A preparation method of high-purity azilsartan medoxomil potassium salt

Abstract

The present invention relates to a method for preparing high-purity azilsartan medoxomil potassium salt. The method comprises the following steps: using 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid ethyl ester as a raw material, carrying out an oximation reaction, a condensation reaction, a hydrolysis reaction, an esterification reaction, and a salt-forming reaction, and finally preparing azilsartan medoxomil potassium salt. The method provided by the present invention has fewer steps, a low product impurity content, a total yield of more than 74%, and is suitable for industrialized scale-up production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a method for preparing high-purity azilsartan medoxomil potassium salt. Background Art

[0002] Hypertension refers to a clinical syndrome characterized by increased systemic arterial blood pressure, which may be accompanied by functional or organic damage to organs such as the heart, brain, and kidneys. Hypertension is a chronic disease that often leads to cardiovascular and cerebrovascular diseases. In recent years, with the improvement of people's living standards and changes in people's dietary habits, the number of people suffering from cardiovascular and cerebrovascular diseases has increased. As a result, hypertension drugs have become widely used in clinical practice and have attracted much attention. Currently, clinically available antihypertensive drugs include beta-blockers, calcium channel antagonists, angiotensin II receptor blockers, etc. Beta-blockers and calcium channel antagonists have relatively large side effects and a slow onset of action. Angiotensin II receptor blockers are currently the most highly regarded class of antihypertensive drugs in China, represented by the "sartan" class of drugs.

[0003] Azilsartan medoxomil potassium (Compound I), also known as Azilsartan Potassium, was developed by Takeda Pharmaceuticals (TaKaDa) of Japan and approved by the U.S. Food and Drug Administration (FDA) on February 25, 2011, for the treatment of hypertension. It is a novel angiotensin II receptor blocker and a prodrug of azilsartan, which is hydrolyzed to azilsartan during gastrointestinal absorption. Currently reported processes for synthesizing azilsartan medoxomil potassium salt suffer from the difficulty of preparing intermediates, the impossibility of industrial production, and low yields, necessitating improved synthesis methods.

[0004] The structure of Azilsartan medoxomil potassium is shown below:

[0005]

[0006] Existing reported preparation processes and their advantages and disadvantages:

[0007] Comprehensive analysis revealed that patents WO2013114305A, CN103588764A, and CN103588765A all discussed this route, using 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester as the raw material. After oximation, hydrolysis, salt formation, side chain esterification, amidino hydroxyl esterification, cyclization, and salt formation, azilsartan medoxomil potassium was finally obtained. In the fourth step of this route, the carboxyl group at position 7 and the hydroxyl group at the 2'amidino group easily react with 4-chloromethyl-5-methyl-1,3-dioxol-2-one, producing various impurities. The low selectivity of the reaction results in low yield and poor purity of the product in this step. During the amidino hydroxyl esterification reaction, the highly toxic reagent ethyl chloroformate was used. Moreover, the penultimate cyclization reaction needs to be carried out at high temperature, which can easily cause the 7-ester bond to break, resulting in a very low yield. Therefore, this route is not suitable for industrial production.

[0008]

[0009] Patent US20130317230 reports that 3-nitro-2-carboxybenzoate is used as the starting material, and after acylation and azidation, it is rearranged in tert-butanol, and then condensed with 2'-cyano-4-bromobiphenyl, and then deprotected, cyclized, condensed, and hydrolyzed to obtain the product Azilsartan. Azilsartan is esterified and salified to obtain Azilsartan potassium. The disadvantage of this method is that the reaction route for synthesizing Azilsartan is long, and a total of 11 chemical reactions are required. The process is relatively cumbersome, and the by-products and impurities produced by the multi-step reaction are relatively large. In addition, the methyl chloroformate and sodium azide used in this process are dangerous compounds, and the post-processing difficulty is large. Taking all factors into consideration, this route is not suitable for scale-up production.

[0010]

[0011] Patent WO2012107814 reports a relatively simple synthesis route, as follows:

[0012]

[0013] The method uses 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester as a raw material, and undergoes oximation, condensation, hydrolysis, esterification, and salt formation to ultimately produce azilsartan medoxomil potassium. However, DBU is used in the second cyclization step, which is relatively costly and can introduce byproducts (as shown below) due to the ring-opening degradation of DBU, resulting in a reduced yield. Furthermore, the impurities are difficult to remove in subsequent processes, affecting product quality. Therefore, the method is not suitable for industrial production.

[0014] Summary of the Invention

[0015] The purpose of the present invention is to overcome the defects in the prior art and provide a method for preparing high-purity potassium salt of azilsartan medoxomil with high yield.

