WO2013156005A1 - Method of preparing potassium salt of azilsartan medoxomil of high purity - Google Patents

Method of preparing potassium salt of azilsartan medoxomil of high purity Download PDF

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Publication number
WO2013156005A1
WO2013156005A1 PCT/CZ2013/000049 CZ2013000049W WO2013156005A1 WO 2013156005 A1 WO2013156005 A1 WO 2013156005A1 CZ 2013000049 W CZ2013000049 W CZ 2013000049W WO 2013156005 A1 WO2013156005 A1 WO 2013156005A1
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Prior art keywords
azilsartan medoxomil
solvate
potassium salt
tetrahydrofuran
acetone
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PCT/CZ2013/000049
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French (fr)
Inventor
Sharmarke MOHAMED
Ludek Ridvan
Stanislav Radl
Josef Cerny
Ondrej Dammer
Lukas KREJCIK
Jan Stach
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Zentiva, K.S.
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Priority to EP13725551.9A priority Critical patent/EP2838896A1/en
Publication of WO2013156005A1 publication Critical patent/WO2013156005A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates to new forms of (5-methyl-2-oxo-l ,3-dioxol-4-yl)methyl ester of l-[[2'- (2,5-dihydro-5-oxo-l ,2,4-oxadiazol-3-yl)[l,l'-biphenyl]-4-yl]methyl]-2-ethoxy-lH- benzimidazole-7-carboxylic acid (azilsartan medoxomil) of formula I and methods of their preparation.
  • the invention also relates to use of these new forms in preparing the potassium salt of azilsartan medoxomil.
  • Azilsartan medoxomil the synthesis of which is described in EP1718641 and EP21 19715, is used in treating high blood pressure.
  • Azilsartan medoxomil is the so-called prodrug, which can be easily enzymatically transformed to azilsartan, a highly selective blocker of angiotensin II ATI receptors.
  • Azilsartan medoxomil is a substance of very low water solubility. Generally, it is know that physico-chemical properties of organic active substances are influenced by their crystal structure. Discovery of new solid forms (polymorphs, solvates and/or salts and co-crystals) is, particularly in substances of low solubility, an opportunity to increase solubility and, subsequently, bio-availability. Currently, experimental finding of new crystal forms is difficult and unpredictable. Examples in EP1718641 mention preparation of salts of azilsartan medoxomil (sodium, potassium, calcium). So far, no solid forms of the neutral form of azilsartan medoxomil have been described and characterized.
  • the invention relates to a method of preparing the potassium salt of azilsartan medoxomil, which consists in preparing a solvate of azilsartan medoxomil of formula (I)
  • a solvent selected from the group consisting of acetone, tetrahydrofuran or 1 ,2- dimethoxyethane which is optionally recrystallized and, in the following step, converted to the potassium salt by means of a source of potassium.
  • the source of potassium is the potassium salt of 2-ethylhexanoic acid.
  • the solvent used in the conversion to the potassium salt is tetrahydrofuran.
  • the invention also relates to solvates of azilsartan medoxomil with acetone, tetrahydrofuran, and 1,2-dimethoxyethane, which are prepared at a temperature ranging from 40°C to the boiling point of the solution.
  • Solid forms of azilsartan medoxomil can be described by methods common in characterizing the solid phase, such as e.g. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and/or Raman spectroscopy.
  • Characteristic for the desolvated crystal form of azilsartan medoxomil are diffraction peaks presented in Table 2 and the XRPD pattern in Figure 1.
  • this form is characterized by the differential scanning calorimetry (DSC) record, see Figure 2.
  • the melting point of this form ranges between roughly 177 and 180°C.
  • Desolvated azilsartan medoxomil contains small amounts of residual organic solvents, namely less than 1.0%, and typically less than 0.5%.
  • the potassium salt of azilsartan medoxomil has characteristic XRPD peaks presented in Table 3 and the XRPD pattern given in Figure 3. In addition, this form is characterized by the differential scanning calorimetry (DSC) record, see Figure 4.
