UA82293C2 - Normal;heading 1;heading 2;PROCESSES FOR THE PREPARATION OF CLOPIDOGREL HYDROGEN SULFATE POLYMORPHIC FORM I - Google Patents

Abstract

Processes for the preparation of clopidogrel hydrogen sulfate of polymorphic form I are described which include use of specific solvents and process measures to avoid formation of undesired by-products.

Description

for pharmaceuticals. - the method according to the invention is suitable for production on an industrial scale and can be easily implemented in a suitable volume.

The second way

This method of obtaining a pure and stable polymorphic form of I! of clopidogrel hydrosulfate includes the following stages: (a) under the protection of an inert gas atmosphere (M, Agg) from 0.01 to 0.05 mol (mostly from 0.02 to 0.0 Zmol) clopidogrel salt is added while cooling to 50 - ЗОbml (mostly 100 ml) of organic Solvent A, obtaining a reaction mixture, and then an aqueous solution of potassium carbonate or sodium carbonate is added dropwise to the reaction mixture while stirring, and the ratio of the amount of potassium carbonate or sodium carbonate to the amount of clopidogrel salt is about 1.0 - 3.0 ( mostly 1.2 - 1.5); in this case, the upper aqueous phase is obtained, the pH of which is maintained at a level greater than 9. (b) in this way, after passing stage (a), the lower phase containing the free base of clopidogrel and the aqueous (upper) phase are obtained, the upper aqueous solution is extracted mainly 30-150 ml of Solvent A, the organic phases are combined and dried, for example, over sodium sulfate or potassium sulfate, and then concentrated, obtaining the free base of clopidogrel. (c) the concentrated base of clopidogrel is dissolved in organic Solvent B, and stirred for approximately one hour until complete dissolution. During this procedure, the temperature is carefully controlled, maintaining it in the range from -207C to 5"C (mostly from -157C to -57C). The corresponding amount

Sulfuric acid solution is added dropwise to the resulting solution, maintaining the temperature from -207С to 57С (mostly from -157С to -57С). After adding the required amount of sulfuric acid solution, the reaction mixture is stirred for another 10 hours at a temperature from -207C to 20"C (preferably from -10C to 107C). (d) the resulting reaction mixture is filtered and washed with Solvent B 4 times, using an amount of 1O0ml each time. The mixture dried in a vacuum at a temperature from 407"C to 70"C (mostly from 50"C to 5570) and pure polymorphic form I of clopidogrel hydrosulfate is obtained.

In stage (a), you can use clopidogrel camphor sulfate, clopidogrel hydrochloride or clopidogrel hydrosulfate as a salt of clopidogrel. As specified Solvent A in stage (a), you can use Methylene dichloride, Ethylene dichloride, Chloroform, Ethyl ether, tert-butyl methyl ether, isopropyl ether, or possibly their mixture.

At stage (c), as specified Solvent B, you can use Ethyl Ether, Methyl Acetate,

Ethyl acetate, Ethyl formate, Isopropyl ether, Methylene dichloride, tert-butyl methyl ether.

At stage (d), you can use or Sulfuric Acid Solution as the specified solution of sulfuric acid

Solvent B with different concentrations, or sulfuric acid with a concentration greater than 80905.

According to this method, it is possible to obtain pure clopidogrel hydrosulfate on an industrial scale. The yield is about 50 - 8595, the melting point of the product is 1817 - 186"C, and the optical rotation constant is from 52.0 to 55.096 (s-1, methanol).

The resulting polymorphic form of clopidogrel hydrosulfate is characterized by the determined parameters of powder X-ray diffraction, Fourier transform infrared spectroscopy (FFT) and differential scanning calorimetry (DSC).

The substance has an infrared spectrum with absorption bands at 2987, 1753, 1222, 1175 and 841 cm'; and peaks on the powder X-ray pattern at 9.2; 10.9; 15.2; 17.9; 18.5; 20.6; 23.0; 23.4 and 25.5:20.2 degrees two-theta.

Differential enthalpy studies (DEL) were performed on a suitable chromatograph at the melting point of form I.