[0016] To achieve the above object, the technical solution adopted by the present invention is:

[0017] The present invention provides a method for preparing high-purity azilsartan medoxomil potassium salt:

[0018]

[0019] S1 Oximation reaction: 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid ethyl ester (Compound II) is reacted with hydroxylamine hydrochloride in DMSO at 60°C to 90°C for 8 to 12 hours, cooled to room temperature, stirred with water, filtered, and the filter cake is washed with pure water and dried to obtain Compound III;

[0020] S2 condensation reaction: Compound III, N,N-carbonyldiimidazole and triethylenediamine are reacted in chloroform at 45°C to 60°C for 3-5 hours, cooled to room temperature, adjusted to pH 2-4, and stirred for 0.3-0.5 hours. The mixture is allowed to stand for separation, and the organic phase is concentrated under reduced pressure, dried after post-treatment to obtain compound IV.

[0021] S3 hydrolysis reaction: add purified water to the reactor, add sodium hydroxide under stirring, add compound IV and acetone at room temperature, raise the temperature to 40°C to 50°C, react for 4 to 6 hours, cool the reaction solution to room temperature, adjust the pH to 2 to 4 with hydrochloric acid solution, continue stirring for 1.5 to 2 hours, filter, wash, and dry to obtain compound V;

[0022] S4 esterification reaction: Compound V, acid binding agent, 4-dimethylaminopyridine, and 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one are stirred in N,N-dimethylacetamide at room temperature, p-toluenesulfonyl chloride is added, the temperature is raised to 40-50°C, the reaction is carried out for 4-6 hours, the temperature is lowered to room temperature, purified water is added, stirring is continued for 0.5-1 hour, and the mixture is filtered and washed with water to obtain a filter cake, which is dried after post-treatment to obtain compound VI.

[0023] S5 salt formation reaction: Add compound VI to acetone at 50°C to 60°C, stir until dissolved, filter, cool to 40-50°C, add potassium isooctanoate and acetone, gradually cool and crystallize, filter, wash the filter cake with acetone, and vacuum dry to obtain compound I.

[0024] As some preferred embodiments of the present invention, the reaction molar ratio of compound II to hydroxylamine hydrochloride in step S1 is 1:5-15.

[0025] As some preferred embodiments of the present invention, in step S2, the reaction molar ratio of triethylenediamine, N,N-dicarbonylimidazole and compound III is 1.5-3.5:1.5-2.5:1.

[0026] As some preferred embodiments of the present invention, the post-treatment method in step S2 is to add methanol equivalent to 3 to 10 parts by mass of compound III to the concentrate, first control the temperature to 20°C to 30°C, keep stirring for 1 hour, then cool to 0°C to 10°C, keep stirring for 2 hours, filter, and wash with methanol.

[0027] Further preferably, the amount of methanol added is 5 times that of compound III.

[0028] As some preferred embodiments of the present invention, the reaction molar ratio of compound IV to sodium hydroxide in step S3 is 1:4-6, the mass ratio of acetone to purified water is 1:12-17, and the mass ratio of compound IV to acetone is 0.9-1.1:1.

[0029] Further preferably, the mass ratio of the acetone to the purified water is 1:15, and the mass ratio of the compound IV to acetone is 1:1.

[0030] As some preferred embodiments of the present invention, in step S4, the reaction molar ratio of the compound 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one to the acid binding agent is 1:1-3, and the reaction molar ratio of the compound V to the compound 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one is 1:1-2.

[0031] As some preferred embodiments of the present invention, the post-treatment method in step S4 is: adding the filter cake to a mixed solvent of N,N-dimethylacetamide and alkyl acetate, controlling the temperature at 20-30°C, keeping the temperature for 1.5-2 hours, filtering, and washing with alkyl acetate, wherein the alkyl acetate is selected from isopropyl acetate, ethyl acetate, and methyl acetate.

[0032] As some preferred embodiments of the present invention, in step S5, the molar ratio of compound VI to potassium isooctanoate is 0.5-1:1, and the mass ratio of acetone to compound VI is 10-15:1.

[0033] Further preferably, in step S5, the molar ratio or mass ratio of compound VI to potassium isooctanoate is 0.91:1, and the mass ratio of acetone to compound VI is 12:1.

[0034] As some preferred embodiments of the present invention, the gradient cooling in step S5 is that when solid precipitates, the temperature is lowered to 40°C~30°C at a rate of 0.2°C / min, stirred for 1 hour, then lowered to 22°C~28°C at a rate of 0.5°C / min, stirred for 1 hour, and then lowered to 12°C~17°C at a rate of 0.5°C / min, and stirred for 2 hours.

