A method for purifying eplerenone
By using a mixture of alcohol and water as a recrystallization solvent and employing a method of heating to dissolve and cooling to crystallize, the problems of poor solubility and low purification efficiency of eplerenone were solved, achieving high-purity and high-yield purification of eplerenone, which is suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- JIANGSU SUZHONG PHARMACEUTICAL RESEARCH INSTITUTE CO LTD
- Filing Date
- 2021-03-19
- Publication Date
- 2026-05-29
AI Technical Summary
Eplerenone has poor solubility, and existing purification methods have low recrystallization yields and require large amounts of solvent, making it difficult to effectively remove impurities A and B.
Eplerenone was purified by using a mixture of alcohol and water as the recrystallization solvent and by heating to dissolve and then cooling to crystallize. The specific steps included heating to dissolve, filtering, and drying.
It improves the purity and yield of eplerenone, reduces solvent consumption, is environmentally friendly, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention relates to a method for purifying compounds, specifically to a method for purifying eplerenone and a method for improving the solubility of eplerenone. Background Technology
[0002] Eplerenone is a novel selective aldosterone receptor antagonist used to treat hypertension, heart failure, and myocardial infarction. Its structural formula is shown in Formula I.
[0003]
[0004] Eplerenone is a steroidal compound with poor solubility. Chinese invention application CN104262450A reports a purification method involving heating and reflux to dissolve eplerenone in solvents such as 2-butanone, followed by cooling and crystallization. Although 2-butanone has a strong ability to dissolve eplerenone, its recrystallization yield is low, and a large amount of solvent is required. CN104844681A reports the purification of eplerenone in a mixed solvent of 1,2-dimethoxyethane and toluene, ethyl acetate, methyl tert-butyl ether, methanol, ethanol, isopropanol, n-propanol, and acetone. A relatively large amount of 1,2-dimethoxyethane or a mixed solvent of 1,2-dimethoxyethane is needed to dissolve the solid, followed by crystallization. A review of existing technologies shows that eplerenone is readily soluble in acetonitrile and dichloromethane, slightly soluble in methanol, and very slightly soluble in water and ethanol. Meanwhile, research has found that eplerenone solid is difficult to dissolve in 10-30 equivalents of methanol, ethanol, isopropanol, n-propanol, or purified water under reflux conditions. Therefore, this invention provides a method for dissolving and purifying eplerenone. Summary of the Invention
[0005] Purpose of the invention: The technical problem to be solved by the present invention is to provide a method for purifying eplerenone.
[0006] Another technical problem that this invention aims to solve is to provide a method for improving the solubility of eplerenone, addressing the shortcomings of existing technologies.
[0007] To address the first technical problem mentioned above, this invention discloses a method for purifying eplerenone, using a mixture of alcohol and water as a recrystallization solvent, i.e., dissolving crude eplerenone in a mixture of alcohol and water and then recrystallizing it.
[0008] In some embodiments, the purity of eplerenone in the crude eplerenone product is 50% or more, in some embodiments it is 60% or more, in some embodiments it is 70% or more, in some embodiments it is 80% or more, and in some embodiments it is 90% or more.
[0009] In some embodiments, the crude eplerenone product further contains any one or a combination of two of impurities A and B. Impurities A and B can affect the quality and safety of eplerenone.
[0010]
[0011] In some embodiments, the alcohol is a lower alcohol or a higher alcohol. In some embodiments, it is a lower alcohol. In some embodiments, it is any one or a combination of methanol, ethanol, isopropanol and n-propanol. In some embodiments, it is any one or a combination of ethanol, isopropanol and n-propanol. In some embodiments, it is any one or a combination of ethanol and n-propanol.
[0012] In some embodiments, the volume ratio of alcohol to water is 0.15-100:1, in some embodiments it is 0.3-50:1, in some embodiments it is 0.6-25:1, in some embodiments it is 0.7-21.25:1, in some embodiments it is 0.8-18.75:1, in some embodiments it is 1.15-13:1, and in some embodiments it is 1.2-12.5:1.
[0013] In some embodiments, the recrystallization involves heating and dissolving crude eplerenone in a solvent.
[0014] In some embodiments, the heating and melting temperature is 50°C - reflux temperature, in some embodiments it is 55°C - reflux temperature, in some embodiments it is 60°C - reflux temperature, in some embodiments it is 65°C - reflux temperature, and in some embodiments it is reflux temperature.