The third way

This method of obtaining polymorphic form I of clopidogrel hydrosulfate is characterized by the fact that (a) clopidogrel salt can be converted into clopidogrel base, although this is not necessary; (b) obtain a solution of clopidogrel base in a solvent, which is ethyl acetate or a mixture of ethyl acetate with methylene chloride or ether, (c) react a solution of clopidogrel base with sulfuric acid, and (d) isolate form I of clopidogrel hydrosulfate.

In optional step (a), a salt of clopidogrel, such as a salt formed by any polymorphic form, such as form I, form II or amorphous form, with hydrochloric or sulfuric acid can be used.

The conversion is usually carried out using a base, and the neutralization is preferably carried out with an aqueous inorganic base, such as sodium bicarbonate, potassium carbonate or sodium carbonate.

It is preferable to dissolve the salt of clopidogrel using a solvent that does not mix with water and is able to dissolve the base of clopidogrel. Such a solvent, in particular, can be methylene chloride, or chloroform alkyl acetate, such as ethyl acetate.

During neutralization, a two-phase system containing organic and aqueous phases is usually formed.

Preferably, the pH of the aqueous solution is maintained at the level of 7-8 in order to reduce the possibility of the formation of undesirable by-products. After phase separation and extraction of the aqueous phase, it is desirable to dry the combined organic phases, for example, over magnesium sulfate. It has been shown that the presence of water can cause the formation of an undesirable form of II, and therefore such drying is preferred.

Although the above-described stage (a) is optional, it is still preferable to carry out this stage when performing the method according to the invention.

At stage (b), a solution of the base of clopidogrel in a solvent is obtained, in which ethyl acetate or a mixture of ethyl acetate with methylene chloride or ether is used. It is preferable to use at this stage a mixture of ethyl acetate with methylene chloride containing up to 100 g. 9o, mostly, from 1 to B5mabs. because of methylene chloride.

Or it is preferable that the mixture used at this stage contains up to Зоmass. 95 simple ether.

The best are ethers containing up to 10 carbon atoms.

At stage (c), the clopidogrel base solution is reacted with sulfuric acid.

For this, it is preferable to use sulfuric acid in the form of a solution in an organic solvent, preferably in ethyl acetate.

It is also preferable to prepare a solution of sulfuric acid in an organic solvent at a temperature below 02С, preferably from -57С to -157С. This measure allows you to prevent the formation of undesirable byproducts, for example, monoethyl sulfate in the case of using ethyl acetate as an organic solvent.

It is also preferable that in the reaction mixture obtained after completion of the reaction, ethyl acetate containing up to 1Omas is present as an organic solvent. 95, mostly from 1 to Bmas. 9, and most preferably, from 0.595 to 4.00 mass. 95 methylene chloride.

It is also shown that sulfuric acid should preferably be used in an amount of no more than 0.9 equivalents relative to the clopidogrel base. The use of a larger amount can lead to the formation of an undesirable form of II.

It is also preferable that the temperature of the mixture obtained during the reaction with sulfuric acid is maintained at the level from -207"C to 5"C, preferably from -15"C to 0"C. It is shown that this condition, as well as long-term stirring during the reaction, are better for obtaining a pure substance of form I.

It is also preferable that the reaction mixture obtained after completion of the reaction with sulfuric acid is stirred for at least 1 hour, preferably for 2-4 hours at a temperature from -157C to 0"C, preferably from 5"C to 0".

It is also shown that slow heating with stirring of the reaction mixture obtained after completion of the reaction with sulfuric acid leads to good results, and the heating rate is preferably from 0.57C to 6C, preferably from 2C to 4C per hour.

Usually, with the described procedure of slow heating, the mixture is heated to 13-17"C for about 8 hours, while increasing its temperature every hour by 33"C, and then for another 8 hours, the mixture is slowly heated to 16-2070C.

It is also preferable to stir the mixture for at least 15 hours after the completion of the reaction. It has been shown that this greatly facilitates the formation of the desired crystals.

At stage (d), clopidogrel hydrosulfate is isolated. For this, the precipitated material is filtered and washed, and then the product is dried, preferably in a vacuum at a temperature from 507C to 70"C, more preferably at 557C - 6076.

The final product, as shown, contains no more than 0.5 wt. 9o unwanted form I! substances

The present invention is illustrated by, but not limited to, the following Examples.

