Azilsartan impurity M as well as preparation method and application thereof
Azisartan impurity M was prepared by a five-step synthesis method, and impurity M was removed by a pulping and refining method, which solved the solubility problem of azisartan and achieved the preparation and quality control of high-purity impurity M.
Patent Information
- Application Number
- CN202511008710.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-22
- Publication Date
- 2025-11-07
Smart Images
Figure CN120904186A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of drug impurities, in particular to azilsartan impurity M and a preparation method and application thereof. BACKGROUND
[0002] Azilsartan is an angiotensin II receptor antagonist (ARB) antihypertensive drug developed by Takeda, which was approved for marketing in Japan in 2012 and is mainly used for treating hypertension. The clinical efficacy and side effects of azilsartan show stronger advantages than candesartan cilexit, and it is regarded as the next generation product of candesartan cilexit, which has a very good market prospect.
[0003] The structure of azilsartan is as follows:
[0004] During the experiment of azilsartan, azilsartan impurity M (2-methyl-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] benzimidazole-7-carboxylic acid) was detected. Since drug impurities are very important for process research and quality control of drugs, but there is no report on azilsartan impurity M and its preparation method. SUMMARY
[0005] In view of the deficiencies of the prior art, the present application provides azilsartan impurity M and a preparation method and application thereof. The present application researches and finds that azilsartan impurity M affects the solubility of azilsartan, so it is necessary to control and remove azilsartan impurity M. The preparation method of azilsartan impurity M provided by the present application has the characteristics of simple process, short process cycle and high purity, and the purity meets the quality research requirements. The provided refining method can effectively remove the impurity.
[0006] The present application is realized by the following technical solutions: One of the purposes of the present application is to provide azilsartan impurity M, the structural formula of which is as follows: .
[0007] The second aspect of the present application is to provide a preparation method of azilsartan impurity M, which comprises the following preparation steps: (1) adding methyl 2-((2'-cyano biphenyl-4-yl) methyl amino)-3-nitrobenzoate A1 and an organic acid into a reaction bottle, stirring and heating, and adding iron powder to obtain A2; (2) A2 reacts in an organic solvent under the action of acid and original acetic acid triethyl ester to obtain A3; (3) A3 reacts with hydroxylamine salt in an organic solvent under basic conditions to obtain A4; (4) A4 is prepared by ring closure with a carbonylation reagent in an organic solvent to obtain A5; (5) A5 is hydrolyzed under basic conditions to obtain azilsartan impurity M.
[0008] Preferably, the organic acid in step (1) is acetic acid.
[0009] Preferably, the molar ratio of A1 to iron powder in step (1) is 1.0:8.0-12.0; preferably 1:10.
[0010] Preferably, the acid in step (2) is acetic acid.
[0011] Further preferably, the molar ratio of A2 to original acetic acid triethyl ester in step (2) is 1.0:1.0-2.0; preferably 1.0:1.5.
[0012] Preferably, the organic solvent in step (2) is toluene.
[0013] Preferably, the organic solvent in step (3) is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and methanol, preferably dimethyl sulfoxide.
[0014] Preferably, the hydroxylamine salt in step (3) is selected from at least one of hydroxylamine sulfate, hydroxylamine hydrochloride and hydroxylamine phosphate.
[0015] Preferably, the base in step (3) is an inorganic base selected from at least one of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.
[0016] Preferably, the molar ratio of A3, hydroxylamine salt and inorganic base in step (3) is 1.0:8.0-11.0:10.0-15.0; preferably 1.0:9.0:12.0.
[0017] Preferably, the carbonylation reagent in step (4) is selected from at least one of ethyl chloroformate, N,N'-carbonyldiimidazole, dimethyl carbonate and diethyl carbonate; preferably dimethyl carbonate.
[0018] Preferably, the molar ratio of A4 to carbonylation reagent in step (4) is 1.0:1.5-3.0; preferably 1.0:2.0.