[0015] In some embodiments, the alcohol in the recrystallization solvent is methanol, and its heating and dissolution temperature is 50°C - reflux temperature, in some embodiments it is 55°C - reflux temperature, in some embodiments it is 60°C - reflux temperature, in some embodiments it is 65°C - reflux temperature, and in some embodiments it is reflux temperature.
[0016] In some embodiments, when the alcohol in the recrystallization solvent is any one or a combination of ethanol, isopropanol, and n-propanol, its heating dissolution temperature is 50°C - reflux temperature, in some embodiments it is 55°C - reflux temperature, in some embodiments it is 60°C - reflux temperature, in some embodiments it is 65°C - reflux temperature, in some embodiments it is 70°C - reflux temperature, in some embodiments it is 75°C - reflux temperature, in some embodiments it is 80°C - reflux temperature, in some embodiments it is 85°C - reflux temperature, and in some embodiments it is reflux temperature.
[0017] In some embodiments, the heating and dissolution time is 10 minutes or more, and in some embodiments, the heating is carried out until the crude eplerenone is dissolved.
[0018] In some embodiments, the heating dissolution is to dissolve the crude eplerenone product by heating and reflux in a solvent.
[0019] In some embodiments, the method for purifying eplerenone specifically involves dissolving crude eplerenone in a mixture of alcohol and water as a solvent, cooling to crystallize, filtering, and drying to obtain purified eplerenone.
[0020] In some embodiments, the cooling and crystallization temperature is 5-50°C, in some embodiments it is 10-50°C, in some embodiments it is 15-45°C, in some embodiments it is 20-40°C, and in some embodiments it is 30°C.
[0021] In some embodiments, the cooling crystallization is a stirring crystallization process.
[0022] The stirring and crystallization time does not affect the recrystallization efficiency. In some embodiments, the stirring and crystallization time is 1-8 hours, in some embodiments it is 2-7 hours, in some embodiments it is 3-6 hours, and in some embodiments it is 4-5 hours.
[0023] In some embodiments, the filter cake is washed with alcohol after filtration.
[0024] In some embodiments, the alcohol is an alcohol in the recrystallization solvent.
[0025] In some embodiments, the drying is vacuum drying or atmospheric pressure drying.
[0026] In some embodiments, the drying temperature is room temperature - 90°C, in some embodiments it is 30-90°C, in some embodiments it is 35-80°C, in some embodiments it is 40-75°C, in some embodiments it is 45-70°C, in some embodiments it is 50-65°C, and in some embodiments it is 55-60°C.
[0027] To address the second technical problem mentioned above, this invention discloses a method for improving the solubility of eplerenone, which involves heating and dissolving eplerenone using a mixture of alcohol and water as a solvent.
[0028] In some embodiments, the alcohol is a lower alcohol or a higher alcohol. In some embodiments, it is a lower alcohol. In some embodiments, it is any one or a combination of methanol, ethanol, isopropanol and n-propanol. In some embodiments, it is any one or a combination of ethanol, isopropanol and n-propanol. In some embodiments, it is any one or a combination of ethanol and n-propanol.
[0029] In some embodiments, the volume ratio of alcohol to water is 0.15-100:1, in some embodiments it is 0.3-50:1, in some embodiments it is 0.6-25:1, in some embodiments it is 0.7-21.25:1, in some embodiments it is 0.8-18.75:1, in some embodiments it is 1.15-13:1, and in some embodiments it is 1.2-12.5:1.
[0030] The method for improving the solubility of eplerenone is to dissolve crude eplerenone in a solvent by heating.
[0031] The heating and melting temperature is 50°C - reflux temperature, in some embodiments it is 55°C - reflux temperature, in some embodiments it is 60°C - reflux temperature, in some embodiments it is 65°C - reflux temperature, and in some embodiments it is reflux temperature.
[0032] In some embodiments, the alcohol in the solvent is methanol, and its heating and dissolution temperature is 50°C - reflux temperature, in some embodiments it is 55°C - reflux temperature, in some embodiments it is 60°C - reflux temperature, in some embodiments it is 65°C - reflux temperature, and in some embodiments it is reflux temperature.
[0033] In some embodiments, when the alcohol in the solvent is any one or a combination of ethanol, isopropanol, and n-propanol, the heating and dissolution temperature is 50°C - reflux temperature, in some embodiments it is 55°C - reflux temperature, in some embodiments it is 60°C - reflux temperature, in some embodiments it is 65°C - reflux temperature, in some embodiments it is 70°C - reflux temperature, in some embodiments it is 75°C - reflux temperature, in some embodiments it is 80°C - reflux temperature, in some embodiments it is 85°C - reflux temperature, and in some embodiments it is reflux temperature.