  • Table 3 XRPD - characteristic diffraction peaks corresponding to the potassium salt of azilsartan medoxomil
  • the solvate of azilsartan medoxomil with acetone has characteristic XRPD peaks presented in Table 4 and the XRPD pattern given in Figure 5. In addition, this form is characterized by the record of differential scanning calorimetry (DSC), see Figure 6. The content of acetone in the crystalline sample ranges roughly between 6 and 10% by weight.
  • the solvate with acetone is prepared from non-solvated azilsartan medoxomil in acetone at temperature ranging from 40°C to the boiling point of the solution.
  • the solvate of azilsartan medoxomil with tetrahydrofuran has characteristic XRPD peaks presented in Table 5 and the XRPD pattern given in Figure 7. In addition, this form is characterized by the record of differential scanning calorimetry (DSC), see Figure 8. The content of tetrahydrofuran in the crystalline sample ranges roughly between 8 and 12% by weight.
  • the solvate with tetrahydrofuran is prepared from non-solvated azilsartan medoxomil in tetrahydrofuran at temperature ranging from 40°C to the boiling point of the solution. Table 5: XRPD - characteristic diffraction peaks corresponding to the solvate of azilsartan medoxomil with tetrahydrofuran
  • the solvate of azilsartan medoxomil with 1 ,2-dimethoxyethane has characteristic. XRPD peaks presented in Table 6 and the XRPD pattern given in Figure 9. In addition, this form is characterized by the record of differential scanning calorimetry (DSC), see Figure 10. The content of 1 ,2-dimethoxyethane in the crystalline sample ranges roughly between 6 and 14% by weight.
  • the solvate with 1 ,2-dimethoxyethane is prepared from non-solvated azilsartan medoxomil in 1 ,2-dimethoxyethane at temperature ranging from 40°C to the boiling point of the solution.
  • Figure 1 XRPD pattern of non-solvated crystal form of azilsartan medoxomil
  • Figure 2 DSC record of non-solvated crystal form of azilsartan medoxomil
  • Figure 3 XRPD pattern of potassium salt of azilsartan medoxomil
  • Figure 4 DSC record of potassium salt of azilsartan medoxomil
  • Figure 5 XRPD pattern of solvate of azilsartan medoxomil with acetone
  • Figure 6 DSC record of solvate of azilsartan medoxomil with acetone
  • Figure 7 XRPD pattern of solvate of azilsartan medoxomil with tetrahydrofuran
  • Figure 8 DSC record of solvate of azilsartan medoxomil with tetrahydrofuran
  • Figure 9 XRPD pattern of solvate of azilsartan medoxomil with 1 ,2-dimethoxyethane
  • Figure 10 DSC record of solvate of azilsartan medoxomil with 1 ,2-dimethoxyethane
  • the samples in the following examples were characterized by the method of powder X-ray diffraction (XRPD) and by differential scanning calorimetry (DSC). The amounts of solvents were determined by GC.
  • the primary optics was adjusted using programmable divergence diaphragms with irradiated area of the sample 10 mm, Soller diaphragm 0.02 rad, and anti-scattering diaphragm 1 ⁇ 4.
  • the secondary optics was adjusted using a detector X'Celerator with maximum opening of the detection aperture, Soller diaphragm 0.02 rad, and anti-scattering diaphragm 5.0 mm.
  • the differential scanning calorimetry (DSC) measurements were performed using a Pyris 1 DSC calorimeter from Perkin Elmer. The weighed amount of the sample in a standard Al pan was 3 - 4 mg, heating rate 10°C/min. The temperature program included stabilization at 50°C for 1 minute and heating to 250°C at a heating rate of 10°C/min. The purge gas was 4.0 N 2 of flow rate 20 ml/min.
  • the solvent was determined by the method of gas chromatography on an instrument Agilent 7890 with FI detection.