[0019] Preferably, the base in step (5) is an inorganic base selected from at least one of sodium hydroxide, potassium hydroxide and potassium carbonate; preferably sodium hydroxide.
[0020] In some embodiments, the preparation route of azilsartan impurity M is as follows: In some embodiments, the preparation route of azilsartan impurity M is as follows:
[0021] The third aspect of the present application provides a method for removing the impurity M from the crude azilsartan by beating and refining the crude azilsartan in an organic solvent. The organic solvent is methanol, ethyl acetate, acetone or isopropyl alcohol, and preferably methanol.
[0022] The fourth aspect of the present application relates to the use of the azilsartan impurity M or the azilsartan impurity M prepared by the above method in the quality control of azilsartan drug substance or azilsartan-containing preparations. The present application has the following advantages: (1) the azilsartan impurity M affects the solubility of azilsartan, so it is necessary to remove or limit the amount of the azilsartan impurity M in azilsartan drugs; (2) the method for preparing the azilsartan impurity M is simple and easy to operate, and the target compound is obtained in 5 steps; (3) the purity of the obtained target compound is high, which can meet the requirements of drug quality research; (4) the provided refining method can effectively remove the impurity M; (5) the synthesized azilsartan impurity M can be used for the quality control of azilsartan drug substance or azilsartan-containing preparations. BRIEF DESCRIPTION OF DRAWINGS
[0023] Figure 1 MS spectrum of the azilsartan impurity M prepared by Method I in Experimental Example 1; Figure 2 HPLC spectrum of the azilsartan impurity M prepared by Method I in Experimental Example 1; 1 H-NMR spectrum of the azilsartan impurity M prepared by Method I in Experimental Example 1; Figure 3 Standard curve of the apparent solubility of azilsartan in Experimental Example 2; Figure 4 HPLC spectrum of the first batch of crude azilsartan in Experimental Example 3; Figure 5 HPLC spectrum of the refined product of the first batch of azilsartan in Experimental Example 3; Figure 6 HPLC spectrum of the second batch of crude azilsartan in Experimental Example 3; Figure 7 HPLC spectrum of the refined product of the second batch of azilsartan in Experimental Example 3; Figure 8 HPLC spectrum of the third batch of crude azilsartan in Experimental Example 3; Figure 9 HPLC spectrum of the refined product of the third batch of azilsartan in Experimental Example 3; Note: Figures 4-9 The high peak at about 21.8 min in the HPLC spectrum of the test sample solution does not show azilsartan, which does not affect the identification of the related substance peaks in the test sample solution. DETAILED DESCRIPTION
[0024] The present application will be further described in conjunction with specific embodiments. The advantages and features of the present application will become more apparent with the description. However, these embodiments are only exemplary and do not constitute any limitation on the scope of the present application. Those skilled in the art should understand that the details and forms of the technical solutions of the present application can be modified or replaced without departing from the spirit and scope of the present application, and such modifications and replacements fall within the protection scope of the present application.
[0025] Experimental Example 1 Synthesis of A2 A2-1: 300 mL of acetic acid and compound A1 (20.00 g, 0.052 mol) were added to a 2 L reaction flask, and stirring was performed to heat to 70-75°C. Iron powder (23.23 g, 0.416 mol) was added to perform the reaction. After the reaction was completed, the temperature was lowered, 500.00 g of dichloromethane and 500.00 g of water were added, and stirring was performed for 20 min. Filtration was performed (diatomite filtration), the filtrate was separated into water and organic phases, 400.00 g of water was added to the organic phase, sodium bicarbonate was used to adjust the pH to 7-8, the water layer was separated, the organic phase was extracted, anhydrous sodium sulfate was used for drying, and concentration was performed under reduced pressure to obtain 16.22 g of an oil, with a yield of 81.10%.
