Finerenone, preparation method therefor and finerenone intermediate

Abstract

The present application belongs to the technical field of preparation and processing of drugs, and particularly relates to finerenone, a preparation method therefor and a finerenone intermediate. In the preparation method provided by the present application, a compound with a diester structure as represented by formula 2 is used as a reaction raw material to carry out a series of reactions, a chiral catalyst is used in the reaction to obtain a product with an S / R configuration ratio of up to 85:15, and the product is resolved by means of using a tartaric acid derivative, so as to prepare a compound with a structure as represented by formula 7, and then the resulting compound is subjected to hydrolysis and amidation reactions to obtain Finerenone. A finerenone drug substance with an ee value of ＞99.9% and a purity of up to 99.9% can be obtained by means of the preparation method of the present application. Moreover, the reactions during the preparation method provided by the present application are all common reactions, not involving dangerous reaction steps such as hydrogenolysis and high-pressure processes. The method has mild reaction conditions, generates no highly toxic by-products, has low requirements for reaction equipment, has low operational costs, and is simple and convenient to operate. Therefore, the method is suitable for industrial production, and has good market prospects.

Description

Finerenone, preparation method thereof, and finerenone intermediate Technical Field

[0001] The present application belongs to the technical field of drug preparation and processing, and specifically relates to finerenone and a preparation method thereof, as well as a finerenone intermediate. Background Art

[0002] Finerenone, chemical name (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide, molecular formula is C 21 H 22 N4O3 is a nonsteroidal selective mineralocorticoid receptor antagonist that has been shown to block the harmful effects of excessive activation of the mineralocorticoid receptor and is used to treat adult patients with chronic kidney disease and type 2 diabetes.

[0003] There are many literature reports on the preparation of finerenone, and the most reported synthetic route is as follows:

[0004] However, since the above preparation method uses 2-cyanoethyl 3-oxobutanoate, highly toxic acrylonitrile is produced during the hydrolysis process. Secondly, this route requires a high-pressure reaction, which has a high risk factor and is not conducive to large-scale production.

[0005] Another method for preparing the raw material of phenelenone is reported in the literature, and its synthetic route is as follows:

[0006] The above-mentioned route uses benzyl ester to protect the carboxylic acid. However, conventional methods make it difficult to hydrolyze the benzyl ester, requiring hydrogenation to obtain the desired carboxylic acid intermediate. This is a dangerous reaction due to the use of hydrogen, making it difficult to scale up production. Furthermore, the hydrogenolysis process requires the use of an expensive palladium catalyst, and the cyano group on the benzene ring can also undergo side reactions, introducing unnecessary impurities.

[0007] In summary, the preparation methods of finerenone disclosed by the two synthetic routes mentioned above have problems such as highly toxic byproducts, expensive palladium catalysts, and hazardous reaction conditions. Furthermore, the resulting S / R configuration ratio is always 1:1. After the desired configuration is resolved, the other half of the isomer cannot be effectively utilized, resulting in waste and increased costs. Therefore, there is an urgent need to develop a preparation method for finerenone with high yield, simple operation, and mild conditions.

[0008] Summary of the Invention

[0009] The purpose of the present application is to provide finerenone, a preparation method thereof, and a finerenone intermediate. The preparation method provided in the present application has mild reaction conditions, no highly toxic by-products are produced, low requirements for the reaction apparatus, low operating costs, simple operation, and a high ratio of desired configuration to undesired configuration, effectively improving the yield of the desired S configuration obtained by resolution. The method is suitable for industrial production and has good market prospects.

