Azilsartan medoxomil without p-toluenesulfonyl chloride

Abstract

The application belongs to the field of pharmaceutical chemistry and synthesis of medical raw materials, and discloses a green esterification process of azilsartan medoxomil without p-toluenesulfonyl chloride, which comprises the following steps: taking azilsartan as raw material, taking 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as condensing agent, and taking 4-dimethylaminopyridine as catalyst, and then carrying out esterification reaction of azilsartan and 4-hydroxymethyl-5-methyl-1,3-dioxolane-2-ketone in a low-toxicity reaction solvent to obtain azilsartan medoxomil. The application discards the traditional p-toluenesulfonyl chloride activation system and high-toxicity dichloromethane solvent, adopts an EDC·HCl / DMAP catalytic system, and matches low-toxicity solvents such as ethyl acetate and methyltetrahydrofuran to realize the esterification reaction of azilsartan, so that the genotoxicity impurities of tosylate are completely eliminated from the source. The yield of azilsartan medoxomil prepared by the application is greater than or equal to 91%, and the purity is greater than or equal to 99.75%.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and pharmaceutical raw material synthesis, and relates to a green esterification process of azilsartan ester without p-toluenesulfonyl chloride. Specifically, it relates to a green esterification process of azilsartan ester, a key intermediate of the angiotensin II receptor antagonist mesartan potassium, and particularly to a low-toxicity and environmentally friendly azilsartan ester synthesis process that avoids genotoxic impurities from the source. Background Technology

[0002] Azilsartan K is a new generation of long-acting angiotensin II receptor antagonist (ARB). It selectively blocks the binding of angiotensin II to its receptor, inhibiting vasoconstriction and aldosterone secretion. Clinically, it is mainly used for the treatment of essential hypertension. This drug has a stable antihypertensive effect, good tolerability, and few adverse reactions. It has been approved for marketing in many countries worldwide, and domestic production, process optimization, and green transformation have become key research directions for the pharmaceutical industry in China.

[0003] Currently, the mainstream synthetic method for measartan potassium adopts the ROS (Route of Synthesis) synthetic route. Figure 1 The process includes: oximation of candesartan methyl ester (or candesartan ethyl ester) to prepare aminooxime methyl ester (or aminooxime ethyl ester), followed by cyclization and hydrolysis to obtain azilsartan. Azilsartan undergoes esterification with the side-chain compound 4-hydroxymethyl-5-methyl-1,3-dioxacyclopenten-2-one to generate azilsartan ester, which is then salted to obtain the final product, meazartan potassium. The esterification of azilsartan ester is the core and critical step in the entire process, directly determining the purity of the intermediate, impurity levels, and the quality of the final product.

[0004] Industrial esterification processes commonly use p-toluenesulfonyl chloride (TsCl) as the carboxyl activator and dichloromethane (DCM) as the reaction solvent. This esterification process has the following main drawbacks:

[0005] 1. Significant risk of genotoxic impurities: When p-toluenesulfonyl chloride participates in esterification reactions, it can directionally generate toluenesulfonate genotoxic impurities (methyl p-toluenesulfonate, ethyl p-toluenesulfonate, and isopropyl p-toluenesulfonate). These substances have strong carcinogenic and mutagenic risks, and domestic and international pharmacopoeias (Chinese Pharmacopoeia, USP, EP) require limits of ppm for them. Regulations strictly control the residual amount of these impurities, and it is difficult to completely remove them by conventional post-treatment methods such as recrystallization and activated carbon adsorption alone. Multiple deep refining processes must be added, which significantly increases the production load and material loss.

[0006] , , .

[0007] 2. Poor safety of solvent system: Dichloromethane is used as the main reaction solvent. Dichloromethane is a highly toxic and volatile organic solvent, which requires high occupational protection and is difficult to control solvent residues. At the same time, the recovery rate of dichloromethane is low, and the emission of organic waste gas and waste solvent is large. As a special pollutant in environmental protection, the treatment cost is high.

[0008] 3. Numerous process side reactions and limited yield: p-Toluenesulfonyl chloride is chemically reactive and easily triggers side reactions such as degradation and isomerization of the azisartan core during the reaction process, resulting in a low yield of esterification products, which is generally 85-90%. There are significant differences in impurity profiles between batches, and the yield and purity fluctuate greatly during large-scale production.