[0026] A2-2: 300 mL of acetic acid and compound A1 (20.00 g, 0.052 mol) were added to a 2 L reaction flask, and stirring was performed to heat to 70-75°C. Iron powder (29.04 g, 0.520 mol) was added to perform the reaction. After the reaction was completed, the temperature was lowered, 500.00 g of dichloromethane and 500.00 g of water were added, and stirring was performed for 20 min. Filtration was performed (diatomite filtration), the filtrate was separated into water and organic phases, 400.00 g of water was added to the organic phase, sodium bicarbonate was used to adjust the pH to 7-8, the water layer was separated, the organic phase was extracted, anhydrous sodium sulfate was used for drying, and concentration was performed under reduced pressure to obtain 17.85 g of an oil, with a yield of 89.25%.
[0027] A2-3: 300 mL of acetic acid and compound A1 (20.00 g, 0.052 mol) were added to a 2 L reaction flask, and stirring was performed to heat to 70-75°C. Iron powder (34.85 g, 0.624 mol) was added to perform the reaction. After the reaction was completed, the temperature was lowered, 500.00 g of dichloromethane and 500.00 g of water were added, and stirring was performed for 20 min. Filtration was performed (diatomite filtration), the filtrate was separated into water and organic phases, 400.00 g of water was added to the organic phase, sodium bicarbonate was used to adjust the pH to 7-8, the water layer was separated, the organic phase was extracted, anhydrous sodium sulfate was used for drying, and concentration was performed under reduced pressure to obtain 17.51 g of an oil, with a yield of 87.55%.
[0028] Synthesis of A3 A3-1 : 60.00 g of toluene was used to dissolve the intermediate A2 (15.00 g, 0.042 mol) prepared from A2-1, which was added to a 250 mL reaction bottle, acetic acid (2.52 g, 0.042 mol) was added, and triethyl orthoacetate (10.22 g, 0.063 mol) was added. The mixture was stirred and heated to 80-85°C. After the reaction was completed by TLC detection, the mixture was cooled in an ice water bath, and yellow solid was precipitated. The mixture was filtered, and the yellow solid was dried to obtain 12.27 g of a light yellow solid with a yield of 81.79%.
[0029] A3-2: 60.00 g of toluene was used to dissolve the intermediate A2 (15.00 g, 0.042 mol) prepared from A2-1, which was added to a 250 mL reaction bottle, acetic acid (2.52 g, 0.042 mol) was added, and triethyl orthoacetate (6.81 g, 0.042 mol) was added. The mixture was stirred and heated to 80-85°C. After the raw material was substantially reacted by TLC detection, the mixture was cooled in an ice water bath, and yellow solid was precipitated. The mixture was filtered, and the yellow solid was dried to obtain 11.34 g of a light yellow solid with a yield of 75.60%.
[0030] A3-3: 60.00 g of toluene was used to dissolve the intermediate A2 (15.00 g, 0.042 mol) prepared from A2-1, which was added to a 250 mL reaction bottle, acetic acid (2.52 g, 0.042 mol) was added, and triethyl orthoacetate (13.63 g, 0.084 mol) was added. The mixture was stirred and heated to 80-85°C. After the reaction was completed by TLC detection, the mixture was cooled in an ice water bath, and yellow solid was precipitated. The mixture was filtered, and the yellow solid was dried to obtain 11.97 g of a light yellow solid with a yield of 79.80%.
[0031] Synthesis of A4: A4-1 : A 1 L reaction bottle was charged with dimethyl sulfoxide 145.00 g, hydroxylamine hydrochloride (23.77 g, 0.342 mol), and sodium bicarbonate (38.31 g, 0.456 mol). The mixture was stirred and heated to 50-60°C, and stirred for 1 h. The intermediate A3 (14.50 g, 0.038 mol) prepared from A3-1 was added, and the mixture was heated to 90-100°C for reaction. After the raw material was substantially reacted by TLC detection, the mixture was cooled to 50-60°C, 290.00 g of water was added, and the mixture was stirred to precipitate crystals. The mixture was filtered, and the filter cake was added to a 500 mL reaction bottle containing 145.00 g of anhydrous methanol. The mixture was stirred and heated to 60-65°C, and the mixture was slurried for 2 h. The mixture was cooled, filtered, and dried to obtain 11.26 g of a light yellow solid with a yield of 77.66%.
