Kenerenone key intermediate and preparation method thereof
Through halogenation, alkaline lysis and nucleophilic substitution reactions, the use of 4-methylbenzonitrile to prepare key intermediates of fennelone, which solves the problems of large impurities, low yields and high costs in the existing processes, and achieves efficient and environmentally friendly industrial production.
Patent Information
- Application Number
- CN202411477073.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-22
- Publication Date
- 2025-02-25
AI Technical Summary
The existing synthesis process of key nonnelone intermediates has problems such as large impurities, low yields, high costs and unfriendly environment, making it difficult to be suitable for industrial production.
4-cyano-2-methoxybenzaldehyde was prepared by halogenation, alkaline lysis and nucleophilic substitution reactions. This method requires only three steps of chemical reaction. The raw materials and reagents used are cheap and easy to obtain, no expensive palladium catalysts and dangerous reagents are required, and the reaction conditions are gentle and controllable.
It has achieved the preparation of key intermediates with high purity and high yield, suitable for industrial production, and is green and environmentally friendly, and is easy to operate.
Smart Images
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Figure BDA0005096394730000022
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pharmaceutical synthesis, in particular to a key intermediate of finerenone and a preparation method thereof. Background Art
[0002] Finerenone is the first non-steroidal selective mineralocorticoid receptor antagonist with confirmed renal and cardiovascular benefits in patients with chronic kidney disease and type 2 diabetes. On July 9, 2021, Bayer announced that the U.S. Food and Drug Administration (FDA) approved the first non-steroidal selective mineralocorticoid receptor antagonist, finerenone, for marketing in the United States. Finerenone 10 mg or 20 mg can be used to reduce the risk of sustained decline in eGFR, end-stage renal disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adult patients with chronic kidney disease and type 2 diabetes. 4-Cyano-2-methoxybenzaldehyde is a key intermediate in the synthesis of finerenone. The synthesis process reported in the existing literature has problems such as large impurities, low yield, and high cost. It is necessary to develop a production process with high product quality and easy industrialization.
[0003] At present, the synthesis of 4-cyano-2-methoxybenzaldehyde mainly includes the following routes:
[0004] Route 1: 4-methyl-3-methoxybenzoic acid is used as the raw material, and it is sequentially subjected to amination, cyanation, bromination, and alkaline hydrolysis to produce aldehyde. The steps are long, requiring a large amount of ammonia water and thionyl chloride, resulting in highly polluted wastewater, and it is difficult to obtain dibromo products with good selectivity through bromination, and the by-product monobromo product greatly affects the atomic utilization rate of the subsequent alkaline hydrolysis.
[0005]
[0006] Route 2: Using 4-bromo-2-hydroxybenzoic acid as the raw material, red aluminum is reduced to aldehyde after esterification and etherification, and finally potassium ferrocyanide is cyanated with palladium reagent to obtain the key intermediate of phenarenic acid. This route uses highly toxic dimethyl sulfate as a methylation reagent, and also uses expensive palladium reagents, which is costly. In addition, the post-treatment of red aluminum uses a large amount of acid water, which is very unfriendly to the environment. The cost of three waste treatments is too high, and it is not suitable for commercialization.
[0007]
[0008] Route 3 already exists in the market: 3-methoxy-4-iodo-bromobenzene is used as the starting material, first hydroformylation, then cyanation to obtain the key intermediate of phenaretin. This method requires expensive 3-methoxy-4-iodo-bromobenzene as the raw material, hydroformylation in an ultra-low temperature environment, the use of dangerous butyl lithium reagents and high energy consumption; cyanation uses precious metal palladium as a catalyst, which is difficult to recycle and reuse, the cost is too high and the reaction is difficult to control, and it is not suitable for industrialization.
[0009]
[0010] Route 4: 3-methoxy-4-methylbenzonitrile is condensed with DMF-DMA and then oxidized to obtain the target product. Although the route is short, high-energy sodium periodate is used as an oxidant. The oxidation process is a dangerous process in production, and its industrialization is greatly restricted.
[0011] Summary of the invention
[0012] Based on the technical problems existing in the background technology, the present invention provides a key intermediate of finerenone and a preparation method thereof.
[0013] A method for preparing a key intermediate of finerenone, which takes 4-methylbenzonitrile as a raw material and sequentially undergoes halogenation, alkaline hydrolysis and nucleophilic substitution reactions to obtain 4-cyano-2-methoxybenzaldehyde.