[0034] In some embodiments, the heating and dissolution time is more than 10 minutes, and in some embodiments, the heating is carried out until the crude eplerenone product is dissolved.
[0035] In some embodiments, the heating dissolution is to dissolve the crude eplerenone product by heating and reflux in a solvent.
[0036] In this invention, the heating and dissolution temperature is the actual dissolution temperature of eplerenone.
[0037] Beneficial effects: Compared with the prior art, the present invention has the following advantages:
[0038] This invention uses a mixed solvent of alcohol and water to completely dissolve eplerenone upon heating. It is environmentally friendly, produces less waste, has low toxicity, and the purified product has a high yield, high purity, and good impurity removal effect. It also requires a small amount of product, making the purification system safer and more suitable for industrial and large-scale production. Detailed Implementation
[0039] The present invention will be further described in detail below with reference to specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.
[0040] In the following embodiments, unless otherwise specified, the experimental methods are conventional methods; and unless otherwise specified, the reagents and materials are commercially available.
[0041] The analytical methods described in the following examples are found in the eplerenone section of the European Pharmacopoeia 9.0.
[0042] In the following embodiments, the structural formulas of impurity A and impurity B are specifically as follows:
[0043]
[0044] Example 1
[0045] In a 250 mL reaction flask, 10.0 g of crude eplerenone (purity 98.08%, impurity A 0.83%, impurity B 0.48%), 120 mL of anhydrous ethanol, and 20 mL of purified water were added. The mixture was heated to reflux at 85 °C for 10 minutes until the solid dissolved. Heating was stopped, and the temperature was lowered to 30 °C. The mixture was kept warm and stirred for 4 hours. The mixture was then filtered, and the filter cake was washed with anhydrous ethanol and dried under vacuum at 55 °C for 12 hours to obtain 9.3 g of purified eplerenone, with a yield of 93.0% and a purity of 99.57%. Impurity A was 0.15%, impurity B was 0.22%, and other single impurities were all less than 0.10%.
[0046] Example 2
[0047] In a 250 mL reaction flask, 10.0 g of crude eplerenone (with the same purity and impurities as in Example 1), 120 mL of anhydrous ethanol, and 100 mL of purified water were added. The mixture was heated to reflux at 85 °C for 10 minutes until the solid dissolved. Heating was stopped, and the mixture was cooled to 30 °C and stirred for 4 hours. The mixture was then filtered, and the filter cake was washed with anhydrous ethanol and dried under vacuum at 55 °C for 12 hours to obtain 9.2 g of purified eplerenone, with a yield of 92.0% and a purity of 99.43%. Among these impurities, impurity A was 0.19%, impurity B was 0.22%, and other single impurities were all less than 0.10%.
[0048] Example 3
[0049] In a 250 mL reaction flask, add 5.0 g of crude eplerenone (with the same purity and impurities as in Example 1), 60 mL of anhydrous ethanol, and 10 mL of purified water. Heat at 75 °C for 20 minutes until the solid dissolves. Stop heating, cool to 30 °C, and stir for 4 hours. Filter the mixture, wash the filter cake with anhydrous ethanol, and dry it under vacuum at 55 °C for 12 hours to obtain 4.5 g of purified eplerenone, with a yield of 90.0% and a purity of 99.71%. Impurity A is 0.06%, impurity B is 0.12%, and other single impurities are all less than 0.10%.
[0050] Example 4
[0051] In a 250 mL reaction flask, 10.0 g of crude eplerenone (with the same purity and impurities as in Example 1), 150 mL of n-propanol, and 12 mL of purified water were added. The mixture was heated to reflux at 90 °C for 10 minutes until the solid dissolved. Heating was stopped, and the mixture was cooled to 30 °C and stirred for 5 hours. The mixture was then filtered, and the filter cake was washed with n-propanol and dried under vacuum at 60 °C for 12 hours to obtain 9.4 g of purified eplerenone, with a yield of 94.0% and a purity of 99.57%. Impurity A was 0.24%, impurity B was 0.19%, and other single impurities were all less than 0.10%.
[0052] Example 5
[0053] In a 250 mL reaction flask, 10.0 g of crude eplerenone (with the same purity and impurities as in Example 1), 120 mL of isopropanol, and 20 mL of purified water were added. The mixture was heated to reflux at 85 °C for 10 minutes until the solid dissolved. Heating was stopped, and the mixture was cooled to 30 °C and stirred for 4 hours. The mixture was then filtered, and the filter cake was washed with anhydrous isopropanol and dried under vacuum at 55 °C for 12 hours to obtain 8.3 g of purified eplerenone, with a yield of 83.0% and a purity of 99.34%. Impurity A was 0.27%, impurity B was 0.22%, and other single impurities were all less than 0.10%.
