Preparation method of eplerenone and intermediate thereof

Abstract

The invention discloses a preparation method of eplerenone and an intermediate of eplerenone, and belongs to the technical field of chemical synthesis of medicines, and the preparation method comprises the following steps: by taking 9 alpha-hydroxy-4-androstene-3, 17-diketone which is low in price and easy to obtain as an initial raw material, firstly, constructing a delta9, 11-double bond with high selectivity through an acidic dehydration reaction; then, a gamma-lactone ring is efficiently constructed through 3-position carbonyl protection, 17-position propynylation and oxidative cyclization reaction, and an intermediate delta 9, 11-canrenone is obtained; further efficiently introducing carboxyl into the C7 site of the intermediate through a photocatalytic flow chemical technology, and finally preparing eplerenone through esterification and 9alpha, 11alpha-stereoselective epoxidation. The method is novel in route design, avoids the difficulty in selectivity and the use of toxic reagents in the traditional method, and is mild in condition in each step, high in yield, high in purity and suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis technology, specifically to a method for preparing eplerenone and its intermediates. Background Technology

[0002] Eplerenone, chemically named 9α,11α-epoxy-7α-methoxycarbonyl-3-oxo-17α-pregn-4-ene-21,17-carboxylactone, is a highly selective, nonsteroidal mineralocorticoid receptor antagonist. Compared to the first-generation drug spironolactone, eplerenone has extremely low affinity for androgen and progesterone receptors, thus significantly reducing the incidence of sex hormone-related side effects (such as gynecomastia in men and menstrual disorders in women). This drug is primarily used to treat hypertension and congestive heart failure following acute myocardial infarction to reduce patient mortality; its clinical importance and market demand continue to grow.

[0003] Δ9,11-canrenone is a crucial advanced intermediate essential for the synthesis of eplerenone. Its molecular structure possesses the three core features required for eplerenone synthesis: the A ring of a Δ4-3-one, the Δ9(11)-double bond (providing a site for the subsequent introduction of the 9α,11α-epoxy group), and the 17α-spironolactone ring (the key pharmacophore). Therefore, the efficient, high-purity, and low-cost preparation of Δ9,11-canrenone is crucial to the overall economic viability and feasibility of the eplerenone synthesis process.

[0004] In the prior art, the synthesis of Δ9,11-canrenone often suffers from the following problems: (1) Poor selectivity and difficulty in separation The traditional "bromination-debromination" route using spironolactone as a starting material generates a large number of structurally similar Δ8,9-isomer byproducts during the construction of the Δ9,11-double bond. These impurities are similar in properties to the target product and are difficult to separate, usually requiring multiple column chromatography steps, resulting in low yields (often below 40%) and making industrialization impossible.

[0005] (2) The reagents are highly toxic or costly. The selenium dioxide oxidation method used to avoid isomer problems poses a high risk of toxicity and does not meet the requirements of modern green production; while the use of high-priced oxidants such as DDQ significantly increases production costs.

[0006] (3) The synthetic route is lengthy and inefficient Other routes starting from basic steroidal raw materials often involve numerous steps and complex operations, resulting in uncompetitive overall yields after multiple steps. Therefore, developing a new synthetic route that avoids isomer formation from the source, avoids the use of highly toxic / expensive reagents, and has simple steps has significant practical and economic value.

[0007] In summary, existing mainstream synthetic routes are all constrained by the contradiction of being unable to simultaneously achieve "high selectivity," "high safety / economy," and "simplified procedures." Therefore, there is an urgent need in this field for a novel synthetic strategy that can avoid isomer formation from the outset, eliminate highly toxic / expensive reagents, and start from more economical raw materials. Summary of the Invention

[0008] The purpose of this invention is to overcome the shortcomings of the prior art and provide a method for preparing eplerenone and its intermediate Δ9,11-canrenone, which uses 9α-hydroxy-4-androsten-3,17-dione as a starting material, is simple to operate, has a high yield, good selectivity, and is easy to produce industrially.