[0014] The synthetic route is:
[0015]
[0016] X is selected from one of fluorine, chlorine, bromine and iodine.
[0017] The present invention provides a method for preparing a key intermediate of finerenone, comprising the following steps:
[0018] S1, dissolving the compound of formula 1 in a solvent, adding a halogenating agent and a catalyst, stirring and reacting at a temperature of T1, extracting, drying and concentrating to obtain a compound of formula 2;
[0019] S2, dissolving the compound of formula 2 and a base in a solvent, raising the temperature to T2 for reaction, cooling to T3 after the reaction, pouring into ice water for crystallization, filtering, and drying to obtain a compound of formula 3;
[0020] S3, dissolving the compound of formula 3 in a solvent, adding methanol, alkali, metal salt, and amide compound, raising the temperature to T4 and stirring for reaction, after the reaction is complete, quenching, extracting, washing, drying, concentrating, and crystallizing to obtain the compound of formula 4, i.e., the key intermediate of finerenone.
[0021] Preferably, in S1, the mass volume ratio of the compound of formula 1 to the solvent is 1:(6-15), preferably 1:(8-12).
[0022] Preferably, in said S1, the temperature T1 is 0-80°C, more preferably 10-40°C.
[0023] Preferably, in S1, the molar ratio of the compound of formula 1, the catalyst and the halogenating agent is 1:(2-9):(2-9), more preferably 1:(3-4):(3-4).
[0024] Preferably, in S1, the catalyst is selected from one or more of hydrochloric acid, sulfurous acid, sodium bisulfite, and sulfuric acid, preferably sulfurous acid; the halogenating agent is selected from one or more of a fluorinating agent, a chlorinating agent, a brominating agent, and an iodizing agent, more preferably a brominating agent.
[0025] Preferably, in S1, the solvent is selected from one or more of THF, acetonitrile, and ethyl acetate, more preferably acetonitrile; and the extraction agent is selected from one or more of DCM, EA, and toluene, more preferably EA.
[0026] Preferably, in S2, the mass volume ratio of the compound of formula 2 to the solvent is 1:(3-15), more preferably 1:(5-10).
[0027] Preferably, in S2, the molar ratio of the compound of formula 2 to the base is 1:(1-4), more preferably 1:(2-3).
[0028] Preferably, in S2, the base is selected from one or more of sodium carbonate, sodium bicarbonate, pyridine and triethylamine, more preferably pyridine.
[0029] Preferably, in said S2, T2 is 80-140°C, T3 is 0-40°C, more preferably T2: 120-140°C, T3: 20-40°C.
[0030] Preferably, in S2, the solvent is selected from one or more of dioxane, DMF, DMAC, and DMSO, more preferably DMSO.
[0031] Preferably, in said S3, T4 is 70-120°C, more preferably 80-90°C.
[0032] Preferably, in S3, the molar ratio of the compound of formula 3 to the alkali, metal salt, and amide compound is 1:(1-3):(0.01-0.1):(0.01-0.1), and more preferably 1:(1.2-1.5):(0.03-0.07):(0.03-0.07).
[0033] Preferably, in S3, the mass volume ratio of the compound of formula 3 to methanol is 1:(1-3).
[0034] Preferably, in S3, the base is selected from one or more of sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate, sodium hydroxide, sodium hydride, and alkali metal salts of alcohols; wherein the alkali metal salts of alcohols are selected from one or more of sodium methoxide and potassium methoxide; the metal salt is selected from one or more of cupric chloride, cuprous chloride, cupric bromide, cuprous bromide, cupric iodide, cuprous iodide, nickel chloride, nickel bromide, and nickel iodide, more preferably cupric chloride; the amide compound is selected from N,N-dimethyloxalyl diamide, N,N-diethyloxalyl diamide, N,N-dimethoxyethyloxalyl diamide, N,N-dimethoxypropyloxalyl diamide, One or more of diamide, oxalamide, N,N-dinaphthyl oxalamide, N,N-dibenzyl oxalamide, N,N-diphenylethyl oxalamide, more preferably oxalamide; the solvent is selected from one or more of 1,4-dioxane, DMSO, acetonitrile, and DMF; the quenching acid for quenching is selected from one or more of hydrochloric acid, acetic acid, and sulfuric acid; the extraction solvent for extraction is selected from one of ethyl acetate, dichloromethane, chloroform, and toluene, more preferably ethyl acetate; the crystallization solvent for crystallization is selected from one or more of methanol, ethanol, ethyl acetate, and acetone, more preferably methanol.
