Preparation method of azilsartan medoxomil potassium salt

Abstract

The invention provides a preparation method of azilsartan medoxomil potassium salt, which comprises the following steps: carrying out heat preservation crystallization on azilsartan medoxomil and potassium isooctanoate in an organic solvent at 30-50 DEG C to obtain a crude wet product of the azilsartan medoxomil potassium salt, and carrying out aging treatment on the crude wet product for at least 10 hours to obtain the azilsartan medoxomil potassium salt. The invention also provides the azilsartan medoxomil potassium salt. According to the preparation method provided by the invention, the target product is prepared through high-temperature insulation crystallization and aging treatment, the yield is high, the purity is good, the impurity content is low, the content of potassium ions is remarkably improved, and the stability is good. The preparation method provided by the invention is milder in process conditions, reduces energy consumption, does not need complex devices or equipment, is convenient to operate and control, and is high in industrial practicability.

Description

Technical Field

[0001] The present invention relates to the field of medicine, in particular to a method for preparing azilsartan medoxomil potassium salt, and also to azilsartan medoxomil potassium salt prepared by the preparation method. Background Art

[0002] Azilsartan medoxomil potassium salt (also known as: Azilsartan potassium), the structural formula is as follows:

[0003]

[0004] The trade name of azilsartan medoxomil potassium salt is EDARBI, which was approved by the FDA in February 2011 for the treatment of hypertension in adults. It is an angiotensin II receptor antagonist (ARB) drug developed by Takeda Pharmaceuticals and can be rapidly converted into the active ingredient azilsartan after oral absorption.

[0005] U.S. Patent No. 7157584B2 (Chinese equivalent patent: CN 100503605C) first disclosed a method for preparing azilsartan medoxomil potassium salt: azilsartan medoxomil is dissolved in acetone at 50° C., the solution is ice-cooled, and an acetone solution of potassium 2-ethylhexanoate is added dropwise. The mixture is then placed in a refrigerator overnight, the precipitated crystals are collected by filtration, and dried under reduced pressure at room temperature. The resulting crystals have a melting point of 196° C. Low crystallization temperatures result in a large amount of impurities (such as azilsartan), and the potassium content in the product azilsartan medoxomil potassium salt is also poorly stable.

[0006] Example 17 of PCT patent application WO 2013186792A2 discloses a method for preparing potassium salt of azilsartan medoxomil: an acetone solution of azilsartan medoxomil is heated to 40-45°C, carbon is added at a constant temperature, the solution is stirred evenly, filtered, and washed with acetone; the filtrate is cooled to 0-5°C and an ethyl acetate solution of potassium 2-ethylhexanoate is added, and the mixture is stirred at this temperature for 90 minutes. The potassium salt of azilsartan medoxomil is filtered to obtain crystals. The product yield of this preparation method is only 70%.

[0007] In summary, it can be seen that there is an urgent need to develop a preparation method for azilsartan medoxomil potassium salt to improve the yield and quality of the target product, especially to increase the potassium ion content and reduce the impurity content. Summary of the Invention

[0008] In order to overcome the deficiencies in the prior art, an object of the present invention is to provide a method for preparing azilsartan medoxomil potassium salt, wherein the target product prepared by the preparation method has excellent yield and product quality, high purity, few impurities and good stability, and in particular, the potassium ion content in the product can be significantly improved.

[0009] Another object of the present invention is to provide azilsartan medoxomil potassium salt.

[0010] The first aspect of the present invention provides a method for preparing azilsartan medoxomil potassium salt, which comprises: crystallizing azilsartan medoxomil and potassium isooctanoate in an organic solvent at a temperature of 30 to 50° C. to obtain a crude wet product of azilsartan medoxomil potassium salt, and subjecting the crude wet product to an aging treatment for at least 10 hours to obtain the azilsartan medoxomil potassium salt.

[0011] The inventors of the present invention have found that, in the current preparation process of azilsartan medoxomil potassium salt (for example, the Chinese patent CN 100503605C and PCT patent application WO 2013186792A2 mentioned above), salification and crystallization are mainly carried out during the low-temperature insulation process. After testing and studying the potassium content, it was found that the potassium content in the product obtained by the process is extremely unstable and significantly lower than the theoretical value (6.45%). In addition, the product obtained by the process has a high impurity content, especially azilsartan impurities, and the yield is also low. The inventors also found that if the azilsartan medoxomil potassium salt crystals contain solvent residues, it is easy to form a solvate and crystallize, which can also reduce the quality of the product, thereby affecting the pharmaceutical activity of the product.