[0009] 4. Insufficient safety of process operation: p-Toluenesulfonyl chloride is highly irritating and can damage the human respiratory tract and skin; fluctuations in the acidity and alkalinity of the reaction system can easily lead to violent local reactions, making production safety control difficult.

[0010] To address these issues, existing technologies primarily focus on adding impurity removal processes after esterification, such as using adsorption resins, alkaline water washing, and multiple recrystallizations to remove toluenesulfonate impurities. This "end-of-pipe" approach fails to eliminate impurity generation at its source and further lengthens the production cycle and increases overall costs. For a long time, a technological bias has existed in this field that "azisartan esterification must use p-toluenesulfonyl chloride as an activator," resulting in a lack of mature industrial solutions that completely replace the activation system and block genotoxic impurities at their source.

[0011] Therefore, developing an azilsartan ester esterification process that is free of p-toluenesulfonyl chloride, low in toxicity and environmentally friendly, with improved yield and purity, and suitable for industrial scale-up, and combining it with existing mature salt formation routes to prepare high-quality meazartan potassium, is a technical bottleneck that urgently needs to be overcome in this field, and has extremely high market value and green chemical significance. Summary of the Invention

[0012] The purpose of this invention is to address the shortcomings of existing azilsartan esterification processes by providing a green azilsartan esterification process that does not require p-toluenesulfonyl chloride.

[0013] Through extensive formulation and process screening, the inventors unexpectedly discovered that by abandoning the traditional p-toluenesulfonyl chloride activation system and highly toxic dichloromethane, and instead using a carbodiimide condensing agent + DMAP (4-dimethylaminopyridine) catalytic system, combined with low-toxicity solvents such as ethyl acetate and methyltetrahydrofuran, a highly efficient esterification reaction of azilsartan with the 4-hydroxymethyl-5-methyl-1,3-dioxolane-2-one side chain can be achieved. The catalytic system of this invention does not generate sulfonyl genotoxic impurities, and the reaction conditions are mild with few side reactions. The purity and yield of the azilsartan ester obtained are superior to those of traditional processes.

[0014] The objective of this invention is achieved through the following technical solution:

[0015] A green esterification process for azilsartan ester without p-toluenesulfonyl chloride includes: using azilsartan as a raw material, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) as a condensing agent, and 4-dimethylaminopyridine (DMAP) as a catalyst, azilsartan reacts with 4-hydroxymethyl-5-methyl-1,3-dioxolane-2-one in a low-toxicity reaction solvent to obtain azilsartan ester.

[0016] The reaction solvent is 2-methyltetrahydrofuran or ethyl acetate.

[0017] The mass-to-volume ratio of azisartan to the reaction solvent is 1:8 to 1:12 g / mL, preferably 10 g / mL.

[0018] The molar ratio of azisartan to 4-hydroxymethyl-5-methyl-1,3-dioxolane-2-one is 1:1.05 to 1:1.2, preferably 1:1.1.

[0019] The molar ratio of azisartan to EDC·HCl is 1:1.1 to 1:1.3, preferably 1:1.2.

[0020] The molar ratio of azisartan to DMAP is 1:0.05 to 1:0.15, preferably 1:0.1.

[0021] The esterification reaction was carried out under nitrogen protection.

[0022] The esterification reaction is carried out at a temperature of 20–35°C, preferably 25°C; the endpoint of the esterification reaction is when the azilsartan raw material residue is ≤0.5%.

[0023] Specifically, an esterification process for azilsartan ester without p-toluenesulfonyl chloride includes: mixing azilsartan, 4-hydroxymethyl-5-methyl-1,3-dioxolane-2-one and a low-toxicity reaction solvent under nitrogen protection, stirring at room temperature until the solid is completely dissolved; cooling to 0-10°C, adding EDC·HCl in batches, and after the addition is complete, maintaining the temperature at 0-10°C and stirring for 40 min to activate the mixture; then adding DMAP, and slowly heating to the esterification reaction temperature to carry out the esterification reaction to generate azilsartan ester.

[0024] Preferably, the activation temperature is 5°C.