[0035] Preferably, in said S3, the concentration of the quenching acid is 0.1-1M.
[0036] The present invention also provides a key intermediate of finerenone obtained by the above preparation method, and the structural formula of the key intermediate of finerenone is as follows:
[0037]
[0038] The beneficial effects of the present invention are:
[0039] The present invention can obtain the final product, the key intermediate of finerenone, through only three steps of chemical reaction. Compared with the prior art, the present invention has a novel synthesis route, fewer reaction steps, and the raw materials and reagents used in the reaction are cheap and easy to obtain, and no expensive palladium catalyst and dangerous reagents are needed. The present invention is green and environmentally friendly, and the reaction conditions are mild and controllable. The operation is simple, the product purity is high, the yield is high, and the product is suitable for industrial production. The present invention has broad prospects and industrial application value. DETAILED DESCRIPTION
[0040] The technical solution of the present invention is described in detail through specific embodiments.
[0041] Unless otherwise specified, the materials, reagents, etc. used in the following examples and comparative examples can be obtained from commercial sources.
[0042] Example 1
[0043] A method for preparing a key intermediate of finerenone comprises the following steps:
[0044] S1. Synthesis of compound of formula 2
[0045] At room temperature, p-methylbenzonitrile (11.7 g of compound 1, 0.1 mol) was dissolved in 94 mL of acetonitrile, and then 60.36 g of sodium bromate (0.4 mol) was added, and sulfurous acid (33.2 g, 0.4 mol) was added dropwise under stirring, and the temperature was controlled at 35°C. After the addition was completed, the reaction was continued for 6 hours. HPLC detected that the raw material had reacted completely, 120 ml of drinking water was added, and 200 mL of EA was added for extraction. After separation, the organic layer was washed once with 80 mL of saturated brine, and finally concentrated and dried to obtain 29.2 g of compound 2 in the form of brown oil, with a purity of 98.5% and a yield of 82.4%.
[0046] The reaction equation is as follows:
[0047]
[0048] S2. Synthesis of compounds of formula 3
[0049] At room temperature, the compound of formula 2 (35.3 g, 0.1 mol) and pyridine (15.8 g, 0.2 mol) were dissolved in 177 mL of dimethyl sulfoxide, and the temperature was raised to 135° C. for reaction for 2 h. After the reaction, the temperature was lowered to 20° C., poured into 400 ml of ice water, stirred and crystallized for 4 h, filtered, and dried at 55° C. to obtain 21.0 g of the compound of formula 3, with a yield of 95.1%;
[0050] The reaction equation is as follows:
[0051]
[0052] S3. Synthesis of compounds of formula 4
[0053] At room temperature, the compound of formula 3 (21.0 g, 0.1 mol) was dissolved in 105 mL of dioxane, and then copper chloride (0.3 g, 0.003 mol), oxalyl diamide (0.26 g, 0.003 mol), sodium methoxide (6.48 g, 0.12 mol), and methanol (42 ml) were added in sequence. After the addition, the temperature was raised to 85 ° C and stirred for 23 h. After the reaction was completed by HPLC, 10 ml of 0.1 M hydrochloric acid was added dropwise to quench, 90 mL of water was added, and then extracted with 200 ml of EA, washed once with saturated NaHCO3 solution, washed twice with saturated brine, and dried. Most of the solvent was concentrated, 60 ml of methanol was added, and crystallization was carried out at 0 ° C for 10 h. After filtering, it was dried at 55 ° C to obtain 14.8 g of solid compound 4 (4-cyano-2-methoxybenzaldehyde), with a yield of 92%;
[0054] The reaction equation is as follows:
[0055]
[0056] Example 2
[0057] A method for preparing a key intermediate of finerenone comprises the following steps:
[0058] S1. Synthesis of compound of formula 2
[0059] At room temperature, p-methylbenzonitrile (11.7 g, 0.1 mol of compound 1) was dissolved in 117 mL of acetonitrile, and then sodium chlorate (32.93 g, 0.3 mol) was added, and sodium bisulfite (31.2 g, 0.3 mol) was added three times under stirring, each time with an interval of 10 min, and the temperature was controlled at 20° C. After the addition was completed, the reaction was continued for 8 hours; HPLC detected that the raw material reaction was complete, 125 ml of drinking water was added, and 200 mL of dichloromethane was added for extraction. After separation, the organic layer was washed once with 80 mL of saturated brine, and finally concentrated and dried to obtain 17.77 g of compound 2 in the form of brown oil, with a purity of 98.5% and a yield of 80.6%;