  • Capillary column DB-624 (30 m, 0.53 mm ID, 3.0 ⁇ df) or equivalent Temperature program: - 2 min, gradient 10°C /min to 170°C - 0 min,
  • Carrier gas helium for chromatography R; 35 cm/s, constant flow rate
  • Example 7 Preparation of the potassium salt of azilsartan medoxomil from the acetone solvate of azilsartan medoxomil
  • the azilsartan medoxomil solvate (7 g) from Example 4 was dissolved in tetrahydrofuran (250 ml). After cooling to 0°C, a solution of 2-ethylhexanoic acid potassium salt (2.2 g) in tetrahydrofuran (20 ml) was added dropwise. After stirring at 0°C for 1 hour, the precipitated crystals were sucked off and dried. Yield: 5.3 g (78%). HPLC purity: 99.8%.
  • Example 8 Preparation of the potassium salt of azilsartan medoxomil from the tetrahydrofuran solvate of azilsartan medoxomil
  • the azilsartan medoxomil solvate (3.5 g) prepared according to Example 5 was dissolved in tetrahydrofuran (150 ml). After cooling to 0°C, a solution of 2-ethylhexanoic acid potassium salt (1.2 g) in tetrahydrofuran (10 ml) was added dropwise. After stirring at 0°C for 1 hour, the precipitated crystals were sucked off and dried. Yield: 2.8 g (85%). HPLC purity: 99.6%.
  • Example 9 Preparation of the potassium salt of azilsartan medoxomil from the 1 ,2- dimethoxyethane solvate of azilsartan medoxomil
  • the azilsartan medoxomil solvate (3 g) prepared according to Example 6 was dissolved in tetrahydrofuran (100 ml). After cooling to 0°C, a solution of 2-ethylhexanoic acid potassium salt (1.2 g) in tetrahydrofuran (10 ml) was added dropwise. After stirring at 0°C for 1 hour, the precipitated crystals were sucked off and dried. Yield: 2.3 g (83%). HPLC purity: 99.7%.
  • Example 13 Preparation of non-solvated azilsartan medoxomil Crude azilsartan medoxomil (1 g) was hot-dissolved in methylacetate and, after cooling, 0.65 g (65%) of the product was obtained. HPLC purity: 98.1%.
  • Example 14 Preparation of non-solvated azilsartan medoxomil
  • Example 16 Preparation of non-solvated azilsartan medoxomil Crude azilsartan medoxomil (1 g) was dissolved in aqueous potassium carbonate (10 ml, 10%); acetone (10 ml) was added and the product was re-precipitated with acetic acid (3 ml). 0.74 g (74%) of the product was obtained. HPLC purity: 98.1 %.
  • Example 17 Preparation of non-solvated azilsartan medoxomil Crude azilsartan medoxomil (1 g) was dissolved in dimethylsulfoxide and, after adding tert- butylmethylether, 0.81 g (81%) of the product was obtained. HPLC purity: 97.4%.

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Abstract

The present solution relates to new forms of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester of 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-yl]methyl]-2-ethoxy-1H- benzimidazole-7-carboxylic acid (azilsartan medoxomil) of formula I and a method of their preparation. The solution also relates to use of these new forms in preparing the potassium salt of azilsartan medoxomil.

Description

METHOD OF PREPARING POTASSIUM SALT OF AZILSARTAN MEDOXOMIL OF HIGH PURITY
Technical Field
This invention relates to new forms of (5-methyl-2-oxo-l ,3-dioxol-4-yl)methyl ester of l-[[2'- (2,5-dihydro-5-oxo-l ,2,4-oxadiazol-3-yl)[l,l'-biphenyl]-4-yl]methyl]-2-ethoxy-lH- benzimidazole-7-carboxylic acid (azilsartan medoxomil) of formula I and methods of their preparation. The invention also relates to use of these new forms in preparing the potassium salt of azilsartan medoxomil.
Figure imgf000002_0001
(I)
Background Art
Azilsartan medoxomil, the synthesis of which is described in EP1718641 and EP21 19715, is used in treating high blood pressure. Azilsartan medoxomil is the so-called prodrug, which can be easily enzymatically transformed to azilsartan, a highly selective blocker of angiotensin II ATI receptors.