[0035] The beneficial effects of adopting the above technical solution are:

[0036] 1. The method provided by the present invention adopts triethylenediamine in the condensation reaction, controls the feeding ratio and the post-processing method, avoids the generation of by-products, greatly improves the purity and yield, and the yield can reach more than 90%.

[0037] 2. The hydrolysis reaction of the present invention can reduce by-products and achieve a yield of up to 99% by adjusting the solvent, temperature and other condition parameters.

[0038] 3. The salt formation step of the present invention is followed by the esterification reaction step post-treatment, and the method of temperature rise dissolution and gradient crystallization is adopted to obtain a product with a purity of more than 99.9% and a yield of up to 90%.

[0039] 4. The present invention provides a method for preparing azilsartan medoxomil with high yield and high purity, which has few steps, low impurity content of the product, and a total yield of more than 74%, and is suitable for industrial scale-up production. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] In order to more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0041] Figure 1 This is the hydrogen spectrum of azilsartan medoxomil potassium salt;

[0042] Figure 2 This is the carbon spectrum of azilsartan medoxomil potassium salt;

[0043] Figure 3 This is the HPLC chart of azilsartan medoxomil potassium salt. DETAILED DESCRIPTION

[0044] In order to make the objectives, technical solutions and advantages of the present invention more clear, the invention is clearly and completely described below in conjunction with specific embodiments.

[0045] Example 1

[0046] S1 Oximation reaction: 700 g of dimethyl sulfoxide was added to a 3 L reaction flask, stirring was started, and 158.0 g of sodium bicarbonate, 163.3 g of hydroxylamine hydrochloride, and 100.0 g of 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid ethyl ester (Compound II) were added. The temperature was controlled to 75° C. and stirred for 11 hours. The reaction solution was cooled to 25° C., 1400 g of purified water was added, and the temperature was controlled at 25° C. and stirred for 1 hour. The mixture was filtered, and the filter cake was washed with 200 g of purified water. The filter cake was vacuum dried at 60° C. for 12 hours to obtain Compound III with a yield of 92.5%.

[0047] S2 Condensation Reaction: Add 1350 g of chloroform to a 2 L reaction flask. With stirring, add 90.0 g of Compound III, 63.7 g of N,N'-carbonyldiimidazole, and 44.0 g of triethylenediamine. Control the temperature to 55°C and maintain the reaction at 55°C for 5 h. Cool the reaction mixture to 20°C, adjust the pH of the aqueous phase to 3 with 6 mol / L dilute hydrochloric acid, and continue stirring at 20°C for 0.5 h. Allow the reaction mixture to stand for separation. Extract the aqueous phase with 180 g of chloroform. Combine the organic phases, wash with 90 g of purified water, and separate the organic phases. Concentrate under reduced pressure in a 45°C water bath to near dryness. Add 450 g of methanol, start stirring, control the temperature to 25°C, maintain stirring for 1 h, then cool to 5°C and maintain stirring for 2 h. Filter, wash the filter cake with 90 g of methanol, and vacuum dry at 60°C for 6 h to obtain Compound IV in a 93.2% yield.

[0048] S3 Hydrolysis: Add 1125 g of purified water to a 2 L reaction flask. Add 31.0 g of sodium hydroxide with stirring. Cool the reaction flask, then add 75.0 g of Compound IV and 75 g of acetone. After addition, raise the temperature to 45°C and stir for 6 hours. Cool the reaction mixture to 20°C, then adjust the pH to 3 with 6 mol / L dilute hydrochloric acid. Continue stirring for 2 hours. Filter the mixture, and wash the filter cake with 50 g of purified water and then with 75 g of acetone. Dry the filter cake in a vacuum at 60°C for 12 hours to obtain Compound V in a yield of 98.8%.

[0049] S4 Esterification: Add 325 g of N,N-dimethylacetamide, 65.0 g of Compound V, 23.6 g of finely powdered potassium carbonate, 1.7 g of 4-dimethylaminopyridine, and 20.4 g of 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one to a 2 L reaction flask. After addition, control the temperature to 20°C and add 29.9 g of p-toluenesulfonyl chloride in batches. After addition, heat the reaction mixture to 45°C and stir at 45°C for 6 h. Slowly add 650 g of purified water at room temperature. After addition, stir at room temperature for 1 h, filter, and wash the filter cake with 130 g of purified water.

[0050] To a 1-L reaction flask, add 325 g of N,N-dimethylacetamide and 650 g of isopropyl acetate. Add the filter cake obtained by filtration and stir at room temperature for 2 h. Filter and wash the filter cake with 130 g of isopropyl acetate. Dry the filter cake under vacuum at 60°C for 6 h to obtain Compound VI in a 94.1% yield.