[0009] To achieve the above objectives, a first aspect of the present invention is to provide a method for preparing an eplerenone intermediate, characterized by using 9α-hydroxy-4-androsten-3,17-dione as a starting material, comprising the following steps: (1) The compound 9α-hydroxy-4-androsten-3,17-dione was dehydrated under acidic conditions to generate the compound Δ9,11-androsten-4,9(11)-diene-3,17-dione. (2) Protect the carbonyl group at the 3-position of compound Δ9,11-androst-4,9(11)-diene-3,17-dione to generate compound 3-methoxy-Δ9,11-androst-3,5,9(11)-triene-17-one; (3) The 17-carbonyl group of compound 3-methoxy-Δ9,11-androst-3,5,9(11)-trien-17-one was added to a propynyl Grignard reagent to obtain compound 3-methoxy-17α-(propynyl)-estr-3,5,9(11)-trien-17β-ol; then, in the presence of a base, boron reagent and an oxidizing agent, compound 3-methoxy-17α-(propynyl)-estr-3,5,9(11)-trien-17β-ol underwent oxidative cyclization to form a γ-lactone ring to obtain compound 3-methoxy-pregn-4,6,9(11)-trien-17β,21-lactone-3,20-dione; (4) The compound 3-methoxy-pregn-4,6,9(11)-triene-17β,21-lactone-3,20-dione was deprotected to obtain the eplerenone intermediate Δ9,11-canrenone.

[0010] A second aspect of this invention is to provide a method for preparing eplerenone, using the intermediate Δ9,11-canrenone prepared by the aforementioned method as a raw material to prepare eplerenone, comprising the following steps: (5) Compound Δ9,11-canrenone was photocatalyzed in an organic solvent under light conditions in the presence of a photosensitizer, a thiol reagent and a base. After the reaction was completed, it was treated with acid to obtain compound 7α-carboxylic acid-9(11)-encanrenone. (6) The compound 7α-carboxylic acid-9(11)-encanrenone was esterified in methanol under sulfuric acid catalysis to obtain the compound 7α-methyl formate-9(11)-encanrenone. (7) Under alkaline conditions, the Δ9,11-double bond of compound 7α-methyl formate-9(11)-encanlione was epoxidized to obtain eplerenone as shown in the compound.

[0011] Further settings are as follows: In step (1): The dehydration reaction is carried out in a 1.0-3.0 M sulfuric acid aqueous solution at a reaction temperature of 50-80℃.

[0012] In step (2): The protection is achieved by catalytically forming enol methyl ether in the presence of methanol, trimethyl orthoformate, and pyridine hydrobromide.

[0013] In step (3): In the oxidative cyclization reaction, the base is LHMDS, the boron reagent is B(OMe)3, and the oxidant is... m -CPBA (m-chloroperoxybenzoic acid), in any one of THF, dichloromethane, and acetonitrile.

[0014] In step (4): The deprotection reaction was carried out in the presence of tetrachlorobenzoquinone.

[0015] In step (5): In the photocatalytic reaction, the photosensitizer is preferably 4-diphenylaminoisopropylnaphthalene (4DPAIPN), the thiol reagent is preferably methyl thiosalicylate, the base is preferably sodium bicarbonate, the light irradiation is preferably carried out under blue light at 467 nm, and the organic solvent is preferably DMSO solvent.

[0016] The photocatalytic reaction is preferably carried out in a microchannel reactor.

[0017] In step (6): The esterification reaction is preferably carried out under reflux in a sulfuric acid-catalyzed methanol solution.

[0018] In step (7): The epoxidation reaction was carried out at 0-10°C in the presence of sodium methoxide and hydrogen peroxide.

[0019] The beneficial effects of this invention are as follows: (1) Raw material innovation and cost advantage: This invention starts with inexpensive and readily available 9α-hydroxy-4-androsten-3,17-dione, eliminating dependence on traditional expensive intermediates and significantly reducing source costs.

[0020] 9α-hydroxy-4-androsten-3,17-dione is an intermediate that can be prepared on a large scale by the efficient, stereospecific hydroxylation of inexpensive phytosterols through microorganisms such as *Pterocarya stenoptera*. It is widely available and inexpensive. Its molecular structure pre-exists and precisely contains 9α-hydroxy and 17-carbonyl groups, providing a potential pathway for the direct and efficient conversion into the core skeleton (Δ9,11-canrenone) of the target molecule. This invention uses this raw material as a starting point and designs a complete and feasible industrial route for the efficient and highly selective transformation of the molecular skeleton and functional groups, ultimately precisely constructing Δ9,11-canrenone. This technical solution has not been successfully reported to date.

[0021] (2) The route design is novel and efficient: This invention employs a "propynylation-oxidative cyclization" strategy to construct the lactone ring and innovatively applies "photocatalysis combined with flow chemistry" to efficiently introduce a carboxyl group at the C7 position. The route is simple and solves the selectivity problem of traditional processes.