[0025] Generally, the total reaction time (the sum of activation time and esterification reaction time) is 6 to 10 hours.

[0026] Preferably, the process also includes post-treatment: quenching the reaction with water to separate the organic phase, washing the organic phase sequentially with dilute hydrochloric acid, saturated sodium bicarbonate solution, and purified water, concentrating under reduced pressure to obtain a concentrated solution, adding n-heptane, and recrystallizing by gradient cooling to 0-5°C for 4-6 hours, filtering to obtain azilsartan ester.

[0027] The concentration of the dilute hydrochloric acid is 0.5 mol / L.

[0028] The volume of the concentrated solution is approximately 1 / 3.5 to 1 / 4 of the volume of the reaction solvent.

[0029] The volume ratio of n-heptane to the concentrate is 2:1.

[0030] The cooling rate is 2℃ / 10 min. Gradient cooling results in larger precipitated azilsartan ester particles, which are easier to filter later.

[0031] Preferably, the solvent recovered by vacuum concentration is collected; the recrystallization mother liquor is heated to 85°C and distilled under normal pressure to collect the fraction; the solvent recovered by vacuum concentration and the solvent recovered by normal pressure distillation are reused in the esterification reaction.

[0032] The inventors combined the esterification process of azisartan ester with the existing salt formation process to form a complete green preparation route from azisartan to meazartan potassium. The entire process does not require acid and alkali regulation, deep refining, and the solvent can be recycled and reused, taking into account quality, environmental protection, cost and industrial feasibility.

[0033] A green method for preparing measartan potassium includes the following steps:

[0034] Step (1): Using azilsartan as raw material, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as condensing agent and 4-dimethylaminopyridine as catalyst, azilsartan reacts with 4-hydroxymethyl-5-methyl-1,3-dioxolane-2-one in a low-toxicity reaction solvent to obtain azilsartan ester.

[0035] Step (2), Esterification reaction: Azilsartan was taken and prepared into high-purity azilsartan ester by the azilsartan ester ...

[0036] Step (3), Decolorization: Azisartan ester is dissolved in acetone by stirring, activated carbon is added for decolorization, and the activated carbon is removed by filtration to obtain the filtrate;

[0037] Step (4), Salt formation reaction: Under nitrogen protection, acetone solution of potassium 2-ethylhexanoate is slowly added dropwise to the filtrate. Salt formation reaction is carried out at a temperature of 25-30℃. After the product is precipitated, the temperature is lowered to 0-5℃ and stirred for maturation.

[0038] Step (5), post-processing: filtration, repeated pulping and washing with cold acetone, drying, to obtain the finished product of measartan potassium.

[0039] In step (3), preferably, at a temperature of 30-35°C, azisartan medoxomil is stirred and dissolved in acetone at a ratio of 1:8 to 1:8.5 g / mL to acetone. Activated carbon is added at a mass ratio of 10:100 to 10.5:100 to azisartan medoxomil. The mixture is decolorized at a temperature of 30-35°C for 0.5-1 h and then filtered through diatomaceous earth to obtain the filtrate.

[0040] In step (4), the molar ratio of potassium 2-ethylhexanoate and azisartan ester is 1:1 to 1.05:1, preferably 1.02:1.

[0041] The potassium 2-ethylhexanoate acetone solution was prepared according to a mass ratio of potassium 2-ethylhexanoate to acetone of 1:1.5.

[0042] Preferably, an acetone solution of potassium 2-ethylhexanoate is slowly added dropwise to the filtrate over a period of 50 to 70 minutes.

[0043] Preferably, the maturation and stirring time is 2 hours.

[0044] In step (5), the pulping and washing process is performed three times.

[0045] When performing a single pulping process, the ratio of acetone to azilsartan medoxomil is 1:1 mL / g.

[0046] The temperature of the acetone is 0–10°C.

[0047] The drying temperature is 30-35°C, and the drying method is vacuum drying.

[0048] The HPLC purity of the finished mesartan potassium product is ≥99.70%, the total impurities are ≤0.20%, the single largest impurity is ≤0.10%, and no toluenesulfonate genotoxic impurities were detected (detection limit ≤0.1 ppm). The crystal form of the finished mesartan potassium product is completely consistent with the commercially available reference preparation, and the solvent residue meets the requirements of ICH Q3C and Chinese Pharmacopoeia.

