A preparation method of azilsartan medoxomil potassium salt impurity a

Abstract

The application provides a preparation method of azilsartan medoxomil potassium salt impurity a, a chemical structural formula of the azilsartan medoxomil potassium salt impurity a is as follows formula (I), which is prepared through esterification reaction, cyclization reaction, hydrolysis reaction and re-esterification reaction in sequence. The raw materials and auxiliary materials involved in the method are cheap and easy to obtain, each step reaction is a conventional chemical reaction, there is no special operation such as high temperature and high pressure, the yield is considerable, the HPLC purity of the obtained impurity a can reach more than 96%, and the structure is confirmed by mass spectrometry, nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum. The prepared impurity a can be used for impurity positioning and impurity content determination, which will help us to study the quality of azilsartan medoxomil potassium salt and optimize the process, so as to reduce or avoid the formation of impurities and improve the product quality. Formula (I).

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, and in particular relates to a method for preparing impurity a of azisartan ester potassium salt. Background Technology

[0002] Azisartan cilexetil potassium is a new generation of angiotensin II receptor antagonists. It was approved by the US FDA in February 2011 for the treatment of hypertension in adults, marketed under the brand name Edarbi. Its structural formula is as follows:

[0003]

[0004] Chinese patent CN115894472A describes a method for preparing high-purity azilsartan ester potassium salt, the main synthesis process of which is as follows:

[0005]

[0006] During the synthesis of compound VI using this process, byproduct impurity a is inevitably generated. A certain amount of impurity a is detected in both compound VI and its mother liquor. If post-treatment is incomplete, impurity a will also be detected in the final product, azilsartan medoxomil potassium salt. The structural formula of impurity a is as follows:

[0007]

[0008] Patent WO2013156005A1 describes a solvate of azilsartan medoxomil and acetone, which can significantly reduce impurity a generated in the process, but does not mention the synthesis method of impurity a; the literature Improved Process for Azilsartan Medoxomil: A New Angiotensin Receptor Blocker, 2013; 17(1): 77-86 published by Stanislav Radl et al. also mentions that impurity a will be generated in the process route of azilsartan medoxomil, but it does not describe the preparation method of impurity a.

[0009] It is evident that impurity 'a' is a significant impurity in the synthesis of azisartan medoxomil potassium salt. In the formulation of drug quality standards, research on impurity limits and synthetic processes is crucial for drug safety, process optimization, and quality control. Only through qualitative and quantitative studies of impurity 'a', understanding its specific formation process, can the reaction route and synthesis conditions of azisartan medoxomil potassium salt be optimized to control impurity 'a' at a reasonable level, resulting in high-purity azisartan medoxomil potassium salt. For qualitative and quantitative studies of impurity 'a', a reference standard for impurity 'a' is indispensable. Currently, the content of impurity 'a' in azisartan medoxomil potassium salt is insufficient to obtain a relatively pure impurity 'a' reference standard through enrichment and purification. Therefore, it is essential to study the preparation method of impurity 'a' in azisartan medoxomil potassium salt to directly synthesize impurity 'a' and obtain a qualified impurity 'a' reference standard. Summary of the Invention

[0010] The purpose of this invention is to provide a method for preparing azisartan ester potassium salt impurity a, so as to directly synthesize impurity a.

[0011] Chemical name of impurity a in azisartan ester potassium salt:

[0012] (5-Methyl-2-oxo-1,3-dioxo-4-yl)methyl-2-ethoxy-1-((2'-(5-(2-ethoxy-1-((2'-(5-oxo)-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazol-7-yl)-1,2,4-oxadiazol-3-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazol-7-carboxylic acid ester.

[0013] The chemical structural formula of impurity a of azisartan ester potassium salt is as follows:

[0014]

[0015] A method for preparing azisartan ester potassium salt impurity a includes the following steps:

[0016]

[0017] Where R is methyl or ethyl.

[0018] Step (1) is an esterification reaction; step (2) is a cyclization reaction; step (3) is a hydrolysis reaction; and step (4) is an esterification reaction.

[0019] The specific processes of each reaction are as follows:

[0020] The specific reaction process of step (1) is as follows:

[0021] Compounds V and III were dissolved in a solvent, and 1-hydroxybenzotriazole (HoBt) and N,N-diisopropylethylamine (DIPEA) were added sequentially. The mixture was stirred and cooled to -5℃ to 15℃. A condensation reagent was added, and the mixture was stirred for 2-5 hours. After the reaction was completed, purified water was added to quench the reaction, and ethyl acetate was added to extract the aqueous phase. The organic phase was washed, dried, and concentrated under reduced pressure to dryness. Ethyl acetate was added to the concentrated residue to crystallize compound d.