[0032] A4-2: Into a 1 L reaction flask, add N,N-dimethylformamide 145.00 g, add hydroxylamine hydrochloride (23.77 g, 0.342 mol), sodium bicarbonate (38.31 g, 0.456 mol), stir and warm to 50-60 °C, stir for 1 h, add intermediate A3 (14.50 g, 0.038 mol) prepared from A3-1, warm to 90-100 °C and react, cool to 50-60 °C after the reactant is substantially reacted as detected by TLC, add 290.00 g of water, stir and crystallize, filter, add the filter cake to a 500 mL reaction flask, stir and warm to 60-65 °C, slurry for 2 h, cool, filter, and dry to give a light yellow solid 9.43 g in 64.83% yield.
[0033] A4-3: Into a 1 L reaction flask, add N,N-dimethylacetamide 145.00 g, add hydroxylamine hydrochloride (23.77 g, 0.342 mol), sodium bicarbonate (38.31 g, 0.456 mol), stir and warm to 50-60 °C, stir for 1 h, add intermediate A3 (14.50 g, 0.038 mol) prepared from A3-1, warm to 90-100 °C and react, cool to 50-60 °C after the reactant is substantially reacted as detected by TLC, add 290.00 g of water, stir and crystallize, filter, add the filter cake to a 500 mL reaction flask, stir and warm to 60-65 °C, slurry for 2 h, cool, filter, and dry to give a light yellow solid 8.92 g in 61.52% yield.
[0034] A4-4: Into a 1 L reaction flask, add dimethyl sulfoxide 145.00 g, add hydroxylamine hydrochloride (23.77 g, 0.342 mol), potassium bicarbonate (45.65 g, 0.456 mol), stir and warm to 50-60 °C, stir for 1 h, add intermediate A3 (14.50 g, 0.038 mol) prepared from A3-1, warm to 90-100 °C and react, cool to 50-60 °C after the reactant is substantially reacted as detected by TLC, add 290.00 g of water, stir and crystallize, filter, add the filter cake to a 500 mL reaction flask, stir and warm to 60-65 °C, slurry for 2 h, cool, filter, and dry to give a light yellow solid 10.03 g in 69.17% yield.
[0035] A4-5: Into a 1 L reaction flask, dimethyl sulfoxide 145.00 g, hydroxylamine hydrochloride (23.77 g, 0.342 mol), sodium carbonate (24.17 g, 0.228 mol) were added, stirred and heated to 50-60 °C, stirred for 1 h, intermediate A3 (14.50 g, 0.038 mol) prepared from A3-1 was added, heated to 90-100 °C, reacted until the starting material was substantially reacted as detected by TLC, cooled to 50-60 °C, 290.00 g of water was added, stirred and crystallized, suction filtered, 145.00 g of anhydrous methanol was added to a 500 mL reaction flask, the filter cake was added, stirred and heated to 60-65 °C, slurried for 2 h, cooled, suction filtered, and dried to give a light yellow solid 8.74 g, a yield of 60.28%.
[0036] Synthesis of A5: A5-1: Into a 500 mL reaction flask, tetrahydrofuran 100.00 g, intermediate A4 (10.0 g, 0.024 mol) prepared from A4-1 was added, stirred and heated to 30-40 °C, dimethyl carbonate (4.32 g, 0.048 mol), sodium methoxide (0.13 g, 2.4 mmol) was added, heated to 40-50 °C, reacted until the starting material was substantially reacted as detected by TLC, cooled to room temperature, 200.00 g of water was added to a 500 mL reaction flask, controlled to 10-15 °C, the reaction liquid was added dropwise, a solid was precipitated, stirred and crystallized, suction filtered, the filter cake was added to 100.00 g of methanol, heated to 60-65 °C, slurried for 10 min, cooled, suction filtered, and dried to give a light yellow solid 8.84 g, a yield of 88.40%.