[0051] S5 salt-forming reaction: Add 960g of acetone to a 2L reaction bottle, start stirring, control the temperature at 55°C, add 80.0g of compound VI, and stir at 55°C for 20min until the solid dissolves. At 45°C, add 24.5g of potassium isooctanoate and 160g of acetone solution, keep warm and stir. When solid precipitates, cool to 35°C at a rate of 0.2°C / min, stir for 1h, then cool to 25°C at a rate of 0.5°C / min, stir for 1h, and then cool to 15°C at a rate of 0.5°C / min, stir for 2h. Filter and wash the filter cake with 80g of acetone. The filter cake is vacuum dried at 45°C for 3h to obtain compound I with a yield of 93.2%. The structure is confirmed by the nuclear magnetic spectrum. Figure 1 and Figure 2 , purity 99.97% Figure 3 .

[0052] Example 2

[0053] S1 Oximation reaction: 700 g of dimethyl sulfoxide was added to a 3 L reaction flask, stirring was started, and 158.0 g of sodium bicarbonate, 163.3 g of hydroxylamine hydrochloride, and 100.0 g of 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid ethyl ester (Compound II) were added. The temperature was controlled to 60° C. and stirred for 12 h. The reaction solution was cooled to 25° C., 1400 g of purified water was added, the temperature was controlled to 25° C. and stirred for 1 h. The reaction solution was filtered, and the filter cake was washed with 200 g of purified water. The filter cake was vacuum dried at 60° C. for 12 h to obtain Compound III with a yield of 91.8%.

[0054] S2 Condensation Reaction: Add 1350 g of chloroform to a 2 L reaction flask. With stirring, add 90.0 g of Compound III, 47.7 g of N,N'-carbonyldiimidazole, and 33.0 g of triethylenediamine. Control the temperature to 45°C and maintain the reaction at 45°C for 5 h. Cool the reaction mixture to 20°C, adjust the pH of the aqueous phase to 2 with 6 mol / L dilute hydrochloric acid, and continue stirring at 20°C for 0.5 h. Allow the reaction mixture to stand for separation. Extract the aqueous phase with 180 g of chloroform. Combine the organic phases, wash with 90 g of purified water, and separate the organic phases. Concentrate under reduced pressure in a 45°C water bath to near dryness. Add 450 g of methanol, start stirring, control the temperature to 25°C, maintain stirring for 1 h, then cool to 5°C and maintain stirring for 2 h. Filter, wash the filter cake with 90 g of methanol, and vacuum dry at 50-60°C for 6 h to obtain Compound IV in a 92% yield.

[0055] S3 Hydrolysis: Add 1125g of purified water to a 2L reaction flask. Add 24.8g of sodium hydroxide with stirring. Cool the reaction flask, then add 75.0g of Compound IV and 75g of acetone. After addition, raise the temperature to 40°C and stir for 4 hours. Cool the reaction mixture to 20°C, then adjust the pH to 3 with 6 mol / L dilute hydrochloric acid. Continue stirring for 2 hours. Filter the mixture, and wash the filter cake with 50g of purified water and then with 75g of acetone. Dry the filter cake in a vacuum at 60°C for 12 hours to obtain Compound V in a yield of 98.5%.

[0056] S4 Esterification: Add 325 g of N,N-dimethylacetamide, 65.0 g of Compound V, 19.7 g of finely powdered potassium carbonate, 1.7 g of 4-dimethylaminopyridine, and 18.5 g of 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one to a 2 L reaction flask. After addition, control the temperature to 20°C and add 29.9 g of p-toluenesulfonyl chloride in batches. After addition, heat the reaction mixture to 45°C and stir at 45°C for 4 h. Slowly add 650 g of purified water at room temperature. Stir at room temperature for 1 h, filter, and wash the filter cake with 130 g of purified water.

[0057] To a 1 L reaction flask, add 325 g of N,N-dimethylacetamide and 650 g of isopropyl acetate. Add the filter cake obtained by filtration and stir at room temperature for 2 h. Filter and wash the filter cake with 130 g of isopropyl acetate. Dry the filter cake under vacuum at 60°C for 6 h to obtain Compound VI in a 93.2% yield.

[0058] S5 Salt Formation Reaction: Add 960g of acetone to a 2L reaction flask and start stirring. At 50°C, add 44.0g of Compound VI and stir at 55°C for 20 minutes until the solid dissolves. At 45°C, add 24.5g of potassium isooctanoate and 160g of acetone solution. Maintain the temperature and stir. When solid precipitates, cool the mixture to 35°C at a rate of 0.2°C / min and stir for 1 hour. Then, cool the mixture to 25°C at a rate of 0.5°C / min and stir for 1 hour. Then, cool the mixture to 15°C at a rate of 0.5°C / min and stir for 2 hours. Filter the mixture and wash the filter cake with 80g of acetone. Dry the filter cake in a vacuum at 45°C for 3 hours to obtain Compound I in a yield of 92.1%.

