WO2014048404A1 - A method of preparing a highly pure potassium salt of azilsartan medoxomil - Google Patents
A method of preparing a highly pure potassium salt of azilsartan medoxomil Download PDFInfo
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- WO2014048404A1 WO2014048404A1 PCT/CZ2013/000114 CZ2013000114W WO2014048404A1 WO 2014048404 A1 WO2014048404 A1 WO 2014048404A1 CZ 2013000114 W CZ2013000114 W CZ 2013000114W WO 2014048404 A1 WO2014048404 A1 WO 2014048404A1
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- azilsartan medoxomil
- solvate
- dimethyl acetamide
- potassium salt
- methyl
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a method of preparation of the potassium salt of (5 -methyl oxo-l,3-dioxol-4-yl)methyl ester of l-[[2'-(2,5-dihydro-5-oxo-l,2 5 4-oxadiazol-3-yl)[l,l'- biphenyl]-4-yl]methyl]-2-ethoxy-lH-benzimidazole-7-carboxylic acid of formula (T)
- azilsartan medoxomil (I), the synthesis of which is described in EP 1 718 641, EP 2 119 715, is used in the treatment of hypertension.
- Azilsartan medoxomil is a "prodrug" that is easily enzymatically transformed to azilsartan, which is a highly selective antagonist of angiotensin II ATI receptors.
- azilsartan medoxomil is prepared by a reaction of the free azilsartan acid with medoxomil alcohol, which provides azilsartan medoxomil as a solvate with dimethyl acetamide. This is then transformed, by crystallization of the product from an acetone/water mixture, to desolvated azilsartan medoxomil, which is subsequently converted to the potassium salt (I). Disclosure of Invention
- This invention provides a method of preparing the potassium salt of azilsartan medoxomil of formula
- a solvent which is dimethyl acetamide or N-methyl pyrrolidone or their mixtures with other solvents, is prepared, the resulting solvate is optionally re-crystallized, and, in the next step, converted, without desolvating, into the potassium salt using a potassium source.
- the potassium source is, e.g., the potassium salt of 2-ethylhexanoic acid, and the solvent used for the conversion to the potassium salt is, e.g., acetone.
- Azilsartan medoxomil (II) obtained in accordance with the patent EP 2 119 715 exhibits a maximum purity of 98.0% as determined by HPLC. Its desolvation according to the patent from an acetone/water mixture does not virtually achieve any further purification of the substance, nor does re-crystallization from an acetone/water mixture. Then, such raw material is not suitable for pharmaceutical production.
- EP2 1 19 715 Azilsartan medoxomil Crystallized from a 90 % 99.77 % 0.03 % 0.09 % solvate with dimethyl dimethyl
- both the solvates can also be prepared from a non-solvated form of azilsartan medoxomil by crystallization from dimethyl acetamide/isopropyl acetate or N- methyl pyrrolidone/isopropyl acetate mixtures, while the structurally similar dimethyl formamide does not form a solvate under these conditions.
- Solid forms of azilsartan medoxomil can be described with methods commonly used for characterization of the solid phase, such as X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC).
- a solvate of azilsartan medoxomil with dimethyl acetamide (1 :1) exhibits the following main characteristic peaks in the X-ray Powder Diffraction measured, with the use of CuKa radiation: 11.0; 12.1 ; 17.2, 25.3 ⁇ 0.2° 2theta, and further the following other characteristic peaks: 11.8; 19.5; 22.2; 24.3 ⁇ 0.2° 2theta.
- Table 2 XRPD - characteristic diffraction peaks corresponding to a solvate of azilsartan medoxomil with dimethyl acetamide.
- a solvate of azilsartan medoxomil with dimethyl acetamide can be prepared by crystallization from dimethyl acetamide and another solvent in which azilsartan medoxomil only dissolves 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 of from 10°C to 100°C.
- the potassium salt of azilsartan medoxomil is characterized by the following main peaks, measured with the use of CuKa radiation: 6.15°, 13.96°, 18.72° and 21.37° 2 ⁇ ⁇ 0.2° 2 ⁇ .