[0049] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0050] (I) Outstanding environmental benefits

[0051] This invention completely eliminates the combination system of irritating p-toluenesulfonyl chloride and highly toxic dichloromethane in traditional processes, blocking the generation of genotoxic impurities in toluenesulfonate esters at the source. It eliminates the need for a dedicated impurity removal process, meeting the impurity control requirements of pharmacopoeias in various countries. This invention replaces the highly toxic solvent dichloromethane (which contains halogen atoms and is considered a special pollutant in environmental protection) with low-toxic solvents such as 2-methyltetrahydrofuran, ethyl acetate, or acetone. The organic solvents are recyclable and reusable, with a solvent recovery rate of ≥90%, reducing occupational health risks and the pressure of waste treatment. The wastewater is a conventional saline aqueous solution, which can meet discharge standards after neutralization and flocculation, producing no genotoxic hazardous waste and minimizing environmental maintenance pressure.

[0052] Based on an annual production of 5 tons of mesartan potassium raw materials: the annual discharge of highly toxic dichloromethane waste liquid can be reduced by about 30 to 40 tons, and the discharge of organic waste gas can be reduced by more than 45%; no genotoxic hazardous waste is generated, the COD value of wastewater is reduced by more than 50%, and the cost of hazardous waste disposal and environmental protection operation and maintenance is significantly reduced, which fully meets the requirements of green production in the pharmaceutical and chemical industry.

[0053] (II) The process of this invention reduces side reactions during esterification, improves the yield and chromatographic purity of azilsartan ester, reduces batch-to-batch quality differences, and enhances process scale-up stability, making it suitable for large-scale continuous production. A multi-dimensional comparison of the process of this invention with the traditional p-toluenesulfonyl chloride esterification process yields the following results: the obtained azilsartan ester yield is ≥91.00%, and the purity is ≥99.70%.

[0054] .

[0055] (III) It is generally believed in the industry that the esterification reaction of azisartan side chain depends on p-toluenesulfonyl chloride for efficient activation. Directly replacing the activating reagent will lead to a significant decrease in reaction conversion rate and esterification failure, forming a bias against solidification technology.

[0056] This invention breaks through conventional industry understanding by employing a carbodiimide condensation activation pathway. Without using p-toluenesulfonyl chloride, it not only ensures the reaction proceeds completely under mild conditions, eliminating the risks of strong exothermic reactions, high pressure, and highly toxic gas leaks, significantly reducing occupational safety concerns in the workshop, but also achieves multiple technical benefits, including increased yield, improved purity, and zero genotoxic impurities in toluenesulfonate esters. This invention overcomes the technical prejudice in the field that "esterification must use p-toluenesulfonyl chloride," a view not readily apparent to those skilled in the art, and possesses outstanding substantive features and significant technological advancements.

[0057] (iv) Significant economic benefits

[0058] This invention's process can be implemented using existing ROS production lines, requiring only the replacement of reactants and solvents. No equipment modifications or new production lines are needed, resulting in zero equipment modification costs. Based on industrial production cost calculations: compared to traditional processes, single-batch material loss is reduced by 8%–12%, solvent and excipient costs are reduced by 18%, and environmental and hazardous waste treatment costs are reduced by over 50%. Overall, the unit production cost of measartan potassium is reduced by approximately 22%. Based on an annual production of 5 tons of raw material, the annual comprehensive production cost savings exceed one million yuan, significantly enhancing market competitiveness.

[0059] (v) Product quality and batch stability

[0060] The azilsartan medoxomil and measartan potassium products prepared by this invention have stable impurity profiles and no risk of genotoxic impurities. Powder X-ray diffraction (PXRD) analysis shows that the crystal form of measartan potassium is completely consistent with the original formulation and the commercially available reference formulation, with no crystal transformation or mixed crystal phenomena. Data from multiple batches of small-scale and pilot-scale tests show that the process parameters have a wide tolerance range, there is no significant scale-up effect in large-scale production, and the yield, purity, and impurity index fluctuate very little between batches. The product quality fully meets the requirements of domestic and international pharmacopoeias and drug application.

