Synthesis method of azilsartan medoxomil

Abstract

The invention provides a synthesis method of azilsartan medoxomil, which comprises the following steps: reacting azilsartan with thionyl chloride to obtain an intermediate reaction solution, and then adding 4-hydroxymethyl-5-methyl-1, 3-dioxole-2-ketone into the intermediate reaction solution to react to obtain the azilsartan medoxomil. According to the synthesis method provided by the invention, the target product is synthesized through the sulfite intermediate, the yield is higher, the purity is better, the subsequent purification pressure is reduced, in addition, the synthesis method provided by the invention does not need to use a high-toxicity and corrosive reagent, the process safety is improved, the reaction condition is mild and easy to control, and the synthesis method is environment-friendly and high in industrial practicability.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a method for synthesizing azilsartan ester. Background Technology

[0002] Azilsartan Medoxomil, chemically named (5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl-2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid ester, is a prodrug of azilsartan. The structural formula of azilsartan Medoxomil is shown below:

[0003]

[0004] Azilsartan is an angiotensin II receptor blocker (ARB) antihypertensive drug developed by Takeda Pharmaceutical Company of Japan. On February 25, 2011, azilsartan ester potassium (trade name: Edarbi) was approved by the US FDA for the treatment of hypertension in adults, and clinical studies have shown that it has a stable and long-lasting antihypertensive effect.

[0005] PCT application WO 2013156005A1 discloses a method for synthesizing azilsartan ester. As described in Example 1, a solution of p-toluenesulfonyl chloride, DMAP, potassium carbonate, azilsartan, and 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one in dimethylacetamide is reacted at 8-10 degrees Celsius for 3 hours. After post-treatment, azilsartan ester is obtained with a yield of 80.1% and an HPLC purity of 97.6%. The content (HPLC peak area) of one impurity exceeds 1.0%, but is generally around 3.0%.

[0006] Based on the synthetic method of azilsartan ester disclosed in WO 2013156005A1, Chinese Patent CN 201410529424.7 has determined that the impurity in this synthetic method is a tetramer impurity formed after the removal of four water molecules from four molecules of azilsartan, the structural formula of which is shown below:

[0007]

[0008] It is evident that this type of synthesis method is prone to producing high levels of impurities, making it difficult for APIs to meet the standards specified in ICH Q7.

[0009] Furthermore, Chinese patent CN 201810288515.4 discloses a method for synthesizing azilsartan ester. Azilsartan is dissolved in dichloromethane under a nitrogen atmosphere, cooled to 0-5°C, and then reacted with oxalyl chloride at 20-25°C for 2 hours to obtain chloroazilsartan. The dichloromethane solution of chloroazilsartan, triethylamine, and DMAP are thoroughly mixed, cooled to 0-5°C, and p-toluenesulfonyl chloride is added at this temperature and reacted for 30 minutes. Then, 4-hydroxymethyl-5-methyl-1,3-dioxacyclopenten-2-one is reacted at 0-5°C for 1 hour, and then the temperature is raised to 5-10°C and reacted for 16 hours until the reaction is complete. After post-treatment, azilsartan ester is obtained. This type of synthesis uses oxalyl chloride as a chlorinating agent; however, oxalyl chloride is highly toxic and corrosive, and easily decomposes upon contact with moisture to produce the toxic gas carbon monoxide, which is unfavorable for large-scale industrial production.

[0010] In summary, there is an urgent need to develop a synthetic method for azilsartan ester that is high in purity, high in yield, low in impurities, environmentally friendly, and suitable for large-scale industrial production. Summary of the Invention

[0011] To overcome the shortcomings of the existing technology, the purpose of this invention is to provide a method for synthesizing azisartan ester, the target product obtained by this method has excellent yield and purity, and the method is also very suitable for large-scale industrial production.

[0012] The method for synthesizing azilsartan ester provided by the present invention is as follows: reacting azilsartan with thionyl chloride to obtain an intermediate reaction solution, and then adding 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one to the intermediate reaction solution to react and obtain azilsartan ester.

