Refining method of eplerenone intermediate
By combining organic solvents and inorganic bases, the problem of difficult removal of hydrolysis impurities in crude eplerenone methyl ester was solved, achieving the preparation of high-yield and high-purity eplerenone methyl ester products suitable for industrial production.
Patent Information
- Application Number
- CN202511727357.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-24
- Publication Date
- 2026-01-13
AI Technical Summary
The crude eplerenone methyl ester contains hydrolytic impurities that are difficult to remove, which increases the difficulty of subsequent purification for the preparation of eplerenone raw material.
The crude eplerenone methyl ester was dissolved and reacted using a combination of organic solvent and inorganic base. The solid was precipitated by adding water, cooled to allow crystals to crystallize, and then filtered and dried to obtain the refined product.
It effectively removes impurities, improves product yield and purity, meets the needs of subsequent reactions, and is suitable for large-scale industrial applications.
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Figure CN121319104A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of medicine and chemical industry, in particular to a refining method of an eplerenone intermediate. BACKGROUND
[0002] The eplerenone intermediate methyl ester, also known as 11alpha-OH-canrenone propenoic acid methyl ester, has the English name of 11alpha-Hydroxy canrenone methyl ester, and has the following structural formula:
[0003] Eplerenone is a steroid drug, white to white powder, is a new type and has the characteristics of selective aldosterone antagonists, can directly combine with aldosterone to inhibit its effect, the effect is similar to spironolactone, long-term use of gonadal adverse reactions are mild. Eplerenone is mainly used for the treatment of primary hypertension and heart failure after myocardial infarction, and is the first selective aldosterone receptor blocker approved for marketing.
[0004] Eplerenone methyl ester is an important intermediate for preparing eplerenone. In the synthesis of eplerenone methyl ester, due to the residual raw materials of the upstream reaction and the hydrolysis of the compound, impurities which are difficult to remove will be produced, especially the hydrolysis impurities which have similar structures, leading to difficulty in removal. With the subsequent preparation of eplerenone reaction transmitted to the drug substance, the difficulty of drug substance purification is increased.
[0005] Therefore, a simple operation, suitable for scale-up eplerenone methyl ester refining method is needed.
[0006] Therefore, the present application provides a refining method of an eplerenone intermediate. SUMMARY
[0007] In order to solve at least one of the above technical problems, the present application provides a refining method of an eplerenone intermediate.
[0008] The present application is realized by the following technical scheme: a refining method of an eplerenone intermediate, the method comprising the following steps: S1: dissolving: eplerenone methyl ester crude product, organic solvent and water are sequentially added to the reaction bottle, and stirring and heating are carried out to completely dissolve; S2: reaction: inorganic base is added to the dissolved reaction system, and temperature control stirring is carried out for sufficient reaction; S3: water analysis: the system is cooled to room temperature, and water is slowly added to precipitate the solid product; S4: crystallization: cooling and crystallization are carried out and sufficient stirring is carried out; S5: filtration and drying: the system is filtered for solid-liquid separation, and eplerenone methyl ester fine product is obtained by drying.
[0009] Preferably, in step S1, the organic solvent is one or more of DMF, acetone, or methanol.
[0010] Preferably, in step S2, the inorganic base is one or more of sodium bicarbonate, sodium carbonate, or potassium carbonate.
[0011] Preferably, in step S1, the volume of the organic solvent is 2-30 times the weight of the crude eplerenone methyl ester.
[0012] Preferably, in step S2, the mass of the inorganic base is 0.1-3 times the weight of the crude eplerenone methyl ester.
[0013] Preferably, in step S2, the stirring reaction time is 1.5-4 hours and the temperature is 35-60°C.
[0014] Preferably, in step S4, the temperature for cooling and crystallization is 0~10℃, and the stirring time is 1-2h.
[0015] Preferably, in step S1, the volume ratio of the organic solvent to water is 1:3-5, and the volume of the organic solvent is 4-10 times the weight of the crude eplerenone methyl ester.
[0016] Preferably, in S2, the mass ratio of the inorganic base to the crude eplerenone methyl ester is 1:(1.25-5).
[0017] Preferably, in step S3, the volume of water is 4-10 times the volume of the organic solvent.
[0018] The synthetic route for the crude eplerenone methyl ester compound of this invention is as follows: The intermediate ketide from the previous step undergoes ring-opening esterification with a strong base to obtain the methyl ester. During the reaction and post-processing, water or water vapor is inevitably introduced, leading to hydrolysis of the methyl ester and the formation of hydrolysates. Furthermore, based on patent and literature research, this ring-opening esterification step is incomplete, with residual ketide ranging from 2% to 8%. Although optimizing process parameters can control the residual ketide to a low level (2% to 3%), the reaction is still incomplete. Therefore, the main impurities in the crude eplerenone methyl ester are the residual ketide and the generated byproduct hydrolysates, the structure of which is as follows:
[0019] Compared with the prior art, the present invention has the following beneficial effects: The crude eplerenone methyl ester was dissolved and reacted using a combination of organic solvent and inorganic base. Water was added to precipitate the solid, and after cooling and crystallization, the product was filtered and dried to obtain the refined eplerenone methyl ester. The impurity limits were all low, which fully met the requirements of subsequent reactions.