[0059] Example 3

[0060] S1 Oximation reaction: 700 g of dimethyl sulfoxide was added to a 3 L reaction flask, stirring was started, and 158.0 g of sodium bicarbonate, 163.3 g of hydroxylamine hydrochloride, and 100.0 g of 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid ethyl ester (Compound II) were added. The temperature was controlled to 90° C. and stirred for 8 h. The reaction solution was cooled to 25° C., 1400 g of purified water was added, and the temperature was controlled at 25° C. and stirred for 1 h. The reaction solution was filtered, and the filter cake was washed with 200 g of purified water. The filter cake was vacuum dried at 60° C. for 12 h to obtain Compound III with a yield of 91.5%.

[0061] S2 Condensation Reaction: Add 1350 g of chloroform to a 2 L reaction flask. With stirring, add 90.0 g of Compound III, 79.6 g of N,N'-carbonyldiimidazole, and 55.0 g of triethylenediamine. Control the temperature to 60°C and maintain the reaction at 55°C for 5 h. Cool the reaction mixture to 20°C. Adjust the pH of the aqueous phase to pH 4 with 6 mol / L dilute hydrochloric acid and continue stirring at 20°C for 0.5 h. Allow the reaction mixture to stand for separation. Extract the aqueous phase with 180 g of chloroform. Combine the organic phases, wash with 90 g of purified water, and separate the organic phases. Concentrate under reduced pressure in a 45°C water bath to near dryness. Add 450 g of methanol, start stirring, control the temperature to 25°C, maintain stirring for 1 h, then cool to 5°C and maintain stirring for 2 h. Filter the mixture, wash the filter cake with 90 g of methanol, and vacuum dry it at 50-60°C for 6 h to obtain Compound IV in a 91.8% yield.

[0062] S3 Hydrolysis: Add 1125 g of purified water to a 2 L reaction flask. Add 37.2 g of sodium hydroxide with stirring. Cool the reaction flask, then add 75.0 g of Compound IV and 75 g of acetone. After addition, raise the temperature to 50°C and stir for 5 h. Cool the reaction mixture to 20°C, then adjust the pH to 3 with 6 mol / L dilute hydrochloric acid. Continue stirring for 2 h. Filter the mixture, and wash the filter cake with 50 g of purified water and then with 75 g of acetone. Dry the filter cake in a vacuum at 60°C for 12 h to obtain Compound V in a 98.3% yield.

[0063] S4 Esterification: Add 325 g of N,N-dimethylacetamide, 65.0 g of Compound V, 118.1 g of finely powdered potassium carbonate, 1.7 g of 4-dimethylaminopyridine, and 37.1 g of 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one to a 2 L reaction flask. After addition, control the temperature to 20°C and add 29.9 g of p-toluenesulfonyl chloride in batches. After addition, raise the temperature of the reaction mixture to 45°C and stir at 45°C for 5 h. Slowly add 650 g of purified water at room temperature. After addition, stir at room temperature for 1 h, filter, and wash the filter cake with 130 g of purified water.

[0064] To a 1 L reaction flask, add 325 g of N,N-dimethylacetamide and 650 g of isopropyl acetate. Add the filter cake obtained by filtration and stir at room temperature for 2 h. Filter and wash the filter cake with 130 g of isopropyl acetate. Dry the filter cake under vacuum at 60°C for 6 h to obtain Compound VI in a 93.1% yield.

[0065] S5 Salt Formation Reaction: Add 960g of acetone to a 2L reaction flask and start stirring. At 60°C, add 88g of Compound VI and stir at 55°C for 20 minutes until the solid dissolves. At 45°C, add 24.5g of potassium isooctanoate and 160g of acetone solution. Maintain the temperature and stir. When solid precipitates, cool the mixture to 35°C at a rate of 0.2°C / min and stir for 1 hour. Then, cool the mixture to 25°C at a rate of 0.5°C / min and stir for 1 hour. Then, cool the mixture to 15°C at a rate of 0.5°C / min and stir for 2 hours. Filter the mixture and wash the filter cake with 80g of acetone. Dry the filter cake in a vacuum at 45°C for 3 hours to obtain Compound I in a yield of 91.5%.