[0061] (vi) The EDC·HCl, DMAP, ethyl acetate, 2-methyltetrahydrofuran, etc. used in this invention are all industrial raw materials with stable procurement channels and moderate prices, and there is no problem of raw material bottleneck.

[0062] In summary, the technical solution of this invention has strong industrial applicability and can be directly applied to the industrial production of mesartan potassium raw materials. Attached Figure Description

[0063] Figure 1 This is a complete process flow diagram of traditional meazartan potassium (azilsartan → azilsartan ester → meazartan potassium).

[0064] Figure 2 The powder X-ray diffraction pattern of measartan potassium prepared in Example 3 is shown.

[0065] Figure 3 This is a powder X-ray diffraction pattern of commercially available mesartan potassium. Detailed Implementation

[0066] The technical solution of the present invention will be further described below through specific embodiments.

[0067] Raw materials and reagents: Azisartan (industrial grade, HPLC purity ≥99.0%), 4-hydroxymethyl-5-methyl-1,3-dioxolane-2-one, EDC·HCl, DMAP, potassium 2-ethylhexanoate, acetone, 2-methyltetrahydrofuran, ethyl acetate, n-heptane, all commercially available industrial grade raw materials; activated carbon, hydrochloric acid, sodium bicarbonate, all conventional chemical reagents.

[0068] Genotoxic impurity detection conditions: Toluenesulfonate impurities were detected by GC-MS, with a detection limit ≤0.1ppm.

[0069] Example 1

[0070] A method for preparing azilsartan medoxomil using an EDC / DMAP system, comprising the following steps:

[0071] 470 mL of 2-methyltetrahydrofuran, 47.0 g (1.0 eq, 102.97 mmol) of azilsartan, and 16.9 g (1.10 eq, 113.27 mmol) of 4-hydroxymethyl-5-methyl-1,3-dioxolane-2-one were added to a 2 L glass-lined reactor under dry nitrogen protection. The mixture was stirred at room temperature until the solids were completely dissolved. The system was then cooled to 5 °C, and 24.0 g (1.20 eq, 123.56 mmol) of EDC·HCl was added in three portions, 8 g each time. After the addition was complete, the mixture was stirred at 5 °C for 40 min. Then, 1.26 g (0.10 eq, 10.30 mmol) of DMAP was added. After the addition was complete, the temperature was slowly raised to 25 °C and stirred at 25 °C for 8 h. At this point, HPLC analysis showed that the azilsartan residue was 0.31%, indicating that the reaction had reached its endpoint.

[0072] The reaction was quenched by adding 400 mL of purified water to the reaction solution, and the mixture was allowed to stand and separate into layers to obtain the organic phase. The organic phase was washed successively with 300 mL of 0.5 mol / L dilute hydrochloric acid, 300 mL of saturated sodium bicarbonate solution, and 300 mL of purified water. After washing, the organic phase was concentrated under reduced pressure to approximately 120 mL, and 240 mL of n-heptane was added. The mixture was then cooled from room temperature to 0°C at a cooling rate of 2°C / 10 min, and crystallized at 0°C for 5 h. The mixture was filtered, and the filter cake was washed with a small amount of pre-cooled n-heptane (approximately 0°C). The mixture was then dried under vacuum at 45–50°C to obtain 54.2 g of azilsartan medoxomil (yield 92.8%, HPLC purity 99.81%, no toluenesulfonate impurities detected).

[0073] Example 2

[0074] Following the method for preparing azilsartan ester in Example 1, the amount of azilsartan was fixed at 47.0 g, the amount of methyltetrahydrofuran at 470 mL, and the reaction temperature and time were adjusted. The side chain, EDC·HCl, and DMAP equivalents were adjusted as shown in Table 1.

[0075] Table 1. Effects of side chain, EDC·HCl, and DMAP dosage on the yield of azilsartan medoxomil

[0076] .

[0077] Note: Side chain refers to 4-hydroxymethyl-5-methyl-1,3-dioxolane-2-one; residue refers to azilsartan residue at the end of the esterification reaction.