- the characteristic XRPD peaks are presented in Table 3.and an XRPD record in Fig. 1. This form is further characterized with a Differential Scanning Calorimetry (DSC) record, see Fig.2.
- a solvate of azilsartan medoxomil with N-methyl pyrrolidone is characterized by the following main characteristic peaks in an X-ray Powder record, measured with the use of CuKa radiation: 10.9; 16.3; 17.2; 18.9; ⁇ 0.2° 2theta.
- the characteristic XRPD peaks are presented in Table 4 and the XRPD record in Fig 5. This form is further characterized with a Differential Scanning Calorimetry (DSC) record, see Fig. 6.
- DSC Differential Scanning Calorimetry
- Table 4 XRPD - characteristic diffraction peaks corresponding to a solvate of azilsartan medoxomil with N-methyl pyrrolidone.
- a solvate of azilsartan medoxomil with N-methyl pyrrolidone can be prepared by crystallization from N-methyl pyrrolidone and another solvent in which azilsartan only dissolves 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 of from 10°C to 100°C.
- Fig. 1 X PD record for the potassium salt of azilsartan medoxomil
- Fig. 2 DSC record for the potassium salt of azilsartan medoxomil
- Fig. 3 XRPD record for a solvate of azilsartan medoxomil with dimethyl acetamide
- Fig. 4 DSC record for a solvate of azilsartan medoxomil with dimethyl acetamide
- Fig. 5 XRPD record for a solvate of azilsartan medoxomil with N-methyl pyrrolidone
- Fig. 6 DSC record for a solvate of azilsartan medoxomil with N-methyl pyrrolidone
- Soller diaphragms 0.02 rad and an anti-dispersion diaphragm 1 ⁇ 4 were used.
- Soller diaphragms 0.02 rad and an anti-dispersion diaphragm 5.0 mm were used.
- the Differential Scanning Calorimetry (DSC) records were measured with a DSC Pyris 1 device made by Perkin Elmer.
- the charge of the sample in a standard Al pot was between 3-4 mg and the heating-up rate was 10°C/min.
- the temperature program used consists of 1 minute of stabilization at the temperature of 50°C and then of heating to 250°C at the heating-up rate of 10°C/min.
- As the carrier gas 4.0 N 2 was used at the flow of 20 ml/min.
- Example 4 Preparation of azilsartan medoxomil as a solvate with dimethyl acetamide Crude azilsartan medoxomil prepared in accordance with Example 2 was dissolved in a mixture of dimethyl acetamide (4 ml) with isopropyl acetate (6 ml) in a hot state; after cooling and aspiration, 3.6 g (90 %) of the product was obtained, HPLC purity 99.77 %.
- Example 5 Preparation of azilsartan medoxomil as a solvate withN-methyl pyrrolidone Crude azilsartan medoxomil prepared in accordance with Example 2 was dissolved in a mixture of N-methyl pyrrolidone (4 ml) with isopropyl acetate (7 ml) in a hot state; after cooling and aspiration, 2.8 g (69 %) of the product was obtained, HPLC purity 99.84 %.
- Example 6 Preparation of the potassium salt of azilsartan medoxomil
- Example 8 Preparation of the ethyl ester of 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH-benzo[i/]-imidazole-7-carboxylic acid (V).
- the starting amidoxime (IV) was suspended in diethyl carbonate (30 g) and sodium ethoxide (21 % in ethanol, 9 g) was added. The mixture was heated at 80°C for 2h, 20 ml of the solvent was removed by distillation, ethanol (20 ml), water (20 ml) and acetic acid (3 g) and more water (20 ml) were added. The suspension was stirred at 50°C for 1 h and cooled to 25°C. 8 g (76 %) of the product was obtained.
- the starting ethyl ester of azilsartan (V, 250 g) was suspended in a solution of sodium hydroxide in water (56 g/800ml). The suspension was heated at 50°C for 4 h, after pH adjustment to 4-5, the product crystallized providing 232 g (98.5 %).