[0013] Existing synthetic processes for azilsartan ester often use common chlorinating agents such as oxalyl chloride and p-toluenesulfonyl chloride to obtain the acyl chloride intermediate of azilsartan, the structural formula of which is shown below:

[0014]

[0015] The inventors of this invention discovered that the acyl chloride intermediate has poor stability and is prone to degradation with increasing storage time during subsequent reactions. Washing with water further promotes the hydrolysis of the acyl chloride intermediate, causing it to revert back to the starting material azilsartan. Therefore, the preparation of azilsartan ester using this acyl chloride intermediate typically results in unsatisfactory yields and high impurity content, especially in the azilsartan starting material, which increases the difficulty of subsequent purification and consequently raises manufacturing costs.

[0016] The synthetic method provided by this invention uses thionyl chloride to react with azilsartan to form a sulfite intermediate as shown in formula (I) (its ESI-MS spectrum is shown in Figure 1). Figure 1 As shown in the figure, this sulfite intermediate has better stability than the acyl chloride intermediate. When preparing azilsartan broth from it, the yield of the target product is higher and the impurity content is lower. Therefore, it can significantly improve the production efficiency of azilsartan broth and reduce the manufacturing cost. The reaction formula is as follows:

[0017]

[0018] In the synthesis method provided by this invention, the structural formula of the raw material 4-hydroxymethyl-5-methyl-1,3-dioxacyclopenten-2-one is shown below:

[0019]

[0020] The synthesis method provided by this invention may further include the following steps:

[0021] S1: The azisartan and thionyl chloride are reacted in an organic solvent in the presence of a catalyst and a first acid-binding agent to obtain the intermediate reaction solution; and

[0022] S2: Add a second acid-binding agent and the 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one to the intermediate reaction solution and react to obtain the azilsartan ester.

[0023] In the synthesis method provided by the present invention, the first acid-binding agent and the second acid-binding agent may be the same or different, and each is independently selected from one or more of triethylamine, DMAP (4-dimethylaminopyridine), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DIPEA (N,N-diisopropylethylamine), sodium carbonate, and potassium carbonate.

[0024] In the synthesis method provided by this invention, the molar ratio of azisartan to the first acid-binding agent can be 1:1 to 4, including but not limited to molar ratios of about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:3.5, about 1:4, or any range of molar ratios. In some preferred embodiments, the molar ratio of azisartan to the first acid-binding agent can be 1:2 to 3.5.

[0025] In the synthesis method provided by this invention, the molar ratio of azilsartan to the second acid-binding agent can be 1:1 to 5, including but not limited to molar ratios of about 1:1, about 1:1.5, about 1:2, about 1:2.5, about 1:3, about 1:3.5, about 1:4, about 1:4.5, about 1:5, or any molar ratio range. In some preferred embodiments, the molar ratio of the first acid-binding agent to the second acid-binding agent can be 1:1 to 3. In the synthesis method provided by this invention, the molar ratio of azilsartan to thionyl chloride can be 1:1 to 3, including but not limited to molar ratios of about 1:1, about 1:1.2, about 1:1.5, about 1:1.8, about 1:2, about 1:2.2, about 1:2.5, about 1:2.8, about 1:3, about 1:3.5, about 1:4, or any molar ratio range. In some preferred embodiments, the molar ratio of azisartan to thionyl chloride can be 1:1.1 to 1.5.

[0026] In the synthesis method provided by this invention, the molar ratio of azilsartan to 4-hydroxymethyl-5-methyl-1,3-dioxacyclopenten-2-one can be 1:1 to 1.5. The amount of 4-hydroxymethyl-5-methyl-1,3-dioxacyclopenten-2-one used is crucial to the quality of the target product. When the amount is too low, the reaction is incomplete and the yield is low, while when the amount is too high, the acidic nature of the raw materials will affect the pH value of the reaction system, thereby affecting the reaction results and leading to a significant decrease in the yield and purity of the target product.

[0027] In the synthesis method provided by the present invention, the catalyst can be one or more of DMAP, PPY (4-pyrrolidinylpyridine), 9-AJ (9-azajulonidine), and TMAJ (4,4,10,10-tetramethyl-5,6,9,10-tetrahydro-4H,8H-pyridyl[3,2,1-IJ][1,6]naphthidine).

[0028] In the synthesis method provided by this invention, the molar ratio of azilsartan to the catalyst (e.g., DMAP) can be 1:0.1 to 1, including but not limited to molar ratios of about 1:0.1, about 1:0.2, about 1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1, or any range of molar ratios. In some preferred embodiments, the molar ratio of azilsartan to the catalyst (e.g., DMAP) can be 1:0.1 to 0.5. In some more preferred embodiments, the molar ratio of azilsartan to the catalyst (e.g., DMAP) can be 1:0.1 to 0.3.