[0022] (3) Green and safe: The key steps of this invention avoid the use of highly toxic selenium dioxide and high-valent reagent DDQ, and mainly use conventional reagents, which is more in line with the principles of green chemistry.

[0023] (4) Good selectivity and high yield: The present invention exhibits excellent selectivity in each step of the reaction, high purity of intermediates and final products, and a significantly better overall yield than traditional methods.

[0024] (5) Easy to industrialize: The reaction conditions of this invention are mild and controllable, the post-processing is simple, and the key purification steps all adopt recrystallization method, which does not require complex chromatographic separation, and has excellent potential for large-scale production.

[0025] The present invention will be further described below with reference to the accompanying drawings and specific embodiments. Attached Figure Description

[0026] Figure 1 This is a schematic diagram of the reaction route of the present invention. Detailed Implementation

[0027] The present invention will be further described below with reference to the accompanying drawings and specific embodiments. Unless otherwise specified, the raw materials and reagents used in the embodiments are all known technologies or commercially available products in the art.

[0028] like Figure 1 As shown, the preparation method of eplerenone according to the present invention has the following process route: Starting from compound 9α-hydroxy-4-androsten-3,17-dione of formula (1), compound Δ9,11-androst-4,9(11)-diene-3,17-dione of formula (2) was prepared by dehydration reaction. After 3-position carbonyl protection, compound 3-methoxy-Δ9,11-androst-3,5,9(11)-trien-17-one of formula (3) was generated. Addition reaction yielded compound 3-methoxy-17α-(propynyl)-estr-3,5,9(11)-trien-17β-ol of formula (4). Oxidative cyclization to form a γ-lactone ring yielded compound 3-methoxy-pregn-4,6,9(11)-trien-17β,21-lactone-3,20-dione of formula (5). Deprotection yielded Δ9,11-canrenone of formula (6). The 7α-carboxyl group was constructed by photocatalytic flow chemistry to obtain compound (7) 7α-carboxylic acid-9(11)-encanrenone; the C7 carboxyl group was esterified to obtain compound (8) 7α-methyl formate-9(11)-encanrenone; and the eplerenone shown in formula (9) was obtained by stereoselective epoxidation.

[0029] The following provides a detailed explanation of each step.

[0030] Example 1

[0031] This embodiment mainly focuses on the preparation of Δ9,11-androst-4,9(11)-diene-3,17-dione(2).

[0032] In a 250 mL three-necked flask equipped with a stirrer, thermometer, and condenser, 120 mL of 1.5 M sulfuric acid aqueous solution was added, followed by stirring and the addition of 12.0 g of 9α-hydroxy-4-androsten-3,17-dione. The mixture was heated to 70 °C and stirred until the starting material disappeared, as monitored by TLC. After cooling, the reaction solution was slowly added dropwise to 250 mL of ice water under stirring and extracted with dichloromethane. The combined organic phases were washed successively with saturated sodium bicarbonate solution and water until neutral, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 40 °C to approximately 30 mL. The concentrate was added dropwise to 150 mL of ice water under stirring to crystallize, filtered, and the filter cake was washed with water and dried under vacuum at 45 °C to obtain 10.9 g of a white solid Δ9(11)-androsten-4,9(11)-diene-3,17-dione, with a yield of 93.5% and an HPLC purity of ≥99.3%.

[0033] Example 2

[0034] This embodiment mainly focuses on the preparation of 3-methoxy-3,5-androsadien-17-one (3).

[0035] In a 250 mL three-necked flask equipped with a stirrer, thermometer, condenser, and nitrogen introduction system, after nitrogen purging and drying, 46.0 g of anhydrous methanol, 2.0 g of pyridine hydrobromide, and 10.0 g (35.2 mmol) of Δ9,11-androst-4,9(11)-diene-3,17-dione were added sequentially at room temperature and under nitrogen protection. The mixture was heated to 30 °C, and 38.2 g (approximately 36.0 mL) of trimethyl orthoformate was added. The reaction was maintained at this temperature for 4 hours, and the reaction was monitored by TLC until the starting material disappeared. After the reaction was complete, the system was cooled to 0 °C, quenched by adding 2.38 g of purified water, and stirred for 0.5 hours. Then, 2.25 g of triethylamine was added to adjust the pH of the reaction solution to neutral. Subsequently, the mixture was further cooled to -5 °C and stirred for 1 hour to allow the product to crystallize completely. The sample was filtered, and the filter cake was washed with 80 mL of pre-cooled anhydrous ethanol. The wet sample was dried under vacuum at 40 °C for 16 hours to obtain 10.5 g of white solid 3-methoxy-Δ9,11-androst-3,5,9(11)-trien-17-one, with a molar yield of 94.2% and HPLC purity ≥99.0%.

