl ether and 140 ml of isopropanol, 10 g of polymorphic form 1 of clopidogrel bisulfate are added and the suspension is cooled to 0 ° C. Thereafter, 10.2 g of 96% sulfuric acid in 50 ml of diisopropyl ether are added dropwise to the reaction mixture over a period of 15 to 20 minutes. After the addition, the reaction mixture was stirred for an additional hour at 0 ° C, filtered, and the crystals were washed with cold diisopropyl ether (2 x 100 mL) and dried at room temperature for 5 days. 49 g (92.8%) of the title product are obtained, m.p. 184C. ¹ H-NMR (DMSO-d ₆ , 00 400): 7.88 (d, J = 6.5 Hz, 1H),

7.64 (dd, J1 = 1.8 Hz, J1 = 7.9 Hz, 1H), 7.52 (m, 2H),

7.42 (d, J = 5.1 Hz, 1H), 6.87 (d, J = 5.1 Hz, 1H), 5.57 (b, 1H), 4.20 (b, 4H), 3.74 (s, 3H); 3.08 (b, 2H). ¹³ C NMR: 167.65, 134.38, 132.07, 131.89, 130.74,

128.46, 125.67, 124.92, 65.77, 53.57, 50.27, 48.86,

22.61.

Example 5

Preparation of Clopidogrel Hydrogen Sulphate Polymorph Form 1

32.2 g of clopidogrel base are dissolved in 200 ml of dichloromethane, the solution is cooled to 0 ° C with stirring, and 9.7 g of 96% sulfuric acid are added. This mixture was added dropwise to a suspension of 850 ml of cyclohexane and 10 g of clopidogrel hydrogen sulfate polymorph Form 1 at 8-10 ° C with stirring for 15-20 minutes. After addition, the reaction mixture was stirred for an additional hour at 8-10 ° C, filtered and the crystalline product was washed with cold cyclohexane (2 x 100 mL) and dried at room temperature for 5 days. 49 g (92.8%) of the title product are obtained, m.p. 184'C.

¹ H-NMR (DMSO-d ₆ , 00 400): 7.88 (d, J = 6.5 Hz, 1H),

7.64 (dd, J1 = 1.8 Hz, J1 = 7.9 Hz, 1H), 7.52 (m, 2H),

7.42 (d, J = 5.1 Hz, 1H), 6.87 (d, J = 5.1 Hz, 1H), 5.57 (b, 1H), 4.20 (b, 4H), 3.74 (s, 3H); 3.08 (b, 2H). ¹³ C NMR: 167.65, 134.38, 132.07, 131.89, 130.74,

128.46, 125.67, 124.92, 65.77, 53.57, 50.27, 48.86,

22.61.

Example 6

Preparation of Clopidogrel Hydrogen Sulphate Polymorph Form 1

32.2 g of clopidogrel base are dissolved in 200 ml of dichloromethane and then 10.2 g of 96% sulfuric acid are added at 0 ° C. The resulting mixture was added dropwise at 20 'C to a suspension of 1000 ml of ethyl acetate and 10 g of polymorph Form 1 clopidogrel bisulfate with stirring for 30 minutes. After the addition, the reaction mixture was stirred for another 15 minutes, filtered, and the crystalline product was washed with cold ethyl acetate (2 x 100 mL) and dried. 44.5 g (82%) of the title product are obtained, m.p. 184'C.

¹ H-NMR (DMSO-d ₆ , 00 400): 7.8 (d, J = 6.5 Hz, 1H), 7.64 (dd, J 1 = 1.8 Hz, J 1 = 7.9 Hz, 1H ), 7.52 (m, 2H), 7.42 (d, J = 5.1 Hz, 1H), 6.87 (d, J = 5.1 Hz, 1H), 5.57 (b,

1H), 4.20 (b, 4H), 3.74 (s, 3H), 3.08 (b, 2H). ¹³ C NMR: 167.65, 134.38, 132.07, 131.89, 130.74,

128.46, 125.67, 124.92, 65.77, 53.57, 50.27, 48.86,

22.61.