[0037] A5-2: Into a 500 mL reaction flask, tetrahydrofuran 100.00 g, intermediate A4 (10.0 g, 0.024 mol) prepared from A4-1 was added, stirred and heated to 30-40 °C, diethyl carbonate (5.67 g, 0.048 mol), sodium methoxide (0.13 g, 2.4 mmol) was added, heated to 40-50 °C, reacted until the starting material was substantially reacted as detected by TLC, cooled to room temperature, 200.00 g of water was added to a 500 mL reaction flask, controlled to 10-15 °C, the reaction liquid was added dropwise, a solid was precipitated, stirred and crystallized, suction filtered, the filter cake was added to 100.00 g of methanol, heated to 60-65 °C, slurried for 10 min, cooled, suction filtered, and dried to give a light yellow solid 8.06 g, a yield of 80.60%.
[0038] A5-3: Into a 500 mL reaction flask, add tetrahydrofuran 100.00 g, intermediate A4 prepared from A4-1 (10.0 g, 0.024 mol), stir and warm to 30-40 °C, add diphenyl carbonate (10.28 g, 0.048 mol), sodium methoxide (0.13 g, 2.4 mmol), warm to 40-50 °C, react until the starting material is substantially consumed according to TLC detection, cool to room temperature, add 200.00 g of water to the 500 mL reaction flask, control the temperature at 10-15 °C, and dropwise add the reaction solution. Solid precipitates, stir and crystallize, filter, add 100.00 g of methanol to the filter cake, warm to 60-65 °C, and beat for 10 min. Cool, filter, and dry to give 7.26 g of a light yellow solid, a yield of 72.60%.
[0039] Synthesis of azilsartan impurity M: Method 1: Into a 250 mL reaction flask, add water 70.00 g, sodium hydroxide (2.56 g, 0.064 mol), stir to dissolve, add intermediate A5 prepared from A5-1 (7.00 g, 0.016 mol), warm to 40-50 °C, cool to 10-20 °C after the reaction is complete according to TLC detection, adjust the pH to 5-6, stir and crystallize, filter, and rinse with 35.00 g of water. Into a 250 mL reaction flask, add 70.00 g of methanol, warm to 40-50 °C, add the filter cake, warm to 50-60 °C, stir for 10 min, cool to room temperature, crystallize for 20 min, filter, and dry to give 5.60 g of a white solid, a yield of 80.00%, and a purity of 99.322%.
[0040] Method 2: Into a 250 mL reaction flask, add water 70.00 g, lithium hydroxide (1.53 g, 0.064 mol), stir to dissolve, add intermediate A5 prepared from A5-1 (7.00 g, 0.016 mol), warm to 40-50 °C, cool to 10-20 °C after the reaction is complete according to TLC detection, adjust the pH to 5-6, stir and crystallize, filter, and rinse with 35.00 g of water. Into a 250 mL reaction flask, add 70.00 g of methanol, warm to 40-50 °C, add the filter cake, warm to 50-60 °C, stir for 10 min, cool to room temperature, crystallize for 20 min, filter, and dry to give 4.80 g of a white solid, a yield of 68.57%, and a purity of 96.211%.
[0041] Method three: 70.00 g of water and 3.59 g of potassium hydroxide (0.064 mol) were added into a 250 mL reaction flask, and stirred to dissolve. Then, the intermediate A5 prepared from A5-1 (7.00 g, 0.016 mol) was added, and the temperature was raised to 40-50°C. After the reaction was completed by TLC detection, the temperature was lowered to 10-20°C, and the pH was adjusted to 5-6. The product was stirred to crystallize, filtered, and washed with 35.00 g of water. Then, 70.00 g of methanol was added into a 250 mL reaction flask, and the temperature was raised to 40-50°C. After 10 min of stirring, the temperature was lowered to room temperature, and the product was crystallized for 20 min. The product was filtered and dried to obtain 5.22 g of white solid with a yield of 74.57% and a purity of 97.385%.