[0022] Preferably, the molar ratio of compound V to compound III is 1:0.9-1.2.

[0023] Preferably, the condensation reagent is EDCI, CDI, or DCC.

[0024] Preferably, the solvent is DMF, DMSO, dichloromethane, chloroform, or tetrahydrofuran.

[0025] The specific reaction process of step (2) is as follows:

[0026] Add DMSO to compound d, stir to dissolve, add acid-binding agent, heat to 20℃-50℃, stir to react for 3h-7h, cool to 0℃-10℃, adjust pH to 5-8 with hydrochloric acid, filter, and vacuum dry the filter cake to obtain compound c.

[0027] Preferably, the molar ratio of compound d to the acid-binding agent is 1:1.2-2.0; the acid-binding agent is potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate or sodium ethoxide.

[0028] Preferably, the concentration of the dilute hydrochloric acid is 0.5-2 mol / L;

[0029] The specific reaction process of step (3) is as follows:

[0030] Methanol was added to compound c and stirred to dissolve. A solution of alkaline reagent and purified water was added, and the mixture was heated to 20℃-50℃ and stirred for 2-4 hours. After the reaction was completed, the temperature was lowered to 0℃-10℃, the pH was adjusted to 3-4 with dilute hydrochloric acid, and the mixture was filtered. The filter cake was then dried under vacuum to obtain compound b.

[0031] Preferably, the molar ratio of compound c to the alkaline reagent is 1:6-10; the alkaline reagent is sodium hydroxide, potassium hydroxide, or lithium hydroxide.

[0032] Preferably, the concentration of the dilute hydrochloric acid is 0.5-2 mol / L.

[0033] The specific reaction process of step (4) is as follows:

[0034] Add DMAc to compound b, stir to dissolve, then add a base reagent, 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one, 4-dimethylaminopyridine, and p-toluenesulfonic acid chloride in sequence. Heat to 20℃-50℃ and stir for 2-8 hours. After the reaction is complete, adjust the pH to 5-6 with dilute hydrochloric acid, filter, and purify the filter cake by column chromatography to obtain impurity a.

[0035] Preferably, the molar ratio of compound b to 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one is 1:0.9-1.6.

[0036] Preferably, the alkaline reagent is sodium carbonate or potassium carbonate.

[0037] Preferably, the concentration of the dilute hydrochloric acid is 0.5-2 mol / L.

[0038] The beneficial effects of this invention are as follows:

[0039] This invention discloses for the first time a method for preparing impurity a from azilsartan medoxomil potassium salt, filling a gap in current methods for preparing this impurity. The method utilizes inexpensive and readily available raw materials and excipients, involves conventional chemical reactions in each step, requires no special operations such as high temperature or high pressure, and yields a considerable amount. The obtained impurity a achieves a purity of over 96% by liquid chromatography, and its structure is confirmed by mass spectrometry, 1H NMR, and 1C NMR. The impurity a prepared by this invention can be used for impurity localization and content determination, thereby helping us optimize process design, improve reaction conditions, reduce or avoid the formation of impurity a during the synthesis of azilsartan medoxomil potassium salt, and ultimately improve product quality. Attached Figure Description

[0040] Figure 1 This is the mass spectrum of impurity a in azisartan ester potassium salt of the present invention.

[0041] Figure 2 This is the 1H NMR spectrum of impurity a of azisartan ester potassium salt in this invention.

[0042] Figure 3 This is the carbon NMR spectrum of impurity a of azisartan ester potassium salt in this invention.

[0043] Figure 4 This is a liquid chromatogram of impurity a in azisartan ester potassium salt according to the present invention.

[0044] Figure 5 This is a liquid chromatogram of azisartan ester potassium salt of the present invention. Detailed Implementation

[0045] The present invention will be further described below with reference to embodiments, but these embodiments do not limit the implementation of the present invention.

[0046] Example 1

[0047] A method for the efficient synthesis of azisartan ester potassium salt impurity a, the process route is as follows:

[0048]

[0049] (1) Compound V and Compound III were esterified to obtain Compound d.