[0010] In order to achieve the above objectives, this application provides the following technical solutions:

[0011] The present application provides a method for preparing finerenone, comprising the following steps:

[0012] 1) mixing a compound of the structure shown in Formula 1, a compound of the structure shown in Formula 2, an organic base, acetic acid, and a first organic solvent to carry out a condensation reaction to obtain a compound of the structure shown in Formula 3;

[0013] II) mixing the compound represented by Formula 3, the compound represented by Formula 4, a chiral catalyst, and a second organic solvent to carry out a cyclization reaction to obtain a compound represented by Formula 5;

[0014] III) mixing the compound of formula 5, triethyl orthoformate, concentrated sulfuric acid, and a third organic solvent to perform an etherification reaction to obtain a compound of formula 6;

[0015] IV) mixing the compound of Formula 6, a tartaric acid derivative, and a fourth organic solvent, performing a first incubation at a first temperature, then cooling to a second temperature and performing a second incubation to obtain a salt of the tartaric acid derivative; mixing the salt of the tartaric acid derivative, water, and a fifth organic solvent, and adjusting the pH to 7.5 to 9.5 with an alkaline pH adjuster to obtain a compound of Formula 7;

[0016] V) mixing the compound of formula 7, a sixth organic solvent, and a basic compound to perform a hydrolysis reaction to obtain a compound of formula 8;

[0017] VI) mixing the compound represented by Formula 8, N,N′-carbonyldiimidazole, a seventh organic solvent, 4-dimethylaminopyridine and aqueous ammonia to carry out an amidation reaction to obtain the finerenone;

[0018] In Formula 2, Formula 3, Formula 5, Formula 6 and Formula 7: R1 is selected from C1-10 alkyl; R2 is selected from hydrogen, C1-10 alkyl, halogen-substituted C1-10 alkyl or cyano-substituted C1-10 alkyl.

[0019] Preferably, in step I), the organic base includes one or more of piperidine, morpholine and pyrrolidine; the first organic solvent includes one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol and sec-butanol; the mass ratio of the compound with the structure represented by Formula 1, the organic base, acetic acid and the compound with the structure represented by Formula 2 is 1:(0.03-0.2):(0.02-0.2):(1.0-2.0); and the temperature of the condensation reaction is 20-50°C.

[0020] Preferably, in step II): the chiral catalyst includes D(+)-10-camphorsulfonic acid or (S)-(+)-binaphthol phosphate; the second organic solvent includes one or more of isopropanol, tert-butanol, sec-butanol and sec-pentanol; the mass ratio of the compound represented by the structure of Formula 3, the compound represented by the structure of Formula 4 and the chiral catalyst is 1:(0.2-1.2):(0.2-2.0); the temperature of the cyclization reaction is 70-120°C.

[0021] Preferably, in step III), the third organic solvent comprises one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; the mass ratio of triethyl orthoformate to the compound represented by Formula 5 is (1 to 5):1; the mass percentage of concentrated sulfuric acid is 98%, and the mass ratio of the compound represented by Formula 5 to concentrated sulfuric acid is 1:(0.02 to 0.3); and the temperature of the etherification reaction is 80 to 130°C.

[0022] Preferably, in step IV), the tartaric acid derivative includes dibenzoyl-L-tartaric acid, L-di(p-methylbenzoyl)tartaric acid, dibenzoyl-D-tartaric acid, or D-di(p-methylbenzoyl)tartaric acid; the mass ratio of the compound represented by Formula 6 to the tartaric acid derivative is 1:(0.4-1.2); the fourth organic solvent includes one or more of methanol, ethanol, isopropanol, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, acetone, and butanone; the first temperature is 30-80° C., and the first insulation treatment time is 1-5 h; the second temperature is 0-25° C., and the second insulation treatment time is 1-24 h;

[0023] The fifth organic solvent includes one or more of ethanol, methanol, isopropanol, n-butanol and sec-butanol; the volume ratio of the fifth organic solvent to water is 1:(3-10); the alkaline pH regulator includes one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium phosphate and potassium phosphate.