[0036] Example 3

[0037] This embodiment mainly focuses on the preparation of 3-methoxy-17α-(propynyl)-estr-3,5,9(11)-trien-17β-ol (4).

[0038] Under nitrogen protection, a solution containing 150 mL of absolutely anhydrous tetrahydrofuran and 63.2 mL of propynyl magnesium bromide (1.0 M THF solution, 63.2 mmol) was slowly added dropwise to a 500 mL reaction flask cooled to -10 °C. This solution was prepared by dissolving 10.0 g (31.6 mmol) of 3-methoxy-Δ9,11-androst-3,5,9(11)-trien-17-one in 50 mL of absolutely anhydrous tetrahydrofuran. The mixture was stirred at 0 °C for 1 h, then slowly heated to 25 °C for 3 h until the starting material was completely removed. The reaction solution was then cooled back to 0 °C, and quenched by slowly adding 100 mL of saturated ammonium chloride aqueous solution. The mixture was transferred to a separatory funnel, and the organic layer was separated. The aqueous phase was extracted with dichloromethane (3 × 80 mL). The organic phases were combined and quenched with saturated brine (50 mL of dichloromethane). Washed with anhydrous magnesium sulfate and filtered; the filtrate was concentrated to dryness under reduced pressure below 35°C to obtain a pale yellow crude product, which was dissolved in the minimum volume (about 15 mL) of warm isopropanol and added dropwise to 100 mL of purified water pre-cooled to 0°C with stirring. A white solid gradually precipitated out. The mixture was stirred at 0°C for 1 h to allow complete crystallization. The mixture was filtered, and the filter cake was washed with ice water (2 × 10 mL) and dried under vacuum at 40°C to constant weight to obtain 10.5 g of white solid product 3-methoxy-17α-(propynyl)-estradiol-3,5,9(11)-trien-17β-ol, with a molar yield of 91.3% and HPLC purity ≥99.0%.

[0039] Example 4

[0040] This embodiment mainly focuses on the preparation of 3-methoxy-pregn-4,6,9(11)-triene-17β,21-lactone-3,20-dione (5).

[0041] Under nitrogen protection, an anhydrous THF (125 mL) solution containing 10.5 g (29.4 mmol) of the product 3-methoxy-17α-(propynyl)-estradiol obtained in Example 3 was added to a 500 mL reaction flask and cooled to 0 °C. LHMDS (1.0 M in THF, 118 mL, 118 mmol) and B(OMe)3 (13.2 mL, 118 mmol) were added slowly in sequence. After stirring at room temperature for 2 h, the mixture was cooled to 0 °C and added in portions. m-CPBA (70%, 37.2 g, 118 mmol) was reacted at room temperature for 0.5 h and then quenched with saturated NaHSO3 aqueous solution (150 mL). After extraction with ethyl acetate (3 × 150 mL), drying with anhydrous Na2SO4 and concentration, the crude product was purified by recrystallization through an acetone-water system to obtain 8.4 g of white solid 3-methoxy-pregn-4,6,9(11)-triene-17β,21-lactone-3,20-dione, yield 80%, HPLC purity ≥98.5%.

[0042] Replacement examples 4-1 to 4-8 The preparation method is the same as in Example 4, except that the base / boron reagent, oxidant, and solvent of the reaction are adjusted, and their effects on the reaction yield are tested, as shown in Table 1.

[0043] Table 1 .

[0044] Analysis: As shown in Table 1, different reaction conditions have a significant impact on the yield of the propyneation-oxidative cyclization reaction for constructing the lactone ring. (1) The synergistic effect of the base / boron reagent determines the reaction efficiency. The yield was optimal (80%) when using the LHMDS / B(OMe)3 combination (Example 4). Changing the base to NaHMDS (Example 4-1) or the boron reagent to B(OiPr)3 (Example 4-2) both resulted in a decrease in yield. Of particular note is that the reaction hardly occurred (yield <10%) without the addition of the boron reagent (Example 4-3), which strongly demonstrates that the formation of the enol borate intermediate is a necessary step in this cyclization reaction.