[0029] In the synthesis method provided by this invention, the organic solvent can be selected from common halogenated aliphatic hydrocarbon solvents, ester solvents, heterocyclic hydrocarbon solvents, etc., including but not limited to dichloromethane, trichloromethane, dichloroethane, tetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, methyl acetate, ethyl acetate, etc. In some preferred embodiments, the organic solvent can be selected from one or more of dichloromethane, trichloromethane, tetrahydrofuran, 1,4-dioxane, and ethyl acetate.

[0030] In the synthesis method provided by this invention, the reaction temperatures of steps S1 and S2 can each be independently set to 5–10°C. In some preferred embodiments, the reaction temperatures can each be independently set to 6–8°C.

[0031] In the synthesis method provided by the present invention, the reaction time of step S1 and step S2 can be adjusted according to different reaction scales, reaction raw materials, etc., for example, each can be independently set to 1 to 10 hours.

[0032] The synthetic method for azilsartan medoxomil provided by this invention utilizes a sulfite intermediate formed from thionyl chloride and azilsartan to synthesize the target product. Compared to common acyl chloride intermediates, this sulfite intermediate exhibits better stability and is less prone to degradation or hydrolysis, resulting in a higher yield and purity of the target product and reducing the burden of subsequent purification. Furthermore, the synthetic method provided by this invention eliminates the need for highly toxic and corrosive reagents such as oxalyl chloride, improving process safety. The reaction conditions are mild and easily controlled, making it environmentally friendly and highly industrially applicable. Using the synthetic method provided by this invention can improve the production efficiency of azilsartan medoxomil and reduce its production cost, thus possessing significant economic and social value. Attached Figure Description

[0033] Figure 1 The ESI-MS spectrum of the sulfite intermediate with the structure shown in formula (I) is shown; according to the spectrum, the molecular weight is 959.2459 and the molecular formula is C. 50 H 39 N8O 11 S. Detailed Implementation

[0034] The technical solution of the present invention will be further described in detail below with reference to specific embodiments.

[0035] Unless otherwise specified, all raw materials or reagents used in the embodiments and comparative examples of this invention are commercially available products.

[0036] Unless otherwise specified, all percentages used in the embodiments and comparative examples of this invention are mass percentages.

[0037] Example 1

[0038] Add 48g (0.105mol) of azilsartan, 2.8g (0.023mol) of DMAP, 955g of dichloromethane, and 26.6g (0.263mol) of triethylamine to a four-necked flask. Under nitrogen protection, cool the flask to 5.0–10.0℃ and maintain the temperature between 5.0℃ and 10.0℃. Add a mixed solution of 15g (0.126mol) of thionyl chloride and 30g of dichloromethane dropwise. After the addition is complete, maintain the temperature of the solution between 5.0℃ and 10.0℃ for 2 hours.

[0039] After the heat preservation is completed, control the temperature of the feed solution at 5.0℃~10.0℃, add 21.2g (0.210mol) of triethylamine, and after the addition is complete, control the temperature of the feed solution at 5.0℃~10.0℃, and dropwise add a mixed solution of 16.4g (0.126mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of dichloromethane, and after the dropwise addition is complete, control the temperature of the feed solution at 5.0~10.0℃ and keep it at this temperature for 4 hours.

[0040] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desolventized. Then, 95g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 58.5g of azilsartan medoxomil, with a yield of 98.0%.

[0041] Example 2

[0042] Add 48g (0.105mol) of azisartan, 1.3g (0.0105mol) of DMAP, 955g of dichloromethane, and 28.3g (0.28mol) of triethylamine to a four-necked flask. Under nitrogen protection, cool the flask to 5.0–10.0℃ and maintain the temperature between 5.0℃ and 10.0℃. Add a mixed solution of 15g (0.126mol) of thionyl chloride and 30g of dichloromethane dropwise. After the addition is complete, maintain the temperature of the solution between 5.0℃ and 10.0℃ for 2 hours.

[0043] After the heat preservation is completed, control the temperature of the feed solution at 5.0℃~10.0℃, add 14.2g (0.14mol) of triethylamine, and after the addition is complete, control the temperature of the feed solution at 5.0℃~10.0℃, and dropwise add a mixed solution of 13.7g (0.105mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of dichloromethane, and after the dropwise addition is complete, control the temperature of the feed solution at 5.0~10.0℃ and keep it at this temperature for 6 hours.