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
A METHOD OF PREPARING A HIGHLY PURE POTASSIUM SALT OF
AZILSARTAN MEDOXOMIL Technical Field
The present invention relates to a method of preparation of the potassium salt of (5 -methyl oxo-l,3-dioxol-4-yl)methyl ester of l-[[2'-(2,5-dihydro-5-oxo-l,254-oxadiazol-3-yl)[l,l'- biphenyl]-4-yl]methyl]-2-ethoxy-lH-benzimidazole-7-carboxylic acid of formula (T)
(potassium salt of azilsartan medoxomil)
Background Art The potassium salt of azilsartan medoxomil (I), the synthesis of which is described in EP 1 718 641, EP 2 119 715, is used in the treatment of hypertension. Azilsartan medoxomil is a "prodrug" that is easily enzymatically transformed to azilsartan, which is a highly selective antagonist of angiotensin II ATI receptors.
According to the EP patent 2 119 715 azilsartan medoxomil is prepared by a reaction of the free azilsartan acid with medoxomil alcohol, which provides azilsartan medoxomil as a solvate with dimethyl acetamide. This is then transformed, by crystallization of the product from an acetone/water mixture, to desolvated azilsartan medoxomil, which is subsequently converted to the potassium salt (I).
Disclosure of Invention
This invention provides a method of preparing the potassium salt of azilsartan medoxomil of formula
which c
with a solvent, which is dimethyl acetamide or N-methyl pyrrolidone or their mixtures with other solvents, is prepared, the resulting solvate is optionally re-crystallized, and, in the next step, converted, without desolvating, into the potassium salt using a potassium source.
The potassium source is, e.g., the potassium salt of 2-ethylhexanoic acid, and the solvent used for the conversion to the potassium salt is, e.g., acetone.
Azilsartan medoxomil (II) obtained in accordance with the patent EP 2 119 715 exhibits a maximum purity of 98.0% as determined by HPLC. Its desolvation according to the patent from an acetone/water mixture does not virtually achieve any further purification of the substance, nor does re-crystallization from an acetone/water mixture. Then, such raw material is not suitable for pharmaceutical production. We have already dealt with the issue of azilsartan medoxomil purification in our prior application No. CZ 2012-274, where we used solvates with acetone, tetrahydrofuran or 1 ,2-dimethoxyethane to produce solvates for purification.
In our new method we have surprisingly found out that the obtained crude product, which is in the form of a solvate with dimethyl acetamide, can be re-crystallized in such a way that the product is still a solvate with dimethyl acetamide or a solvate with N-methyl pyrrolidone, and the solvates obtained this way can be easily transformed to the pure potassium salt. The biggest advantage of this method is the fact that crystallization of azilsartan medoxomil in the
form of solvates with dimethyl acetamide or N-methyl pyrrolidone clears the substance of both the impurities A and B, which are virtually not removed by desolvation according to the primary patent. Impurity A:
Impurity B:
Table 1: HPLC purity of forms prepared by crystallization of azilsartan medoxomil
Solid form Note Yield HPLC Content of Content of purity impurity A impurity B
Azilsartan medoxomil Starting material 80.1 97.59 % 0.5 % 0.34 % crude Prepared in %
accordance with
EP2 1 19 715
Azilsartan medoxomil Crystallized from an 96 % 98.2 % 0.35 % 0.34 % non-solvated acetone/water mixture
in accordance with
EP2 1 19 715
Azilsartan medoxomil Crystallized from a 90 % 99.77 % 0.03 % 0.09 % solvate with dimethyl dimethyl
acetamide acetamide/isopropyl
acetate mixture
Azilsartan medoxomil Crystallized from a 69 % 99.84 % 0.02 % 0.08 % solvate with N-methyl
N-methyl pyrrolidone pyrrolidone/isopropyl
acetate mixture
What is interesting is that both the solvates can also be prepared from a non-solvated form of azilsartan medoxomil by crystallization from dimethyl acetamide/isopropyl acetate or N- methyl pyrrolidone/isopropyl acetate mixtures, while the structurally similar dimethyl formamide does not form a solvate under these conditions. Solid forms of azilsartan medoxomil can be described with methods commonly used for characterization of the solid phase, such as X-ray Powder Diffraction (XRPD), Differential Scanning Calorimetry (DSC). A solvate of azilsartan medoxomil with dimethyl acetamide (1 :1) exhibits the following main characteristic peaks in the X-ray Powder Diffraction measured, with the use of CuKa radiation: 11.0; 12.1 ; 17.2, 25.3 ± 0.2° 2theta, and further the following other characteristic peaks: 11.8; 19.5; 22.2; 24.3 ± 0.2° 2theta.
