CZ300352B6 - Process for preparing aripiprazole phosphate - Google Patents

Abstract

In the present invention, there is disclosed a process for preparing a salt of phosphoric acid with 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-1,2,3,4-tetrahydroquinolin-2-one of the general formula II in a crystalline form, having purity according to HPLC 99.5 percent and higher, containing less than 0.1 percent individual contaminants, with melting temperature within the range of 186 to 191 degC, having DSC with maximum near to 189 degC, including tautomer and solvates thereof, wherein the preparation process is characterized by reacting 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-1,2,3,4-tetrahydroquinolin-2-one of the general formula I with a concentrated phosphoric acid whereby the reaction is carried out in ethanol or ethyl acetate, optionally in a mixture thereof with water at a temperature ranging from 60 degC to boiling point of the solvent being used.

Description

Process for preparing aripiprazole phosphate

Technical field

The invention relates to the preparation of a salt of aripiprazole, i.e. 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one, with phosphoric acid ( H3PO4), with advantageous physico-chemical properties. Said salt may be used for the preparation of a medicament for the treatment of schizophrenia and bipolar disorders,

BACKGROUND OF THE INVENTION

ARIPIPRAZOL, chemically 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3 ', 4-tetra15-hydrochirtolin-2-one of formula I

H

(I) is known antipsychotic, which was first described in EP 367141 (1989) by Otsuka

Pharmaceutical. Aripiprazole is currently used in free base form. The basic patent EP 367141 describes several salts of aripiprazole, both with mineral acids (hydrochloride, sulphate) and with organic acids (fumarate, maleate).

Our solution includes a process for preparing a salt of aripiprazole I with phosphoric acid, which exhibits a number of advantageous properties not previously observed in the salts described above.

SUMMARY OF THE INVENTION

The present invention relates to a process for preparing a salt of aripiprazole, i.e. 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one, with phosphoric acid (H3PO4). This process makes it possible to obtain the hitherto unwritten salt of aripiprazole I with phosphoric acid (H3PO4) in high yield and in the quality required for pharmaceutical substances.

For example, the aripiprazole base obtained by the known process of EP 367141 has reached a purity

97.8%. The phosphate produced according to Example 1 of the present invention had a purity of 99.21%. Moreover, Aripiprazole phosphate is not hygroscopic, as shown in some crystalline forms of aripiprazole base (WO 03/026659).

From a chemical point of view, our product is a salt containing the component described by formula I and phosphoric acid (H3PO4) in a 1: 1 ratio. The chemical structure of the salt we obtain can be described by the formula ΓΙ

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(Π)

The salt obtained can be expected to be effective in the treatment of schizophrenia and bipolar disorders as well as aripiprazole free base. An economical process for the preparation of this salt has been found which can also be used on a production scale.

The present invention provides a process for the preparation of a salt of the phosphoric acid with 7- {4- [4- (2,3-dichlorophenyl) 1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one of formula II in crystalline form, having an HPLC purity of 99.5% and above, with individual impurity contents below 0.1%, with a melting point also in the range of 186-191 ° C, having a DSC with a maximum near 189 ° C, including tautomers and solvates thereof.

The process of the present invention is characterized by reacting 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one I with concentrated phosphoric acid or its solution in ethanol, the reaction being carried out in ethanol or ethyl acetate, optionally mixed with water. The production of salt II is carried out at a temperature of from 60 ° C to the boiling point of the solvent used, ensuring good solubility of the starting component I. The process for preparing salt II is described in the equations in Scheme 1.

Scheme 1

The choice of solvent depends on the solubility of the starting material and the product. If a pre-prepared acid solution is used, it is a solution in ethanol or water.

An extraordinary advantage of the preparation of the new aripiprazole salt is its easy isolation and excellent cleaning ability to convert to salt. With a simple operation it is easy to achieve a chemical purity of at least 99.5% and higher, with individual impurity contents below 0.1%, ie. API substance purity;

The preferred salt form II is the crystalline form, which is chemically stable, chemically highly pure (HPLC over 99.5%), which can be prepared with high yields in a defined crystal modification. These conditions meet the crystalline form of salt II prepared by us.