[0012] The preparation method provided by the present invention changes the common low-temperature insulation process into a relatively high-temperature (30-50° C.) insulation process, and subjects the obtained crude wet product to a sufficient aging treatment for at least 10 hours to avoid the appearance of mixed crystals or solvates. The yield and quality of the obtained azilsartan medoxomil potassium salt product are greatly improved, the impurity content is significantly reduced, the potassium ion content is also significantly increased, and the stability of the product is also improved, with only a slight increase in the impurity content after long-term storage.

[0013] In the preparation method provided by the present invention, the temperature of the heat preservation crystallization can be further 30-35°C.

[0014] In the preparation method provided by the present invention, the aging treatment can be performed by reducing the pressure to a vacuum degree of 0.05-0.2 MPa and heating to 40-60° C. for heat preservation and drying. In some preferred embodiments, the aging treatment can be performed by reducing the pressure to a vacuum degree of 0.08-0.1 MPa and heating to 45-50° C. for heat preservation and drying.

[0015] In the preparation method provided by the present invention, the decompression process during the aging treatment can be carried out for more than 4 hours, and the vacuum can be gradually drawn to reach the desired vacuum degree. In some preferred embodiments, the decompression process can be carried out for between 4 and 8 hours.

[0016] In the preparation method provided by the present invention, the heat preservation and drying time can be at least 12 hours. If the heat preservation and drying time is insufficient, it is difficult to completely remove the residual organic solvent, thereby making it difficult to avoid the formation of mixed crystals. In some preferred embodiments, based on product quality and cost considerations, the heat preservation and drying time can be 12 to 24 hours.

[0017] In the preparation method provided by the present invention, the heat preservation and crystallization time can be 2 to 10 hours. In some preferred embodiments, the heat preservation and crystallization time can be 3 to 5 hours.

[0018] In the preparation method provided by the present invention, the molar ratio of the azilsartan medoxomil to the potassium 2-ethylhexanoate can be 1:1 to 3. In some preferred embodiments, the molar ratio of the azilsartan medoxomil to the potassium 2-ethylhexanoate can be 1:1 to 1.2, for example, 1:1 to 1.1.

[0019] In the preparation method provided by the present invention, the organic solvent may be acetone, and its amount by mass may be 5 to 20 times that of the azilsartan medoxomil. In some preferred embodiments, the amount of acetone by mass may be 8 to 12 times that of the azilsartan medoxomil, for example, 10 to 11 times.

[0020] The preparation method provided by the present invention may further include: mixing the azilsartan medoxomil with acetone and heating the mixture to 50-55° C. to dissolve the azilsartan medoxomil, then cooling the mixture to 30-50° C., adding the acetone solution of potassium isooctanoate, and keeping the mixture warm for crystallization.

[0021] In the preparation method provided by the present invention, the amount of acetone in the acetone solution of potassium isooctanoate can be 1 to 5 times the amount of the potassium isooctanoate by mass. In some preferred embodiments, the amount of acetone in the acetone solution of potassium isooctanoate can be 2 to 3.5 times the amount of the potassium isooctanoate by mass, for example, 2 to 2.5 times.

[0022] The second aspect of the present invention provides azilsartan medoxomil potassium salt, which is prepared by the preparation method described in any one of the above technical solutions.

[0023] The azilsartan medoxomil potassium salt provided by the present invention can significantly increase the potassium ion content therein. In the crude wet product of the obtained azilsartan medoxomil potassium salt, the potassium ion content (detection value) can reach 5.5 to 5.8 wt.%. In the refined product obtained after aging treatment, the potassium ion content (detection value) can reach 6.3 to 6.5 wt.%, which is very close to its theoretical value. It can be seen that the azilsartan medoxomil potassium salt provided by the present invention has excellent product quality.

[0024] The potassium salt of azilsartan medoxomil provided by the present invention also has a single specific crystal form, namely, crystal form A, which is consistent with the original crystal form.