The list of characteristic peaks is shown in Table 2 and an XRPD record in Fig. 3. This form is also characterized with a Differential Scanning Calorimetry (DSC) record, see Fig. 4. The melting point of this form is 110°C - 113°C.
Table 2: XRPD - characteristic diffraction peaks corresponding to a solvate of azilsartan medoxomil with dimethyl acetamide.
Pos. Interplanar Rel. Int.
[°2Th.] distance [A] [%]
= 0.1nm
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
A solvate of azilsartan medoxomil with dimethyl acetamide can be prepared by crystallization from dimethyl acetamide and another solvent in which azilsartan medoxomil only dissolves 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 of from 10°C to 100°C.
The potassium salt of azilsartan medoxomil is characterized by the following main peaks, measured with the use of CuKa radiation: 6.15°, 13.96°, 18.72° and 21.37° 2Θ ± 0.2° 2Θ. The characteristic XRPD peaks are presented in Table 3.and an XRPD record in Fig. 1. This form is further characterized with a Differential Scanning Calorimetry (DSC) record, see Fig.2.
Table 3: XRPD - characteristic diffraction peaks corresponding to the potassium salt of azilsartan medoxomil
Interplanar
Pos. distance [A] Rel. Int.
[°2Th.] = 0.1nm [%]
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
A solvate of azilsartan medoxomil with N-methyl pyrrolidone is characterized by the following main characteristic peaks in an X-ray Powder record, measured with the use of CuKa radiation: 10.9; 16.3; 17.2; 18.9; ± 0.2° 2theta. The characteristic XRPD peaks are presented in Table 4 and the XRPD record in Fig 5. This form is further characterized with a Differential Scanning Calorimetry (DSC) record, see Fig. 6.
Table 4: XRPD - characteristic diffraction peaks corresponding to a solvate of azilsartan medoxomil with N-methyl pyrrolidone.
Pos. Interplanar Rel. Int.
[°2Th.] distance [A] [%]
= 0.1nm
5.86 15.062 14.5
10.85 8.144 100.0
11.72 7.544 38.7
12.23 7.233 31.4
12.54 7.052 13.2
14.06 6.292 4.9
14.87 5.954 14.0
15.29 5.791 25.8
16.25 5.449 48.2
17.19 5.155 46.5
18.87 4.700 55.0
19.26 4.604 26.1
21.82 4.070 17.9
22.12 4.016 24.5
22.71 3.913 26.2
23.49 3.785 10.3
24.19 3.676 38.6
25.27 3.522 27.6
26.25 3.392 23.1
27.08 3.290 18.4
28.02 3.182 6.2
28.35 3.145 7.5
28.92 3.085 7.9
A solvate of azilsartan medoxomil with N-methyl pyrrolidone can be prepared by crystallization from N-methyl pyrrolidone and another solvent in which azilsartan only dissolves 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 of from 10°C to 100°C.
Brief Description of Drawings
Fig. 1: X PD record for the potassium salt of azilsartan medoxomil
Fig. 2: DSC record for the potassium salt of azilsartan medoxomil
Fig. 3: XRPD record for a solvate of azilsartan medoxomil with dimethyl acetamide
Fig. 4: DSC record for a solvate of azilsartan medoxomil with dimethyl acetamide
Fig. 5: XRPD record for a solvate of azilsartan medoxomil with N-methyl pyrrolidone
Fig. 6: DSC record for a solvate of azilsartan medoxomil with N-methyl pyrrolidone
The invention is clarified in a more detailed way in the working examples below. The examples have an exclusively illustrative character and do not limit the scope of the invention in any respect.