[0045] (2) The type of oxidant has a decisive influence on the cyclization efficiency. m -CPBA is the best oxidant for achieving efficient cyclization. The yields decreased to 52% and 28% when peroxyacetone (Examples 4-4) or Oxone (Examples 4-5), respectively, indicating that this cyclization reaction requires a strong peroxyacid oxidant that is soluble in the organic phase.

[0046] (3) Solvent polarity significantly affects reaction yield As shown in Table 1, THF performed best as a solvent. Dichloromethane (Examples 4-6) and acetonitrile (Examples 4-7), which have similar polarities, also achieved high yields (78% and 75%, respectively), while the nonpolar solvent toluene (Examples 4-8) reduced the yield to 58%, indicating that the reaction requires a certain polar environment to stabilize the intermediates.

[0047] In summary: In the "propynylation-oxidative cyclization" strategy for constructing lactone rings, LHMDS / B(OMe)3 / m-CPBA / THF constitutes a highly synergistic optimized system. Any change in a single condition leads to a significant decrease in reaction efficiency, which fully demonstrates the condition sensitivity and design precision of the system, and also reflects the innovative value of the "propynylation-oxidative cyclization" strategy of this invention.

[0048] Example 5

[0049] This embodiment mainly focuses on the preparation of the intermediate Δ-9,11-canrenone (6).

[0050] Under nitrogen protection, 53.0 g of dichloromethane, 19.2 g of methanol, and 12.2 g of water were added to a reactor containing 10.0 g (28.0 mmol) of 3-methoxy-pregn-4,6,9(11)-triene-17β,21-lactone-3,20-dione obtained in Example 4, and the mixture was stirred and cooled to 0°C. Maintaining this temperature, 6.96 g (28.3 mmol) of tetrachlorobenzoquinone was added, and the reaction was carried out at 0°C for 3 hours until the starting material was completely converted. The reaction solution was quenched with 30.0 g of water and 3.22 g of sodium sulfite, stirred at 10°C, and then filtered. The filtrate was separated, washed with alkali (4 times with a 20.0 g aqueous solution of 0.8 g sodium hydroxide), and purified by adsorption with anhydrous sodium sulfate and alumina, and then concentrated to dryness. The concentrate was dissolved in 7.92 g of methanol at 60 °C, and 10.0 g of water was slowly added dropwise. The temperature was then gradually reduced to 0 °C to crystallize. The solution was filtered and dried to obtain 8.31 g of white solid Δ-9,11-canrenone (6), with a yield of 90.9% and an HPLC purity of ≥99.0%.

[0051] Example 6

[0052] This embodiment mainly focuses on 7α-carboxylic acid-9(11)-encanristone (7). Under nitrogen protection, the product obtained in Example 5, Δ9,11-canrenone (10.00 g, 29.7 mmol), 2,4,5,6-tetra(diphenylamino)isophthalonitrile (4DPAIPN, 119 mg, 0.297 mmol), sodium bicarbonate (5.00 g, 59.4 mmol), and methyl thiosalicylate (5.45 g, 32.7 mmol) were dissolved in anhydrous DMSO and brought to a final volume of 500 mL to prepare a reaction solution. This reaction solution was pumped into a 50 mL PFA microchannel reactor with a built-in 467 nm blue LED light strip at a flow rate of 1.0 mL / min for photocatalytic reaction. The residence time was 50 minutes. The reaction solution was directly collected in 500 mL of 2M hydrochloric acid aqueous solution at 0°C, stirred for 1 hour, and then diluted with ethyl acetate (3 × 300 mL). Extracted by extraction with 1 mL, the combined organic phases were washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product; the crude product was dissolved in hot methanol (80 mL), added dropwise to ice water (600 mL) for recrystallization, filtered, the filter cake was washed with cold methanol-water (1:4, 50 mL), dried under vacuum at 40℃ to obtain 9.25 g of white solid 7α-carboxylic acid-9(11)-encanristone (7), yield 70%, HPLC purity ≥98.5%.

[0053] Replacement examples 6-1 to 6-8 The preparation method is the same as in Example 6, except that the photosensitizer, thiol reagent, base, and reaction wavelength are adjusted, and their effects on the reaction yield are tested, as shown in Table 2.

[0054] Table 2 .