[0020] The purification method for eplerenone methyl ester provided in this invention has a high product yield, low cost, and uses a common and low-toxicity organic solvent, which has good industrial application value and is very suitable for large-scale industrial applications. Attached Figure Description
[0021] Figure 1 This is a flowchart of the purification method of eplerenone methyl ester in the embodiments of the present invention; Figure 2 These are the HPLC spectra of the crude eplerenone methyl ester products to be purified in Examples 1, 2, and Comparative Example 1 of this invention; Figure 3 This is the HPLC chromatogram of the purified eplerenone methyl ester in Example 1 of the present invention; Figure 4 This is the HPLC spectrum of the purified eplerenone methyl ester in Example 2 of the present invention; Figure 5 This is the HPLC spectrum of the purified eplerenone methyl ester in Comparative Example 1 of this invention; Figure 6 These are the HPLC spectra of the crude eplerenone methyl ester products to be purified in Examples 3 and 4 and Comparative Example 2 of the present invention; Figure 7 This is the HPLC spectrum of the purified eplerenone methyl ester in Example 3 of the present invention; Figure 8 This is the HPLC chromatogram of the purified eplerenone methyl ester in Example 4 of the present invention; Figure 9 This is the HPLC chromatogram of the purified eplerenone methyl ester in Comparative Example 2 of the present invention. Detailed Implementation
[0022] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the embodiments will be briefly described below. Obviously, the drawings described below are merely some embodiments of the present invention, and those skilled in the art can obtain other drawings based on these drawings without any creative effort.
[0023] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments. The embodiments cannot be described in detail here, but the embodiments of the present invention are not limited to the following embodiments.
[0024] Combination Figure 1 The crude eplerenone methyl ester was synthesized according to the synthetic route (as shown below). Crude eplerenone methyl ester 1 was obtained, and its HPLC detection results are shown in the appendix. Figure 2 .
[0025] Example 1: A method for purifying an eplerenone intermediate, comprising the following steps: 50g of crude eplerenone methyl ester was dissolved in 400mL of DMF by stirring and heating. 20g of sodium bicarbonate was dissolved in 200mL of water and added to the reaction solution. The mixture was stirred at 40-50℃ for 2 hours. The system was then cooled to 20-25℃, and 600mL of water was slowly added dropwise. A solid gradually precipitated during the addition. After the addition was complete, the temperature was lowered to 0-10℃ for crystallization for 1 hour. The crystals were filtered, washed with 100mL of water, and dried to obtain 42.26g of purified eplerenone methyl ester, with a yield of 84.52%, purity of 99.390%, 0.000% ketide impurities, and 0.052% hydrolysate. HPLC results are shown in the appendix. Figure 3 .
[0026] Example 2:
[0027] A method for purifying an eplerenone intermediate, comprising the following steps: 50g of crude eplerenone methyl ester was dissolved in 800mL of methanol and 200mL of acetone by stirring and heating. 40g of sodium carbonate was dissolved in 200mL of water and added to the reaction solution. The mixture was stirred at 50-60℃ for 1.5 hours. The system was then cooled to 20-25℃, and 800mL of water was slowly added dropwise. A solid gradually precipitated during the addition. After the addition was complete, the temperature was lowered to 0-10℃ for crystallization for 1 hour. The crystals were filtered, washed with water, and dried to obtain 42.84g of purified eplerenone methyl ester, with a yield of 85.68%, purity of 99.328%, 0.000% ketide impurities, and 0.218% hydrolysate. HPLC results are shown in the appendix. Figure 4 .
[0028] Comparative Example 1: A method for purifying an eplerenone intermediate, comprising the following steps: 30g of crude eplerenone methyl ester was dissolved in 450mL of methanol and 100mL of acetone by stirring and heating. The solvent was removed by concentration under reduced pressure until a small amount remained. The solution was then cooled to 0-5℃ to crystallize for 2 hours. After filtration and drying, 22.61g of purified eplerenone methyl ester was obtained, with a yield of 75.36% and a purity of 95.579%. Impurities included 1.313% ketide and 0.786% hydrolysate. The HPLC results are shown in the appendix. Figure 5 .
[0029] The crude eplerenone methyl ester used in Examples 1, 2 and Comparative Example 1 is crude eplerenone methyl ester 1.
[0030] Example 3:
[0031] Another batch of crude eplerenone methyl ester product 2 was taken, and its HPLC detection results are shown in the appendix. Figure 6 .