The crystalline structure of the salt of formula II was unambiguously characterized by the results of the following analytical methods; X-ray powder diffraction (XRPD), melting point, differential scanning calorimetry (DSC), ¹³ C CP-MAS NMR. The results of the analyzes are presented in examples and annexes.

The novel aripiprazole II salt obtained can in practice be advantageously used for the purification of aripiprazole.

The following examples illustrate the invention in more detail, but do not affect the scope of the invention as defined in the claims.

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Summary of the drawings

Giant. 1 is an XRPD pattern of the crystalline aripiprazole phosphate salt.

Giant. 2 shows a DSC curve of the crystalline aripiprazole phosphate salt.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 - Preparation of phosphate in ethanol

To a solution of 4 g of Aripiprazole in 100 ml of ethanol at 60 ° C was added 0.5 ml of H 3 PO 4 phosphoric acid. After cooling to room temperature, a viscous mass precipitated at the bottom of the flask and boiled to form a thick white slurry at reflux for 30 min. The product was filtered off and dried at 60 ° C. Melting point 186-191 ° C. Water content 0.3% wt. HPLC purity was 99.21%,

Example 2 - Preparation of phosphate in ethyl acetate

To a solution of 10 g of Aripiprazole in 200 mL of ethyl acetate at 65 ° C was added 1.3 mL of H 3 PO 4 phosphoric acid. After cooling to room temperature, a viscous mass precipitated at the bottom of the flask and boiled to form a thick white slurry at reflux for 50 min. The product was filtered off and dried at 60 ° C. Melting point 186-191 ° C. Water content 0.15% wt.

Analytical Data (A-G): The following analytical data unambiguously characterizes the crystalline salt of aripiprazole phosphate of Formula II.

A X-ray powder diffraction (XRPD)

The XRPD pattern of the crystalline aripiprazole phosphate II salt prepared according to Example 1 is shown in Figure 1.

The diffraction pattern was measured using an X'PERT PRO MPD PANalytical diffractometer under the following experimental conditions:

Radiation: CuKa (λ = 1.5402 Å)

Monochromator: graphite

Excitation voltage: 45 kV Anode current: 40 mA Measured range: 4 - 40 ° 20 Step size: 0,004 20

Flat sample with a surface / thickness of 10 / 0.5 mm

B Melting point

The melting point of crystalline aripiprazole phosphate II salts was measured on a Kofler block with a sample heating rate of 10 ° C (up to 150 ° C) and 4 ° C (above 150 ° C) per minute. The measured melting points are in the temperature range of 180 to 200 ° C. Typical melting points are given in Examples 1 and 2.

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C Differential Scanning Calorimetry (DSC)

DSC records were measured on a Perkin Elmer PYRIS I. The measurements were made for samples weighing 3-6 mg of the substance. The samples are heated in the temperature range of 20 to 210 ° C with a heating rate of 10 ° C per minute. The measured DSC curve is shown in Figure 2. The crystalline salt of aripiprazole phosphate II shows a maximum at 189.2 ° C.

Claims (2)

PATENT CLAIMS A process for the preparation of a phosphoric acid salt of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] 15-butoxy} -1,2,3,4-tetrahydroquinolin-2-one of formula II (Π) in crystalline form, having an HPLC purity of 99,5% or more, with individual impurity contents of 20 below 0,1%, with a melting point in the range of 186 to 191 ° C, having a DSC with a maximum near 189 ° C, including tautomers thereof; solvates, characterized in that 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -1,2,3,4-tetrahydroquinolin-2-one of formula I is reacted with concentrated acid The reaction is carried out in ethanol or ethyl acetate, optionally mixed with water, at a temperature of from 60 ° C to the boiling point of the solvent used. The process according to claim 1, wherein the reaction is carried out in ethanol at 30 reflux.