[0042] The MS spectrum of azilsartan impurity M prepared by method one and 1 The H-NMR spectrum is shown in Figure 1 , Figure 2 .
[0043] Experimental example 2: Effect of azilsartan impurity M on the solubility of azilsartan The azilsartan impurity M used in this experimental example was synthesized by method one in experimental example 1.
[0044] The apparent solubility of azilsartan was tested by high performance liquid chromatography (Agilent 1100 HPLC) with peak area calculation. The chromatographic column was octadecylsilane-bonded silica gel, the mobile phase A was 0.1% phosphoric acid aqueous solution: acetonitrile = 80:20, the mobile phase B was 0.1% phosphoric acid aqueous solution: acetonitrile = 20:80, linear gradient elution was used, the detection wavelength was 220 nm, the flow rate was 1.0 mL / min, and the column temperature was 25°C.
[0045] Preparation of standard curve: azilsartan reference substance, azilsartan experimental substance 1 with 1% impurity M, and azilsartan experimental substance 2 with 3% impurity M were accurately weighed, and completely dissolved in 100 mL of ultrapure water under ultrasonic conditions to obtain the standard solution. Then, the solutions of the reference substance and the test samples were filtered with a filter membrane, 5-25 μL of the reference substance and the test sample solutions were injected, the data were collected, and the standard concentration curve was drawn.
[0046] The fitting linear regression equation of the reference substance was y = 29.48x + 11.6 (R² = 0.999); the fitting linear regression equation of experimental substance 1 was y = 26.36x + 4.2 (R² = 0.999); and the fitting linear regression equation of experimental substance 2 was y = 23.22x + 3.7 (R² = 0.999). From the test results, the apparent solubility of the reference substance (2.15×10 -3mg / mL) was better than that of Experimental Product 1 (1.92 x 10 -3 mg / mL) and Experimental Product 2 (1.67 x 10 -3 mg / mL). The specific curve diagram is shown in Figure 3 .
[0047] Experimental Example 3: Impurity removal experiment of azilsartan Experimental 1: 200.00 g of acetone was added into a 1 L reaction bottle, and the temperature was raised to 40-50°C. 20.00 g of azilsartan crude product was added, and the temperature was raised to reflux. The slurry refining was performed for 30 min, the temperature was lowered to room temperature, and the crystal was precipitated for 30 min. After filtration and drying, 12.56 g of white solid was obtained, and the yield was 62.80%.
[0048] Experimental 2: 200.00 g of isopropyl alcohol was added into a 1 L reaction bottle, and the temperature was raised to 40-50°C. 20.00 g of azilsartan crude product was added, and the temperature was raised to reflux. The slurry refining was performed for 30 min, the temperature was lowered to room temperature, and the crystal was precipitated for 30 min. After filtration and drying, 15.46 g of white solid was obtained, and the yield was 77.30%.
[0049] Experimental 3: 200.00 g of ethyl acetate was added into a 1 L reaction bottle, and the temperature was raised to 40-50°C. 20.00 g of azilsartan crude product was added, and the temperature was raised to reflux. The slurry refining was performed for 30 min, the temperature was lowered to room temperature, and the crystal was precipitated for 30 min. After filtration and drying, 14.52 g of white solid was obtained, and the yield was 72.60%.
[0050] Experimental 4: 200.00 g of methanol was added into a 1 L reaction bottle, and the temperature was raised to 40-50°C. 20.00 g of azilsartan crude product was added, and the temperature was raised to reflux. The slurry refining was performed for 30 min, the temperature was lowered to room temperature, and the crystal was precipitated for 30 min. After filtration and drying, 16.42 g of white solid was obtained, and the yield was 82.10%. The results of the refining solvent screening experiment of azilsartan impurity removal are shown in Table 1.