[0060] The reaction equation is as follows:
[0061]
[0062] S2. Synthesis of compounds of formula 3
[0063] At room temperature, the compound of formula 2 (22.1 g, 0.1 mol) and sodium bicarbonate (25.2 g, 0.3 mol) were dissolved in 221 mL of dimethylformamide, and the temperature was raised to 125°C for reaction for 4 h. After the reaction, the temperature was lowered to 20°C, poured into 400 ml of ice water, stirred for crystallization for 5 h, filtered, and dried at 55°C to obtain 15.65 g of the compound of formula 3 with a yield of 94.5%;
[0064] The reaction equation is as follows:
[0065]
[0066] S3. Synthesis of compounds of formula 4
[0067] At room temperature, the compound of formula 3 (16.6 g, 0.1 mol) was dissolved in 100 mL of dioxane, and then cuprous chloride (0.69 g, 0.007 mol), N,N-dimethyloxalyl diamide (0.81 g, 0.007 mol), sodium carbonate (15.89 g, 0.15 mol), and methanol (41.5 ml) were added in sequence. After the addition, the temperature was raised to 85°C and stirred for reaction for 27 h. After HPLC detection, the reaction was complete, 10 ml of 1M hydrochloric acid was added dropwise to quench, 90 mL of water was added, and then extracted with 200 ml of toluene, washed once with saturated NaHCO3 solution, washed twice with saturated brine, and then dried. Most of the solvent was concentrated, 60 ml of acetone was added, and crystallization was carried out at 0°C for 10 h. After filtering, it was dried at 55°C to obtain 14.6 g of a solid compound of formula 4 (4-cyano-2-methoxybenzaldehyde) with a yield of 90.6%.
[0068] The reaction equation is as follows:
[0069]
[0070] Example 3
[0071] A method for preparing a key intermediate of finerenone comprises the following steps:
[0072] S1. Synthesis of compounds of formula 2
[0073] At room temperature, p-methylbenzonitrile (11.7 g of compound 1, 0.1 mol) was dissolved in 100 mL of acetonitrile, and then 58.45 g of potassium bromate (0.35 mol) was added. Under stirring conditions, 98% sulfuric acid (35 g, 0.35 mol) was added, and the temperature was controlled at 25°C. After the addition was completed, the reaction was continued for 7 hours. HPLC detected that the raw material reaction was complete, 150 ml of drinking water was added, and 300 mL of toluene was added for extraction. After separation, the organic layer was washed once with 100 mL of saturated brine, and finally concentrated and dried to obtain 27.8 g of compound 2 in the form of brown oil with a purity of 98.2% and a yield of 78.6%.
[0074] The reaction equation is as follows:
[0075]
[0076] S2. Synthesis of compounds of formula 3
[0077] At room temperature, the compound of formula 2 (35.3 g, 0.1 mol) and potassium carbonate (34.55 g, 0.25 mol) were dissolved in 280 mL of dimethylacetamide, and the temperature was raised to 130° C. for reaction for 4 h. After the reaction, the temperature was lowered to 30° C., poured into 600 ml of ice water, stirred and crystallized for 5 h, filtered, and dried at 55° C. to obtain 20.8 g of the compound of formula 3, with a yield of 94.2%;
[0078] The reaction equation is as follows:
[0079]
[0080] S3. Synthesis of compounds of formula 4
[0081] At room temperature, the compound of formula 3 (21.0 g, 0.1 mol) was dissolved in 110 mL of dioxane, and then copper bromide (1.12 g, 0.005 mol), N, N-diethyloxalyl diamide (0.72 g, 0.005 mol), potassium methoxide (10.52 g, 0.15 mol), and methanol (53 ml) were added in sequence. After the addition, the temperature was raised to 80°C and stirred for reaction for 20 h. After HPLC detection of the reaction was complete, 20 ml of 0.1 M acetic acid was added dropwise to quench, 50 mL of water was added, and then extracted with 400 ml of dichloromethane, washed once with saturated NaHCO3 solution, washed twice with saturated brine, and then dried. Most of the solvent was concentrated, 50 ml of ethanol was added, and crystallization was carried out at 0°C for 10 h. After filtration, it was dried at 55°C to obtain 14.70 g of solid compound of formula 4 (4-cyano-2-methoxybenzaldehyde) with a yield of 91.2%.
