EA028171B1 - Method of preparing a highly pure potassium salt of azilsartan medoxomil - Google Patents

Abstract

A method of preparing the potassium salt of azilsartan medoxomil of formula I, in which a solvate of azilsartan medoxomil of formula II with a solvent selected from the group that consists of dimethyl acetamide or N-methyl pyrrolidone or their mixtures with other solvents is prepared, or re-crystallized from dimethyl acetamide or N-methyl pyrrolidine or their mixtures with other solvents, and, in the next step, converted to the potassium salt using a potassium source in a suitable solvent.

Description

The present invention relates to a method for producing potassium salt of (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester 1 - [[2 '- (2,5-dihydro-5-oxo-1,2, 4-oxadiazol-3-yl) [1,1'-diphenyl] -4-yl] methyl] -2-ethoxy-1H-benzimidazole-7-carboxylic acid of the formula (I) (potassium salt of azilsartan medoxomil)

The potassium salt of azilsartan medoxomil (I), the synthesis of which is disclosed in documents EP 1718641, EP 2119715, is used in the treatment of hypertension. Azilsartan medoxomil is a prodrug that is readily converted enzymatically to azilsartan, a highly selective angiotensin II AT1 receptor antagonist.

According to patent EP 2119715, azilsartan medoxomil is obtained by reacting the free acid of azilsartan with alcohol medoxomil, resulting in the preparation of azilsartan medoxomil as a solvate with dimethylacetamide. It is then converted by crystallization of the product from an acetone / water mixture to desolvated azilsartan medoxomil, which is then converted to the potassium salt (I).

The present invention provides a method for producing a potassium salt of azilsartan medoxomil of formula (I)

which consists in first obtaining the solvate of azilsartan medoxomil of formula II

with a solvent consisting of dimethylacetamide or Ν-methylpyrrolidone or mixtures thereof with other solvents, the resulting solvate is optionally recrystallized, and in the next step it is converted without desolvation to a potassium salt using a potassium source.

The potassium source is, for example, the potassium salt of 2-ethylhexanoic acid, and the solvent used to convert to the potassium salt is, for example, acetone.

Azilsartan medoxomil (II), obtained in accordance with patent EP 2119715, exhibits a maximum purity of 98.0%, determined using high performance liquid chromatography (HPLC). Neither its desolvation according to the patent from an acetone / water mixture, nor recrystallization from an acetone / water mixture practically leads to any additional purification of the substance. Thus, such a crude substance is unsuitable for pharmaceutical production. The inventors have already dealt with the purification of azilsartan medoxomil in their previous application C / 2012-274, where they used solvates with acetone, tetrahydrofuran or 1,2-dimethoxyethane to obtain solvates for purification.

With the new method, the inventors unexpectedly found that the resulting crude

- 1 028171 a product in the form of a solvate with dimethylacetamide can be recrystallized in such a way that the product is still in the form of a solvate with dimethylacetamide or a solvate with Ν methylpyrrolidone, and the solvates obtained in this way can be easily converted to a pure potassium salt. The biggest advantage of this method is that crystallization of azilsartan medoxomil in the form of solvates with dimethylacetamide or Ν-methylpyrrolidone cleans the substance from both impurities A and B, which are practically not removed by desolvation according to the previous patent.

Admixture A

Admixture In

ABOUT

Table 1

HPLC purity of forms obtained by crystallization of azilsartan medoxomil

T verifying the form Note Exit Purity HPLC Contained Ie impurities A Contained Ie impurities B Azilsartan medoxomil uncleaned th Starting material received in accordance with EP 2119715 80.1% 97.59% 0.5% 0.34% Azilsartan medoxomil nonsolvatir o-bath Crystallized from the mixture acetone / water in accordance with EP 2119715 96% 98.2% 0.35% 0.34% Azilsartan medoxomil MES dimethyl acetate amide Crystallized from the mixture dimethylacetamide / isopropyl- acetate 90% 99.77% 0.03% 0.09% Azilsartan medoxomil MES Ν- methylpyrro lidon Crystallized from the mixture Ν- methylpyrrolidone / isopropyl- acetate 69% 99.84% 0.02% 0.08%

Interestingly, both of these solvates can also be obtained from the unsolvated form of azilsartan medoxomil by crystallization from dimethylacetamide / isopropyl acetate or Ν methylpyrrolidone / isopropyl acetate mixtures, while structurally similar dimethylformamide does not form a solvate under these conditions. Solid forms of azilsartan medoxomil can be described by methods commonly used to characterize the solid phase, such as X-ray powder diffraction (XRD), differential scanning calorimetry (DSC). The solvate of azilsartan medoxomil with dimethylacetamide (1: 1) exhibit the following main characteristic peaks in a powder X-ray diffractogram measured using CuKa radiation: 11.0; 12.1; 17.2, 25.3 ± 0.2 ° 2θ, and, in addition, the following additional characteristic peaks: 11.8; 19.5; 22.2; 24.3 ± 0.2 ° 2θ.