[0025] The preparation method of the potassium salt of azilsartan medoxomil provided by the present invention is obtained by "high temperature insulation crystallization" and "aging treatment", which is consistent with the original crystal form, with high yield, good purity, low impurity content, especially the content of azilsartan impurities is significantly reduced, and the content of potassium ions in the target product is significantly improved, approaching the theoretical value. In addition, the potassium salt of azilsartan medoxomil product obtained by the preparation method of the present invention also has good stability, and the variation range of impurity content and potassium ion content under long-term placement is relatively small. The preparation method process conditions provided by the present invention are more gentle, reduce energy consumption, do not need complex devices or equipment, are easy to operate and control, and have strong industrial practicality. The preparation method provided by the present invention can improve the production efficiency and product quality of potassium salt of azilsartan medoxomil, reduce its production cost, and thus have important economic and social value. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is the X-ray powder diffraction pattern of the potassium salt of azilsartan medoxomil prepared in Example 1.

[0027] Figure 2 This is the X-ray powder diffraction pattern of the potassium salt of azilsartan medoxomil prepared in Comparative Example 5. DETAILED DESCRIPTION

[0028] The technical solution of the present invention is further described in detail below with reference to specific embodiments.

[0029] Unless otherwise specified, the raw materials or reagents used in the examples and comparative examples of the present invention are commercially available products.

[0030] Unless otherwise specified, the percentages used in the examples and comparative examples of the present invention are all percentages by mass.

[0031] The potassium ion detection method used in the embodiments of the present invention and the comparative examples includes the following process:

[0032] 1. Instruments and reagents

[0033] Ion chromatograph: Dionex Integrion HPIC (Thermo Fisher Scientific High Pressure Ion System) equipped with a conductivity detector; Data processing system: Chromeleon 7 workstation (Chromatography Data System);

[0034] Water: Milli-Q ultrapure water; Potassium hydroxide: analytical grade; Methanol: analytical grade.

[0035] 2. Chromatographic conditions

[0036] 1) Chromatographic column

[0037] Analytical column: Dionex Ionpac CS12A 4.0 × 250 mm;

[0038] Guard column: Dionex Ionpac CG12A 4.0×50 mm;

[0039] 2) Eluent: methanesulfonic acid solution;

[0040] 3) Mobile phase: ultrapure water;

[0041] 4) Detector: conductivity detector;

[0042] 5) Diluent 1: methanol-water (volume ratio 80:20), diluent 2: ultrapure water;

[0043] 6) Column temperature: 30°C;

[0044] 7) Injection volume: 25 μl;

[0045] 8) Gradient operation schedule:

[0046] Time (min) 0 20 Flow rate (ml / min) 1.0 1.0 Concentration (mmol / l) 10 10 Curve 5 5

[0047] 3. Preparation of solution:

[0048] 1) Blank solution: dilution 2;

[0049] 2) KCl stock solution (K + Concentration is approximately 0.26mg / ml):

[0050] Take about 25 mg of KCl reference substance, accurately weigh it, place it in a 50 ml volumetric flask, dissolve it with diluent 2 and dilute it to the scale, shake well;

[0051] 3) Reference solution (K + The concentration is approximately 0.52 μg / ml, which is 6.56% relative to the test sample):

[0052] Accurately measure 200 μl of KCl stock solution and place it in a 100 ml volumetric flask. Dilute to the mark with diluent 2 and shake well. The KCl concentration is about 1 μg / ml.

[0053] 4) Test solution:

[0054] Take about 25 mg of the potassium salt of azilsartan test sample, accurately weigh it, place it in a 25 ml volumetric flask, dissolve it with diluent 1 and dilute it to the mark, shake it well, filter it through a C18 cartridge, and then accurately pipette 200 μl of the above solution into a 25 ml volumetric flask, add diluent 2 and dilute it to the mark, shake it well, and prepare two parallel aliquots. The test sample concentration is about 0.008 mg / ml.

[0055] 5) Operation steps:

[0056] After the instrument is stable, inject the blank solution, and then inject the reference solution six times. The K + The relative standard deviation of the peak area shall not exceed 15%. After meeting the requirements, inject the test solution (one injection for each test solution) and the reference solution and record the chromatogram. The last injection is for K + The peak area of K + The relative standard deviation of the peak area should not exceed 15%.