[0051] Table 1: Refining solvent screening table
[0052] Three batches of methanol were used as the solvent for impurity removal experiment. The HPLC chromatographic conditions are shown in Experimental Example 2, and the HPLC detection data are shown in Table 2. After refining, the impurity M was not detected, which can be effectively removed.
[0053] Table 2: HPLC data table of methanol refining impurity removal experiment
[0054] The chromatograms before and after refining of the three batches are shown in Figures 4-9 , and the specific data of the chromatograms are shown in Tables 3-5.
[0055] Table 3: HPLC profile data of first batch of azilsartan crude product
[0056] Table 4: HPLC profile data of first batch of azilsartan refined product
[0057] Table 5: HPLC profile data of second batch of azilsartan crude product
[0058] Table 6: HPLC profile data of second batch of azilsartan refined product
[0059] Table 7: HPLC profile data of third batch of azilsartan crude product
[0060] Table 8: HPLC profile data of third batch of azilsartan refined product
[0061] The above detailed description is a specific description of one of the possible embodiments of the present application, which is not intended to limit the patent scope of the present application, and any equivalent implementation or change that does not deviate from the present application shall be included in the scope of the technical solutions of the present application.
Claims
1. Azilsartan impurity M characterized in that, The azilsartan impurity M has the following structural formula: 。 2. A process for preparing azilsartan impurity M according to claim 1, characterized by, The preparation method comprises the following preparation steps: (1) adding methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-nitrobenzoate A1 and an organic acid into a reaction bottle, stirring to warm, adding iron powder, cooling after the reaction is complete, extracting, and concentrating the organic phase under reduced pressure to obtain A2; (2) reacting A2 in an organic solvent under the action of an acid and original acetic acid triethyl ester to obtain A3; (3) reacting A3 with a hydroxylamine salt under alkaline conditions in an organic solvent to obtain A4; (4) ring-closing A4 by a carbonylation reagent in an organic solvent to obtain A5; (5) hydrolyzing A5 under alkaline conditions to obtain azilsartan impurity M.
3. The preparation method according to claim 2, characterized in that, The organic acid in step (1) is acetic acid, the mass-volume ratio of A1 to acetic acid is 1 g: 10-20 mL, and the molar ratio of A1 to iron powder is 1.0: 8.0-12.
0.
4. The production method according to claim 2, characterized by, The acid in step (2) is acetic acid, the molar ratio of A2, original acetic acid triethyl ester and acetic acid is 1.0: 1.0-2.0: 1.0, and the organic solvent is toluene.
5. The preparation method according to claim 4, characterized in that, The molar ratio of A2, original acetic acid triethyl ester and acetic acid is 1.0: 1.5: 1.
0.
6. The preparation method according to claim 2, characterized in that, The organic solvent in step (3) is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and methanol, the base is an inorganic base selected from at least one of potassium carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate, and the molar ratio of A3, hydroxylamine salt and inorganic base is 1.0: 8.0-11.0: 10.0-15.
0.
7. The preparation method according to claim 6, characterized in that, The organic solvent is dimethyl sulfoxide, and the molar ratio of A3, hydroxylamine salt and inorganic base is 1.0: 9.0: 12.
0.
8. The preparation method according to claim 2, characterized in that, The organic solvent in step (4) is selected from at least one of N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran and dichloromethane, the carbonylation reagent is selected from at least one of ethyl chloroformate, N,N'-carbonyldiimidazole, dimethyl carbonate and diethyl carbonate, and the molar ratio of A4 to carbonylation reagent is 1.0: 1.5-3.
0.
9. The production method according to claim 8, characterized by, The organic solvent is tetrahydrofuran, the carbonylation reagent is dimethyl carbonate, and the molar ratio of A4 to dimethyl carbonate is 1.0: 2.
0.
10. Application of azilsartan impurity M according to claim 1 or azilsartan impurity M prepared by the preparation method according to any one of claims 2-9 in quality control of azilsartan drug substance or a preparation containing azilsartan.