The list of characteristic peaks is given in table. 2, and the XRD pattern is shown in FIG.

- 2 028171

3. This form is also characterized by a differential scanning calorimetry (DSC) graph, see FIG. 4. The melting point of this form is 110-113 ° C.

table 2

PRD - characteristic diffraction peaks corresponding to the solvate of azilsartan medoxomil with dimethylacetamide

Position [° 2 Theta] Interplanar spacing [A] = 0.1 nm Relative intensity [%] 5.89 14,981 18.8 10.95 8,074 100.0 11.78 7,506 24.3 12.14 7,283 50,4 12.59 7,027 17.9 15.26 5,800 20.3 16.24 5,454 35.5 17.16 5,164 50.3 19.04 4,657 59.6 19.45 4,561 28,4 20.28 4,376 10.7 21.79 4,076 26.3 22.25 3,992 39.9 22.64 3,925 22.6 22.93 3,875 18,4 24.30 3,661 35.5 25.27 3,521 38,0 26.19 3,400 18.0 27.15 3,282 21.5 28.37 3,143 6.9 29.19 3,057 6.6

The solvate of azilsartan medoxomil with dimethylacetamide can be obtained by crystallization from dimethylacetamide and another solvent in which azilsartan medoxomil is soluble only to a limited extent, such as isopropyl acetate, isobutyl acetate, ethyl acetate, methyl acetate, acetone, methyl ethyl ketone and methyl isobutyl ketone. Crystallization is carried out at a temperature in the range from 10 to 100 ° C.

The potassium salt of azilsartan medoxomil is characterized by the following main peaks measured using CuKa radiation: 6.15, 13.96, 18.72 and 21.37 ± 0.2 ° 2θ. The characteristic peaks of the PRD are presented in table. 3, and the XRD pattern is shown in FIG. 1. This form is further characterized by a differential scanning calorimetry (DSC) graph, see FIG. 2.

Table 3

PRD - characteristic diffraction peaks corresponding to the potassium salt of azilsartan medoxomil

Position [° 2 Theta] Interplanar spacing [A] = 0.1 nm Relative intensity [%] 6.15 14,366 100.0 13.33 6,635 3.8 13.96 6,338 7.4 14.74 6,007 4.1 15,55 5,693 4.1 16.98 5,217 2.2 18.72 4,736 9.6 21.37 4,156 8.0 22.78 3,900 5.0 23.76 3,742 3.5 24.40 3,645 3.1 25.56 3,482 2.8 26.83 3,320 2.6 27.47 3,244 3.7 31.26 2,859 2.2 33.76 2,653 2.2

- 3 028171

The solvate of azilsartan medoxomil with метил-methylpyrrolidone is characterized by the following main characteristic peaks in the X-ray powder diffraction pattern, measured using CuKa radiation: 10.9; 16.3; 17.2; 18.9 ± 0.2 ° 2θ. The characteristic peaks of the PRD are presented in table. 4, and the XRD pattern is shown in FIG. 5. This form is further characterized by a differential scanning calorimetry (DSC) graph, see FIG. 6.

Table 4

PRD - characteristic diffraction peaks corresponding to the solvate of azilsartan medoxomil with метил-methylpyrrolidone

The solvate of azilsartan medoxomil with метил-methylpyrrolidone can be obtained by crystallization from Ν-methylpyrrolidone and another solvent in which azilsartan is only soluble to a limited extent, such as isopropyl acetate, isobutyl acetate, ethyl acetate, methyl acetate, acetone, methyl ethyl ketone and methyl isobutyl. Crystallization is carried out at a temperature in the range from 10 to 100 ° C.

A brief description of the graphic materials

FIG. 1 - XRD pattern for the potassium salt of azilsartan medoxomil; FIG. 2 is a DSC graph for the potassium salt of azilsartan medoxomil;

FIG. 3 - XRD pattern for solvate of azilsartan medoxomil with dimethylacetamide; FIG. 4 is a DSC graph for a solvate of azilsartan medoxomil with dimethylacetamide; FIG. 5 is an XRD pattern for a solvate of azilsartan medoxomil with ила-methylpyrrolidone; FIG. 6 is a DSC graph for a solvate of azilsartan medoxomil with метил-methylpyrrolidone.

The invention is explained below in more detail in the working examples. These examples are for illustrative purposes only and do not limit the scope of the invention in any aspect.

Examples

The samples in the examples below were characterized using powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC) methods. The amount of solvent was determined using gas chromatography (GC).

HPLC Measurements.