[0082] The reaction equation is as follows:
[0083]
[0084] Example 4
[0085] A method for preparing a key intermediate of finerenone comprises the following steps:
[0086] S1. Synthesis of compound of formula 2
[0087] At room temperature, p-methylbenzonitrile (11.7 g of compound 1, 0.1 mol) was dissolved in 100 mL of acetonitrile, and then 42.8 g of potassium iodate (0.2 mol) was added. Under stirring conditions, 37% hydrochloric acid (30.4 g, 0.3 mol) was added, and the temperature was controlled at 5°C. After the addition was completed, the reaction was continued for 12 hours. HPLC detected that the raw material reaction was complete, 100 ml of drinking water was added, and 300 mL of dichloromethane was added for extraction. After separation, the organic layer was washed once with 200 mL of saturated brine, and finally concentrated and dried to obtain 39.59 g of compound 2 as a brown oil with a purity of 98.7% and a yield of 80%.
[0088] The reaction equation is as follows:
[0089]
[0090] S2. Synthesis of compounds of formula 3
[0091] At room temperature, the compound of formula 2 (49.5 g, 0.1 mol) and triethylamine (15.18 g, 0.15 mol) were dissolved in 200 mL of dioxane, and the temperature was raised to 100 ° C for reaction for 7 h. After the reaction, the temperature was lowered to 10 ° C, poured into 400 ml of ice water, stirred and crystallized for 6 h, filtered, and dried at 55 ° C to obtain 23.528 g of the compound of formula 3, with a yield of 91.5%;
[0092] The reaction equation is as follows:
[0093]
[0094] S3. Synthesis of compounds of formula 4
[0095] At room temperature, the compound of formula 3 (25.7g, 0.1mol) was dissolved in 100mL of dioxane, and then cuprous iodide (0.29g, 0.0015mol), oxalyl diamide (0.26g, 0.003mol), sodium methoxide (6.48g, 0.12mol), and methanol (42ml) were added in sequence. After the addition, the temperature was raised to 85°C and stirred for reaction for 23h. After HPLC detection of the reaction was complete, 10ml of 0.1M sulfuric acid was added dropwise to quench, 120mL of water was added, and then extracted with 200ml of chloroform, washed once with saturated NaHCO3 solution, washed twice with saturated brine, and then dried. Most of the solvent was concentrated, 60ml of ethanol was added, and crystallization was carried out at 0°C for 10h. After filtering, it was dried at 55°C to obtain 14.67g of a solid compound of formula 4 (4-cyano-2-methoxybenzaldehyde), with a yield of 91%;
[0096] The reaction equation is as follows:
[0097]
[0098] Example 5
[0099] The difference between Example 5 and Example 1 is that in the synthesis of S1 and the compound of formula 2: the reaction temperature is 10°C and the insulation time is 72h, and 26.89g of the compound of formula 2 is obtained with a purity of 95.5% and a yield of 76%; the rest is the same as Example 1, and 14.5g of the compound of formula 4 (4-cyano-2-methoxybenzaldehyde) is obtained with a yield of 90.1%.
[0100] Example 6
[0101] The difference between Example 6 and Example 1 is that in the synthesis of S1, the compound of formula 2: the reaction temperature is 75°C, the insulation time is 1.5h, and 24.41g of the compound of formula 2 is obtained, the purity is 82.8%, and the yield is 69%; the rest is the same as Example 1, and 14.2g of the compound of formula 4 (4-cyano-2-methoxybenzaldehyde) is obtained, and the yield is 88.3%.
[0102] Example 7-Example 12
[0103] The difference between Example 7 to Example 12 and Example 1 is that in the synthesis of S3 and the compound of Formula 4, the types and contents of the metal salt and the amide compound are different, as shown in Table 1. The amount and yield of the obtained compound of Formula 4 (4-cyano-2-methoxybenzaldehyde) are shown in Table 1.
[0104] Comparative Example 1-Comparative Example 3
[0105] The difference between Comparative Examples 1 to Comparative Examples 3 and Example 1 is that in the synthesis of S3 and the compound of Formula 4, the types and contents of the metal salt and the amide compound are different, as shown in Table 1. The amount and yield of the obtained compound of Formula 4 (4-cyano-2-methoxybenzaldehyde) are shown in Table 1.