Examples
The samples in the examples below were characterized using the X-ray Powder Diffraction (XRPD) and Differential Scanning Calorimetry (DSC) methods. The amounts of solvents were determined by means of GC.
HPLC measurements:
Luna C 18 column, 5 μ, 250 x 4.6 mm,
Conditions, buffer (Na]¾P04), pH=3; phase A, phase B - acetonitrile
Time (min) Phase A (%) Phase B (%)
5 60 40
25 10 90
30 10 90
35 60 40
XRPD measurement parameters: The diffraction patterns were measured using an X'PERT PRO MPD PANalytical diffractometer with a graphite monochromator, used radiation CuKa (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 that was placed on a Si plate. For the primary optic setting programmable divergence diaphragms with the irradiated sample area of 10 mm, Soller diaphragms 0.02 rad and an anti-dispersion diaphragm ¼ were used. For the secondary optic setting an X'Celerator detector with the maximum opening of the detection slot, Soller diaphragms 0.02 rad and an anti-dispersion diaphragm 5.0 mm were used.
The Differential Scanning Calorimetry (DSC) records were measured with a DSC Pyris 1 device made by Perkin Elmer. The charge of the sample in a standard Al pot was between 3-4 mg and the heating-up rate was 10°C/min. The temperature program used consists of 1 minute of stabilization at the temperature of 50°C and then of heating to 250°C at the heating-up rate of 10°C/min. As the carrier gas 4.0 N2 was used at the flow of 20 ml/min.
Example 1: Preparation of crude azilsartan medoxomil according to EP 2 119 715
4-Toluenesulfonyl chloride (19 g), 4-dimethyl aminopyridine (2.5 g) and potassium carbonate (18 g) were added too a solution of 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)biphenyl-4-yl)methyl)-lH-benzo[i ]-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 dimethyl acetamide (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 using diluted hydrochloric acid and the insoluble fraction, separated after addition of water, was aspirated and washed with water. After that, the crude
product was suspended in a water-acetone mixture 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 aspirated, washed with water and dried in vacuo at 40°C. 42.7 g of the substance (80.1 %) was obtained. HPLC purity: 97.6 %.
Example 2: Preparation of crude azilsartan medoxomil as a solvate with dimethyl acetamide according to EP 2 119 715
4-Toluenesulfonyl chloride (22 g), 4-dimethyl aminopyridine (1,6 g) and potassium carbonate (18.4 g) were added to a solution of 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)biphenyl-4-yl)memyl)-lH-benzo[i^-irnidazole-7-carboxylic acid (40 g) and 4- hydroxymethyl-5-methyl-l,3-dioxol-2-one (15 g) in dimethyl acetamide (400 ml) under cooling and the mixture was stirred at 30°C 3 for 3 hours. Then, pH of the mixture was adjusted to 4.5-5 with the use of acetic acid and, after addition of water (210 ml), a product, 49.7 g (86.4 %) precipitated as a solvate with dimethyl acetamide. HPLC 97.3 %.
Example 3: Preparation of non-solvated azilsartan medoxomil
Crude azilsartan medoxomil prepared in accordance with Example 2 (10 g) was dissolved in an acetone/water mixture (7:3, 150 ml) under reflux conditions. After cooling to the laboratory temperature (25 °C) the separated crystals were aspirated and dried. Yield 7.8 g (78 %). HPLC purity: 98.2 %.
Example 4: Preparation of azilsartan medoxomil as a solvate with dimethyl acetamide Crude azilsartan medoxomil prepared in accordance with Example 2 was dissolved in a mixture of dimethyl acetamide (4 ml) with isopropyl acetate (6 ml) in a hot state; after cooling and aspiration, 3.6 g (90 %) of the product was obtained, HPLC purity 99.77 %.