[0078] The results showed that the azilsartan medoxomil prepared using the EDC / DMAP system achieved a yield of no less than 91%, an HPLC purity greater than 99.5%, and no toluenesulfonate impurities were detected. In particular, the optimal balance between yield and purity of azilsartan medoxomil was achieved when the molar ratios of azilsartan to 4-hydroxymethyl-5-methyl-1,3-dioxolane-2-one were 1:1.10, the molar ratios of azilsartan to EDC·HCl were 1:1.20, and the molar ratios of azilsartan to DMAP were 1:0.10.

[0079] Example 3

[0080] Take 52.7 g (1.0 eq, 92.69 mmol) of azisartan medoxomil prepared in Example 1, put it into a reaction vessel, add 422 mL of acetone, heat to 35°C, and stir for 30 min until completely dissolved; add 5.3 g of activated carbon, keep warm at 30-35°C for 45 min to decolorize, filter with diatomaceous earth to remove activated carbon, and obtain filtrate.

[0081] The solution was prepared by dissolving 17.2 g (1.02 eq, 94.54 mmol) of potassium 2-ethylhexanoate in 25.8 g of acetone.

[0082] Under nitrogen protection, the filtrate was cooled to 25°C, and the above-mentioned potassium 2-ethylhexanoate acetone solution was slowly added dropwise to the filtrate over 60 min. After the addition was completed, the filtrate was cooled to 0°C and stirred for 2 h to mature, resulting in the precipitation of a large amount of solid.

[0083] The filter cake was filtered and pulped with pre-cooled acetone (0-10℃) in three batches, with each batch using 52.7 mL of acetone for 10 min. The filter cake was then filtered after each batch. The filter cake was placed in a vacuum oven and dried under reduced pressure at 30-35℃ to obtain 44.0 g of measartan potassium product (yield 77.9%, HPLC purity 99.78%, total impurities 0.16%, single maximum impurity 0.08%, and no toluene sulfonate impurities detected).

[0084] The total yield of meazartan potassium, based on azilsartan, is 72.3%.

[0085] The powder X-ray diffraction pattern of the measartan potassium prepared in this embodiment is shown in the figure. Figure 2 Compared with commercially available asartan potassium ( Figure 3 The crystal form α disclosed in patent application CN115197205A is completely consistent with that of the crystal form α.

[0086] Comparative Example 1

[0087] Traditional p-toluenesulfonyl chloride process (original process): 47.0 g (1.0 eq, 102.97 mmol) of azilsartan and 16.9 g (1.10 eq, 113.27 mmol) of 4-hydroxymethyl-5-methyl-1,3-dioxolane-2-one were esterified with dichloromethane (94 mL) as solvent and p-toluenesulfonyl chloride (1.15 eq) as activator at 2 °C. The remaining post-treatment conditions were the same as in Example 1, yielding 52.7 g of azilsartan ester (yield 90.03%, HPLC purity 99.25%; 2.2 g of toluenesulfonate impurities were detected). After two-stage recrystallization to remove impurities using tetrahydrofuran as the recrystallization solvent, no toluene sulfonate impurities were detected. Following the salt formation process of Example 3, measartan potassium product (purity 99.41%, total impurities 0.42%) was obtained, with the overall production cycle extended by 30% compared to the present invention.

[0088] Comparative Example 2

[0089] Take 47.0 g of azilsartan and prepare azilsartan ester according to the method in Example 1, except that the amount of 2-methyltetrahydrofuran is adjusted to 235 mL, and the rest is the same as in Example 1.

[0090] Experimental results: Azilsartan was not completely dissolved in the reaction system, which led to impaired mass transfer. After 12 h of reaction at 25°C, 4.2% of azilsartan remained. The yield of azilsartan ester was only 76.5%, with a purity of 98.63%, and the amount of by-products was significantly increased.

[0091] Example 4

[0092] Kilogram-scale pilot-scale verification (50 L reactor)

[0093] Batch P-01: Starting with 1.0 kg of azilsartan, the EDC / DMAP esterification process of Example 1 was used, and the material usage was scaled up proportionally to obtain azilsartan ester; then, continuous production was carried out according to the salt formation process of Example 3. All process parameters were strictly scaled up according to the small-scale test.