Azilsartan medoxomil is a substance of very low water solubility. Generally, it is know that physico-chemical properties of organic active substances are influenced by their crystal structure. Discovery of new solid forms (polymorphs, solvates and/or salts and co-crystals) is, particularly in substances of low solubility, an opportunity to increase solubility and, subsequently, bio-availability. Currently, experimental finding of new crystal forms is difficult and unpredictable. Examples in EP1718641 mention preparation of salts of azilsartan medoxomil (sodium, potassium, calcium). So far, no solid forms of the neutral form of azilsartan medoxomil have been described and characterized.
Summary of Invention
The invention relates to a method of preparing the potassium salt of azilsartan medoxomil, which consists in preparing a solvate of azilsartan medoxomil of formula (I)
Figure imgf000003_0001
(I)
with a solvent selected from the group consisting of acetone, tetrahydrofuran or 1 ,2- dimethoxyethane, which is optionally recrystallized and, in the following step, converted to the potassium salt by means of a source of potassium. The source of potassium is the potassium salt of 2-ethylhexanoic acid. The solvent used in the conversion to the potassium salt is tetrahydrofuran.
The invention also relates to solvates of azilsartan medoxomil with acetone, tetrahydrofuran, and 1,2-dimethoxyethane, which are prepared at a temperature ranging from 40°C to the boiling point of the solution.
All these forms are chemically stable and can be repeatedly prepared in the given crystalline form. Another advantage of these forms includes the fact that, during their preparation, their chemical purity is increased. By converting crude azilsartan medoxomil, obtained according to the procedure described in EP 2 1 19 715 with a HPLC purity of at most 98.0%, to the above- mentioned solid forms, it is possible to prepare a substance of chemical purity more than 99.0% and, using repeated crystallization, more than 99.5% (Table 1). Particularly preferred is azilsartan medoxomil, a solvate with acetone, which remarkably and surprisingly purifies the impurity A which is formed in the preceding steps and is difficult to purify; practically, it is not purified unless solvated forms are formed. Impurity A:
Figure imgf000004_0001
Table 1: HPLC purity of forms prepared by crystallization of crude azilsartan medoxomil
Figure imgf000004_0002
Solid forms of azilsartan medoxomil can be described by methods common in characterizing the solid phase, such as e.g. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and/or Raman spectroscopy. Characteristic for the desolvated crystal form of azilsartan medoxomil are diffraction peaks presented in Table 2 and the XRPD pattern in Figure 1. In addition, this form is characterized by the differential scanning calorimetry (DSC) record, see Figure 2. The melting point of this form ranges between roughly 177 and 180°C. Desolvated azilsartan medoxomil contains small amounts of residual organic solvents, namely less than 1.0%, and typically less than 0.5%.
Table 2: XRPD - characteristic diffraction peaks corresponding to desolvated crystal form of azilsartan medoxomil
Figure imgf000005_0001
The potassium salt of azilsartan medoxomil has characteristic XRPD peaks presented in Table 3 and the XRPD pattern given in Figure 3. In addition, this form is characterized by the differential scanning calorimetry (DSC) record, see Figure 4. Table 3: XRPD - characteristic diffraction peaks corresponding to the potassium salt of azilsartan medoxomil
Figure imgf000006_0001
The solvate of azilsartan medoxomil with acetone has characteristic XRPD peaks presented in Table 4 and the XRPD pattern given in Figure 5. In addition, this form is characterized by the record of differential scanning calorimetry (DSC), see Figure 6. The content of acetone in the crystalline sample ranges roughly between 6 and 10% by weight. The solvate with acetone is prepared from non-solvated azilsartan medoxomil in acetone at temperature ranging from 40°C to the boiling point of the solution.