Example 5: Preparation of azilsartan medoxomil as a solvate withN-methyl pyrrolidone Crude azilsartan medoxomil prepared in accordance with Example 2 was dissolved in a mixture of N-methyl pyrrolidone (4 ml) with isopropyl acetate (7 ml) in a hot state; after cooling and aspiration, 2.8 g (69 %) of the product was obtained, HPLC purity 99.84 %.
Example 6: Preparation of the potassium salt of azilsartan medoxomil
The solvate of azilsartan medoxomil with dimethyl acetamide (3 g) was dissolved in 60 ml of acetone at 45°C and the potassium salt of 2-ethyhexanoic acid (1.1 g, 75 % solution) was added. After cooling and aspiration of the product and its drying at 65°C and in vacuo, 2.14 g (77 %) was obtained, HPLC purity 99.90 %, water content 0.02 %.
Example 7: Preparation of the potassium salt of azilsartan medoxomil
The solvate of azilsartan medoxomil with N-methyl pyrrolidone (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 aspiration of the product and its drying at 65°C and in vacuo, 2.2 g (80.7 %) was obtained, HPLC purity 99.91 %, water content 0.04 %.
The starting 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- lH-benzo[if]-imidazole-7-carboxylic acid (III) was prepared in accordance with the following scheme:
IV v III
Example 8: Preparation of the ethyl ester of 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4- oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH-benzo[i/]-imidazole-7-carboxylic acid (V).
The starting amidoxime (IV) was suspended in diethyl carbonate (30 g) and sodium ethoxide (21 % in ethanol, 9 g) was added. The mixture was heated at 80°C for 2h, 20 ml of the solvent was removed by distillation, ethanol (20 ml), water (20 ml) and acetic acid (3 g) and more water (20 ml) were added. The suspension was stirred at 50°C for 1 h and cooled to 25°C. 8 g (76 %) of the product was obtained.
Example 9: Preparation of 2-ethoxy-l-((2'-(5-oxo-455-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl- 4-yl)methyl)-lH-benzo[ ]-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/800ml). The suspension was heated at 50°C for 4 h, after pH adjustment to 4-5, the product crystallized providing 232 g (98.5 %).
Claims
1 . A method of preparing the potassium salt of azilsartan medoxomil of formula I,
characterized in that 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, which solvate is optionally 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.
2. The method according to claim 1, characterized in that the solvate with dimethyl acetamide is obtained by crystallization from a mixture of dimethyl acetamide and another solvent in which azilsartan medoxomil only dissolves to a limited extent, the other solvent being selected from the group comprising isopropyl acetate, isobutyl acetate, ethyl acetate, methyl acetate, acetone, methyl ethyl ketone and methyl isobutyl ketone.
3. The method according to claims 1 or 2, characterized in that the other solvent is isopropyl acetate.
4. A solvate of azilsartan medoxomil with dimethyl acetamide.
5. The solvate of azilsartan medoxomil with dimethyl acetamide according to claim 4, exhibiting the following main characteristic peaks in the X-ray Powder Diffraction, measured with the use of CuKa radiation: 11.0; 12.1 ; 17.2, 25.3 ± 0.2° 2theta.
6. The solvate of azilsartan medoxomil with dimethyl acetamide according to claim 5, exhibiting the following further characteristic X-ray powder peaks: 11.8; 19.5; 22.2; 24.3 + 0.2° 2theta.
7. A solvate of azilsartan medoxomil with dimethyl acetamide, prepared by the method of claims 1 to 3.
8. A solvate of azilsartan medoxomil with N-methyl pyrrolidone.
9. The solvate of azilsartan medoxomil with N-methyl pyrrolidone according to claim 7, characterized in that it exhibits the following main characteristic peaks in an X-ray powder record with the use of CuKoc radiation: 10.9; 16.3; 17.2; 18.9 + 0.2° 2theta.
10. The solvate of azilsartan medoxomil with N-methyl pyrrolidone according to claim 8, exhibiting the following further characteristic peaks in X-ray powder diffraction with the use of CuKa radiation: 1 1.7; 24.2; 26.3.