[0024] Preferably, in step V): the alkaline compound includes sodium hydroxide and / or potassium hydroxide, and the mass ratio of the alkaline compound to the compound having the structure shown in Formula 7 is (0.2-2.0):1; the sixth organic solvent includes one or more of methanol, ethanol, dichloromethane and ethylene glycol dimethyl ether; and the temperature of the hydrolysis reaction is 0-30°C.

[0025] Preferably, in step VI), the seventh organic solvent comprises one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and tetrahydrofuran; the mass percentage of the ammonia water is 25-28%; the mass ratio of the compound represented by the structure of Formula 8, N,N′-carbonyldiimidazole, 4-dimethylaminopyridine and ammonia water is 1:(0.3-1.5):(0.02-0.2):(3-10); and the temperature of the amidation reaction is 70-120°C.

[0026] Preferably, in step VI), the amidation reaction obtains an amidation reaction liquid, further comprising: subjecting the amidation reaction liquid to water precipitation to obtain a crude product; and refining the crude product with an alcohol solvent to obtain pure fenarenon; the alcohol solvent comprises one or more of methanol, an aqueous ethanol solution, and isopropanol, and the mass percentage of ethanol in the aqueous ethanol solution is 95-100%.

[0027] In step V), the hydrolysis reaction obtains a hydrolysis reaction liquid, further comprising: neutralizing the hydrolysis reaction liquid with an acid and then performing hydrolysis to obtain a compound with a structure shown in Formula 8; the acid comprises one or more of hydrochloric acid, sulfuric acid, acetic acid and formic acid.

[0028] The present application provides finerenone prepared by the preparation method described in the above technical solution, wherein the ee value of the finerenone is greater than 99.9%.

[0029] The present application provides a finerenone intermediate prepared by the preparation method described in the above technical solution, which has a structure shown in Formula 3, Formula 5, Formula 6 or Formula 7:

[0030] The present application provides a method for preparing finerenone. This application utilizes a compound having a diester structure represented by Formula 2 as a reaction raw material to conduct a series of reactions, and uses a chiral catalyst to obtain a product having an S / R configuration ratio of up to 85:15 (a compound having a structure represented by Formula 5 and a compound having a structure represented by Formula 6). The above product is then split using a tartaric acid derivative to obtain a compound having a structure represented by Formula 7, which is then hydrolyzed and amidated to obtain finerenone. The preparation method of the present application can produce a finerenone API with an ee value greater than 99.9% and a purity of up to 99.9%. The preparation method provided in the present application has the following advantages:

[0031] The present application utilizes a compound of formula 2 obtained by esterification of a 3-hydroxy ester with a carboxylic acid as a reaction raw material. After the compound of formula 2 reacts with a compound of formula 1 to generate a compound of formula 3, the ester structure formed by the compound of formula 2 has good stability in the first four reaction steps (steps I to IV) of the present application, and the ester structure can be easily hydrolyzed to obtain the desired carboxylic acid intermediate (compound of formula 8). At the same time, the present application utilizes a compound of formula 2 as a raw material, utilizes the diester structure of the compound of formula 2 in combination with a chiral catalyst to induce the formation of a chiral center of the target product, and obtains a compound of formula 5 with a ratio of the desired configuration to the undesired configuration (S:R configuration ratio) of up to 85:15, effectively improving the yield of the desired S configuration obtained by resolution. Moreover, the reaction process of the preparation method provided in the present application is entirely ordinary reaction, does not involve hazardous reaction steps such as hydrogenolysis and high pressure, has mild reaction conditions, does not produce highly toxic byproducts, has low requirements for the reaction apparatus, has low operating costs, is simple to operate, is suitable for industrial production, and has good market prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIG1 is a hydrogen NMR spectrum of phenaretone prepared in Example 6 of the present application;

[0033] FIG2 is a carbon NMR spectrum of phenaretone prepared in Example 6 of the present application;

[0034] FIG3 is a high performance liquid chromatogram of phenerenone prepared in Example 6 of the present application. DETAILED DESCRIPTION