[0057] The injection sequence is shown in the following table:

[0058] Injection order Injection Name Number of injections 1 blank solution 1 (at least) 2 Reference solution 6 3 Test solution 1 1 4 Test solution 2 1 5 Reference solution 1

[0059] 6) Calculation of results (external standard method, take the arithmetic mean of the parallel determination results as the determination result):

[0060]

[0061] Where:

[0062] Cs - the concentration of KCl in the reference solution, in mg / ml;

[0063] C T ——Concentration of the test solution, in mg / ml;

[0064] R T ——K in the test solution + Peak area;

[0065] Rs——K in 6 injections of reference solution + The average peak area.

[0066] Example 1

[0067] Add 48 g (0.084 mol) of azilsartan medoxomil and 495 g of acetone to a four-necked flask, raise the temperature to 50.0-55.0°C, cool to 30.0°C after the liquid dissolves, and add a mixed solution of 16.4 g (0.09 mol) of potassium isooctanoate and 40 g of acetone dropwise. After the addition is complete, control the temperature at 30.0°C and keep warm for 5 hours. After the insulation is completed, filter the liquid to obtain 49.5 g of wet azilsartan medoxomil potassium salt.

[0068] The wet product of potassium salt of azilsartan medoxomil obtained in the above step was placed in a vacuum drying oven, the vacuum degree was controlled to be above 0.09 MPa, cold-extraction was carried out at room temperature for 6 hours, and then the temperature was increased, the water bath temperature was controlled to be between 45° C. and 50° C., and the product was dried for 12 hours. The product was discharged to obtain 43.5 g of potassium salt of azilsartan medoxomil, with a yield of 84.5%.

[0069] Example 2

[0070] Add 48 g (0.084 mol) of azilsartan medoxomil and 495 g of acetone to a four-necked flask, raise the temperature to 50.0-55.0°C, cool to 35.0°C after the liquid dissolves, and add a mixed solution of 16.4 g (0.09 mol) of potassium isooctanoate and 40 g of acetone dropwise. After the addition is complete, control the temperature at 35.0°C and keep warm for 5 hours. After the insulation is completed, filter the liquid to obtain 49 g of wet azilsartan medoxomil potassium salt.

[0071] The wet product of azilsartan medoxomil potassium salt obtained in the above step was placed in a vacuum drying oven, the vacuum degree was controlled to be above 0.08 MPa, cold-extraction was carried out at room temperature for 4 hours, and then the temperature was increased, the water bath temperature was controlled to be between 45° C. and 50° C., and the product was dried for 10 hours. The product was discharged to obtain 43.0 g of azilsartan medoxomil potassium salt with a yield of 83.5%.

[0072] Example 3

[0073] Add 48 g (0.084 mol) of azilsartan medoxomil and 495 g of acetone to a four-necked flask, raise the temperature to 50.0-55.0°C, cool to 40.0°C after the liquid dissolves, and add a mixed solution of 16.4 g (0.09 mol) of potassium isooctanoate and 40 g of acetone dropwise. After the addition is complete, control the temperature at 40.0°C and keep warm for 5 hours. After the insulation is completed, filter the liquid to obtain 48.4 g of wet azilsartan medoxomil potassium salt.

[0074] The wet product of azilsartan medoxomil potassium salt obtained in the above step was placed in a vacuum drying oven, the vacuum degree was controlled to be above 0.1 MPa, cold-extracted at room temperature for 8 hours, then heated, the water bath temperature was controlled at 45-50°C, dried for 18 hours, and discharged to obtain 42.3 g of azilsartan medoxomil potassium salt with a yield of 82.4%.

[0075] Example 4

[0076] Add 48 g (0.084 mol) of azilsartan medoxomil and 495 g of acetone to a four-necked flask, raise the temperature to 50.0-55.0°C, cool to 45.0°C after the liquid dissolves, and add a mixed solution of 16.4 g (0.09 mol) of potassium isooctanoate and 40 g of acetone dropwise. After the addition is complete, control the temperature at 45.0°C and keep warm for 5 hours. After the insulation is completed, filter the liquid to obtain 48.5 g of wet potassium salt of azilsartan medoxomil.

[0077] The wet product of azilsartan medoxomil potassium salt obtained in the above step was placed in a vacuum drying oven, the vacuum degree was controlled to be above 0.09 MPa, cold-extraction was carried out at room temperature for 6 hours, and then the temperature was increased, the water bath temperature was controlled to be between 45° C. and 50° C., and the product was dried for 20 hours. The product was discharged to obtain 42.5 g of azilsartan medoxomil potassium salt with a yield of 82.5%.