Table 4: XRPD - characteristic diffraction peaks corresponding to the solvate of azilsartan medoxomil with acetone
Figure imgf000007_0001
The solvate of azilsartan medoxomil with tetrahydrofuran has characteristic XRPD peaks presented in Table 5 and the XRPD pattern given in Figure 7. In addition, this form is characterized by the record of differential scanning calorimetry (DSC), see Figure 8. The content of tetrahydrofuran in the crystalline sample ranges roughly between 8 and 12% by weight. The solvate with tetrahydrofuran is prepared from non-solvated azilsartan medoxomil in tetrahydrofuran at temperature ranging from 40°C to the boiling point of the solution. Table 5: XRPD - characteristic diffraction peaks corresponding to the solvate of azilsartan medoxomil with tetrahydrofuran
Figure imgf000008_0001
The solvate of azilsartan medoxomil with 1 ,2-dimethoxyethane has characteristic. XRPD peaks presented in Table 6 and the XRPD pattern given in Figure 9. In addition, this form is characterized by the record of differential scanning calorimetry (DSC), see Figure 10. The content of 1 ,2-dimethoxyethane in the crystalline sample ranges roughly between 6 and 14% by weight. The solvate with 1 ,2-dimethoxyethane is prepared from non-solvated azilsartan medoxomil in 1 ,2-dimethoxyethane at temperature ranging from 40°C to the boiling point of the solution.
Table 6: XRPD - characteristic diffraction peaks corresponding to the solvate of azilsartan medoxomil with 1,2-dimethoxyethane
Interplanar
Pos. distance [A] Rel. Int.
[°2Th.] = 0.1nm [%]
8.67 10.186 100.0
9.85 8.977 17.8
12.43 7.1 14 2.9
13.04 6.781 7.4
13.95 6.343 4.5
16.09 5.504 9.2
16.81 5.269 4.7
17.46 5.074 8.0
18.49 4.794 5.4
19.35 4.585 8.3
19.83 4.474 6.4
20.66 4.296 12.9
21.85 4.064 16.0
22.94 3.874 6.3
23.57 3.771 3.7
25.76 3.456 4.2
26.31 3.385 6.0
Thanks to their physico-chemical properties, all the-above described forms of azilsartan medoxomil can be used not only as intermediates for purification but also directly in preparing the dosage form.
Brief Description of Drawings
Figure 1: XRPD pattern of non-solvated crystal form of azilsartan medoxomil Figure 2: DSC record of non-solvated crystal form of azilsartan medoxomil Figure 3: XRPD pattern of potassium salt of azilsartan medoxomil Figure 4: DSC record of potassium salt of azilsartan medoxomil
Figure 5: XRPD pattern of solvate of azilsartan medoxomil with acetone Figure 6: DSC record of solvate of azilsartan medoxomil with acetone Figure 7: XRPD pattern of solvate of azilsartan medoxomil with tetrahydrofuran Figure 8: DSC record of solvate of azilsartan medoxomil with tetrahydrofuran Figure 9: XRPD pattern of solvate of azilsartan medoxomil with 1 ,2-dimethoxyethane Figure 10: DSC record of solvate of azilsartan medoxomil with 1 ,2-dimethoxyethane
Examples
The samples in the following examples were characterized by the method of powder X-ray diffraction (XRPD) and by differential scanning calorimetry (DSC). The amounts of solvents were determined by GC. XRPD measuring parameters: The diffraction patterns were measured using an X'PERT PRO MPD PANalytical diffractometer with graphite monochromator, radiation used: CuKa (λ = 0.1542 nm = 1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, step: 0.01° 2Θ. During the measurement, a flat powder sample was placed on a Si plate. The primary optics was adjusted using programmable divergence diaphragms with irradiated area of the sample 10 mm, Soller diaphragm 0.02 rad, and anti-scattering diaphragm ¼. The secondary optics was adjusted using a detector X'Celerator with maximum opening of the detection aperture, Soller diaphragm 0.02 rad, and anti-scattering diaphragm 5.0 mm.