[0035] The present application provides a method for preparing finerenone, comprising the following steps:

[0036] 1) mixing a compound of the structure shown in Formula 1, a compound of the structure shown in Formula 2, an organic base, acetic acid, and a first organic solvent to carry out a condensation reaction to obtain a compound of the structure shown in Formula 3;

[0037] II) mixing the compound represented by Formula 3, the compound represented by Formula 4, a chiral catalyst, and a second organic solvent to carry out a cyclization reaction to obtain a compound represented by Formula 5;

[0038] III) mixing the compound of formula 5, triethyl orthoformate, concentrated sulfuric acid, and a third organic solvent to perform an etherification reaction to obtain a compound of formula 6;

[0039] IV) mixing the compound of Formula 6, a tartaric acid derivative, and a fourth organic solvent, performing a first incubation at a first temperature, then cooling to a second temperature and performing a second incubation to obtain a salt of the tartaric acid derivative; mixing the salt of the tartaric acid derivative, water, and a fifth organic solvent, and adjusting the pH to 7.5 to 9.5 with an alkaline pH adjuster to obtain a compound of Formula 7;

[0040] V) mixing the compound of formula 7, a sixth organic solvent, and a basic compound to perform a hydrolysis reaction to obtain a compound of formula 8;

[0041] VI) mixing the compound represented by Formula 8, N,N′-carbonyldiimidazole, a seventh organic solvent, 4-dimethylaminopyridine and aqueous ammonia to carry out an amidation reaction to obtain the finerenone;

[0042] In Formula 2, Formula 3, Formula 5, Formula 6 and Formula 7: R1 is selected from C1-10 alkyl; R2 is selected from hydrogen, C1-10 alkyl, halogen-substituted C1-10 alkyl or cyano-substituted C1-10 alkyl.

[0043] In this application, unless otherwise specified, all preparation raw materials / components are commercially available products well known to those skilled in the art.

[0044] The preparation method of finerenone provided in this application, the synthetic route is as follows:

[0045] The preparation method provided in this application is described in detail below in conjunction with the synthetic route of finerenone provided in this application.

[0046] In the present application, a compound having the structure described in Formula 1, a compound having the structure described in Formula 2, an organic base, acetic acid and a first organic solvent are mixed (hereinafter referred to as the first mixture) for condensation reaction to obtain a compound having the structure described in Formula 3. In the present application, in Formula 2: R1 is preferably a C1-8 alkyl group, more preferably a C1-6 alkyl group, specifically a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group or a tert-butyl group, and most preferably a methyl group or an ethyl group. In the present application, in R2: the halogen in the halogen-substituted C1-10 alkyl group is preferably F, Cl or Br. R2 is preferably hydrogen, C1-5 alkyl group, halogen-substituted C1-5 alkyl group or cyano-substituted C1-5 alkyl group, further preferably hydrogen, C1-3 alkyl group, halogen-substituted C1-3 alkyl group or cyano-substituted C1-3 alkyl group, and specifically preferably Most preferably The organic base preferably includes one or more of piperidine, morpholine, and pyrrolidine; the first organic solvent preferably includes one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, and sec-butanol. The mass ratio of the compound represented by Formula 1, the organic base, and acetic acid to the compound represented by Formula 2 is preferably 1:(0.03-0.2):(0.02-0.2):(1.0-2.0), more preferably 1:(0.03-0.05):(0.02-0.05):(1.0-1.5). The volume ratio of the first organic solvent to the mass of the compound represented by Formula 1 is preferably (5-20) mL:1 g, more preferably (6-15) mL:1 g. The first mixing preferably includes the following steps: adding the compound represented by Formula 1 to the first organic solvent, then sequentially adding acetic acid and the organic base to obtain a mixed solution; and slowly dropwise adding the compound represented by Formula 2 to the mixed solution. The temperature of the condensation reaction is preferably 20-50°C, more preferably 25-45°C. The condensation reaction is carried out until the raw materials are completely converted. After the condensation reaction is complete, the present application preferably removes the solvent from the obtained condensation reaction solution to obtain a compound having a structure shown in Formula 3. The specific embodiment of the solvent removal is preferably concentration.