[0050] Add 5.0 g (11.0 mmol) of compound V and 5.2 g (11.6 mmol) of compound III to a 250 mL reaction flask, then add 50 mL of DMF and stir to dissolve. At 10℃-30℃, add 1.5 g of HoBt (11.0 mmol) and 2.8 g (22.0 mmol) of DIPEA sequentially. Cool to 0℃-5℃, then add 2.3 g (12.1 mmol) of EDCI. After the addition is complete, stir the reaction mixture at 0℃-5℃ for 3 h. After the reaction is complete, quench the reaction mixture with 300 mL of purified water, and extract the aqueous phase with ethyl acetate (150 mL × 3). Wash the organic phase with saturated brine (300 mL) and dry with anhydrous sodium sulfate (20.0 g). Filter off the drying agent, concentrate the filtrate to dryness under reduced pressure, add 50 mL of ethyl acetate to the concentrate, and stir at 0℃-10℃ for 1 h. The mixture was filtered, and the filter cake was dried under vacuum at 45℃-55℃ to obtain 8.6 g of a white solid compound d, with a yield of 87.1%.

[0051] (2) Compound d undergoes a cyclization reaction to obtain compound c.

[0052] 8.0 g (8.9 mmol) of compound d and 80 mL of DMSO were added to a 250 mL reaction flask and stirred to dissolve. 0.75 g (13.4 mmol) of potassium hydroxide was added at 10 °C–30 °C. The mixture was heated to 30 °C–40 °C and stirred for 5 h. After the reaction was complete, 100 mL of purified water was added to the reaction solution, and the temperature was lowered to 0 °C–10 °C. The pH was adjusted to 6–7 with 1 mol / L hydrochloric acid. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C–55 °C to obtain 5.5 g of a white solid, compound c, with a yield of 70.3%.

[0053] (3) Compound c undergoes a hydrolysis reaction to obtain compound b.

[0054] 5.0 g (5.7 mmol) of compound c and 50 mL of ethanol were added to a 250 mL reaction flask and stirred to dissolve. A mixture of 1.9 g (48.5 mmol) of sodium hydroxide and 10 mL of purified water was added at 10 °C–30 °C. The mixture was heated to 30 °C–40 °C and stirred for 3 h. After the reaction was complete, the temperature was lowered to 0 °C–10 °C, and the pH was adjusted to 3–4 with 1 mol / L hydrochloric acid. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C–55 °C to give 3.9 g of a white solid, compound b, with a yield of 80.6%.

[0055] (4) Compound b was esterified with 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one to obtain target compound a (impurity a).

[0056] Add 3.5 g (4.1 mmol) of compound b and 35 mL of DMAC to a 250 mL reaction flask and stir to dissolve. Add 0.8 g (5.8 mmol) of potassium carbonate, 0.7 g (5.4 mmol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one, and 0.07 g (0.62 mmol) of 4-dimethylaminopyridine at 10℃-30℃. After the addition is complete, stir at 10℃-30℃ for 0.5 h, then add 1.0 g (5.1 mmol) of p-toluenesulfonic acid chloride, and maintain the temperature at 30℃-40℃, stirring for 4 h. After the reaction is complete, cool the reaction solution to below 15℃, add 120 mL of purified water, and adjust the pH to 5-6 with 1 mol / L hydrochloric acid. The filter cake was filtered and purified by column chromatography (200-300 mesh silica gel, methanol:dichloromethane = 1:100-30). The mobile phase of the target compound was collected and concentrated to dryness to give 2.3 g of light yellow solid compound a, with a yield of 68.2%.

[0057] Example 2

[0058] Another synthetic method for synthesizing impurity a of azisartan ester potassium salt is as follows:

[0059]

[0060] (1) Compound V and compound VII undergo esterification to obtain compound e.

[0061] Add 5.0 g (11.0 mmol) of compound V and 5.9 g (13.2 mmol) of compound VII to a 250 mL reaction flask, then add 50 mL of DMF and stir to dissolve. At 10℃-30℃, add 1.8 g of HoBt (13.2 mmol) and 3.1 g (24.2 mmol) of DIPEA sequentially. Cool to 0℃-5℃, then add 2.5 g (13.2 mmol) of EDCI. After the addition is complete, stir the reaction mixture at 0℃-5℃ for 3 h. After the reaction is complete, quench the reaction mixture with 300 mL of purified water, and extract the aqueous phase with ethyl acetate (150 mL × 3). Wash the organic phase with saturated brine (300 mL) and dry with anhydrous sodium sulfate (20.0 g). Filter off the drying agent, concentrate the filtrate to dryness under reduced pressure, add 60 mL of ethyl acetate to the concentrate, and stir at 0℃-10℃ for 1 h. The mixture was filtered, and the filter cake was dried under vacuum at 45℃-55℃ to obtain 7.8 g of a white solid compound e, with a yield of 80.3%.

[0062] (2) Compound e undergoes a cyclization reaction to give compound f.