[0044] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desolventized. Then, 90g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 56.7g of azilsartan medoxomil, with a yield of 95.0%.

[0045] Example 3

[0046] Add 48g (0.105mol) of azisartan, 2.6g (0.021mol) of DMAP, 955g of dichloromethane, and 30.3g (0.30mol) of triethylamine to a four-necked flask. Under nitrogen protection, cool the flask to 5.0–10.0℃ and maintain the temperature between 5.0℃ and 10.0℃. Add a mixed solution of 15g (0.126mol) of thionyl chloride and 30g of dichloromethane dropwise. After the addition is complete, maintain the temperature of the solution between 5.0℃ and 10.0℃ for 2 hours.

[0047] After the heat preservation is completed, control the temperature of the liquid solution at 5.0℃~10.0℃, add 22.8g (0.225mol) of triethylamine, and after the addition is complete, control the temperature of the liquid solution at 5.0℃~10.0℃, and dropwise add a mixed solution of 17g (0.131mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of dichloromethane, and after the addition is complete, control the temperature of the liquid solution at 5.0~10.0℃ and keep it at this temperature for 5 hours.

[0048] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desolventized. Then, 90g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 57.3g of azilsartan medoxomil, with a yield of 96.0%.

[0049] Example 4

[0050] Add 48g (0.105mol) of azisartan, 3.9g (0.0315mol) of DMAP, 955g of dichloromethane, and 37.2g (0.368mol) of triethylamine to a four-necked flask. Under nitrogen protection, cool the solution to 5.0–10.0℃ and maintain the temperature between 5.0℃ and 10.0℃. Add a mixed solution of 15g (0.126mol) of thionyl chloride and 30g of dichloromethane dropwise. After the addition is complete, maintain the temperature of the solution between 5.0℃ and 10.0℃ and keep it at this temperature for 2 hours.

[0051] After the heat preservation is completed, control the temperature of the feed solution at 5.0℃~10.0℃, add 31.9g (0.315mol) of triethylamine, and after the addition is complete, control the temperature of the feed solution at 5.0℃~10.0℃, and dropwise add a mixed solution of 20.5g (0.158mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of dichloromethane, and after the dropwise addition is complete, control the temperature of the feed solution at 5.0~10.0℃ and keep it at this temperature for 5 hours.

[0052] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desolventized. Then, 90g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 56.1g of azilsartan medoxomil, with a yield of 94.0%.

[0053] Example 5

[0054] Add 48g (0.105mol) of azilsartan, 1.3g (0.0105mol) of DMAP, 955g of dichloromethane, and 30g (0.296mol) of triethylamine to a four-necked flask. Under nitrogen protection, cool the solution to 5.0–10.0℃, and control the temperature at 6.0℃–8.0℃. Add a mixed solution of 15g (0.126mol) of thionyl chloride and 30g of dichloromethane dropwise. After the addition is complete, control the temperature of the solution at 5.0℃–10.0℃ and keep it at this temperature for 2 hours.

[0055] After the heat preservation is completed, control the temperature of the liquid solution at 5.0℃~10.0℃, add 21g (0.207mol) of triethylamine, and after the addition is complete, control the temperature of the liquid solution at 5.0℃~10.0℃, and dropwise add a mixed solution of 13.6g (0.105mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of dichloromethane, and after the dropwise addition is complete, control the temperature of the liquid solution at 5.0~10.0℃ and keep it at this temperature for 6 hours.

[0056] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desolventized. Then, 90g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 56.7g of azilsartan medoxomil, with a yield of 95.0%.

[0057] Example 6

[0058] Add 48g (0.105mol) of azilsartan, 3.9g (0.0315mol) of DMAP, 955g of dichloromethane, and 29g (0.286mol) of triethylamine to a four-necked flask. Under nitrogen protection, cool the solution to 5.0–10.0℃, and control the temperature at 6.0℃–8.0℃. Add a mixed solution of 15g (0.126mol) of thionyl chloride and 30g of dichloromethane dropwise. After the addition is complete, control the temperature of the solution at 5.0℃–10.0℃ and keep it at this temperature for 2 hours.