[0055] Analysis: This invention employs "photocatalysis combined with flow chemistry to efficiently introduce carboxyl groups at the C7 position," as shown in Table 2. Different photosensitizers, thiols, bases, and reaction wavelengths have a significant impact on the yield of the C7 carboxylation reaction. (1) Photocatalytic conditions are the core of reaction initiation. When no photosensitizer is added to the reaction system (Example 6-2), the reaction cannot proceed at all, and the yield is zero. This directly confirms that the photocatalytic process is a necessary condition for this reaction, rather than the traditional thermal reaction pathway.

[0056] (2) Precise matching of photosensitizer and light source wavelength is a key influencing factor. When using the thermally activated delayed fluorescence material 4DPAIPN (Example 6), which matches the absorption of 467 nm blue light, the reaction yield reached an optimal 70%. However, when using eosin Y (Examples 6-8), which has a different absorption wavelength, even after adjusting the light source wavelength to its optimal absorption band, the yield significantly decreased to 25%. This demonstrates the importance of matching the photosensitizer's spectrum with the light source in the photocatalytic system.

[0057] (3) The molecular structure of thiol reagents has a decisive influence on reaction efficiency. When no thiol reagent is added to the reaction system (Examples 6-3), the reaction cannot proceed at all, and the yield is zero. Thiosyl salicylate containing an aromatic ring structure (Example 6) shows the best results, while aliphatic thiols such as methyl mercaptopropionate (Examples 6-4) have a yield of only 15%, showing a significant difference in efficiency. This result supports the involvement of a hydrogen atom transfer process in the reaction mechanism, and that aromatic thiols can provide more stable radical intermediates.

[0058] (4) The properties and strength of the alkali need to be precisely controlled. Sodium bicarbonate, a weak base (Example 6), provided the optimal reaction environment. Potassium carbonate, which is too alkaline (Examples 6-5), may have increased side reactions, reducing the yield to 45%; disodium hydrogen phosphate, which is too weakly alkaline (Examples 6-6), had an insufficient proton neutralization capacity, resulting in a yield of only 30%. This demonstrates the importance of pH regulation of the reaction microenvironment for the proton transfer step.

[0059] In summary, this invention employs a photocatalytic flow chemistry system to efficiently introduce a carboxyl group at the C7 position using a combination of photocatalysis and flow chemistry. The high yield achieved relies on a precise synergistic system comprised of a photosensitizer, thiol, base, and light source. The conditions established in Example 6 represent the optimal embodiment of this synergistic system.

[0060] Example 7

[0061] This embodiment mainly focuses on methyl 7α-formate-9(11)-encanristone (8). Under nitrogen protection, 5.00 g (11.4 mmol) of 7α-carboxylic acid-9(11)-encanrenone was dissolved in 100 mL of anhydrous methanol. Concentrated sulfuric acid (2.0 mL, about 37 mmol) was slowly added dropwise under ice bath cooling, with the temperature controlled not exceeding 30 °C. After the addition was completed, the mixture was heated to 65 °C and refluxed for 18 hours. After cooling, the reaction solution was poured into ice water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed successively with saturated sodium bicarbonate solution, water, and saturated brine. After drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure. The crude product was recrystallized from the methanol-water system, filtered, and dried to obtain 4.40 g of white solid methyl 7α-formate-9(11)-encanrenone (8), with a yield of 84.6% and an HPLC purity of ≥98.5%.

[0062] Example 8

[0063] This embodiment mainly focuses on the preparation of eplerenone (9). 10.0 g (23.8 mmol) of methyl 7α-formate-9(11)-encanrenone (8) was dissolved in a mixed solvent of 150 mL methanol and 50 mL tetrahydrofuran, and cooled to 0 °C under nitrogen protection and stirring. At this temperature, 10.0 mL (approximately 52.4 mmol) of a 30% sodium methoxide methanol solution and 7.3 mL (approximately 71.4 mmol) of a 30% hydrogen peroxide aqueous solution were slowly added dropwise. After the addition was complete, the reaction temperature was maintained at 0 °C and the reaction was stirred for 6 hours. The reaction mixture was monitored by TLC (evolving solvent: dichloromethane / methanol = 10:1) until the starting material was completely converted. After the reaction was completed, saturated sodium sulfite solution was added to the reaction solution to quench the excess oxidant. The reaction mixture was concentrated under reduced pressure to remove most of the solvent. The residue was diluted with water and extracted with dichloromethane. The organic phases were combined, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude eplerenone. The crude product was recrystallized from an acetone-water mixture (acetone:water = 4:1) to obtain 8.5 g of white crystalline powder eplerenone, with a molar yield of 85.3% and an HPLC purity of ≥99.5%.