Column Type C18, 5 μm, 250x4.6 mm, conditions: buffer (No. I ₂ PO ₄ ), pH 3; phase A, phase B - acetonitrile._

Time (min) Phase A (%) Phase B (%) 5 60 40 25 10 90 thirty 10 90 35 60 40

- 4 028171

Parameters of measurement X-ray diffraction patterns were measured using an X'REKT analytical diffractometer with a graphite monochromator using CuKa radiation (λ = 1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2-40 ° 2θ, increment: 0 , 01 ° 2θ. The measurement was carried out using a flat powder sample placed on a δί plate. For the primary optical setup, diaphragms with programmable divergence with a sample irradiation area of 10 mm, a Soller diaphragm of 0.02 rad, and an anti-dispersion diaphragm of% were used. For a secondary optical setup, an X'Se1et1ot detector was used with a maximum opening of the detector slit, a Soller diaphragm of 0.02 rad, and an anti-dispersion diaphragm of 5.0 mm.

Differential scanning calorimetry (DSC) plots were measured using a DSC Root18 1 device manufactured by Regksh E1teg. The loading of the sample into a standard aluminum container was 3-4 mg and the heating rate was 10 ° C./min. The temperature program used consists of 1 min of stabilization at a temperature of 50 ° C, and then heating to 250 ° C at a heating rate of 10 ° C / min. As a carrier gas, 4.0 Ν _{2 was used} at a flow rate of 20 ml / min.

Example 1. Obtaining crude azilsartan medoxomil according to EP 2119715.

4-Toluenesulfonyl chloride (19 g), 4-dimethylaminopyridine (2.5 g) and potassium carbonate (18 g) were added to a solution of 2-ethoxy-1 - ((2 '- (5-oxo-4,5-dihydro-1 , 2,4-oxadiazol-3-yl) diphenyl-4-yl) methyl) -1H-benzo [b] imidazole-7-carboxylic acid (42.8 g, 0.1 mol) and 4-hydroxymethyl-5- methyl-1,3-dioxol-2-one (16.3 g, 0.125 mol) in dimethylacetamide (450 ml) under cooling and the mixture was stirred at 810 ° C for 3 hours. Then the pH of the mixture was adjusted to 4.5- 5, using dilute hydrochloric acid and the insoluble fraction separated after the addition of water, were suctioned off and washed with water. After this, the crude product was suspended in water-acetone and the mixture was stirred at 35 ° C for 2 hours. After stirring for another 2 hours in an ice bath, the insoluble fraction was sucked off, washed with water and dried in vacuum at 40 ° C. Received 42.7 g of substance (80.1%). HPLC purity: 97.6%.

Example 2. Obtaining crude azilsartan medoxomil in the form of a solvate with dimethylacetamide according to EP 2119715.

4-Toluenesulfonyl chloride (22 g), 4-dimethylaminopyridine (1.6 g) and potassium carbonate (18.4 g) were added to the solution of 2-ethoxy-1 - ((2 '- (5-oxo-4,5-dihydro -1,2,4-oxadiazol-3-yl) diphenyl-4-yl) methyl) -1Nbenzo [b] imidazole-7-carboxylic acid (40 g) and 4-hydroxymethyl-5-methyl-1,3- dioxol-2-one (15 g) in dimethylacetamide (400 ml) under cooling and the mixture was stirred at 30 ° C for 3 hours. Then the pH of the mixture was adjusted to 4.5-5 using acetic acid, and after adding water (210 ml) product, 49.7 g (86.4%), precipitated as a solvate with dimethylacetamide. HPLC 97.3%.

Example 3. Obtaining unsolvated azilsartan medoxomil.

The crude azilsartan medoxomil obtained in accordance with Example 2 (10 g) was dissolved in acetone / water (7: 3, 150 ml) under reflux. After cooling to laboratory temperature (25 ° C), the separated crystals were sucked off and dried. Yield 7.8 g (78%). HPLC purity: 98.2%.

Example 4. Obtaining azilsartan medoxomil in the form of a solvate with dimethylacetamide.

The crude azilsartan medoxomil obtained in accordance with Example 2 was dissolved in a hot mixture of dimethylacetamide (4 ml) and isopropyl acetate (6 ml); after cooling and suction, 3.6 g (90%) of the product are obtained, HPLC purity 99.77%.

Example 5. Obtaining azilsartan medoxomil in the form of a solvate with Ν-methylpyrrolidone.

The crude azilsartan medoxomil obtained in accordance with Example 2 was dissolved in a mixture of Ν-methylpyrrolidone (4 ml) with isopropyl acetate (7 ml) while hot; after cooling and suction, 2.8 g (69%) of the product are obtained, HPLC purity 99.84%.

Example 6. Obtaining the potassium salt of azilsartan medoxomil.