[0054] Example 6
[0055] In a 250 mL reaction flask, 10.0 g of crude eplerenone (with the same purity and impurities as in Example 1), 120 mL of isopropanol, and 20 mL of purified water were added. The mixture was heated to reflux at 85 °C for 10 minutes until the solid dissolved. Heating was stopped, and the mixture was cooled to 30 °C and stirred for 4 hours. The mixture was then filtered, and the filter cake was washed with anhydrous isopropanol and dried under vacuum at 55 °C for 12 hours to obtain 8.8 g of purified eplerenone, with a yield of 88.0% and a purity of 99.64%. Impurity A was 0.14%, impurity B was 0.17%, and other single impurities were all less than 0.10%.
[0056] Example 7
[0057] In a 100 mL reaction flask, add 5.0 g of crude eplerenone (with the same purity and impurities as in Example 1), 50 mL of methanol, and 5 mL of purified water. Heat under reflux at 70 °C for 10 minutes until the solid dissolves. Stop heating, cool to 30 °C, and stir for 2 hours. Filter the mixture, wash the filter cake with methanol, and dry it under vacuum at 50 °C for 12 hours to obtain 3.6 g of purified eplerenone, with a yield of 72.0% and a purity of 99.67%. Impurity A is 0.10%, impurity B is 0.11%, and other impurities are all less than 0.10%.
[0058] Example 8
[0059] In a 100 mL reaction flask, add 5.0 g of crude eplerenone (with the same purity and impurities as in Example 1), 50 mL of methanol, and 5 mL of purified water. Heat at 60 °C for 15 minutes until the solid dissolves. Stop heating, cool to 30 °C, and stir for 2 hours. Filter the mixture, wash the filter cake with methanol, and dry it under vacuum at 50 °C for 12 hours to obtain 3.8 g of purified eplerenone, with a yield of 76.0% and a purity of 99.62%. Impurity A is 0.11%, impurity B is 0.12%, and other impurities are all less than 0.10%.
[0060] Comparative Example 1
[0061] 10.0 g of crude eplerenone (with the same purity and impurities as in Example 1) and 120 mL of purified water were added to a 250 mL reaction flask. The mixture was heated at 85 °C for 30 minutes. The solid could not be completely dissolved. Heating was stopped, and the temperature was lowered to 30 °C. The mixture was stirred at this temperature for 4 hours. The mixture was then filtered. The filter cake was washed with purified water and dried under vacuum at 55 °C for 12 hours. The purified eplerenone obtained had a purity of 98.19%, with impurity A accounting for 0.79% and impurity B accounting for 0.43%.
[0062] Comparative Example 2
[0063] 10.0 g of crude eplerenone (with the same purity and impurities as in Example 1) and 120 mL of anhydrous ethanol were added to a 250 mL reaction flask. The mixture was heated to reflux at 85 °C for 30 minutes. The solid could not be completely dissolved. Heating was stopped, and the temperature was lowered to 30 °C. The mixture was stirred at this temperature for 4 hours, filtered, and the filter cake was washed with anhydrous ethanol and dried under vacuum at 55 °C for 12 hours. The purity of the obtained purified eplerenone product was 98.67%, with impurity A accounting for 0.57% and impurity B accounting for 0.31%.
[0064] Compared with Example 4 in CN201410484717.8: 10.0 g of the crude product (purity 98.3%) obtained in Example 2 was transferred to a 500 mL glass reaction flask, 200 mL of anhydrous ethanol was added, and the mixture was heated to reflux and stirred for 1 h (until the system was completely dissolved). Heating was stopped, and the mixture was allowed to cool naturally to room temperature while stirring to crystallize for 4-8 h. The mixture was filtered, the filter cake was washed with an appropriate amount of anhydrous ethanol, and dried to obtain 8.0 g of eplerenone, with a purification yield of 80% and a liquid phase purity of 96.4%.
[0065] Compared with Example 5 in CN201410484717.8: 10.0 g of the crude product (purity 98.3%) obtained in Example 2 was transferred to a 500 mL glass reaction flask, 200 mL of n-propanol was added, and the mixture was heated to reflux and stirred for 1 h (until the system was completely dissolved). Heating was stopped, and the mixture was allowed to cool naturally to room temperature while stirring to crystallize for 4-8 h. After filtration, the filter cake was washed with an appropriate amount of n-propanol and dried to obtain 7.6 g of eplerenone, with a purification yield of 76% and a liquid phase purity of 96.2%.