[0078] Example 5

[0079] Add 48 g (0.084 mol) of azilsartan medoxomil and 495 g of acetone to a four-necked flask, raise the temperature to 50.0-55.0°C, cool to 50.0°C after the liquid dissolves, and add a mixed solution of 16.4 g (0.09 mol) of potassium isooctanoate and 40 g of acetone dropwise. After the addition is complete, control the temperature at 50.0°C and keep warm for 5 hours. After the insulation is completed, filter the liquid to obtain 50 g of wet azilsartan medoxomil potassium salt.

[0080] The wet product of azilsartan medoxomil potassium salt obtained in the above step was placed in a vacuum drying oven, the vacuum degree was controlled at above 0.09 MPa, cold-extraction was carried out at room temperature for 6 hours, and then the temperature was increased, the water bath temperature was controlled at 45-50° C., and drying was carried out for 24 hours. The product was discharged to obtain 43.6 g of azilsartan medoxomil potassium salt with a yield of 85.0%.

[0081] Comparative Example 1

[0082] Add 48 g (0.084 mol) of azilsartan medoxomil and 495 g of acetone to a four-necked flask, raise the temperature to 50.0-55.0°C, cool to 0°C after the liquid dissolves, and add a mixed solution of 16.4 g (0.09 mol) of potassium isooctanoate and 40 g of acetone dropwise. After the addition is complete, control the temperature at 0°C and keep warm for 5 hours. After the insulation is completed, filter the liquid to obtain 45 g of wet azilsartan medoxomil potassium salt.

[0083] The wet product of azilsartan medoxomil potassium salt obtained in the above step was placed in a vacuum drying oven, the vacuum degree was controlled to be above 0.09 MPa, cold-extraction was carried out at room temperature for 6 hours, and then the temperature was increased, the water bath temperature was controlled to be between 45° C. and 50° C., and the product was dried for 12 hours. The product was discharged to obtain 38.4 g of azilsartan medoxomil potassium salt with a yield of 75.0%.

[0084] Comparative Example 2

[0085] Add 48 g (0.084 mol) of azilsartan medoxomil and 495 g of acetone to a four-necked flask, raise the temperature to 50.0-55.0°C, cool to 20.0°C after the liquid dissolves, and add a mixed solution of 16.4 g (0.09 mol) of potassium isooctanoate and 40 g of acetone dropwise. After the addition is complete, control the temperature at 20.0°C and keep warm for 5 hours. After the insulation is completed, filter the liquid to obtain 43.5 g of wet potassium salt of azilsartan medoxomil.

[0086] The wet product of azilsartan medoxomil potassium salt obtained in the above step was placed in a vacuum drying oven, the vacuum degree was controlled to be above 0.09 MPa, cold-extraction was carried out at room temperature for 6 hours, and then the temperature was increased, the water bath temperature was controlled to be between 45° C. and 50° C., and the product was dried for 12 hours. The product was discharged to obtain 37.2 g of azilsartan medoxomil potassium salt with a yield of 73.0%.

[0087] Comparative Example 3

[0088] Add 48 g (0.084 mol) of azilsartan medoxomil and 495 g of acetone to a four-necked flask, raise the temperature to 50.0-55.0°C, cool to 25.0°C after the liquid dissolves, and add a mixed solution of 16.4 g (0.09 mol) of potassium isooctanoate and 40 g of acetone dropwise. After the addition is complete, control the temperature at 25.0°C and keep warm for 5 hours. After the insulation is completed, filter the liquid to obtain 45 g of wet azilsartan medoxomil potassium salt.

[0089] The wet product of azilsartan medoxomil potassium salt obtained in the above step was placed in a vacuum drying oven, the vacuum degree was controlled at above 0.09 MPa, cold-extraction was carried out at room temperature for 6 hours, and then the temperature was increased, the water bath temperature was controlled at 45-50°C, and drying was carried out for 12 hours. The product was discharged to obtain 38.5 g of azilsartan medoxomil potassium salt with a yield of 74.0%.

[0090] Comparative Example 4

[0091] Add 48 g (0.084 mol) of azilsartan medoxomil and 495 g of acetone to a four-necked flask, raise the temperature to 50.0-55.0°C, and after the liquid is dissolved, raise the temperature to 60.0°C. Add a mixed solution of 16.4 g (0.09 mol) of potassium isooctanoate and 40 g of acetone dropwise. After the addition is complete, control the temperature at 60.0°C and keep warm for 5 hours. After the insulation is completed, filter the liquid to obtain 43.0 g of wet potassium salt of azilsartan medoxomil.