Example 1

In an atmosphere of gaseous nitrogen, clopidogrel hydrochloride (7.15 g) was added to 100 ml of dichloromethane in a 250 ml reactor with stirring and cooling with ice water to obtain a mixture. Then, a solution of potassium carbonate (2.5 g) in deionized water (ZOml) was added dropwise to the reactor and the mixture was stirred for an hour. The pH level of the upper aqueous phase was maintained above 9. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (2 times 50 ml each). The organic phases were combined, dried over Ma5Ox and concentrated, obtaining the free base of clopidogrel.

Methyl acetate (150 ml) was added dropwise to the concentrated free base and stirred for more than an hour until the clopidogrel free base was completely dissolved. The solution was cooled to a temperature from -1570 to -5"C, and then 9095 sulfuric acid (2g) was added dropwise, maintaining the temperature between -572 and 570. After adding the required amount of sulfuric acid, the reaction mixture was stirred for another 10 hours. the mixture was filtered and washed with methyl acetate (4 times of 1 Oml). Next, vacuum drying was carried out at a temperature from 507C to 557C and form I of clopidogrel hydrosulfate (5.6g) with an optical rotation constant of "54.196 (s-1, methanol) and a melting point of 182 ,3 - 183.5"C, output 6495.

Example 2

In an atmosphere of gaseous nitrogen, clopidogrel camphor sulfate (1 kg) was added to 10 liters of dichloromethane in a 25-liter glass reactor, with stirring and cooling in a salt bath. Then a solution of potassium carbonate (0.31 kg) in deionized water was added dropwise to the reactor and the mixture was stirred for another hour.

The pH level of the upper aqueous phase was maintained above 9. The lower organic phase was separated, and the aqueous phase was extracted with dichloromethane (2 times 5 l each). The organic phases were combined and dried over Mag5Oa (kg), and then concentrated to give the free base of clopidogrel.

Methyl acetate (15 L) was added dropwise to the concentrated free base with stirring for one hour until the clopidogrel free base was completely dissolved.

The resulting solution was cooled to a temperature from -157C to -5"7C, and then 9595 sulfuric acid (2.1 kg) was added dropwise at a temperature from -107C to 0"C. After adding the required amount of sulfuric acid, the reaction mixture was stirred for another 5 hours. Then it was filtered and washed with methyl acetate (3 times for 7 l). Then vacuum drying was carried out at a temperature from 50"C to 55"C and a form of clopidogrel hydrosulfate (5.6 bkg) with an optical rotation constant of 53.296 (s-1, methanol) and a melting point of 182.17 - 183.00 was obtained.

Example C

In an atmosphere of gaseous nitrogen, a crystalline mixture of clopidogrel hydrosulfate (8.7 g) was added to 100 ml of dichloromethane in a 250 ml chemical reactor with stirring and cooling with ice water. Then a solution of potassium carbonate (Zg) in deionized water (5 Oml) was added dropwise to the reactor and stirred for one hour. The pH level of the upper aqueous phase was maintained above 9. The lower organic phase was separated, and the aqueous solution was extracted with dichloromethane (2 times 5 Oml each). The organic phases were combined, dried over

Ma"50", then concentrated.

Ethyl acetate (150 ml) was added to the concentrated free base and the mixture was stirred for more than one hour until the clopidogrel free base was completely dissolved. The resulting solution was cooled to a temperature from -157C to -57C, and then 9090 sulfuric acid (2g) was added dropwise to it at a temperature from -10"C to 0"C. After adding the required amount of sulfuric acid, the reaction mixture was stirred for another 5 hours. Then it was filtered and washed with ethyl acetate (4 times 1 Oml each). Then vacuum drying was carried out at a temperature from 507C to 557C and clopidogrel hydrosulfate form I was obtained (4.3g) with an optical rotation constant of 53.596 (s-1, methanol) and a melting point of 182-1832C, yield 5795.

Example 4

Under the protection of an atmosphere of gaseous argon, clopidogrel hydrosulfate (12.6g) was added to 300ml of chloroform in a 500ml flask with stirring and cooling with ice water to obtain a mixture, then a solution of potassium carbonate (4.5g) in deionized water was added dropwise to the flask ( 40ml) and stirred the mixture for one hour, maintaining the pH above 9. The organic phase was separated, and the aqueous phase was extracted with chloroform (150ml). The organic phases were combined, dried over potassium sulfate and concentrated to obtain the free base of clopidogrel.

Tert-butyl methyl ether (ZbOml) was added dropwise to the concentrated free base and the mixture was stirred for approximately one hour until the clopidogrel free base was completely dissolved.

The solution was cooled to a temperature of -15"7C, and then a solution of 4095 sulfuric acid in tert-butyl methyl ether was added dropwise at a temperature from approximately -157C to -576C.

After adding the required amount of sulfuric acid solution, the reaction mixture was stirred for another 10 hours at a temperature from -107C to 10"C. Then it was filtered and washed with tert-butyl methyl ether (4 times 10ml each). Then vacuum drying was carried out at a temperature from 40"C to 70"C, and the form of clopidogrel hydrosulfate (10.7g) was obtained with an optical rotation constant of 5296 (s-1, methanol) and a melting point of 181 - 186"C, yield 8595. The powder X-ray pattern of the obtained substance has peaks at degrees 9.2; 10.9; 15.2; 17.9; 18.5; 20.6; 23.00; 23.4 and 25.550.2.

The obtained substance has peaks in the infrared spectrum at 2987, 1753, 1222, 1175 and 841cm";

The obtained substance has a DSC chromatogram with a melting point at 181 - 18670.

Example 5

Under the protection of an atmosphere of gaseous nitrogen, clopidogrel camphor sulfate (5.39 g) was added to 50 ml of ethylene dichloride in a 250 ml flask with stirring and cooling with ice water to obtain a mixture. Then, a solution of potassium carbonate (1.48 g) in deionized water (ZOml) was added dropwise to the flask and stirred for an hour. The pH level of the upper aqueous phase was maintained above 9. The organic phase was separated, and the aqueous phase was extracted with ethylene dichloride (3 mL). The organic phases were combined, dried over sodium sulfate and concentrated to give the free base of clopidogrel.

Ethyl acetate (150 ml) was added dropwise to the concentrated free base and the mixture was stirred for more than one hour until the clopidogrel free base was completely dissolved. The solution was cooled to a temperature of -5"C, then 9095 sulfuric acid solution (2.2g) was added dropwise, maintaining the temperature from -20"C to -57C. After adding the required amount of sulfuric acid, the reaction mixture was stirred for another 10 hours at a temperature from -207"C to 20"C. Then it was filtered and washed with ethyl acetate (4 times 1 Oml each). Then, vacuum drying was carried out at a temperature from 507"C to 557C, obtaining form I of clopidogrel hydrosulfate (2.4g) with an optical rotation constant k"53.726 (s-1, methanol) and a melting point of 182"C - 183"C, yield 57905 .

Example 6

Clopidogrel hydrochloride (7.15 g) was added to 100 ml of methylene dichloride in a 250 ml flask under the protection of an atmosphere of gaseous nitrogen with stirring and cooling with ice water. Then, a solution of potassium carbonate (2.5 g) in deionized water (ZOml) was added dropwise to the flask and the mixture was stirred for one hour. The pH level of the upper aqueous phase was maintained above 9. The lower organic phase was separated, and the aqueous phase was extracted with methylene dichloride (50 ml). The organic phases were combined and dried over sodium sulfate, and then concentrated to give clopidogrel free base.

To the concentrated free base, methyl acetate (150 ml) was added dropwise with stirring for one hour until complete dissolution of the clopidogrel free base.

The obtained solution was cooled to a temperature of -10"C, then concentrated sulfuric acid (2g) was added dropwise to it at a temperature from -57C to 5"C. After adding the necessary amount of sulfuric acid solution, the reaction mixture was heated and stirred for another 10 hours at a temperature of 0"С - 1576. It was then filtered and washed with methyl acetate (4 times 1 Oml each). Then vacuum drying was carried out at a temperature from 50"С to 55" C, obtaining the form of clopidogrel hydrosulfate (5.4g) with an optical rotation constant k54.17C (c-1, methanol) and a melting point of 182.3-183.57C, yield 64905.