11. A solvate of azilsartan medoxomil with N-methyl pyrrolidone, prepared by method of claim 1.
12. The method according to claim 1, characterized in that the source of potassium is the potassium salt of 2-ethylhexanoic acid.
13. The method according to claims 1 or 12, characterized in that the solvent used for conversion of azilsartan medoxomil to the potassium salt is acetone.
14. The potassium salt of azilsartan medoxomil, prepared according to claims 1, 12 or 13, which exhibits the following main characteristic peaks in X-ray Powder Diffraction, measured with the use of CuKa radiation: 6.15°; 13.96°; 18.72° and 21.37° 2Θ ± 0.2° 2Θ.
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BR112015006572A BR112015006572A2 (en) | 2012-09-26 | 2013-09-25 | method of preparation of azilsartan medoxomil potassium salt, solvate, and azilsartan medoxomil potassium salt |
| EP13779507.6A EP2900662A1 (en) | 2012-09-26 | 2013-09-25 | A method of preparing a highly pure potassium salt of azilsartan medoxomil |
| KR1020157007800A KR20150060733A (en) | 2012-09-26 | 2013-09-25 | A method of preparing a highly pure potassium salt of azilsartan medoxomil |
| MX2015003209A MX2015003209A (en) | 2012-09-26 | 2013-09-25 | A method of preparing a highly pure potassium salt of azilsartan medoxomil. |
| EA201590657A EA028171B1 (en) | 2012-09-26 | 2013-09-25 | Method of preparing a highly pure potassium salt of azilsartan medoxomil |
| JP2015533448A JP2015532267A (en) | 2012-09-26 | 2013-09-25 | Method for producing high purity azilsartan medoxomil potassium salt |
| CN201380050044.9A CN104662019A (en) | 2012-09-26 | 2013-09-25 | A method of preparing a highly pure potassium salt of azilsartan medoxomil |
| UAA201503960A UA113668C2 (en) | 2012-09-26 | 2013-09-25 | A method of preparing a highly pure potassium salt of azilsartan medoxomil |
| IL237884A IL237884A0 (en) | 2012-09-26 | 2015-03-22 | A method of preparing a highly pure potassium salt of azilsartan medoxomil |
| HK15106026.8A HK1205505A1 (en) | 2012-09-26 | 2015-06-24 | A method of preparing a highly pure potassium salt of azilsartan medoxomil |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ2012-663A CZ305318B6 (en) | 2012-09-26 | 2012-09-26 | Process for preparing extremely pure azilsartan medoxomil potassium salt |
| CZPV2012-663 | 2012-09-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2014048404A1 true WO2014048404A1 (en) | 2014-04-03 |
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| PCT/CZ2013/000114 WO2014048404A1 (en) | 2012-09-26 | 2013-09-25 | A method of preparing a highly pure potassium salt of azilsartan medoxomil |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP2900662A1 (en) |
| JP (1) | JP2015532267A (en) |
| KR (1) | KR20150060733A (en) |
| CN (1) | CN104662019A (en) |
| BR (1) | BR112015006572A2 (en) |
| CZ (1) | CZ305318B6 (en) |
| EA (1) | EA028171B1 (en) |
| HK (1) | HK1205505A1 (en) |
| IL (1) | IL237884A0 (en) |
| MX (1) | MX2015003209A (en) |
| UA (1) | UA113668C2 (en) |
| WO (1) | WO2014048404A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016058563A1 (en) * | 2014-10-15 | 2016-04-21 | Zentiva, K.S. | A process for preparing highly pure azilsartan |
| CN105753854A (en) * | 2014-12-16 | 2016-07-13 | 重庆朗天制药有限公司 | New preparation method of azilsartan kamedoxomil |
Families Citing this family (2)
| 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 |
