One-pot synthesis of eplerenone intermediate N-1
The one-pot synthesis of eplerenone intermediate N-1 solves the problems of large solvent consumption, excessive wastewater and solid waste generation in existing technologies, and achieves the production of eplerenone intermediate with high purity, high yield and low cost, thus achieving the goal of green chemistry.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIANGXI JUNYE BIOLOGICAL PHARM CO LTD
- Filing Date
- 2026-03-11
- Publication Date
- 2026-06-05
AI Technical Summary
The existing synthetic route for eplerenone intermediate N-1 involves a large amount of reaction solvent, generates a large amount of wastewater, uses metallic iron as a reducing agent to generate a large amount of solid waste, and uses a large amount of organic solvent during the purification process, resulting in high production costs and environmental problems.
A one-pot method was used to synthesize eplerenone intermediate N-1. This method involves a series of reactions including ring opening, rearrangement, ozonolysis, reduction, and methyl esterification, omitting column chromatography purification steps. Reagents such as potassium carbonate, hydrochloric acid, and sodium sulfite were used to carry out the reaction within a specific temperature and time range, and finally, the purified eplerenone intermediate N-1 was obtained.
This approach reduces the amount of organic solvents used and wastewater discharge, simplifies process steps, improves the purity and yield of eplerenone intermediate N-1, reduces production costs, and achieves a green chemical process.
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Figure CN122145541A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology, and specifically relates to a one-pot method for synthesizing eplerenone intermediate N-1. Background Technology
[0002] Eplerenone is a novel selective aldosterone receptor antagonist with the following structural formula: Eplerenone exerts its blood pressure-lowering effect by blocking the action of aldosterone in the renin-angiotensin-aldosterone system (RAAS) through aldosterone receptors. Clinical studies have confirmed that eplerenone has a good effect on improving the survival rate of stable patients with left ventricular systolic dysfunction (cardiac ejection fraction ≤40%) and congestive heart failure after acute myocardial infarction.
[0003] Eplerenone intermediate N-1 (chemical name: methyl 7a-formate-9(11)-encanrenone, structural formula: N-1 is a key intermediate in the synthesis of eplerenone. Eplerenone is obtained by epoxidation of 9,11-ene in one step. Therefore, it is of great significance to develop a new synthetic method for eplerenone N-1 to reduce the production cost of eplerenone.
[0004] Patent application CN111018934A discloses a method for synthesizing methyl 7a-formate-9(11)-encanristone, the synthetic route of which is as follows:
[0005] In this route, N-4 to N-1 is obtained through ring opening, rearrangement, ozonation, followed by reduction esterification with a metal reducing agent, and finally column chromatography. This process involves a large amount of solvent, generates a large amount of wastewater, uses metallic iron as a reducing agent, produces a large amount of solid waste, and uses column chromatography with a large amount of organic solvent during purification. Summary of the Invention
[0006] In view of this, the present invention provides a one-pot method for synthesizing eplerenone intermediate N-1, which aims to solve at least one of the technical problems in the background art.
[0007] This invention is implemented as follows: A one-pot method for synthesizing eplerenone intermediate N-1, wherein the method uses eplerenone intermediate N-4 as a raw material and achieves a continuous reaction of ring opening, rearrangement, ozonolysis, reduction and methyl esterification in a one-pot process to synthesize eplerenone intermediate N-1. The structure of the eplerenone intermediate N-4 is shown in the following formula: ; The structure of the eplerenone intermediate N-1 is shown in the following formula: ; The one-pot method specifically includes: dissolving eplerenone intermediate N-4 in dichloromethane, adding potassium carbonate aqueous solution and dibromohydantoin for ring-opening reaction; after the reaction, directly adding hydrochloric acid for rearrangement reaction; then separating the water and adding methanol to the organic layer for ozonolysis reaction; then adding sodium sulfite for reduction reaction; then adding hydrochloric acid for methyl esterification reaction to obtain crude eplerenone intermediate N-1, and finally refining to obtain purified eplerenone intermediate N-1.