[0063] 7.0 g (7.9 mmol) of compound e and 70 mL of DMSO were added to a 250 mL reaction flask and stirred to dissolve. 0.67 g (11.9 mmol) of potassium hydroxide was added at 10 °C–30 °C. The mixture was heated to 30 °C–40 °C and stirred for 4 h. After the reaction was complete, 100 mL of purified water was added to the reaction solution, and the temperature was lowered to 0 °C–10 °C. The pH was adjusted to 6–7 with 2 mol / L hydrochloric acid. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C–55 °C to give 5.0 g of a white solid, compound f, with a yield of 73.2%.

[0064] (3) Compound f undergoes a hydrolysis reaction to obtain compound b.

[0065] 4.5 g (5.2 mmol) of compound f and 45 mL of methanol were added to a 250 mL reaction flask and stirred to dissolve. A mixture of 1.8 g (44.2 mmol) of sodium hydroxide and 10 mL of purified water was added at 10 °C–30 °C. The mixture was heated to 30 °C–40 °C and stirred for 4 h. After the reaction was complete, the temperature was lowered to 0 °C–10 °C, and the pH was adjusted to 3–4 with 1 mol / L hydrochloric acid. The mixture was filtered, and the filter cake was dried under vacuum at 45 °C–55 °C to give 3.5 g of a white solid, compound b, with a yield of 79.2%.

[0066] (4) Compound b was esterified with 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one to obtain the target compound.

[0067] Add 3.0 g (3.5 mmol) of compound b and 30 mL of DMAC to a 250 mL reaction flask and stir to dissolve. Add 0.7 g (5.3 mmol) of potassium carbonate, 0.6 g (4.6 mmol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one, and 0.06 g (0.53 mmol) of 4-dimethylaminopyridine at 10℃-30℃. After the addition is complete, stir at 10℃-30℃ for 0.5 h, then add 0.9 g (4.6 mmol) of p-toluenesulfonic acid chloride, and maintain the temperature at 30℃-40℃, stirring for 4 h. After the reaction is complete, cool the reaction solution to below 15℃, add 100 mL of purified water, and adjust the pH to 5-6 with 1 mol / L hydrochloric acid. The filter cake was filtered and purified by column chromatography (200-300 mesh silica gel, methanol: dichloromethane = 1:100-30). The mobile phase of the target compound was collected and concentrated to dryness to give 2.1 g of a light yellow solid compound a, with a yield of 62.3%.

[0068] Impurity a was identified by mass spectrometry, proton NMR, and carbon NMR spectra. The spectra are shown below. Figures 1-3 Impurity a has the molecular formula C. 54 H 42 N8O 10The molecular formula contains 42 hydrogen atoms, and 42 hydrogen signals appear in the hydrogen spectrum; the molecular formula contains 54 carbon atoms, and 45 carbon signals appear in the carbon spectrum. This is because some carbon atoms have overlapping peaks due to the same chemical environment.

[0069] ESI-MS (m / z): 963.3 [M+H] +

[0070] 1 H-NMR(400MHz,DMSO-d6)δ:1.269-1.304(t,3H,CH3),1.373-1.408(t,3H,CH3),2.092(s,3H,CH3),4.483-4.518(q,2H, CH2),4.583-4.619(q,2H,CH2),5.004(s,2H,CH2),5.419-5.465(d,4H,CH2),6.694-6.715(d,2H,Ar-H),6.870-6.890( d,2H,Ar-H), 7.066-7.179(m,5H,Ar-H), 7.287-7.326(m,2H,Ar-H), 7.427-7.547(m,5H,Ar-H), 7.596-7.632(m,3H,Ar-H), 7.683-7.739(m,2H,Ar-H), 7.782-7.804(m,1H,Ar-H), 12.362(s,1H,NH); the solvent peaks at chemical shifts of 1.960, 2.787, and 2.945 are the hydrogen elution peaks of DMAC.

[0071] 13 C-NMR (600MHz, DMSO-d6) δ: 9.28, 14.70, 14.79, 46.65, 46.87, 55.05, 67.06, 67.30, 107.62, 114.95, 121.29, 12 2.03,122.58,123.77,125.23,126.49,126.62,128.29,129.15,129.49,130.62,130.84,130.88,131.03,131. 39, 131.58, 132.24, 133.54, 136.56, 136.69, 138.23, 139.57, 140.80, 141.10, 141.56, 142.15, 142.32, 152.20, 158.62, 158.84, 158.93, 159.91, 165.50, 169.19, 173.15; the solvent peaks are located at chemical shifts of 21.87, 37.91, 39.58, and 170.04, which are the carbon elution peaks of DMAC.