The differential scanning calorimetry (DSC) measurements were performed using a Pyris 1 DSC calorimeter from Perkin Elmer. The weighed amount of the sample in a standard Al pan was 3 - 4 mg, heating rate 10°C/min. The temperature program included stabilization at 50°C for 1 minute and heating to 250°C at a heating rate of 10°C/min. The purge gas was 4.0 N2 of flow rate 20 ml/min.
Gas chromatography (GC): Method A: Monitoring of solvent content in the sample
The solvent was determined by the method of gas chromatography on an instrument Agilent 7890 with FI detection.
Chromatographic conditions:
Capillary column: DB-624 (30 m, 0.53 mm ID, 3.0 μιη df) or equivalent Temperature program: - 2 min, gradient 10°C /min to 170°C - 0 min,
Carrier gas: helium for chromatography R; 35 cm/s, constant flow rate
Injection: 1 μΐ
Injector: 200°C, split ratio 5: 1
Detector: FID, 260°C
Example 1: Preparation of crude azilsartan medoxomil according to EP21 19715
4-toluenesulfonyl chloride (19 g), 4-dimethylaminopyridine (2.5 g), and potassium carbonate (18 g) were added to a solution of 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3- yl)bifenyl-4-yl)methyl)-lH-benzo[ ]-imidazole-7-carboxylic acid (42.8 g, 0.1 mol) and 4- hydroxymethyl-5-methyl-l,3-dioxol-2-one (16.3 g, 0.125 mol) in dimethylacetamide (450 ml) under cooling, and the mixture was stirred at a temperature of 8 - 10°C for 3 hours. Then, pH of the mixture was adjusted to 4.5 - 5 by means of diluted hydrochloric acid and, after adding water, the precipitated insoluble portion was sucked off and washed with water. Then, the crude product was suspended in a water-acetone mixture and the mixture was stirred at 35°C for 2 hours. After additional stirring in an ice bath for 2 hours, the insoluble portion was sucked off, washed with water, and dried under vacuum at 40°C. 42.7 g of the substance (80.1%) was obtained. HPLC purity: 97.6%.
Example 2: Preparation of non-solvated azilsartan - comparative example
Crude azilsartan medoxomil prepared according to Example 1 (10 g) was dissolved in an acetone-water mixture (7:3, 150 ml) under reflux. After cooling to laboratory temperature (25°C), the precipitated crystals were sucked off and dried. Yield: 7.8 g (78%). HPLC purity: 98.2%.
Example 3: Preparation of non-solvated azilsartan medoxomil - comparative example
Crude azilsartan medoxomil from Example 1 (10 g) was hot-dissolved in 1 ,4-dioxane (100 ml); after cooling to 25°C, the suspension was filtered and the crystals were dried. Yield: 3.5 g (35%). HPLC purity: 98.1%. Example 4: Preparation of a solvate of azilsartan medoxomil with acetone
Crude azilsartan medoxomil prepared according to Example 1 (10 g), was dissolved in acetone (150 ml) under reflux. After cooling to laboratory temperature, the precipitated crystals were sucked off and dried. Yield: 9.0 g (82%). HPLC purity: 99.5%. Repeated crystallization provided a product of HPLC purity 99.7% and yield 88%.
Example 5: Preparation of a solvate of azilsartan medoxomil with tetrahydrofuran
Crude azilsartan medoxomil prepared according to Example 1 (10 g) was hot-dissolved in tetrahydrofuran (100 ml); after cooling to 25°C, the suspension was sucked off and 8.9 g (79%) was obtained. HPLC purity: 99.2%.
Example 6: Preparation of a solvate of azilsartan medoxomil with 1 ,2-dimethoxyethane
Crude azilsartan medoxomil prepared according to Example 1 (10 g) was hot-dissolved in 1 ,2- dimethoxyethane (100 ml); after cooling and filtration, 7.0 g (60%) was obtained. HPLC purity: 99.1%.