[0047] After obtaining the compound of Formula 3, the present application mixes the compound of Formula 3, the compound of Formula 4, a chiral catalyst, and a second organic solvent (hereinafter referred to as the second mixture) to perform a cyclization reaction to obtain the compound of Formula 5. In the present application, the chiral catalyst preferably includes D(+)-10-camphorsulfonic acid or (S)-(+)-binaphthol phosphate. The second organic solvent preferably includes one or more of isopropyl alcohol, tert-butyl alcohol, sec-butyl alcohol, and sec-pentanol. The mass ratio of the compound of Formula 3, the compound of Formula 4, and the chiral catalyst is preferably 1:(0.2-1.2):(0.2-2.0), more preferably 1:(0.2-0.4):(0.2-0.4). The ratio of the volume of the second organic solvent to the mass of the compound of Formula 3 is preferably (5-20) mL:1 g, more preferably (5.2-18) mL:1 g. The second mixing preferably includes the following steps: adding the compound of Formula 3, the compound of Formula 4, and the chiral catalyst to the second organic solvent in sequence. The temperature of the cyclization reaction is preferably 70-120°C, and the reaction is preferably carried out under heating and reflux. The reaction is preferably carried out under stirring. The cyclization reaction is carried out until the raw materials are completely converted. After the cyclization reaction is completed, a cyclization reaction liquid is obtained. In this application, the obtained cyclization reaction liquid is preferably cooled to room temperature and subjected to solid-liquid separation to obtain a solid product; the solid product is dried to obtain a compound with the structure represented by Formula 5. The solid-liquid separation is preferably performed by filtration, and the drying is preferably performed by oven drying.

[0048] After obtaining the compound of Formula 5, the present application further comprises mixing the compound of Formula 5, triethyl orthoformate, concentrated sulfuric acid, and a third organic solvent (hereinafter referred to as the third mixture) for an etherification reaction to obtain the compound of Formula 6. In the present application, the mass percentage of the concentrated sulfuric acid is preferably 98%. The third organic solvent preferably comprises one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone. The mass ratio of triethyl orthoformate to the compound of Formula 5 is preferably (1-5):1, more preferably (2-3):1. The mass ratio of the compound of Formula 5 to concentrated sulfuric acid is preferably 1:(0.02-0.3), more preferably 1:(0.1-0.2). The ratio of the volume of the third organic solvent to the mass of the compound of Formula 5 is preferably (2-10) mL:1 g, more preferably (2.5-9) mL:1 g. The third mixing preferably includes the following steps: adding the compound of the structure shown in Formula 5 and triethyl orthoformate to the third organic solvent in sequence, controlling the temperature preferably to 100°C, and adding concentrated sulfuric acid. The temperature of the etherification reaction is preferably 80-130°C, more preferably 100°C. The etherification reaction is carried out until the raw materials are completely converted. After the etherification reaction is completed, an etherification reaction liquid is obtained. The present application preferably cools the obtained etherification reaction liquid in sequence, precipitates it with water, separates the solid and liquid, and dries it to obtain a compound of the structure shown in Formula 6. The cooling is preferably cooled to room temperature, and the solid-liquid separation obtains a solid product for drying. The solid-liquid separation is preferably filtration, and the drying is preferably oven drying.