[0059] After the heat preservation is completed, control the temperature of the liquid solution at 5.0℃~10.0℃, add 26g (0.257mol) of triethylamine, and after the addition is complete, control the temperature of the liquid solution at 5.0℃~10.0℃, and dropwise add a mixed solution of 20.5g (0.158mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of dichloromethane, and after the dropwise addition is complete, control the temperature of the liquid solution at 5.0~10.0℃ and keep it at this temperature for 5 hours.

[0060] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desolventized. Then, 90g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 56.1g of azilsartan medoxomil, with a yield of 94.0%.

[0061] Example 7

[0062] Add 48g (0.105mol) of azilsartan, 3.1g (0.021mol) of 4-pyrrolylpyridine, 955g of dichloromethane, and 26.6g (0.263mol) of triethylamine to a four-necked flask. Under nitrogen protection, cool the flask to 5.0–10.0℃ and maintain the temperature between 5.0℃ and 10.0℃. Add a mixed solution of 15g (0.126mol) of thionyl chloride and 30g of dichloromethane dropwise. After the addition is complete, maintain the temperature of the solution between 5.0℃ and 10.0℃ for 2 hours.

[0063] After the heat preservation is completed, control the temperature of the feed solution at 5.0℃~10.0℃, add 21.2g (0.210mol) of triethylamine, and after the addition is complete, control the temperature of the feed solution at 5.0℃~10.0℃, and dropwise add a mixed solution of 16.4g (0.126mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of dichloromethane, and after the dropwise addition is complete, control the temperature of the feed solution at 5.0~10.0℃ and keep it at this temperature for 4 hours.

[0064] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desolventized. Then, 95g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 58.8g of azilsartan medoxomil, with a yield of 98.3%.

[0065] Example 8

[0066] Add 48g (0.105mol) of azilsartan, 2.8g (0.023mol) of DMAP, 955g of chloroform, and 26.6g (0.263mol) of triethylamine to a four-necked flask. Under nitrogen protection, cool the solution to 5.0–10.0℃ and maintain the temperature between 5.0℃ and 10.0℃. Add a mixed solution of 15g (0.126mol) of thionyl chloride and 30g of chloroform dropwise. After the addition is complete, maintain the temperature of the solution between 5.0℃ and 10.0℃ for 2 hours.

[0067] After the heat preservation is completed, control the temperature of the liquid solution at 5.0℃~10.0℃, add 21.2g (0.210mol) of triethylamine, and after the addition is complete, control the temperature of the liquid solution at 5.0℃~10.0℃, and dropwise add a mixed solution of 16.4g (0.126mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of chloroform, and after the dropwise addition is complete, control the temperature of the liquid solution at 5.0~10.0℃ and keep it at this temperature for 4 hours.

[0068] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desoluble. Then, 95g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 58.2g of azilsartan medoxomil, with a yield of 97.3%.

[0069] Example 9

[0070] Add 48g (0.105mol) of azisartan, 2.8g (0.023mol) of DMAP and 955g of dichloromethane to a four-necked flask. Under nitrogen protection, cool the flask to 5.0–10.0℃ and maintain the temperature between 5.0℃ and 10.0℃. Add 40.0g (0.263mol) of DBU dropwise. After the addition is complete, keep the flask at this temperature for 10 minutes. Then, maintain the temperature between 5.0℃ and 10.0℃ and add a mixed solution of 15g (0.126mol) of thionyl chloride and 30g of dichloromethane dropwise. After the addition is complete, maintain the temperature between 5.0℃ and 10.0℃ and keep the flask at this temperature for 2 hours.

[0071] After the heat preservation is completed, control the temperature of the feed solution at 5.0℃~10.0℃, and add 32.0g (0.210mol) of DBU dropwise. After the addition is completed, control the temperature of the feed solution at 5.0℃~10.0℃, and add a mixed solution of 16.4g (0.126mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of dichloromethane dropwise. After the addition is completed, control the temperature of the feed solution at 5.0~10.0℃ and keep it at this temperature for 4 hours.

[0072] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desolventized. Then, 95g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 57.7g of azilsartan medoxomil, with a yield of 96.5%.