Example 7: Preparation of the potassium salt of azilsartan medoxomil from the acetone solvate of azilsartan medoxomil The azilsartan medoxomil solvate (7 g) from Example 4 was dissolved in tetrahydrofuran (250 ml). After cooling to 0°C, a solution of 2-ethylhexanoic acid potassium salt (2.2 g) in tetrahydrofuran (20 ml) was added dropwise. After stirring at 0°C for 1 hour, the precipitated crystals were sucked off and dried. Yield: 5.3 g (78%). HPLC purity: 99.8%.
Example 8: Preparation of the potassium salt of azilsartan medoxomil from the tetrahydrofuran solvate of azilsartan medoxomil
The azilsartan medoxomil solvate (3.5 g) prepared according to Example 5 was dissolved in tetrahydrofuran (150 ml). After cooling to 0°C, a solution of 2-ethylhexanoic acid potassium salt (1.2 g) in tetrahydrofuran (10 ml) was added dropwise. After stirring at 0°C for 1 hour, the precipitated crystals were sucked off and dried. Yield: 2.8 g (85%). HPLC purity: 99.6%.
Example 9: Preparation of the potassium salt of azilsartan medoxomil from the 1 ,2- dimethoxyethane solvate of azilsartan medoxomil
The azilsartan medoxomil solvate (3 g) prepared according to Example 6 was dissolved in tetrahydrofuran (100 ml). After cooling to 0°C, a solution of 2-ethylhexanoic acid potassium salt (1.2 g) in tetrahydrofuran (10 ml) was added dropwise. After stirring at 0°C for 1 hour, the precipitated crystals were sucked off and dried. Yield: 2.3 g (83%). HPLC purity: 99.7%.
Comparative Examples:
Example 10: Preparation of non-solvated azilsartan medoxomil
Crude azilsartan medoxomil (1 g) was hot-dissolved in methylisobutylketone and, after cooling, 0.76 g (76%) of the product was obtained. HPLC purity: 98.1%>.
Example 11: Preparation of non-solvated azilsartan medoxomil
Crude azilsartan medoxomil (1 g) was hot-dissolved in ethylmethylketone and, after cooling, 0.70 g (70%) of the product was obtained. HPLC purity: 98.5%.
Example 12: Preparation of non-solvated azilsartan medoxomil
Crude azilsartan medoxomil (1 g) was hot-dissolved in ethylacetate and, after cooling, 0.50 g (50%>) of the product was obtained. HPLC purity: 98.7%.
Example 13: Preparation of non-solvated azilsartan medoxomil Crude azilsartan medoxomil (1 g) was hot-dissolved in methylacetate and, after cooling, 0.65 g (65%) of the product was obtained. HPLC purity: 98.1%. Example 14: Preparation of non-solvated azilsartan medoxomil
Crude azilsartan medoxomil (1 g) was hot-dissolved in butylacetate and, after cooling, 0.64 g (64%) of the product was obtained. HPLC purity: 97.5%.
Example 15: Preparation of non-solvated azilsartan medoxomil
Crude azilsartan medoxomil (1 g) was hot-dissolved in acetonitrile and, after cooling, 0.84 g (84%) of the product was obtained. HPLC purity: 97.9%.
Example 16: Preparation of non-solvated azilsartan medoxomil Crude azilsartan medoxomil (1 g) was dissolved in aqueous potassium carbonate (10 ml, 10%); acetone (10 ml) was added and the product was re-precipitated with acetic acid (3 ml). 0.74 g (74%) of the product was obtained. HPLC purity: 98.1 %.
Example 17: Preparation of non-solvated azilsartan medoxomil Crude azilsartan medoxomil (1 g) was dissolved in dimethylsulfoxide and, after adding tert- butylmethylether, 0.81 g (81%) of the product was obtained. HPLC purity: 97.4%.

Claims

1. A method of preparing the potassium salt of azilsartan medoxomil, characterized in that a solvate of azilsartan medoxomil of formula I
Figure imgf000015_0001
with a solvent selected from the group consisting of acetone, tetrahydrofuran, or 1 ,2- dimethoxyethane is prepared, which is optionally recrystallized and, in the following step, converted to the potassium salt with a source of potassium in a solvent.