[0106] Table 1
[0107]
[0108]
[0109] It can be seen that the synthesis route of the present invention is novel, the reaction steps are few, and the product yield is high. From Comparative Example 1, Comparative Example 2 and Example 1, it can be seen that no metal salt or amide compound is added to S3, and the yield of the prepared compound of formula 4 (4-cyano-2-methoxybenzaldehyde) is low; from Comparative Example 3 and Example 1, it can be seen that the content of copper chloride in S3 is too high, which will affect the yield of the compound of formula 4.
[0110] In summary, the preparation method of the key intermediate of finerenone provided by the present invention is simple to operate, green and environmentally friendly, has a high product yield, and is suitable for industrial production.
[0111] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.
Claims
1. A method for preparing a key intermediate of finerenone, characterized in that: Using 4-methylbenzonitrile as the raw material, 4-cyano-2-methoxybenzaldehyde is obtained through halogenation, alkaline hydrolysis and nucleophilic substitution reactions in sequence; The synthetic route is: X is selected from one of fluorine, chlorine, bromine and iodine; The preparation method comprises the following steps: S1, dissolving the compound of formula 1 in a solvent, adding a halogenating agent and a catalyst, stirring and reacting at a temperature of T1, extracting, drying and concentrating to obtain a compound of formula 2; S2, dissolving the compound of formula 2 and a base in a solvent, raising the temperature to T2 for reaction, cooling to T3 after the reaction, pouring into ice water for crystallization, filtering, and drying to obtain a compound of formula 3; S3, dissolving the compound of formula 3 in a solvent, adding methanol, alkali, metal salt, and amide compound, raising the temperature to T4 and stirring for reaction, after the reaction is complete, quenching, extracting, washing, drying, concentrating, and crystallizing to obtain the compound of formula 4, i.e., the key intermediate of finerenone.
2. The preparation method according to claim 1, characterized in that: In the S1, the temperature T1 is 0-80°C; the molar ratio of the compound of formula 1, the catalyst and the halogenating agent is 1:(2-9):(2-9), and the mass volume ratio of the compound of formula 1 and the solvent is 1:(6-15).
3. The preparation method according to claim 1, characterized in that: In the S1, the catalyst is selected from one or more of hydrochloric acid, sodium sulfite, and sulfuric acid; the halogenating agent is selected from one or more of fluorinating agents, chlorinating agents, brominating agents, and iodinating agents.
4. The preparation method according to claim 1, characterized in that: In the S2, the base is selected from one or more of sodium carbonate, sodium bicarbonate, pyridine, and triethylamine, and the molar ratio of the compound 2 to the base is 1:(1-4).
5. The preparation method according to claim 1, characterized in that: In the S2, T2 is 80-140° C., T3 is 0-40° C.; the solvent is selected from one or more of dioxane, DMF, DMAC, and DMSO; and the mass volume ratio of the compound of formula 2 to the solvent is 1:(3-15).
6. The preparation method according to claim 1, characterized in that: In the S3, T4 is 70-120° C.; the molar ratio of the compound of formula 3 to the alkali, metal salt, and amide compound is 1:(1-3):(0.01-0.1):(0.01-0.1).
7. The preparation method according to claim 1, characterized in that: In the S3, the base is selected from one or more of sodium carbonate, potassium carbonate, potassium phosphate, sodium phosphate, sodium hydroxide, sodium hydride, and alkali metal salts of alcohols; the metal salt is selected from one or more of cupric chloride, cuprous chloride, cupric bromide, cuprous bromide, cupric iodide, cuprous iodide, nickel chloride, nickel bromide, and nickel iodide; the amide compound is selected from one or more of aromatic acid amide, sulfonamide, oxalic acid amide, N,N-dimethyl oxalyl diamide, N,N-diethyl oxalyl diamide, N,N-dimethoxyethyl oxalyl diamide, N,N-dimethoxypropyl oxalyl diamide, oxalyl diamide, and N,N-dinaphthylmethyl oxalyl diamide; the solvent is selected from one or more of 1,4-dioxane, DMSO, acetonitrile, and DMF; the quenching acid is selected from one or more of hydrochloric acid, acetic acid, and sulfuric acid; the extraction solvent is selected from one of ethyl acetate, dichloromethane, chloroform, and toluene; the crystallization solvent is selected from one or more of methanol, ethanol, ethyl acetate, and acetone.
8. A key intermediate of finerenone obtained by the preparation method according to any one of claims 1 to 7, characterized in that: The structural formula of the key intermediate of finerenone is as follows: