SI21749A - Process for the preparation of clopidogrel hydrogen sulfate polymorphic form i - Google Patents

Abstract

There is disclosed a process for the preparation of clopidogrel hydrogen sulphate polymorphic form I having the purity of minimum 99%, wherein a clopidogrel salt such as clopidogrel hydrochloride or a crystalline mixture of clopidogrel hydrogen sulphate or clopidogrel camphor sulphate is neutralized with potassium carbonate in an organic solvent, extracted, separated, the organic phase is dried and concentrated to a free clopidogrel base, said base is brought into a dry solution with an organic solvent, cooled to a temperature of between -20 and +25 degrees Celsius and treated with 0.6 to 1.1 equivalents of concentrated sulphuric acid under controlling the temperature between -30 and +5 degrees Celsius in order to achieve the crystallization of the precipitated clopidogrel hydrogen sulphate form I.

Description

A process for the preparation of polymorphic Form I clopidogrel hydrogen sulfate

The field of technology

The present invention relates to a novel process for the preparation of polymorphic Form I clopidogrel hydrogen sulfate, i.e. polymorphic forms I of methyl - (+) - S-? - (2-chlorophenyl) -4,56,7-tetrahydrothieno [3,2-c] pyridine-5-acetate hydrogen sulfate, from various clopidogrel salts.

The proposed new process enables the preparation of a very pure and stable form I material, namely with a purity of at least 99%.

The state of the art

Clopidogrel hydrogen sulphate is a known valuable pharmaceutical substance useful as a platelet aggregation inhibitor, originally described in EP 281459. A process for the preparation of clopidogrel hydrogen sulphate, called polymorphic form I, is disclosed. WO 03/051362 describes new crystalline powder polymorphic forms III, IV, V, VI and the amorphous form of clopidogrel hydrogen sulfate as well as the process for the preparation of forms I and II. The above literature has described the differences between different polymorphic forms of clopidogrel hydrogen sulfate.

Different polymorphic forms have different characteristics that depend on the conformation and orientation of molecules in a single cell. The characteristics of polymorphic forms are determined by the following measurement methods:

FIG. 1 to 3 show the characteristics of the shape 1 with individual figures representing: FIG. 1: Form I FT-IR spectrum,

FIG. 2: X-ray powder diffractogram of Form I,

FIG. 3: DSC.

There are numerous further publications in the prior art that are very broad, but a very pure product can only be obtained under the well-defined conditions established by the inventors in the design of the present invention.

The solution to a technical problem

The subject of the invention is the development of a new process method for the production of stable and pure form I clopidogrel hydrogen sulfate.

The process for the preparation of polymorphic Form I clopidogrel hydrogen sulfate with a purity of at least 99% is characterized in that the clopidogrel hydrochloride salt, such as clopidogrel hydrochloride or the crystalline mixture of clopidogrel hydrogen sulfate or clopidogrel camphor sulfate, is neutralized with potassium carbonate in an organic solvent, extracted, separated The phase is dried and concentrated to a free clopidogrel base, the base is stored in a dry solution with an organic solvent, cooled to a temperature between -20 ° C and +25 ° C and treated with 0.6 to 1.1 equivalents of concentrated sulfuric acid while controlling the temperature between - 30 ° C and 5 ° C to crystallize precipitated Form I clopidogrel hydrogen sulfate.

Dichloromethane, chloroform, ethyl ether, t-butyl methyl ether, isopropyl ether, etc. may be used as the organic solvent for neutralization with potassium carbonate.

Methyl acetate, ethyl acetate, dichloromethane or t-butyl methyl ether may be used as the organic solvent to dissolve the concentrated free clopidogrel base.

Preferably, the same solvent is used to neutralize and dissolve the concentrated free base.

The preferred solvent is dichloromethane.

The precipitation can be optionally supported by grafting with Form I crystals.

The process will be described in more detail below. Various clopidogrel salts, such as clopidogrel hydrochloride or a crystalline mixture of clopidogrel hydrogen sulfate or clopidogrel camphor sulfate, are introduced under an inert gas atmosphere into a non-polar organic solvent to form the reaction mixture. It was cooled with ice water, then an aqueous solution of potassium carbonate was added to the reaction mixture to give an organic phase containing clopidogrel free base and an aqueous (upper) phase. The aqueous phase is controlled to have a pH above 9. The upper aqueous phase is extracted, preferably with the same solvent as above. The organic phases are combined and dried, e.g. above Na2SO4 or MgSO4 and then concentrated to give a free clopidogrel base.

The concentrated clopidogrel base is dissolved in an organic solvent, such as methyl acetate, ethyl acetate, dichloromethane or t-butyl methyl ether, and stirred for several hours to complete the dissolution. During this process, the temperature should be controlled between -20 and +25 ° C. Then the amount of concentrated sulfuric acid is introduced dropwise into the complete solution and the temperature is controlled between -30 and +5 ° C. After the drop-off is complete, the reaction mixture is stirred for another 5 to 15 hours at a temperature between -5 and +15 ° C. It is filtered and preferably washed with the same solvent as above. It is dried in vacuo at temperatures between 30 ° C and 70 ° C, preferably between 50 ° C and 55 ° C, to obtain pure Form I clopidogrel hydrogen sulfate as originally described in EP 281459.

It has an IR spectrum with absorption bands at 2987, 1753, 1222, 1175 and 841 cm ^-1 and a powder X-ray diffraction pattern with spots at 9.2, 10.9, 15.2, 17.9, 18.5, 20.6 , 23.0 23.2, 23.4, and 25.5 ± 0.2 degrees 2Θ.

The key parameters for obtaining Form I Clopidogrel Hydrogen Sulphate with very good properties are as follows:

- The concentrated clopidogrel base must be dissolved in a suitable organic solvent such as methyl acetate, ethyl acetate, dichloromethane or t-butyl methyl ether.

- The moisture content of the above organic solution of clopidogrel base must be well controlled.

- When sulfuric acid is added dropwise to obtain clopidogrel hydrogen sulfate, the temperature should be well controlled, preferably between -30 and +5 ° C.

- The wet cake of clopidogrel hydrogen sulfate should be dried in vacuo and at elevated temperature.

The advantages of the present invention are:

• the process of the invention provides a very pure and stable form I of clopidogrel of constant quality, while in the prior art it is difficult to achieve this advantage.

• The morphologically uniform product of the invention is stable after storage for 12 months.

• no special storage conditions are required. Can be stored under general conditions for pharmacists.

• The process of the invention is readily adaptable to a larger scale and is suitable for industrial scale production.

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

Example 1

Clopidogrel hydrochloride (7.15 g) in dichloromethane (100 ml) was introduced under gas nitrogen into a 250 ml reactor with stirring and cooling with ice water to give the mixture. Then a solution of potassium carbonate (2.5 g) in deionized water (30 ml) was added and stirred for one hour. The pH of the upper aqueous phase was maintained above 9. The organic phase was separated and the aqueous phase was extracted with dichloromethane (2x50 ml). The organic phases are combined, dried over Na2SO4 and concentrated to a free clopidogrel base.

Methyl acetate (150 ml) was added dropwise to the concentrated free base and stirred for more than one hour until the free base of clopidogrel was completely dissolved.

The solution was cooled to a temperature between -15 ° C and -5 ° C, then 90% sulfuric acid (2 g) was added dropwise at a controlled temperature between -5 ° C and 5 ° C while dripping. After the end of the dripping, the reaction mixture was stirred for another 10 hours. It was filtered and washed with methyl acetate (4x10 ml). Dry in vacuo between 50 ° C and 55 ° C to give Form I clopidogrel hydrogen sulfate (5.6 g) with a specific rotation of +54.1 ° (c = 1, methanol), m.p. 182.3-183.5 ° C, 64% yield.

Example 2

Under gas nitrogen, clopidogrel camphor sulfate (1 kg) in dichloromethane (101) is introduced into a 25 l glass reactor while stirring and cooling with cold salt water. Then the reactor was added dropwise to a solution of potassium carbonate (0.31 kg) in deionized water (5 L) and stirred for 1 hour. The pH of the upper aqueous phase was kept above 9. The lower organic phase was separated and the aqueous phase was extracted with dichloromethane (2x5 l). The organic phases were combined and dried over Na2SO4 (1 kg) and then concentrated to give a free clopidogrel base. Methyl acetate (15 L) was added dropwise to the concentrated free bases with stirring for 1 hour until the free base of clopidogrel was completely dissolved.

The complete solution was cooled to -15 ° C to -5 ° C, then 95% sulfuric acid (2.1 kg) was added dropwise at -10 ° C to 0 ° C. At the end of the dripping, the reaction mixture was stirred for another 5 hours. Filter and wash with methyl acetate (3x1 l). It was dried under vacuum between 50 ° C and 55 ° C to give Form I clopidogrel hydrogen sulfate (5.6 kg) with a specific rotation of + 53.2 ° (c = 1, methanol), m.p. 182.1183.0 ° C.

Example 3

A crystalline mixture of clopidogrel hydrogen sulfate (8.7 g) in dichloromethane (100 ml) was introduced under gas nitrogen into a 250 ml reactor with stirring and cooling with cold water. A solution of potassium carbonate (3 g) in deionized water (50 ml) was then added to the reactor and stirred for 1 hour. The pH of the upper aqueous phase was maintained above 9. The lower organic phase was separated and the aqueous phase was extracted with dichloromethane (2x50 ml). The organic phases are combined and dried over Na2SO4, then concentrated. Ethyl acetate (150 ml) was added to the concentrated free base and stirred for more than 1 hour until the free base of clopidogrel was completely dissolved.

The complete solution was cooled to a temperature between -15 ° C and -5 ° C, then 90% sulfuric acid (2 g) was added dropwise at a temperature between -10 ° C and 0 ° C. The reaction mixture was stirred for 5 hours at the end of the drip. It was filtered and washed with ethyl acetate (4x10 ml). It was dried under vacuum between 50 ° C and 55 ° C to give Form I clopidogrel hydrogen sulfate (4, 3 g) with a specific rotation of +53,5 ° (c = 1, methanol), m.p. 182-183 ° C, 57% yield.

Claims (4)

Patent claims A process for the preparation of polymorphic Form I clopidogrel hydrogen sulphate with a purity of at least 99%, characterized in that the clopidogrel hydrochloride salt or crystalline mixture of clopidogrel hydrogen sulphate or clopidogrel camphor sulphate is neutralized with potassium carbonate in an organic solvent, extracted, extracted , the organic phase is dried and concentrated to a free clopidogrel base, stored in a dry solution with an organic solvent, cooled to a temperature between -20 ° C and +25 ° C and treated with 0.6 to 1.1 equivalents of concentrated sulfuric acid while controlling the temperature between - 30 ° C and +5 ° C to crystallize precipitated Form I clopidogrel hydrogen sulfate. Process according to claim 1, characterized in that the organic solvent for dissolving the free clopidogrel base is methyl acetate, ethyl acetate, dichloromethane or t-butyl methyl ether. Process according to claim 2, characterized in that the solvent is dichloromethane. Method according to claim 1, characterized in that the precipitation can be optionally supported by grafting with Form I crystals.