[0049] After obtaining the compound of the structure shown in Formula 6, the present application mixes the compound of the structure shown in Formula 6, a tartaric acid derivative, and a fourth organic solvent (hereinafter referred to as the fourth mixture), performs a first insulation treatment at a first temperature, and then cools to a second temperature for a second insulation to obtain a salt of the tartaric acid derivative; the salt of the tartaric acid derivative, water, and a fifth organic solvent are mixed (hereinafter referred to as the fifth mixture), and the pH value is adjusted to 7.5 to 9.5 with an alkaline pH regulator to obtain a compound of the structure shown in Formula 7. In the present application, the tartaric acid derivative preferably includes dibenzoyl-L-tartaric acid, L-di(p-methylbenzoyl)tartaric acid, dibenzoyl-D-tartaric acid, or D-di(p-methylbenzoyl)tartaric acid. The mass ratio of the compound of the structure shown in Formula 6 to the tartaric acid derivative is preferably 1:(0.4 to 1.2), more preferably 1:(0.5 to 0.8). The fourth organic solvent preferably includes one or more of methanol, ethanol, isopropanol, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, acetone, and butanone, and more preferably includes one or two of methanol, ethanol, isopropanol, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, acetone, and butanone. When the fourth organic solvent is preferably any two of the above, the volume ratio of the two solvents is preferably 1:1. In a specific embodiment of the present application, the fourth organic solvent is preferably ethyl acetate and / or methanol. The ratio of the volume of the fourth organic solvent to the mass of the compound represented by Formula 6 is preferably (10-30) mL:1 g, more preferably (12-26) mL:1 g. The fourth mixing preferably includes the following steps: adding the compound represented by Formula 6 and a tartaric acid derivative to the fourth organic solvent. The first temperature is preferably 30-80°C, more preferably 70°C. The first insulated treatment time is preferably 1-5 hours, more preferably 2 hours. The first insulated treatment is preferably performed under stirring. The second temperature is preferably 0-25°C, more preferably 15-23°C; the second insulation treatment time is preferably 1-24 hours, more preferably 8 hours. The second insulation treatment is preferably carried out under stirring. After the second insulation treatment, the present application preferably performs solid-liquid separation on the resulting reaction liquid to obtain the salt of the tartaric acid derivative. The solid-liquid separation is preferably performed by filtration.

[0050] After obtaining the salt of the tartaric acid derivative, the present application further comprises a fifth mixing step of the tartaric acid derivative salt, water, and a fifth organic solvent, and adjusting the pH to 7.5 to 9.5 with an alkaline pH adjuster to obtain a compound having the structure represented by Formula 7. In the present application, the fifth organic solvent preferably comprises one or more of ethanol, methanol, isopropanol, n-butanol, and sec-butanol; the volume ratio of the fifth organic solvent to water is preferably 1:(3-10), more preferably 1:(4-8). The volume ratio of the fifth organic solvent to the mass of the compound having the structure represented by Formula 6 is preferably (10-30) mL:1 g, more preferably (11-28) mL:1 g. The fifth mixing step preferably comprises the following steps: mixing the water and the fifth organic solvent, and then adding the salt of the tartaric acid derivative. The alkaline pH adjuster preferably comprises one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium phosphate, and potassium phosphate. The pH is preferably adjusted to 7.5. After the pH value is adjusted to 7.5 to 9.5, the present invention performs solid-liquid separation on the feed liquid, and the obtained solid product is dried to obtain a compound with a structure represented by Formula 7. The solid-liquid separation is preferably performed by filtration. The drying is preferably performed by oven drying.