[0073] Example 10

[0074] Add 48g (0.105mol) of azisartan, 2.8g (0.023mol) of DMAP, 955g of dichloromethane, and 66.8g (0.63mol) of sodium carbonate to a four-necked flask. Stir for 30 minutes, and under nitrogen protection, cool to 5.0-10.0℃. Control the temperature at 5.0-10.0℃, and add a mixed solution of 15g (0.126mol) of thionyl chloride and 30g of dichloromethane dropwise. After the addition is complete, control the temperature of the solution at 5.0-10.0℃ and keep it at this temperature for 2 hours.

[0075] After the heat preservation is completed, control the temperature of the liquid at 5.0℃~10.0℃, and add a mixed solution of 16.4g (0.126mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of dichloromethane dropwise. After the addition is completed, control the temperature of the liquid at 5.0~10.0℃ and keep it at this temperature for 4 hours.

[0076] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desolventized. Then, 95g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 57.9g of azilsartan medoxomil, with a yield of 96.8%.

[0077] Comparative Example 1

[0078] Add 48g (0.105mol) of azilsartan, 2.8g (0.023mol) of DMAP, 955g of dichloromethane, and 26.6g (0.263mol) of triethylamine to a four-necked flask. Under nitrogen protection, cool the flask to 5.0–10.0℃ and maintain the temperature between 5.0℃ and 10.0℃. Add a mixed solution of 24g (0.126mol) of p-toluenesulfonyl chloride and 30g of dichloromethane dropwise. After the addition is complete, maintain the temperature of the solution between 5.0℃ and 10.0℃ for 2 hours.

[0079] After the heat preservation is completed, control the temperature of the feed solution at 5.0℃~10.0℃, add 21.2g (0.210mol) of triethylamine, and after the addition is complete, control the temperature of the feed solution at 5.0℃~10.0℃, and dropwise add a mixed solution of 16.4g (0.126mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of dichloromethane, and after the dropwise addition is complete, control the temperature of the feed solution at 5.0~10.0℃ and keep it at this temperature for 4 hours.

[0080] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desoluble. Then, 95g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 46.6g of azilsartan medoxomil, with a yield of 78.0%.

[0081] Comparative Example 2

[0082] Add 48g (0.105mol) of azilsartan, 2.8g (0.023mol) of DMAP, 955g of dichloromethane, and 22.8g (0.225mol) of triethylamine to a four-necked flask. Under nitrogen protection, cool the flask to 5.0–10.0℃ and maintain the temperature between 5.0℃ and 10.0℃. Add a mixed solution of 15g (0.126mol) of thionyl chloride and 30g of dichloromethane dropwise. After the addition is complete, maintain the temperature of the solution between 5.0℃ and 10.0℃ for 2 hours.

[0083] After the heat preservation is completed, control the temperature of the liquid solution at 5.0℃~10.0℃, add 9.1g (0.090mol) of triethylamine, and after the addition is complete, control the temperature of the liquid solution at 5.0℃~10.0℃, and dropwise add a mixed solution of 16.4g (0.126mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of dichloromethane, and after the addition is complete, control the temperature of the liquid solution at 5.0~10.0℃ and keep it at this temperature for 4 hours.

[0084] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desolventized. Then, 95g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 48.4g of azilsartan medoxomil, with a yield of 81.0%.

[0085] Comparative Example 3

[0086] Add 48g (0.105mol) of azilsartan, 2.8g (0.023mol) of DMAP, 955g of dichloromethane, and 47.8g (0.472mol) of triethylamine to a four-necked flask. Under nitrogen protection, cool the flask to 5.0–10.0℃ and maintain the temperature between 5.0℃ and 10.0℃. Add a mixed solution of 15g (0.126mol) of thionyl chloride and 30g of dichloromethane dropwise. After the addition is complete, maintain the temperature of the solution between 5.0℃ and 10.0℃ for 2 hours.

[0087] After the heat preservation is completed, control the temperature of the liquid solution at 5.0℃~10.0℃, add 42.5g (0.42mol) of triethylamine, and after the addition is complete, control the temperature of the liquid solution at 5.0℃~10.0℃, and dropwise add a mixed solution of 16.4g (0.126mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of dichloromethane, and after the dropwise addition is complete, control the temperature of the liquid solution at 5.0~10.0℃ and keep it at this temperature for 4 hours.

[0088] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desolventized. Then, 95g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 46.0g of azilsartan medoxomil, with a yield of 77.0%.