2. The method according to Claim 1, characterized in that the preparation of the solvate with acetone is carried out in acetone at a temperature ranging between 40°C and the boiling point of the solution.
3. The method according to Claim 1, characterized in that the preparation of the solvate with tetrahydrofuran is carried out in tetrahydrofuran at a temperature ranging between 40°C and the boiling point of the solution.
4. The method according to Claim 1, characterized in that the preparation of solvate with dimethoxyethane is carried out in dimethoxyethane at a temperature ranging between 40°C and the boiling point of the solution.
5. The method according to Claim 1, characterized in that the source of potassium is the potassium salt of 2-ethylhexanoic acid.
6. The method according to Claims 1 or 5, characterized in that the solvent used for conversion to the potassium salt is tetrahydrofuran.
7. A solvate of azilsartan medoxomil with acetone prepared according to Claims 1 or 2, which shows the following main characteristic peaks in the powder X-ray diffraction, measured using the radiation CuKa: 4.45°, 8.94°, 10.66°, 14.47°, and 22.73°; 2Θ ± 0.2° 2Θ.
8. The solvate according to Claim 7, which contains acetone in the range of 6 to 10% by weight.
9. A solvate of azilsartan medoxomil with tetrahydrofuran prepared according to Claims 1 or 3, which shows the following main characteristic peaks in the powder X-ray diffraction, measured using the radiation CuKa: 10.44°, 14.52°, 22.28°, and 24.14°; 2Θ ± 0.2° 2Θ.
10. The solvate according to Claim 9, which contains tetrahydrofuran in the range of 8 to 12% by weight.
1 1. A solvate of azilsartan medoxomil with 1 ,2-dimethoxyethane prepared according to Claims 1 or 4, which shows the following main characteristic peaks in the powder X- ray diffraction, measured using the radiation CuKa: 8.67°, 9.85°, and 21.85°; 2Θ ± 0.2° 2Θ.
12. The solvate according to Claim 1 1, which contains 1 ,2-dimethoxyethane in the range of 6 to 14% by weight.
13. The potassium salt of azilsartan medoxomil prepared according to any one of Claims 1 to 5, which shows the following main characteristic peaks in the powder X-ray diffraction measured using the radiation CuKa: 6.15°, 13.96°, 18.72°, and 21.37°; 2Θ ± 0.2° 2Θ.
PCT/CZ2013/000049 2012-04-19 2013-04-15 Method of preparing potassium salt of azilsartan medoxomil of high purity WO2013156005A1 (en)

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WO2017131218A1 (en) * 2016-01-28 2017-08-03 株式会社トクヤマ Azilsartan and method for producing same

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CZ305318B6 (en) * 2012-09-26 2015-07-29 Zentiva, K.S. Process for preparing extremely pure azilsartan medoxomil potassium salt

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EP2119715A1 (en) * 2004-02-25 2009-11-18 Takeda Pharmaceutical Company Limited Benzimidazole derivative and its use as aii receptor antagonist
WO2012090043A1 (en) * 2010-12-29 2012-07-05 Jubilant Life Sciences Limited Novel solid state forms of azilsartan medoxomil and preparation thereof
WO2013042067A1 (en) * 2011-09-20 2013-03-28 Ranbaxy Laboratories Limited Process for the preparation of potassium salt of azilsartan medoxomil

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EP2119715A1 (en) * 2004-02-25 2009-11-18 Takeda Pharmaceutical Company Limited Benzimidazole derivative and its use as aii receptor antagonist
WO2012090043A1 (en) * 2010-12-29 2012-07-05 Jubilant Life Sciences Limited Novel solid state forms of azilsartan medoxomil and preparation thereof
WO2013042067A1 (en) * 2011-09-20 2013-03-28 Ranbaxy Laboratories Limited Process for the preparation of potassium salt of azilsartan medoxomil

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017131218A1 (en) * 2016-01-28 2017-08-03 株式会社トクヤマ Azilsartan and method for producing same

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