Comparative Examples Comparative Example A

Preparation of Clopidogrel Hydrogen Sulphate Polymorph Form 2 (CLP-130)

38.4 g of clopidogrel base are dissolved in 119 ml of acetone. The solution is poured into a 500 ml Schmizo double walled variable speed stirrer. A Lauda RE-306 programmable thermostat is connected to the unit to provide accurate temperature control or to run a cooling or heating program. Using a thermostat, adjust the temperature of the solution to 6 'C. 1.0 g of polymorphic Form 1 clopidogrel hydrogen sulfate is added. Then 6 ml of cc was added dropwise over 5 minutes. sulfuric acid so that the temperature of the reaction mixture does not rise above 10 ° C. The crystalline slurry was stirred for an additional 4.5 hours at 5 ° C, then filtered, washed with cold acetone and dried at 40 ° C for 24 hours.

Yield: 40.09 g (80%) (polymorph Form 2) Comparative Example B

Preparation of clopidogrel hydrogen sulfate amorphous form

32.2 g of clopidogrel base are dissolved in 140 ml of dichloromethane, the solution is cooled to 10-15 ° C with stirring, and 10.2 g of 96% sulfuric acid are added. This mixture was added dropwise to 850 ml of diisopropyl ether at 0 ° C with stirring for 15-20 minutes. After addition, the reaction mixture was stirred for an additional hour at 0 ° C, filtered, and washed with cold diisopropyl ether (2 x 100 mL).

39 g (92.8%) of the title product are obtained (amorphous form).

Claims (7)

PATENT CLAIMS A process for the preparation of clopidogrel hydrogen sulfate [S - (+) - (2-chlorophenyl) -2- (6,7-dihydro-4H-thieno [3,2-c] pyridine) -5 -iI) -acetic acid methyl ester hydrogen sulfate] type 1 polymorph, characterized in that the clopidogrel base is dissolved in a halogenated solvent, an aliphatic ketone solvent or 2-propanol, Sulfuric acid or, optionally, a mixture of sulfuric acid with a halogenated solvent, an aliphatic ketone solvent, 2-propanol, an ethereal solvent, a saturated hydrocarbon solvent, or an ester solvent, is added and the resulting clopidogrel hydrogen sulfate solution is added. in the presence of a Type 1 polymorph of hydrogen sulfate with an ether type solvent, a saturated hydrocarbon type solvent or an ester type solvent, with the proviso that when clopidogrel base is dissolved in an aliphatic ketone type solvent or 2-propanol, an ether type solvent is employed. then the resulting mass of material is separated from the mother liquor and dried. Process according to claim 1, characterized in that the halogenated solvent is preferably chlorinated aliphatic hydrocarbons, most preferably dichloromethane, lower ketone aliphatic ketones, most preferably acetone. The process according to claim 1, wherein the ether-type solvent is preferably diethyl ether, tetrahydrofuran, diisopropyl ether, most preferably diisopropyl ether. The process according to claim 1, wherein the saturated hydrocarbon solvent is preferably cyclohexane, hexane or heptane. 5. A process according to claim 1 wherein the ester-type solvent is preferably ethyl acetate. 6. The process according to claim 1, wherein the clopidogrel base is dissolved in dichloromethane, the mixture is cooled to 0 ° C with stirring, and 96% sulfuric acid is added, followed by a solution containing clopidogrel hydrogen sulfate. clopidogrel hydrogen sulfate type 1 polymorph is suspended in cyclohexane slurry at 8-10 ° C and the resulting mass is separated from the mother liquor and dried. 7. The process according to claim 1, wherein the clopidogrel base is dissolved in dichloromethane, the mixture is cooled to 0 ° C with stirring, and 96% sulfuric acid is added and the resulting solution containing clopidogrel hydrogen sulfate is obtained. clopidogrel bisulfate type 1 polymorph is added dropwise to ethyl acetate in suspension at 20 ° C, and the resulting mass is separated from the mother liquor and dried.