[0066] Comparative Example 1: Investigation of Step S2

[0067] The specific method is the same as step S2 in Example 1, except that DBN, MTBD, TBD and DBU are used instead of triethylenediamine. The yield and purity of compound IV are shown in Table 1:

[0068] Table 1

[0069] name Structural formula Yield purity triethylenediamine <![CDATA[C6H 12 N2]]> 90％ 99.97％ DBN <![CDATA[C7H 12 N2]]> 60％ 95.2％ MTBD <h2 style=";text-align:left;direction:ltr"><![CDATA[C8H <h2 style=";text-align:left;direction:ltr"> 15 <h2 style=";text-align:left;direction:ltr"> N3]]><h2 style=";text-align:left;direction:ltr"> 64.2％ 94.8％ TBD <h2 style=";text-align:left;direction:ltr"><![CDATA[C7H <h2 style=";text-align:left;direction:ltr"> 13 <h2 style=";text-align:left;direction:ltr"> N3]]><h2 style=";text-align:left;direction:ltr"> 70.1％ 96.5％ DBU <![CDATA[C9H 12 N6]]> 68％ 95.7％

[0070] Comparative Example 2 Investigation of Step S2

[0071] 2-1: Add 1350 g of toluene to a 2 L reaction flask. With stirring, add 90.0 g of compound III, 63.7 g of N,N'-carbonyldiimidazole, and 44.0 g of triethylenediamine. Control the temperature to 55°C and maintain the reaction at 55°C for 5 h. Cool the reaction mixture to 20°C. Adjust the pH of the aqueous phase to 3 with 6 mol / L dilute hydrochloric acid and continue stirring at 20°C for 0.5 h. Allow the reaction mixture to stand for separation. Extract the aqueous phase with 180 g of chloroform. Combine the organic phases, wash with 90 g of purified water, and separate the organic phases. Concentrate under reduced pressure in a 45°C water bath to near dryness. Add 450 g of methanol, start stirring, control the temperature to 25°C, maintain stirring for 1 h, then cool to 5°C and maintain stirring for 2 h. Filter, wash the filter cake with 90 g of methanol, and vacuum dry at 50-60°C for 6 h to obtain compound IV in an 86.4% yield.

[0072] 2-2: Add 1350 g of chloroform to a 2 L reaction flask. With stirring, add 90.0 g of compound III, 95.5 g of N,N'-carbonyldiimidazole, and 66.1 g of triethylenediamine. Control the temperature to 55°C and maintain the reaction at 55°C for 5 h. Cool the reaction mixture to 20°C. Adjust the pH of the aqueous phase to 3 with 6 mol / L dilute hydrochloric acid and continue stirring at 20°C for 0.5 h. Allow the reaction mixture to stand for separation. Extract the aqueous phase with 180 g of chloroform. Combine the organic phases, wash with 90 g of purified water, and separate the organic phases. Concentrate under reduced pressure in a 45°C water bath to near dryness. Add 450 g of methanol, start stirring, control the temperature to 25°C, maintain stirring for 1 h, then cool to 5°C and maintain stirring for 2 h. Filter, wash the filter cake with 90 g of methanol, and vacuum dry at 50-60°C for 6 h to obtain compound IV in an 88.3% yield.

[0073] 2-3: Add 1350 g of chloroform to a 2 L reaction flask. With stirring, add 90.0 g of compound III, 111.4 g of N,N'-carbonyldiimidazole, and 77.1 g of triethylenediamine. Control the temperature to 55°C and maintain the reaction at 55°C for 5 h. Cool the reaction mixture to 20°C, adjust the pH of the aqueous phase to 3 with 6 mol / L dilute hydrochloric acid, and continue stirring at 20°C for 0.5 h. Allow the reaction mixture to stand for separation. Extract the aqueous phase with 180 g of chloroform. Combine the organic phases, wash with 90 g of purified water, and concentrate under reduced pressure in a 45°C water bath to near dryness. Add 450 g of methanol, start stirring, control the temperature to 25°C, maintain the stirring for 1 h, then cool to 5°C and maintain the stirring for 2 h. Filter, wash the filter cake with 90 g of methanol, and vacuum dry at 50-60°C for 6 h to obtain compound IV in an 89.5% yield.

[0074] Comparative Example 3: Investigation of Step S3

[0075] S3 was investigated, and the specific test methods and results are as follows:

[0076] 3-1: Add 1500g of purified water to a 2L reaction flask. Add 31.0g of sodium hydroxide with stirring. Cool the mixture, then add 75.0g of Compound IV and 75g of acetone. After addition, raise the temperature to 45°C and stir for 6 hours. Cool the reaction mixture to 20°C, adjust the pH to 3 with 6 mol / L dilute hydrochloric acid, and continue stirring for 2 hours. Filter the mixture, and wash the filter cake with 50g of purified water and then with 75g of acetone. Dry the filter cake in a vacuum at 60°C for 12 hours to obtain Compound V in a 93.4% yield.