[0094] Batch P-02: Repeat the operation of batch P-01 to verify process reproducibility.

[0095] Table 2. Summary of Pilot-Scale Data

[0096] .

[0097] The results showed that the data deviation between the two batches was minimal, and the process had excellent stability for scale-up. All quality indicators of the finished product met the pharmacopoeia requirements, and no genotoxic impurities were detected.

[0098] Example 5

[0099] Solvent recovery and application experiment

[0100] Collect the solvent recovered from vacuum concentration and recrystallization in Example 1. Heat the mother liquor to 85°C and distill at atmospheric pressure until no liquid drips from the recovery condenser. Collect the distillate. Combine the solvent recovered from vacuum concentration and atmospheric distillation. GC analysis shows the purity of 2-methyltetrahydrofuran in the recovered solvent is ≥95%. Add a small amount of fresh 2-methyltetrahydrofuran and reuse it directly in the next batch of esterification reactions (esterification conditions are the same as in Example 1). After five consecutive batches, the yield of azilsartan medoxomil remained stable at 92.2%–92.9%, with a purity ≥99.75%. Solvent reuse has no negative impact and can be recycled long-term.

[0101] Table 3. Results of Solvent Recovery and Utilization Experiments

[0102] .

Claims

1. A green esterification process for azilsartan ester without p-toluenesulfonyl chloride, characterized in that: include: Under nitrogen protection, azisartan, 4-hydroxymethyl-5-methyl-1,3-dioxolane-2-one, and a low-toxicity reaction solvent were mixed and stirred at room temperature until the solid was completely dissolved. The mixture was then cooled to 0–10 °C and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added in batches. After the addition was complete, the mixture was kept at 0–10 °C and stirred for 40 min to activate it. Then, 4-dimethylaminopyridine was added, and the temperature was raised to the esterification reaction temperature to carry out the esterification reaction. Post-processing: The reaction was quenched with water to separate the organic phase. The organic phase was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate solution and purified water. The solution was concentrated under reduced pressure to obtain a concentrated solution. Heptane was added and the solution was gradually cooled to 0-5℃ for recrystallization. The crystals were cultured for 4-6 hours and then filtered to obtain azilsartan ester. The reaction solvent is 2-methyltetrahydrofuran or ethyl acetate; the mass-to-volume ratio of azisartan to the reaction solvent is 1:8 to 1:12 g / mL. The esterification reaction is carried out at a temperature of 20–35°C. The volume of the concentrated solution is 1 / 3.5 to 1 / 4 of the volume of the reaction solvent; the volume ratio of n-heptane to the concentrated solution is 2:1; and the cooling rate is 2℃ / 10 min.

2. The green esterification process for azilsartan ester without p-toluenesulfonyl chloride according to claim 1, characterized in that: The molar ratio of azisartan to 4-hydroxymethyl-5-methyl-1,3-dioxolane-2-one is 1:1.05 to 1:1.

2.

3. The green esterification process for azilsartan ester without p-toluenesulfonyl chloride according to claim 1 or 2, characterized in that: The molar ratio of azisartan to 4-hydroxymethyl-5-methyl-1,3-dioxolane-2-one is 1:1.

1.

4. The green esterification process for azilsartan ester without p-toluenesulfonyl chloride according to claim 1, characterized in that: The molar ratio of azilsartan to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 1:1.1 to 1:1.3; the molar ratio of azilsartan to 4-dimethylaminopyridine is 1:0.05 to 1:0.

15.

5. The green esterification process for azilsartan ester without p-toluenesulfonyl chloride according to claim 1 or 4, characterized in that: The molar ratio of azilsartan to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 1:1.2; the molar ratio of azilsartan to 4-dimethylaminopyridine is 1:0.

1.

6. The green esterification process for azilsartan ester without p-toluenesulfonyl chloride according to claim 1, characterized in that: The esterification reaction was carried out at a temperature of 25°C.

7. The green esterification process for azilsartan ester without p-toluenesulfonyl chloride according to claim 1, characterized in that: The recrystallization mother liquor is heated to 85°C and distilled under normal pressure. The fractions are collected, and the solvent recovered by normal pressure distillation and the solvent recovered by vacuum concentration are reused in the esterification reaction.

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