The solvate of azilsartan medoxomil with dimethylacetamide (3 g) was dissolved in 60 ml of acetone at 45 ° C and the potassium salt of 2-ethylhexanoic acid (1.1 g, 75% solution) was added. After cooling and suctioning the product and drying it at 65 ° C and in vacuum, 2.14 g (77%) were obtained, HPLC purity 99.90%, water content 0.02%.

Example 7. Obtaining the potassium salt of azilsartan medoxomil.

The solvate of azilsartan medoxomil with метил-methylpyrrolidone (3 g) was dissolved in 60 ml of acetone at 45 ° C and the potassium salt of 2-ethylhexanoic acid (1.1 g, 75% solution) was added. After cooling and suctioning the product and drying it at 65 ° C and in vacuum, 2.2 g (80.7%) were obtained, HPLC purity 99.91%, water content 0.04%.

Starting 2-ethoxy-1 - ((2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) diphenyl-4-yl) methyl) -1Nbenzo [b] imidazole -7-carboxylic acid (III) was obtained in accordance with the following scheme:

- 5 028171

Example 8. Obtaining ethyl ester 2-ethoxy-1 - ((2 '- (5-oxo-4,5-dihydro-1,2,4oxadiazol-3-yl) diphenyl-4-yl) methyl) -1 N -benzo [ά] -imidazole-7-carboxylic acid (V).

The starting amidoxime (IV) was suspended in diethyl carbonate (30 g) and sodium ethylate (21% in ethanol, 9 g) was added. The mixture was heated at 80 ° C for 2 hours, 20 ml of the solvent was removed by distillation, ethanol (20 ml), water (20 ml) and acetic acid (3 g) were added, as well as additional water (20 ml). The suspension was stirred at 50 ° C for 1 h and cooled to 25 ° C. Received 8 g (76%) of the product.

Example 9. Obtaining 2-ethoxy-1 - ((2 '- (5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) diphenyl-4yl) methyl) -1H-benzo [b ] -imidazole-7-carboxylic acid (III).

The starting ethyl ester of azilsartan (V, 250 g) was suspended in a solution of sodium hydroxide in water (56 g / 800 ml). The suspension was heated at 50 ° C for 4 hours, after adjusting the pH to 4-5, the product crystallized to give 232 g (98.5%).

Claims (13)

CLAIM 1. A method of producing a potassium salt of azilsartan medoxomil of formula I characterized in that a solvate of azilsartan medoxomil of formula II is obtained with a solvent selected from the group consisting of dimethylacetamide or Ν-methylpyrrolidone, wherein the solvate is recrystallized from dimethylacetamide or Ν-methylpyrrolidone, or mixtures thereof with other solvents selected from the group consisting of isopropyl acetate, isobutyl acetate, ethyl acetate, methyl acetate, acetone, methyl ethyl ketone and methyl isobutyl ketone, and in the next step convert it to potassium using a source of potassium in a suitable solvent. 2. The method according to claim 1, characterized in that the other solvent is isopropyl acetate. 3. Solvate of azilsartan medoxomil with dimethylacetamide. 4. The solvate of azilsartan medoxomil with dimethylacetamide according to claim 3, exhibiting the following main characteristic peaks in a powder X-ray diffractogram measured using CuKa radiation: 11.0; 12.1; 17.2, 25.3 ± 0.2 ° 2θ. 5. The solvate of azilsartan medoxomil with dimethylacetamide according to claim 4, showing the following additional characteristic peaks in the powder x-ray diffractogram: 11.8; 19.5; 22.2; 24.3 ± 0.2 ° 2θ. 6. The solvate of azilsartan medoxomil with dimethylacetamide obtained by the method according to claim 1 or 2. 7. Solvate of azilsartan medoxomil with метил-methylpyrrolidone. 8. The solvate of azilsartan medoxomil with метил-methylpyrrolidone according to claim 7, showing the following main characteristic peaks in a powder X-ray diffraction pattern using CuKa radiation: 10.9; 16.3; 17.2; 18.9 ± 0.2 ° 2θ. 9. The solvate of azilsartan medoxomil with метил-methylpyrrolidone according to claim 8, showing the following additional characteristic peaks in a powder X-ray diffraction pattern using CuKa radiation: 11.7; 24.2; 26.3. 10. The solvate of azilsartan medoxomil with метил-methylpyrrolidone obtained by the method according to claim 1. 11. The method according to claim 1, characterized in that the potassium source is a potassium salt of 2 ethylhexanoic acid. 12. The method according to claim 1 or 11, characterized in that the solvent used for conversion - 6,028,171 azilsartan medoxomil in potassium salt, is acetone. 13. The potassium salt of azilsartan medoxomil, obtained according to any one of claims 1, 11 or 12, exhibiting the following main characteristic peaks in a powder X-ray diffraction pattern, measured using CuKa radiation: 6.15; 13.96; 18.72 and 21.37 ± 0.2 ° 2θ.