[0089] Comparative Example 4

[0090] Add 48g (0.105mol) of azilsartan, 1.0g (0.008mol) of DMAP, 955g of dichloromethane, and 26.6g (0.263mol) of triethylamine to a four-necked flask. Under nitrogen protection, cool the flask to 5.0–10.0℃ and maintain the temperature between 5.0℃ and 10.0℃. Add a mixed solution of 15g (0.126mol) of thionyl chloride and 30g of dichloromethane dropwise. After the addition is complete, maintain the temperature of the solution between 5.0℃ and 10.0℃ for 2 hours.

[0091] After the heat preservation is completed, control the temperature of the feed solution at 5.0℃~10.0℃, add 21.2g (0.210mol) of triethylamine, and after the addition is complete, control the temperature of the feed solution at 5.0℃~10.0℃, and dropwise add a mixed solution of 21.9g (0.168mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of dichloromethane, and after the dropwise addition is complete, control the temperature of the feed solution at 5.0~10.0℃ and keep warm for 4 hours.

[0092] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desoluble. Then, 95g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 46.6g of azilsartan medoxomil, with a yield of 78.0%.

[0093] Comparative Example 5

[0094] Add 48g (0.105mol) of azisartan, 5.1g (0.042mol) of DMAP, 955g of dichloromethane, and 26.6g (0.263mol) of triethylamine to a four-necked flask. Under nitrogen protection, cool the flask to 5.0–10.0℃ and maintain the temperature between 5.0℃ and 10.0℃. Add a mixed solution of 15g (0.126mol) of thionyl chloride and 30g of dichloromethane dropwise. After the addition is complete, maintain the temperature of the solution between 5.0℃ and 10.0℃ for 2 hours.

[0095] After the heat preservation is completed, control the temperature of the feed solution at 5.0℃~10.0℃, add 21.2g (0.210mol) of triethylamine, and after the addition is complete, control the temperature of the feed solution at 5.0℃~10.0℃, and dropwise add a mixed solution of 11.0g (0.085mol) of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one and 60g of dichloromethane, and after the dropwise addition is complete, control the temperature of the feed solution at 5.0~10.0℃ and keep it at this temperature for 4 hours.

[0096] After the reaction was completed, the pH of the reaction solution was adjusted to 4-5.5 using dilute hydrochloric acid solution. The mixture was allowed to stand and separate into layers. The organic layer was separated and desoluble. Then, 95g of dichloromethane was added, the temperature was raised to 35-40℃, and the mixture was stirred and filtered to obtain 48.3g of azilsartan medoxomil, with a yield of 81.0%.

[0097] Experimental Example

[0098] The azilsartan medoxomil products obtained in the examples and comparative examples were analyzed using high-performance liquid chromatography (HPLC). The equipment information and detection conditions are as follows:

[0099] High performance liquid chromatograph: Agilent 1260 (UV detector) or equivalent instrument;

[0100] Data processing system: Empower workstation or other equivalent workstation;

[0101] Column: ZORBAX Eclipse XDB-C8, 150×4.6mm, 5μm, or equivalent;

[0102] Column temperature: 30℃;

[0103] Detection wavelength: 200nm;

[0104] Injection volume: 10 μL;

[0105] Running time: 35 minutes;

[0106] Sample tray temperature: 5℃;

[0107]

[0108] Diluent / Blank Solution: Acetonitrile-water (50:50);

[0109] Reference solution: Take about 25 mg of azisartan medoxomil reference standard, place it in a 50 mL volumetric flask, dissolve and dilute to the mark with diluent, shake well, and the concentration of azisartan medoxomil in the solution is about 0.5 mg / mL.

[0110] Test solution: Take about 25 mg of the test sample and place it in a 50 mL volumetric flask. Dissolve and dilute to the mark with diluent and shake well. The concentration of azisartan medoxomil in the solution is about 0.5 mg / mL.

[0111] The data obtained from the test are shown in Table 1.