[0077] 3-2: Add 1125g of purified water to a 2L reaction flask. Add 31.0g of sodium hydroxide with stirring. Cool the mixture, then add 75.0g of Compound IV and 75g of tetrahydrofuran. After addition, raise the temperature to 45°C and stir for 6 hours. Cool the reaction mixture to 20°C, adjust the pH to 3 with 6 mol / L dilute hydrochloric acid, and continue stirring for 2 hours. Filter the mixture, and wash the filter cake with 50g of purified water and then with 75g of acetone. Dry the filter cake in a vacuum at 60°C for 12 hours to obtain Compound V in a 95.0% yield.

[0078] 3-3: Add 1125g of purified water to a 2L reaction flask. Add 31.0g of sodium hydroxide with stirring. Cool the mixture, then add 75.0g of Compound IV and 75g of anhydrous ethanol. After addition, raise the temperature to 45°C and stir for 6 hours. Cool the reaction mixture to 20°C. Adjust the pH to 3 with 6 mol / L dilute hydrochloric acid and continue stirring for 2 hours. Filter the mixture, wash the filter cake with 50g of purified water and then with 75g of acetone. Dry the filter cake in a vacuum at 60°C for 12 hours to obtain Compound V in a yield of 91.3%.

[0079] 3-4: Add 1500g of purified water to a 2L reaction flask. Add 31.0g of sodium hydroxide with stirring. Cool the flask, then add 75.0g of Compound IV and 100g of acetone. After addition, raise the temperature to 45°C and stir for 6 hours. Cool the reaction mixture to 20°C. Adjust the pH to 3 with 6 mol / L dilute hydrochloric acid and continue stirring for 2 hours. Filter the mixture, wash the filter cake with 50g of purified water and then with 75g of acetone. Dry the filter cake in a vacuum at 60°C for 12 hours to obtain Compound V in a 93.7% yield.

[0080] 3-5: Add 1125g of purified water to a 2L reaction flask. Add 31.0g of sodium hydroxide with stirring. Cool the mixture, then add 75.0g of Compound IV and 65g of acetone. After addition, raise the temperature to 45°C and stir for 6 hours. Cool the reaction mixture to 20°C. Adjust the pH to 3 with 6 mol / L dilute hydrochloric acid and continue stirring for 2 hours. Filter the mixture, wash the filter cake with 50g of purified water and then with 75g of acetone. Dry the filter cake in a vacuum at 60°C for 12 hours to obtain Compound V in a 95.8% yield.

[0081] Comparative Example 4: Investigation of Step S4

[0082] 4-1: Add 2240g of acetone to a 2L reaction flask and start stirring. At 55°C, add 80.0g of Compound VI and stir at 55°C for 20 minutes until the solid dissolves. At 45°C, add 24.5g of potassium isooctanoate and 160g of acetone solution. Maintain the temperature and stir. When solid precipitates, cool the mixture to 35°C at a rate of 0.2°C / min and stir for 1 hour. Then, cool the mixture to 25°C at a rate of 0.5°C / min and stir for 1 hour. Cool the mixture again at a rate of 0.5°C / min and stir for 2 hours. Filter the mixture and wash the filter cake with 80g of acetone. Dry the filter cake in a vacuum at 45°C for 3 hours to obtain Compound I with a yield of 85% and a purity of 99.0%.

[0083] 4-2: Add 960g of acetone to a 2L reaction flask and start stirring. At 55°C, add 80.0g of Compound VI and stir at 55°C for 20 minutes until the solid dissolves. At 30°C, add 24.5g of potassium isooctanoate and 160g of acetone solution. Maintain the temperature and stir. When solid precipitates, cool to 0°C at a rate of 1°C / min and stir for 2 hours. Filter and wash the filter cake with 80g of acetone. Dry the filter cake in a vacuum at 45°C for 3 hours to obtain Compound I with a yield of 84.1% and a purity of 98.8%.

[0084] 4-3: Add 960g of acetone to a 2L reaction flask and start stirring. At 55°C, add 80.0g of Compound VI and stir at 55°C for 20 minutes until the solid dissolves. At 45°C, add 24.5g of potassium isooctanoate and 160g of acetone solution. Maintain stirring. When solid precipitates, cool to 15°C at a rate of 1°C / min, filter, and wash the filter cake with 80g of acetone. The filter cake is vacuum-dried at 45°C for 3 hours to obtain Compound I with a yield of 82.5% and a purity of 97.2%.