[0008] Furthermore, in the ring-opening reaction, the reaction temperature is 10℃~20℃ and the time is 1h~2h; According to the mass ratio, potassium carbonate: eplerenone intermediate N-4 = 0.3~0.4:1, dibromohydantoin: eplerenone intermediate N-4 = 0.3~0.5:1.
[0009] Furthermore, in the rearrangement reaction, the reaction temperature is 10℃~20℃ and the time is 2h~4h; The hydrochloric acid concentration is 30%~40%; according to the mass ratio, hydrochloric acid: eplerenone intermediate N-4 = 0.3~0.4:1.
[0010] Furthermore, in the ozonation reaction, the reaction temperature is -60℃ to -50℃ and the time is 5h to 8h.
[0011] Furthermore, in the reduction reaction, the reaction temperature is -20℃ to -10℃ and the time is 2h to 4h; According to the mass ratio, sodium sulfite: eplerenone intermediate N-4 = 0.3~0.5:1.
[0012] Furthermore, the temperature of the methyl esterification reaction is 45℃~50℃; the time is 4h~6h; The hydrochloric acid concentration is 30%~40%; according to the mass ratio, hydrochloric acid: eplerenone intermediate N-4 = 0.1~0.15:1.
[0013] Further, after the methyl esterification reaction is completed, an aqueous solution of sodium bicarbonate is added, and the organic solvents dichloromethane and methanol are concentrated under reduced pressure. The mixture is then filtered to obtain crude eplerenone intermediate N-1.
[0014] Further, the refining step is as follows: acetone and water are added to the crude eplerenone intermediate N-1 and the temperature is raised to 50°C~55°C; then the temperature is lowered to 5°C~10°C, filtered and dried to obtain the refined eplerenone intermediate N-1.
[0015] Compared with existing technologies, this invention achieves the one-pot synthesis of eplerenone intermediate N-1 from eplerenone intermediate N-4 through a series of reactions including ring opening, rearrangement, ozonolysis, reduction, and methyl esterification. At the same time, it avoids column chromatography purification, making it a green chemical process route that greatly reduces the amount of organic solvents used and wastewater.
[0016] This invention ensures a high yield and high purity of eplerenone intermediate N-1 while simplifying the process steps. Attached Figure Description
[0017] Figure 1 The HNMR spectrum of the product of Example 1 of this invention; Figure 2 The CNMR spectrum of the product of Example 1 of this invention; Figure 3 The MS spectrum of the product of Example 1 of this invention; Figure 4 This is the HPLC chromatogram of the product of Example 1 of the present invention; Figure 5 This is the HPLC chromatogram of the product of Comparative Example 1 of the present invention. Detailed Implementation
[0018] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.
[0019] Example 1 This embodiment describes a one-pot synthesis method for eplerenone intermediate N-1, and the synthetic route is as follows:
[0020] The steps of this method are as follows: 1 kg of eplerenone intermediate N-4 was dissolved in 5 L of dichloromethane. A potassium carbonate aqueous solution (0.33 kg potassium carbonate + 1 L water) was added, and the mixture was cooled to 10°C–20°C. 0.4 kg of dibromohydantoin was added to initiate a ring-opening reaction, which lasted 1.5 h. After the reaction, 0.35 kg of 37% hydrochloric acid was added dropwise at 10°C–20°C to initiate a rearrangement reaction, which lasted 3 h. After the reaction, the mixture was allowed to stand and separate into layers. 5 L of methanol was added to the organic layer, and the mixture was cooled to -60°C–-50°C and subjected to ozonation for 6.5 h. After the reaction, the mixture was heated to -20°C, and 0.4 kg of sodium sulfite was added to initiate a reduction reaction, which was maintained at -20°C–-10°C for 3 h. After the reaction, 0.117 kg of 37% hydrochloric acid was added, and the mixture was heated to 45°C–50°C to initiate a methyl esterification reaction for 5 h. After the reaction, a sodium bicarbonate aqueous solution (0.105 kg sodium bicarbonate + 2 L water) was slowly added. L), the organic solvent was concentrated under reduced pressure, and filtered to obtain crude eplerenone intermediate N-1; 0.5 L acetone and 0.5 L water were added, and the mixture was heated to 50℃~55℃ and stirred for 1 hour, then cooled to 5℃~10℃, filtered, and dried to obtain 0.61 Kg of purified eplerenone intermediate N-1 (HPLC purity: 99.7%, molar yield: 64%). The HNMR, CNMR, MS, and HPLC spectra of the product in this example are shown below. Figures 1 to 4 As shown.