[0072] Example 3

[0073] The content of impurity a in azisartan cilexetil potassium salt was determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). The specific steps are as follows:

[0074] (1) Preparation of test solution: Take an appropriate amount of azisartan ester potassium salt, accurately weigh it, dissolve it in acetonitrile and dilute it to prepare a solution containing about 0.5 mg per ml.

[0075] (2) Preparation of azisartan medoxomil potassium salt impurity a reference standard: Take an appropriate amount of azisartan medoxomil potassium salt impurity a reference standard, accurately weigh it, dissolve it in acetonitrile and dilute it to prepare a solution containing about 0.5 μg per ml.

[0076] (3) Determination: Accurately measure the test solution and the azisartan ester potassium salt impurity a positioning solution, inject them into the liquid chromatograph, and determine them under the following chromatographic conditions, and record the chromatogram.

[0077] Limit: If the chromatogram of the test solution contains a peak with the same retention time as impurity a (a) of azisartan medoxomil potassium salt, the content of impurity a (a) of azisartan medoxomil potassium salt shall not exceed 0.10% by area normalization method.

[0078] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; phosphate buffer (6.8 g potassium dihydrogen phosphate, 1000 ml water, pH adjusted to 3.0 with phosphoric acid)-acetonitrile-methanol (60:30:10) was used as mobile phase A, and acetonitrile-methanol (90:10) was used as mobile phase B, with linear gradient elution according to the table below; column temperature was 30℃; detection wavelength was 250 nm; injection volume was 20 μl.

[0079]

[0080] The HPLC purity of impurity a is shown in the figure. Figure 4 Impurity a had a purity of 96.0%; the HPLC purity of azisartan cilexetil potassium salt is shown in [reference needed]. Figure 5 The purity of azisartan cilexetil potassium salt is 99.7%, with impurity a content of 0.029%.

Claims

1. A method for preparing impurity a of azilsartan ester potassium salt, characterized in that, Includes the following steps: ； Wherein, R is methyl or ethyl; Step (1) involves dissolving compounds V and III in a solvent, sequentially adding 1-hydroxybenzotriazole and N,N-diisopropylethylamine, stirring and cooling to -5℃ to -15℃, adding a condensing reagent, and stirring for 2-5 hours. After the reaction is complete, purified water is added to quench the reaction, ethyl acetate is added to extract the aqueous phase, the organic phase is washed, dried, and concentrated under reduced pressure to dryness, and ethyl acetate is added to the concentrated residue to crystallize and obtain compound d. The molar ratio of compound V to compound III is 1:0.9-1.

2. The condensing reagent is EDCI, CDI, or DCC. The solvent is DMF, DMSO, dichloromethane, chloroform, or tetrahydrofuran. Step (2) involves adding DMSO to compound d, stirring to dissolve, adding an acid-binding agent, heating to 20℃-50℃, stirring for 3-7 hours, cooling to 0℃-10℃, adjusting the pH to 5-8 with dilute hydrochloric acid, filtering, and vacuum drying the filter cake to obtain compound c; the molar ratio of compound d to the acid-binding agent is 1:1.2-2.0; the concentration of the dilute hydrochloric acid is 0.5-2 mol / L; the acid-binding agent is potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, or sodium ethoxide. Step (3) involves adding methanol to compound c, stirring to dissolve it, adding a solution of alkaline reagent and purified water, heating to 20℃-50℃, stirring for 2h-4h; after the reaction is complete, cooling to 0℃-10℃, adjusting the pH to 3-4 with dilute hydrochloric acid, filtering, and vacuum drying the filter cake to obtain compound b. Step (4) involves adding DMAc to compound b, stirring to dissolve it, then sequentially adding an alkaline reagent, 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one, 4-dimethylaminopyridine, and p-toluenesulfonic acid chloride. The mixture is heated to 20°C-50°C and stirred for 2-8 hours. After the reaction is complete, the pH is adjusted to 5-6 with dilute hydrochloric acid, filtered, and the filter cake is purified by column chromatography to obtain impurity a.

2. The method for preparing azisartan ester potassium salt impurity a according to claim 1, characterized in that, In step (3), the molar ratio of compound c to the alkaline reagent is 1:6-10; the alkaline reagent is sodium hydroxide, potassium hydroxide or lithium hydroxide, and the concentration of the dilute hydrochloric acid is 0.5-2 mol / L.

3. The method for preparing azisartan ester potassium salt impurity a according to claim 1, characterized in that, In step (4), the molar ratio of compound b to 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one is 1:0.9-1.6; the alkaline reagent is sodium carbonate or potassium carbonate.

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