[0085] 4-4: Add 960g of acetone to a 2L reaction flask and start stirring. At 55°C, add 80.0g of Compound VI and stir at 55°C for 20 minutes until the solid dissolves. At 45°C, add 24.5g of potassium isooctanoate and 160g of acetone solution. Maintain the temperature and stir. When solid precipitates, cool the mixture to 30°C at a rate of 1°C / min, stir for 1 hour, then cool to 15°C at a rate of 0.5°C / min, and stir for 2 hours. Filter the mixture and wash the filter cake with 80g of acetone. Dry the filter cake in a vacuum at 45°C for 3 hours to obtain Compound I with a yield of 83.6% and a purity of 98.5%.

[0086] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing high-purity azilsartan medoxomil potassium salt, characterized in that: The steps include: S1 Oximation reaction: 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid ethyl ester (Compound II) is reacted with hydroxylamine hydrochloride in DMSO at 60°C-90°C for 8-12 hours, cooled to room temperature, stirred with water, filtered, and the filter cake is washed with pure water and dried to obtain Compound III; S2 condensation reaction: Compound III, N,N-carbonyldiimidazole and triethylenediamine are reacted in chloroform at 45°C-60°C for 3-5 hours, cooled to room temperature, adjusted to pH 2-4, and stirred for 0.3-0.5 hours. The mixture is allowed to stand for separation, and the organic phase is concentrated under reduced pressure, dried after post-treatment, and obtained Compound IV; S3 hydrolysis reaction: add purified water to the reactor, add sodium hydroxide under stirring, add compound IV and acetone at room temperature, raise the temperature to 40°C~50°C, react for 4~6 hours, cool the reaction solution to room temperature, adjust the pH to 2~4 with hydrochloric acid solution, continue stirring for 1.5~2 hours, filter, wash, and dry to obtain compound V; S4 esterification reaction: Compound V, an acid-binding agent, 4-dimethylaminopyridine, and 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one are stirred in N,N-dimethylacetamide at room temperature, p-toluenesulfonyl chloride is added, and the temperature is raised to 40-50°C for reaction for 4-6 hours. Purified water is added after cooling to room temperature and stirring is continued for 0.5-1 hour. The mixture is filtered and washed with water to obtain a filter cake, which is dried after post-treatment to obtain Compound VI. S5 salt formation reaction: Add compound VI to acetone at 50°C-60°C, stir until dissolved, filter, cool to 40-50°C, add potassium isooctanoate and acetone, gradually cool and crystallize, filter, wash the filter cake with acetone, and vacuum dry to obtain compound I; The reaction molar ratio of compound II to hydroxylamine hydrochloride in step S1 is 1:5-15; In step S3, the mass ratio of acetone to purified water is 1:12-17, and the mass ratio of compound IV to acetone is 0.9-1.1:1; In step S5, the gradient cooling is as follows: when solid precipitates, the temperature is lowered to 40°C-30°C at a rate of 0.2°C / min, stirred for 1 hour, then lowered to 22°C-28°C at a rate of 0.5°C / min, stirred for 1 hour, and then lowered to 12°C-17°C at a rate of 0.5°C / min, stirred for 2 hours.

2. The method for preparing high-purity azilsartan medoxomil potassium salt according to claim 1, wherein In step S2, the reaction molar ratio of triethylenediamine, N,N-dicarbonylimidazole and compound III is 1.5-2.5:1.5-2.5:

1.

3. The method for preparing high-purity azilsartan medoxomil potassium salt according to claim 1, wherein The post-treatment method in step S2 is to add methanol equivalent to 3 to 10 parts by mass of compound III to the concentrated material, first control the temperature to 20°C to 30°C, keep it warm and stir for 1 hour, then cool it to 0°C to 10°C, keep it warm and stir for 2 hours, filter it, and wash it with methanol.

4. The method for preparing high-purity azilsartan medoxomil potassium salt according to claim 1, wherein In step S3, the reaction molar ratio of compound IV to sodium hydroxide is 1:4-6.

5. The method for preparing high-purity azilsartan medoxomil potassium salt according to claim 1, wherein In step S4, the reaction molar ratio of the compound 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one to the acid binding agent is 1:1-3, and the reaction molar ratio of the compound V to the compound 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one is 1:1-2.

6. The method for preparing high-purity azilsartan medoxomil potassium salt according to claim 1, wherein The post-treatment method in step S4 is: adding the filter cake to a mixed solvent of N,N-dimethylacetamide and alkyl acetate, controlling the temperature at 20-30° C., keeping the temperature for 1.5-2 hours, filtering, and washing with alkyl acetate, wherein the alkyl acetate is selected from isopropyl acetate, ethyl acetate, and methyl acetate.

7. The method for preparing high-purity azilsartan medoxomil potassium salt according to claim 1, wherein In step S5, the molar ratio of compound VI to potassium isooctanoate is 0.5-1:1, and the mass ratio of acetone to compound VI is 10-15:1.

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