[0021] The specific details of HNMR, CNMR, and MS spectra are as follows: 1 H NMR (400 MHz, CDCl3) δ H / ppm:5.71 (s, 1 H), 5.66-5.64 (d, J = 8.0Hz,1 H), 3.59 (s, 3 H), 2.99-2.96(m, 1 H), 2.86-2.80 (m, 1 H), 2.59-2.46 (m, 6H), 2.33-2.17 (m, 5 H), 1.96-1.84 (m, 4 H), 1.51-1.48 (m, 2H), 1.40 (s, 3H), 0.95 (s, 3H).
[0022] 13 C NMR (100 MHz, CDCl3) δ C / ppm: 196.5, 176.41, 172.59, 166.58,142.33, 125.68, 118.94, 95.02, 51.38, 44.45, 43.76, 43.06, 40.53, 40.34,35.71, 35.41, 34.16, 33.73, 32.89, 31.41, 29.16, 27.16, 23.25, 14.03.
[0023] MS (ESI) m / z calcd for C 24 H 30 O5 + (M+H) + 399.2 found: 399.6.
[0024] Comparative Example 1 The difference between this comparative example and Example 1 is that it does not use a one-pot method but a stepwise method, purifying the products of each reaction (ring-opening, rearrangement, ozonolysis, reduction, and methyl esterification) before proceeding to the next reaction. Specifically: 1 kg of eplerenone intermediate N-4 was dissolved in 5 L of dichloromethane, and an aqueous solution of potassium carbonate (0.33 kg of potassium carbonate + 1 L of water) was added. The mixture was cooled to 10℃~20℃, and 0.4 kg of dibromohydantoin was added to initiate a ring-opening reaction. The reaction was carried out for 1.5 h. The organic phase was then separated into layers, and the organic phase was concentrated under reduced pressure to obtain the ring-opening product. After adding 2 L of dichloromethane to the ring-opening product, 0.35 Kg of 37% hydrochloric acid was added dropwise at a controlled temperature of 10℃~20℃ to carry out the rearrangement reaction for 3 h; then the organic phase was separated into layers, and the organic phase was concentrated under reduced pressure to obtain the rearranged product. The rearrangement product was added to 5 L of dichloromethane and 5 L of methanol, cooled to -60℃ to -50℃, and subjected to ozonation reaction for 6.5 h. The temperature was raised to -20℃, and 0.4 kg of sodium sulfite was added to carry out the reduction reaction. The reaction was maintained at -20℃ to -10℃ for 3 hours. Then the reaction solution was concentrated under reduced pressure to obtain the reduction product. The reduction product was added to 0.117 kg of 37% hydrochloric acid, and the mixture was heated to 45℃~50℃ for methyl esterification for 5 hours. After the reaction was complete, an aqueous solution of sodium bicarbonate (0.105 kg of sodium bicarbonate + 2 L of water) was slowly added, and the organic solvent was concentrated under reduced pressure. The mixture was filtered to obtain crude eplerenone intermediate N-1. 0.5 L of acetone and 0.5 L of water were added, and the mixture was heated to 50℃~55℃ and stirred for 1 hour. Then the temperature was lowered to 5℃~10℃, and the mixture was filtered and dried to obtain 0.59 kg of purified eplerenone intermediate N-1 (HPLC chromatogram shown). Figure 5 As shown, the HPLC purity was 98.8%, and the molar yield was 62%.