[0092] The wet product of azilsartan medoxomil potassium salt obtained in the above step was placed in a vacuum drying oven, the vacuum degree was controlled to be above 0.09 MPa, cold-extraction was carried out at room temperature for 6 hours, and then the temperature was increased, the water bath temperature was controlled to be between 45° C. and 50° C., and the product was dried for 12 hours. The product was discharged to obtain 36.2 g of azilsartan medoxomil potassium salt with a yield of 70.0%.

[0093] Comparative Example 5

[0094] Add 48 g (0.084 mol) of azilsartan medoxomil and 495 g of acetone to a four-necked flask, raise the temperature to 50.0-55.0°C, cool to 30.0°C after the liquid dissolves, and add a mixed solution of 16.4 g (0.09 mol) of potassium isooctanoate and 40 g of acetone dropwise. After the addition is complete, control the temperature at 30.0°C and keep warm for 5 hours. After the insulation is completed, filter the liquid to obtain 48 g of wet potassium salt of azilsartan medoxomil.

[0095] The wet product of azilsartan medoxomil potassium salt obtained in the above step was placed in a vacuum drying oven, the vacuum degree was controlled to be above 0.09 MPa, cold-drying was carried out at room temperature for 6 hours, then the temperature was raised, the water bath temperature was controlled to be 45-50°C, and drying was carried out for 8 hours. The product was discharged to obtain 42.4 g of azilsartan medoxomil potassium salt with a yield of 82.0%.

[0096] Experimental Example 1: Impurity Content Detection

[0097] The potassium salt of azilsartan medoxomil prepared in Examples 1-5, Comparative Examples 1-4 and Example 5 of Chinese Patent CN 100503605C was tested for impurities, and the obtained data are shown in Table 1.

[0098] Table 1 Impurity content test results

[0099]

[0100]

[0101] In Table 1, the detection standards for each impurity are: U-2 < 4.5%, U-1 < 0.2%, and U-4 < 0.25%.

[0102] The structural formula of impurity U-2 is shown below:

[0103]

[0104] The structural formula of impurity U-1 is shown below:

[0105]

[0106] The structural formula of impurity U-4 is shown below:

[0107]

[0108] As shown in Table 1, the azilsartan medoxomil potassium salt product prepared by the preparation method of the present invention has an extremely low impurity content, and the contents of the three impurities are all well below the detection standard value. The product impurity content prepared by the comparative example and the prior art is higher, and especially the content of azilsartan (i.e., U-2) is substantially higher than the detection standard value, and although the content of other impurities does not exceed the detection standard value, it is also significantly higher than the product prepared by the embodiment.

[0109] Experimental Example 2: Product Purity and Potassium Content Detection

[0110] The azilsartan medoxomil potassium salt products prepared in Examples 1-5, Comparative Examples 1-4 and Example 5 of Chinese Patent CN 100503605C were tested for product purity and potassium content. The obtained data are shown in Table 2.

[0111] Table 2 Product purity and potassium content test results

[0112]

[0113] As shown in Table 2, the potassium salt of azilsartan medoxomil prepared by the preparation method of the present invention is significantly superior to the products prepared in the comparative example and the prior art in terms of product purity and potassium ion content.

[0114] Experimental Example 3 Crystal form detection

[0115] The potassium salt of azilsartan medoxomil prepared in Example 1 and Comparative Example 5 was subjected to X-ray powder diffraction analysis. The analysis results are shown in Table 3 and Table 4, respectively. The spectra are shown in Table 3 and Table 4, respectively. Figure 1 and Figure 2 shown.

[0116] Table 3 X-ray powder diffraction analysis results of the product of Example 1

[0117]

[0118]

[0119] The results in Table 3 and Figure 1 It can be seen that the crystal form of the potassium salt of azilsartan medoxomil prepared in Example 1 is crystal form A, which is single and consistent with the original crystal form.

[0120] Table 4 X-ray powder diffraction analysis results of the product of Comparative Example 5

[0121]

[0122]

[0123] The results in Table 4 and Figure 2 It can be seen that the crystal form of the potassium salt of azilsartan medoxomil prepared in Comparative Example 5 is not Form A. It is speculated that the reason may be that the aging time is too short, crystal transformation occurs, and it may contain acetone solvate.