[0064] The above embodiments are merely illustrative examples of the present invention and do not constitute a limitation on the scope of protection of the present invention. The scope of protection of the present invention shall be determined by the scope set forth in the claims.

Claims

1. A method for preparing an eplerenone intermediate, characterized in that: Using compound 9α-hydroxy-4-androsten-3,17-dione as a starting material, the following steps are included: (1) The compound 9α-hydroxy-4-androsten-3,17-dione was dehydrated under acidic conditions to generate the compound Δ9,11-androsten-4,9(11)-diene-3,17-dione. (2) Protect the carbonyl group at the 3-position of compound Δ9,11-androst-4,9(11)-diene-3,17-dione to generate compound 3-methoxy-Δ9,11-androst-3,5,9(11)-triene-17-one; (3) The 17-carbonyl group of compound 3-methoxy-Δ9,11-androst-3,5,9(11)-trien-17-one was added to a propynyl Grignard reagent to obtain compound 3-methoxy-17α-(propynyl)-estr-3,5,9(11)-trien-17β-ol; then, in the presence of a base, boron reagent and an oxidizing agent, compound 3-methoxy-17α-(propynyl)-estr-3,5,9(11)-trien-17β-ol underwent oxidative cyclization to form a γ-lactone ring to obtain compound 3-methoxy-pregn-4,6,9(11)-trien-17β,21-lactone-3,20-dione; (4) The compound 3-methoxy-pregn-4,6,9(11)-triene-17β,21-lactone-3,20-dione was deprotected to obtain the eplerenone intermediate Δ9,11-canrenone.

2. The method for preparing an eplerenone intermediate according to claim 1, characterized in that: In step (1): the dehydration reaction is carried out in a 1.0-3.0 M sulfuric acid aqueous solution at a reaction temperature of 50-80℃.

3. The method for preparing an eplerenone intermediate according to claim 1, characterized in that: In step (2): the protection is achieved by catalytically forming enol methyl ether in the presence of methanol, trimethyl orthoformate and pyridine hydrobromide.

4. The method for preparing an eplerenone intermediate according to claim 1, characterized in that: In step (3): In the oxidative cyclization reaction, the base is LHMDS, the boron reagent is B(OMe)3, and the oxidant is... m -CPBA (m-chloroperoxybenzoic acid).

5. The method for preparing an eplerenone intermediate according to claim 1, characterized in that: In step (3): the oxidative cyclization reaction is carried out in the presence of a solvent, which is any one of THF, dichloromethane and acetonitrile.

6. The method for preparing an eplerenone intermediate according to claim 1, characterized in that: In step (4): the deprotection reaction is carried out in the presence of tetrachlorobenzoquinone.

7. A method for preparing eplerenone, characterized in that, The preparation of eplerenone from the intermediate Δ9,11-canrenone prepared by the method of claim 1 includes the following steps: (5) Compound Δ9,11-canrenone was photocatalyzed in an organic solvent under light conditions in the presence of a photosensitizer, a thiol reagent and a base. After the reaction was completed, it was treated with acid to obtain compound 7α-carboxylic acid-9(11)-encanrenone. (6) The compound 7α-carboxylic acid-9(11)-encanrenone was esterified in methanol under sulfuric acid catalysis to obtain the compound 7α-methyl formate-9(11)-encanrenone. (7) Under alkaline conditions, the Δ9,11-double bond of compound 7α-methyl formate-9(11)-encanlione was epoxidized to obtain eplerenone as shown in the compound.

8. A method for preparing eplerenone according to claim 7, characterized in that, In step (5): the photocatalytic reaction uses 4-diphenylaminoisopropylnaphthalene as the photosensitizer, methyl thiosalicylate as the thiol reagent, sodium bicarbonate as the base, and is carried out under blue light at 467 nm. The organic solvent is DMSO.

9. The method for preparing eplerenone according to claim 7, characterized in that, In step (6): the esterification reaction is carried out under reflux in a sulfuric acid-catalyzed methanol solution.

10. The method for preparing eplerenone according to claim 7, characterized in that, In step (7): the epoxidation reaction is carried out at 0-10°C under the action of sodium methoxide and hydrogen peroxide.

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