| CN108727356A (en) * | 2018-06-28 | 2018-11-02 | 江苏新瑞药业有限公司 | A kind of synthetic method of olmesartan medoxomil alkali metal salt |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050187269A1 (en) * | 2004-02-25 | 2005-08-25 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and use thereof |
| WO2013042067A1 (en) * | 2011-09-20 | 2013-03-28 | Ranbaxy Laboratories Limited | Process for the preparation of potassium salt of azilsartan medoxomil |
| WO2013104342A1 (en) * | 2012-01-14 | 2013-07-18 | Sunshine Lake Pharma Co., Ltd. | Crystalline forms of azilsartan medoxomil potassium and preparation and uses thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012090043A1 (en) * | 2010-12-29 | 2012-07-05 | Jubilant Life Sciences Limited | Novel solid state forms of azilsartan medoxomil and preparation thereof |
| EP2673274B1 (en) * | 2011-02-08 | 2019-07-17 | Jubilant Generics Limited | An improved process for the preparation of azilsartan medoxomil |
| CZ2012274A3 (en) * | 2012-04-19 | 2013-10-30 | Zentiva, K.S. | Process for preparing extremely pure potassium salt of azilsartan medoxomil |
-
2012
- 2012-09-26 CZ CZ2012-663A patent/CZ305318B6/en not_active IP Right Cessation
-
2013
- 2013-09-25 JP JP2015533448A patent/JP2015532267A/en active Pending
- 2013-09-25 WO PCT/CZ2013/000114 patent/WO2014048404A1/en active Application Filing
- 2013-09-25 KR KR1020157007800A patent/KR20150060733A/en not_active Application Discontinuation
- 2013-09-25 CN CN201380050044.9A patent/CN104662019A/en active Pending
- 2013-09-25 UA UAA201503960A patent/UA113668C2/en unknown
- 2013-09-25 MX MX2015003209A patent/MX2015003209A/en unknown
- 2013-09-25 EP EP13779507.6A patent/EP2900662A1/en not_active Withdrawn
- 2013-09-25 EA EA201590657A patent/EA028171B1/en not_active IP Right Cessation
- 2013-09-25 BR BR112015006572A patent/BR112015006572A2/en not_active IP Right Cessation
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2015
- 2015-03-22 IL IL237884A patent/IL237884A0/en unknown
- 2015-06-24 HK HK15106026.8A patent/HK1205505A1/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050187269A1 (en) * | 2004-02-25 | 2005-08-25 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and use thereof |
| EP1718641A2 (en) | 2004-02-25 | 2006-11-08 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and its use as aii receptor antagonist |
| EP2119715A1 (en) | 2004-02-25 | 2009-11-18 | Takeda Pharmaceutical Company Limited | Benzimidazole derivative and its use as aii receptor antagonist |
| WO2013042067A1 (en) * | 2011-09-20 | 2013-03-28 | Ranbaxy Laboratories Limited | Process for the preparation of potassium salt of azilsartan medoxomil |
| WO2013104342A1 (en) * | 2012-01-14 | 2013-07-18 | Sunshine Lake Pharma Co., Ltd. | Crystalline forms of azilsartan medoxomil potassium and preparation and uses thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016058563A1 (en) * | 2014-10-15 | 2016-04-21 | Zentiva, K.S. | A process for preparing highly pure azilsartan |
| CN105753854A (en) * | 2014-12-16 | 2016-07-13 | 重庆朗天制药有限公司 | New preparation method of azilsartan kamedoxomil |
Also Published As
| Publication number | Publication date |
|---|---|
| CZ305318B6 (en) | 2015-07-29 |
| UA113668C2 (en) | 2017-02-27 |
| HK1205505A1 (en) | 2015-12-18 |
| EA201590657A1 (en) | 2015-08-31 |
| IL237884A0 (en) | 2015-05-31 |
| KR20150060733A (en) | 2015-06-03 |
| MX2015003209A (en) | 2015-07-14 |
| EP2900662A1 (en) | 2015-08-05 |
| CN104662019A (en) | 2015-05-27 |
| CZ2012663A3 (en) | 2014-04-02 |
| JP2015532267A (en) | 2015-11-09 |
| BR112015006572A2 (en) | 2017-07-04 |
| EA028171B1 (en) | 2017-10-31 |
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