Example 7

Under the protection of an atmosphere of gaseous nitrogen, clopidogrel camphor sulfate (10.78 g) was added to 100 ml of isopropyl ether in a 250 ml flask with stirring and cooling with ice water. Then a solution of potassium carbonate (2.2 g) in deionized water (5 Oml) was added dropwise to the flask and the mixture was stirred for one hour. The pH level of the upper aqueous phase was maintained above 9. The lower organic phase was separated and the aqueous solution was extracted with isopropyl ether (5 Oml). The organic phases were combined and dried over potassium sulfate, then concentrated.

Isopropyl ether (150 ml) was added dropwise to the concentrated free base and the mixture was stirred for one hour until complete dissolution of the clopidogrel free base.

The resulting solution was cooled to a temperature of -10"C, then relatively concentrated sulfuric acid was added dropwise at a temperature from -57C to 5"C. After adding the required amount of sulfuric acid, the reaction mixture was stirred for another 10 hours at a temperature from -5°C to 1570°C. It was then filtered and washed with isopropyl ether (4 times 1 Oml each). Vacuum drying was then carried out at a temperature from 507°C to 55°C. C, obtaining form I! of clopidogrel hydrosulfate (4.2 g) with an optical rotation constant k53.596 (s-1, methanol) and a melting point of 182 - 1832С, yield 5096.

Example 8

Clopidogrel hydrochloride (7.15 g) was added to 100 ml of methylene dichloride in a 250 ml reactor under the protection of an atmosphere of gaseous nitrogen with stirring and cooling with ice water to obtain a mixture. Then, a solution of potassium carbonate (2.5 g) in deionized water (3 ml) was added dropwise to the reactor and the mixture was stirred for one hour. The pH level of the upper aqueous phase was maintained no lower

The organic phase was separated, the aqueous phase was extracted with dichloromethane (2 times 5 Oml each). The organic phases were combined, dried over Mag5Ox and concentrated, obtaining the free base of clopidogrel.

Methyl acetate (150 ml) and methylene dichloride (15 ml) were added to the concentrated free base, then the mixture was stirred for more than an hour until the clopidogrel free base was completely dissolved.

The solution was cooled to a temperature from -157C to -57C, then a solution of 1095 sulfuric acid in methylene dichloride (2g) was added dropwise to it, while maintaining the temperature from -157C; to -1076.

After adding the required amount of sulfuric acid solution, the reaction mixture was stirred for another 20 hours. Then it was filtered and washed with methyl acetate (4 times 1 Oml). Then vacuum drying was carried out at a temperature from 50"С to 55"С, obtaining the shape! clopidogrel hydrosulfate (4.9g) with an optical rotation constant of 54.196 (s-1, methanol) and a melting point of 181-182.52C, yield 5695.

Example 9

Under the protection of a nitrogen atmosphere, a crystalline mixture of clopidogrel hydrosulfate (8.7 kg) was added to 100 L of dichloromethane in a 250 L chemical reactor with stirring and cooling with cold water. Then, a solution of potassium carbonate (3.0 kg) in deionized water (50 L) was added dropwise to the reactor and the mixture was stirred for one hour. The pH level of the upper aqueous phase was maintained above 8. The lower organic phase was separated, and the aqueous phase was extracted with dichloromethane (2 times 50 l each). The organic phases were combined and dried over Mo?zoa, and then concentrated. Ethyl acetate (100 L) and isopropyl ether (20 L) were added to the concentrated free base, and the mixture was then stirred for 30 minutes until the clopidogrel free base was completely dissolved.

The resulting solution was cooled to a temperature from -157C to -57C, then a solution of concentrated sulfuric acid (1.9 kg) in ethyl acetate (ZOl) was added dropwise at a temperature from -107C to 0"C. After adding the required amount of sulfuric acid solution, the reaction mixture was stirred for another 5 hours. Then it was filtered and washed with ethyl acetate (3 times, 2 liters each). Then vacuum drying was carried out at a temperature from 502C to 55"C, obtaining form I of clopidogrel hydrosulfate (4.9 kg) with an optical rotation constant of "53.7 96 (c-1, methanol) and a melting point of 181.2 -182.37С, yield 6595.