[0066] Compared with Example 2 in CN201410050764.1: 50g of eplerenone ethanol solvate (containing 2.72% ethanol) was added to 1.2L of 1,2-dimethoxyethane, refluxed to dissolve, filtered, and the filtrate was transferred to a 2L reaction flask. The mixture was stirred and cooled to -5 to 0℃, stirred to crystallize for 10h, filtered, and the filter cake was dried at 60℃ for 6h to obtain 40g of L-crystal eplerenone. The yield was 82%, and the purity was 99.97%.
[0067] In contrast to these, the present invention has significant advantages by using alcohol and water as solvents.
[0068] This invention provides a method for dissolving and purifying eplerenone. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.
Claims
1. A method for purifying eplerenone, characterized in that, A mixture of alcohol and water is used as the recrystallization solvent; the alcohol is any one or a combination of methanol, ethanol, isopropanol and n-propanol; the volume ratio of the alcohol to water is 1.2-12.5:
1.
2. The method as described in claim 1, characterized in that, The alcohol is any one or a combination of ethanol, isopropanol and n-propanol.
3. The method as described in claim 1, characterized in that, The alcohol is any one or a combination of two of ethanol and n-propanol.
4. The method according to any one of claims 1-3, characterized in that, The crude eplerenone was dissolved in a solvent by heating.
5. The method as described in claim 4, characterized in that, The heating and dissolving temperature is 50℃ - reflux temperature, and the heating and dissolving time is more than 10 minutes.
6. The method as described in claim 4, characterized in that, The heating and dissolution temperature is 55°C - reflux temperature, heated until the crude eplerenone product dissolves.
7. The method as described in claim 4, characterized in that, The heating and melting temperature is 60℃ minus the reflux temperature.
8. The method as described in claim 4, characterized in that, The heating and melting temperature is 65℃ minus the reflux temperature.
9. The method as described in claim 4, characterized in that, The heating and dissolving process is a heating and reflux dissolving process.
10. The method as described in claim 1, characterized in that, The recrystallization process includes cooling crystallization, filtration, and drying.
11. The method as described in claim 10, characterized in that, The cooling crystallization is a stirred crystallization process, the cooling crystallization temperature is 5-50℃, the cooling crystallization time is 1-8h, and the drying temperature is room temperature-90℃; after filtration, the filter cake is washed with alcohol.
12. The method as described in claim 11, characterized in that, The cooling crystallization temperature is 10-50℃, the cooling crystallization time is 2-7 hours, the drying temperature is 30-90℃, and the alcohol is an alcohol in the recrystallization solvent.
13. The method as described in claim 10, characterized in that, The cooling and crystallization temperature is 15-45℃, the cooling and crystallization time is 3-6 hours, and the drying temperature is 35-80℃.
14. The method as described in claim 10, characterized in that, The cooling and crystallization temperature is 20-40℃, the cooling and crystallization time is 4-5 hours, and the drying temperature is 40-75℃.
15. The method as described in claim 10, characterized in that, The cooling and crystallization temperature is 30°C, and the drying temperature is preferably 50-65°C.
16. The method as described in claim 10, characterized in that, The drying temperature is preferably 55-60℃.
17. A method for improving the solubility of eplerenone, characterized in that, Eplerenone is dissolved by heating using a mixture of alcohol and water as a solvent; the alcohol is any one or a combination of methanol, ethanol, isopropanol and n-propanol; the volume ratio of alcohol to water is 1.2-12.5:
1.
18. The method as described in claim 17, characterized in that, The alcohol is any one or a combination of ethanol, isopropanol and n-propanol.
19. The method as described in claim 17, characterized in that, The alcohol is any one or a combination of two of ethanol and n-propanol.
20. The method according to any one of claims 17-19, characterized in that, The crude eplerenone was dissolved in a solvent by heating.
21. The method as described in claim 20, characterized in that, The heating and dissolving temperature is 50℃ - reflux temperature, and the heating and dissolving time is more than 10 minutes.
22. The method as described in claim 20, characterized in that, The heating and dissolution temperature is 55°C - reflux temperature, heated until the crude eplerenone product dissolves.
23. The method as described in claim 20, characterized in that, The heating and melting temperature is 60℃ minus the reflux temperature.
24. The method as described in claim 20, characterized in that, The heating and melting temperature is 65℃ minus the reflux temperature.
25. The method as described in claim 20, characterized in that, The heating and dissolving process is a heating and reflux dissolving process.