[0112] Table 1

[0113] Azisartan medoxomil content U-2 content U-1 content U-4 content Example 1 97.50％ 0.51％ Not detected 0.11％ Example 2 98.17％ 0.48％ 0.11％ Not detected Example 3 97.13％ 0.52％ 0.12％ Not detected Example 4 98.31％ 0.39％ Not detected 0.07％ Example 5 99.53％ 0.18％ Not detected Not detected Example 6 99.67％ 0.11％ Not detected Not detected Example 7 98.63％ 0.33％ Not detected Not detected Example 8 98.43％ 0.54％ Not detected Not detected Example 9 96.83％ 0.65％ 0.16％ 0.14％ Example 10 97.08％ 0.87％ 0.13％ Not detected Comparative Example 1 88.57％ 5.75％ 1.73％ 1.18％ Comparative Example 2 89.35％ 5.06％ 1.96％ 1.03％ Comparative Example 3 90.52％ 4.95％ 1.65％ 1.11％ Comparative Example 4 88.23％ 5.98％ 1.46％ 1.07％ Comparative Example 5 87.85％ 6.03％ 1.59％ 1.33％

[0114] In Table 1, the detection standards for each impurity are: U-2 < 4.5%, U-1 < 0.2%, and U-4 < 0.25%. The structural formula of impurity U-2 is shown below:

[0115]

[0116] The structural formula of impurity U-1 is shown below:

[0117]

[0118] The structural formula of impurity U-4 is shown below:

[0119]

[0120] As shown in Table 1, the synthesis method provided by this invention yields significantly higher and purer products, with a substantial reduction in the content of several key impurities. Comparative Example 1, which uses p-toluenesulfonyl chloride to form an acyl chloride intermediate, fails to achieve the synthesis effect of this invention. In Comparative Example 2, the amount of the second acid-binding agent is too small, resulting in insufficient acid binding and thus also failing to achieve the synthesis effect of this invention. In Comparative Example 3, the amount of the first acid-binding agent, triethylamine, is excessive. The organic amine is soluble in the reaction system, and excessive amounts lead to incomplete reactions, resulting in unsatisfactory yields and purity of the target product. Comparative Examples 4 and 5 demonstrate that the amount of 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one should not be too much or too little, as both will affect the synthesis effect.

[0121] Unless otherwise specified, the terms used in this invention have the meanings commonly understood by those skilled in the art.

[0122] The embodiments described in this invention are for illustrative purposes only and are not intended to limit the scope of protection of this invention. Those skilled in the art can make various other substitutions, changes and improvements within the scope of this invention. Therefore, this invention is not limited to the above embodiments, but is only defined by the claims.

Claims

1. A method for synthesizing azilsartan ester, characterized in that, Azisartan is reacted with thionyl chloride to obtain an intermediate reaction solution. Then, 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one is added to the intermediate reaction solution to carry out the reaction, thereby obtaining the azisartan ester.

2. The synthesis method according to claim 1, characterized in that, The synthesis method includes the following steps: S1: The azisartan and thionyl chloride are reacted in an organic solvent in the presence of a catalyst and a first acid-binding agent to obtain the intermediate reaction solution; and S2: Add a second acid-binding agent and the 4-hydroxymethyl-5-methyl-1,3-dioxane-2-one to the intermediate reaction solution and react to obtain the azilsartan ester.

3. The synthesis method according to claim 2, characterized in that, The first acid-binding agent and the second acid-binding agent are each independently selected from one or more of triethylamine, DMAP, DBU, DIPEA, sodium carbonate, and potassium carbonate.

4. The synthesis method according to claim 2 or 3, characterized in that, The molar ratio of azisartan to the first acid-binding agent is 1:1 to 4, preferably 1:2 to 3.

5.

5. The synthesis method according to any one of claims 2-4, characterized in that, The molar ratio of azisartan to the second acid-binding agent is 1:1 to 5, preferably 1:1 to 3.

6. The synthesis method according to any one of claims 2-5, characterized in that, The molar ratio of azisartan to thionyl chloride is 1:1 to 3, preferably 1:1.1 to 1.

5.

7. The synthesis method according to any one of claims 2-6, characterized in that, The molar ratio of azisartan to 4-hydroxymethyl-5-methyl-1,3-dioxacyclopenten-2-one is 1:1 to 1.

5.

8. The synthesis method according to any one of claims 2-7, characterized in that, The catalyst is one or more of DMAP, PPY, 9-AJ, and TMAJ; and / or The molar ratio of azisartan to the catalyst is 1:0.1 to 1, preferably 1:0.1 to 0.

3.

9. The synthesis method according to any one of claims 2-8, characterized in that, The organic solvent is selected from one or more of dichloromethane, trichloromethane, tetrahydrofuran, 1,4-dioxane, and ethyl acetate.

10. The synthesis method according to any one of claims 2-9, characterized in that, The reaction temperature for steps S1 and S2 is 5–10°C.

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