[0124] Experimental Example 4: Stability Test

[0125] The azilsartan medoxomil potassium salt products prepared in Examples 1, 2 and 5, Comparative Examples 1, 3-5 and Example 5 of Chinese Patent CN 100503605C were subjected to stability testing, and the obtained data are shown in Tables 5 to 12.

[0126] Table 5 Stability test results of the product of Example 1

[0127]

[0128] Table 6 Stability test results of the product of Example 2

[0129]

[0130]

[0131] Table 7 Stability test results of the product of Example 5

[0132]

[0133] Table 8 Stability test results of the product of Comparative Example 1

[0134]

[0135]

[0136] Table 9 Stability test results of comparative example 3 products

[0137]

[0138] Table 10 Stability test results of the product of Comparative Example 4

[0139]

[0140]

[0141] Table 11 Stability test results of comparative example 5 products

[0142]

[0143] Table 12 Stability test results of CN 100503605C product

[0144]

[0145] As can be seen from Tables 5-7, the crude wet product and the refined product obtained by the preparation method of the present invention have good stability, and the impurity content changes little and can be maintained at a lower level. As can be seen from Tables 8-10, when the crystallization temperature is lower than or higher than the crystallization temperature of the present invention, the purity of the crude wet product and the refined product obtained decreases significantly, and the stability is also worse. As can be seen from Table 11, when the aging time is insufficient, the product purity and stability of the crude wet product and the refined product obtained are also significantly worse. As can be seen from Table 12, the crude wet product and the refined product obtained by prior art CN 100503605C are also obviously inferior to the crude wet product and the refined product obtained by the preparation method of the present invention in terms of product purity and stability.

[0146] Unless otherwise defined, the terms used in the present invention have the same meanings as those commonly understood by those skilled in the art.

[0147] The embodiments described in the present invention are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Those skilled in the art may make various other substitutions, changes and improvements within the scope of the present invention. Therefore, the present invention is not limited to the above-mentioned embodiments, but is only limited by the claims.

Claims

1. A method for preparing azilsartan medoxomil potassium salt, characterized in that, Azilsartan medoxomil and potassium isooctanoate are crystallized in an organic solvent at a temperature of 30 to 50° C. to obtain a crude wet product of azilsartan medoxomil potassium salt. The crude wet product is aged for at least 10 hours to obtain the azilsartan medoxomil potassium salt.

2. The preparation method according to claim 1, characterized in that The aging treatment is to reduce the pressure to a vacuum degree of 0.05-0.2 MPa and heat it up to 40-60° C. for heat preservation and drying; preferably, to reduce the pressure to a vacuum degree of 0.08-0.1 MPa and heat it up to 45-50° C. for heat preservation and drying.

3. The preparation method according to claim 2, characterized in that The heat preservation and drying time is at least 12 hours, preferably 12 to 24 hours.

4. The preparation method according to any one of claims 1 to 3, characterized in that The heat preservation crystallization time is 2 to 10 hours, preferably 3 to 5 hours.

5. The preparation method according to any one of claims 1 to 4, characterized in that The molar ratio of the azilsartan medoxomil to the potassium isooctanoate is 1:1 to 3, preferably 1:1 to 1.

2.

6. The preparation method according to any one of claims 1 to 5, characterized in that The organic solvent is acetone, and its usage amount is 5 to 20 times, preferably 8 to 12 times, of the azilsartan medoxomil by mass.

7. The preparation method according to claim 6, characterized in that The preparation method further comprises: mixing the azilsartan medoxomil with acetone and heating the mixture to 50-55° C. to dissolve the azilsartan medoxomil, then cooling the mixture to 30-50° C., adding the acetone solution of potassium 2-octanoate, and keeping the mixture warm for crystallization.

8. The preparation method according to claim 7, characterized in that In the acetone solution of potassium isooctanoate, the amount of acetone used is 1 to 5 times, preferably 2 to 3.5 times, the mass of the potassium isooctanoate.

9. Azilsartan medoxomil potassium salt, characterized in that It is prepared by the preparation method according to any one of claims 1 to 8.

10. The potassium salt of azilsartan medoxomil according to claim 9, characterized in that The potassium ion content of the azilsartan medoxomil potassium salt is 6.3-6.5 wt.%.

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