[0025] Table 1
[0026] Table 1 shows that, compared to Comparative Example 1, which underwent purification after each intermediate reaction (ring-opening, rearrangement, ozonolysis, reduction), the one-pot method of Example 1 of this invention for preparing eplerenone intermediate N-1 resulted in higher purity and better yield. Furthermore, because this invention omits the intermediate purification step, the process is simpler, less time-consuming, and significantly reduces waste dosage.
[0027] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.
Claims
1. A method for one-pot synthesis of eplerenone intermediate N-1, characterized in that, The method uses eplerenone intermediate N-4 as raw material and synthesizes eplerenone intermediate N-1 through a one-pot process involving ring opening, rearrangement, ozonolysis, reduction and methyl esterification. The structure of the eplerenone intermediate N-4 is shown in the following formula: ； The structure of the eplerenone intermediate N-1 is shown in the following formula: ； The one-pot method specifically includes: dissolving eplerenone intermediate N-4 in dichloromethane, adding potassium carbonate aqueous solution and dibromohydantoin for ring-opening reaction; after the reaction, directly adding hydrochloric acid for rearrangement reaction; then separating the water and adding methanol to the organic layer for ozonolysis reaction; then adding sodium sulfite for reduction reaction; then adding hydrochloric acid for methyl esterification reaction to obtain crude eplerenone intermediate N-1, and finally refining to obtain purified eplerenone intermediate N-1.
2. The method for one-pot synthesis of eplerenone intermediate N-1 according to claim 1, characterized in that, In the ring-opening reaction, the reaction temperature is 10℃~20℃ and the time is 1h~2h; According to the mass ratio, potassium carbonate: eplerenone intermediate N-4 = 0.3~0.4:1, dibromohydantoin: eplerenone intermediate N-4 = 0.3~0.5:
1.
3. The method for one-pot synthesis of eplerenone intermediate N-1 according to claim 1, characterized in that, In the rearrangement reaction, the reaction temperature is 10℃~20℃ and the time is 2h~4h; The hydrochloric acid concentration is 30%~40%; according to the mass ratio, hydrochloric acid: eplerenone intermediate N-4 = 0.3~0.4:
1.
4. The method for one-pot synthesis of eplerenone intermediate N-1 according to claim 1, characterized in that, In the ozonation reaction, the reaction temperature is -60℃ to -50℃ and the time is 5h to 8h.
5. The method for one-pot synthesis of eplerenone intermediate N-1 according to claim 1, characterized in that, In the reduction reaction, the reaction temperature is -20℃ to -10℃ and the time is 2h to 4h; According to the mass ratio, sodium sulfite: eplerenone intermediate N-4 = 0.3~0.5:
1.
6. The method for one-pot synthesis of eplerenone intermediate N-1 according to claim 1, characterized in that, The methyl esterification reaction is carried out at a temperature of 45℃~50℃ for 4h~6h. The hydrochloric acid concentration is 30%~40%; according to the mass ratio, hydrochloric acid: eplerenone intermediate N-4 = 0.1~0.15:
1.
7. The method for one-pot synthesis of eplerenone intermediate N-1 according to claim 1, characterized in that, After the methyl esterification reaction is completed, an aqueous solution of sodium bicarbonate is added, and the organic solvents dichloromethane and methanol are concentrated under reduced pressure. The mixture is then filtered to obtain crude eplerenone intermediate N-1.
8. The method for one-pot synthesis of eplerenone intermediate N-1 according to claim 7, characterized in that, The refining steps are as follows: acetone and water are added to the crude eplerenone intermediate N-1 and the temperature is raised to 50°C~55°C; then the temperature is slowly lowered to 5°C~10°C, filtered and dried to obtain the refined eplerenone intermediate N-1.