[0032] 100g of crude eplerenone methyl ester was dissolved in 600mL of DMF by stirring and heating. 20g of sodium bicarbonate was dissolved in 150mL of water and added to the reaction solution. The mixture was stirred at 45-55℃ for 2 hours. The system was then cooled to 15-20℃, and 750mL of water was slowly added dropwise. A solid gradually precipitated during the addition. After the addition was complete, the temperature was lowered to 0-10℃ for crystallization for 1 hour. The crystals were filtered, washed with 100mL of water, and dried to obtain 86.67g of purified eplerenone methyl ester, with a yield of 86.67%, purity of 99.057%, 0.000% ketide impurities, and 0.442% hydrolysate. HPLC results are shown in the appendix. Figure 7 .
[0033] Example 4:
[0034] The crude eplerenone methyl ester was the same as in Example 3.
[0035] 100g of crude eplerenone methyl ester was dissolved in 250mL of DMF and 100mL of acetone by stirring and heating. 30g of potassium carbonate was dissolved in 120mL of water and added to the reaction mixture. The mixture was stirred at 35-45℃ for 4 hours. The system was then cooled to 20-25℃, and 500mL of water was slowly added dropwise. A solid gradually precipitated during the addition. After the addition was complete, the mixture was cooled to 0-10℃ for 1 hour to allow crystals to crystallize. The crystals were filtered, washed with water, and dried to obtain 85.31g of purified eplerenone methyl ester, with a yield of 85.31%, purity of 98.489%, 0.000% ketide impurities, and 0.128% hydrolysate. HPLC results are shown in the appendix. Figure 8 .
[0036] Comparative Example 2: The crude eplerenone methyl ester is the same as in Example 1.
[0037] 20g of crude eplerenone methyl ester was dissolved in 300mL of methanol and 80mL of acetone by stirring and heating. The solvent was removed by concentration under reduced pressure until a small amount remained. The solution was then cooled to 0-5℃ to crystallize for 2 hours. After filtration and drying, 15.63g of purified eplerenone methyl ester was obtained, with a yield of 78.15% and a purity of 93.901%. Impurities included 1.230% ketide and 0.856% hydrolysate. The HPLC results are shown in the appendix. Figure 9 .
[0038] In the embodiments of the present invention, the detection methods for crude and refined eplerenone methyl ester are the same, both based on HPLC (high performance liquid chromatography). The detection results of crude and refined products in the embodiments are summarized as follows:
[0039] In summary, it can be seen that the purification method for eplerenone methyl ester provided in the embodiments of the present invention has a high product yield, effectively removes ketides, and significantly improves purity.
[0040] The above provides a detailed description of the purification method for eplerenone methyl ester provided by the present invention. Specific examples have been used to illustrate the principle and implementation of the present invention. The description of the above embodiments is only for the purpose of helping to understand the method and core idea of the present invention. At the same time, for those skilled in the art, there will be changes in the specific implementation and application scope based on the idea of the present invention. Therefore, the content of this specification should not be construed as a limitation of the present invention.
Claims
1. A method for purifying an eplerenone intermediate, characterized in that, The method includes the following steps: S1: Dissolution: Add crude eplerenone methyl ester, organic solvent and water to the reaction flask in sequence, stir and heat to dissolve completely; S2: Reaction: Add an inorganic base to the dissolved reaction system, and stir under controlled temperature to ensure complete reaction; S3: Water precipitation: Cool the system to room temperature and slowly add water to precipitate the solid product. S4: Crystallization: Cool down to allow crystallization and stir thoroughly; S5: Filtration and drying: The system is filtered to separate solids and liquids, and then dried to obtain the high-quality eplerenone methyl ester.
2. The purification method for an eplerenone intermediate according to claim 1, characterized in that, In step S1, the organic solvent is one or more of DMF, acetone, or methanol.
3. The purification method for an eplerenone intermediate according to claim 1, characterized in that, In S2, the inorganic base is one or more of sodium bicarbonate, sodium carbonate, or potassium carbonate.
4. The method for purifying an eplerenone intermediate according to claim 1, characterized in that, In step S1, the volume of the organic solvent is 2-30 times the weight of the crude eplerenone methyl ester.
5. The purification method for an eplerenone intermediate according to claim 1, characterized in that, In step S2, the mass of the inorganic base is 0.1-3 times the weight of the crude eplerenone methyl ester.
6. The purification method for an eplerenone intermediate according to claim 1, characterized in that, In step S2, the stirring reaction time is 1.5-4 hours, and the temperature is 35-60℃.
7. The purification method for an eplerenone intermediate according to claim 1, characterized in that, In step S4, the temperature for cooling and crystallization is 0~10℃, and the stirring time is 1-2h.
8. The method for purifying an eplerenone intermediate according to claim 4, characterized in that, In step S1, the volume ratio of the organic solvent to water is 1:3-5, and the volume of the organic solvent is 4-10 times the weight of the crude eplerenone methyl ester.
9. The method for purifying an eplerenone intermediate according to claim 5, characterized in that, In S2, the mass ratio of the inorganic base to the crude eplerenone methyl ester is 1:(1.25-5).
10. The method for purifying an eplerenone intermediate according to claim 1, characterized in that, In step S3, the volume of water is 4-10 times the volume of the organic solvent.