[0051] After obtaining the compound of Formula 7, the present application mixes the compound of Formula 7, a sixth organic solvent, and an alkaline compound (hereinafter referred to as the sixth mixture) and performs a hydrolysis reaction to obtain the compound of Formula 8. In the present application, the alkaline compound preferably includes sodium hydroxide and / or potassium hydroxide. The sixth organic solvent preferably includes one or more of methanol, ethanol, dichloromethane, and ethylene glycol dimethyl ether, and more preferably one or two of methanol, ethanol, dichloromethane, and ethylene glycol dimethyl ether. When the sixth organic solvent is preferably any two of the above substances, the volume ratio of any two solvents is preferably 1:1. In a specific embodiment of the present application, the sixth organic solvent is specifically preferably methanol and / or dichloromethane. The mass ratio of the alkaline compound to the compound of Formula 7 is preferably (0.2-2.0):1, preferably (0.3-1.5):1. The volume ratio of the sixth organic solvent to the mass of the compound of Formula 7 is preferably (5-30) mL:1 g, preferably (6-25) mL:1 g. The sixth mixing preferably includes the following steps: adding the compound of the structure shown in Formula 7 to the sixth organic solvent, controlling the temperature to 0-30°C, and adding an alkaline compound. The temperature of the hydrolysis reaction is preferably 0-30°C, more preferably 5-10°C. The hydrolysis reaction is carried out under stirring. React until the raw materials are completely converted. After the hydrolysis reaction is completed, a hydrolysis reaction liquid is obtained. The present application preferably further includes: neutralizing the hydrolysis reaction liquid with an acid and then performing hydrolysis to obtain a compound of the structure shown in Formula 8; the preferred acid includes one or more of hydrochloric acid, sulfuric acid, acetic acid and formic acid, more preferably hydrochloric acid.

[0052] After obtaining the compound represented by Formula 8, the present invention further comprises a mixture of the compound represented by Formula 8, N,N′-carbonyldiimidazole (CDI), a seventh organic solvent, 4-dimethylaminopyridine (DMAP), and aqueous ammonia (hereinafter referred to as the seventh mixture) for an amidation reaction to obtain the finerenone. In the present invention, the seventh organic solvent preferably comprises one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and tetrahydrofuran. The aqueous ammonia preferably has a mass percentage of 25-28%. The mass ratio of the compound represented by Formula 8, N,N′-carbonyldiimidazole, 4-dimethylaminopyridine, and aqueous ammonia is preferably 1:(0.3-1.5):(0.02-0.2):(3-10), and more preferably 1:(0.35-1.4):(0.03-0.16):(3.5-8). The volume ratio of the seventh organic solvent to the mass of the compound represented by Formula 8 is preferably (3-10) mL:1 g, more preferably (3.5-8) mL:1 g. The seventh mixing preferably includes the following steps: adding the compound represented by Formula 8 and N,N′-carbonyldiimidazole to the seventh organic solvent, stirring at room temperature for 2 hours, and then adding 4-dimethylaminopyridine and aqueous ammonia. The temperature of the amidation reaction is preferably 70-120°C, more preferably 80-100°C. The amidation reaction is carried out under stirring. The reaction is continued until the raw materials are completely converted. The amidation reaction produces an amidation reaction liquid, and the present application preferably further includes: precipitating the amidation reaction liquid to obtain a crude product; and refining the crude product with an alcoholic solvent to obtain pure phenelline. The alcoholic solvent preferably includes one or more of methanol, aqueous ethanol, and isopropanol, and the weight percentage of ethanol in the aqueous ethanol is preferably 95-100%. The specific steps of the purification preferably include: heating and dissolving the crude product in the alcohol solvent to obtain a crude product solution; and sequentially concentrating the crude product solution, performing crystallization by cooling, solid-liquid separation, and drying to obtain the pure finerenone. In the present application, the volume ratio of the concentrated solution obtained by concentration to the crude product solution is preferably 1:(5-7). The initial temperature of the crystallization by cooling is preferably 50-60°C, the terminal temperature of the crystallization by cooling is preferably -5-5°C, and the cooling rate of the crystallization by cooling is preferably 1-3°C / min. The solid-liquid separation is preferably filtration.

[0053] The present application provides finerenone prepared by the preparation method described in the above technical solution, wherein the ee value of the finerenone is greater than 99.9%.

[0054] The present application provides a finerenone intermediate prepared by the preparation method described in the above technical solution, which has a structure shown in Formula 3, Formula 5, Formula 6 or Formula 7:

[0055] In order to further illustrate the present application, the technical solutions provided in the present application are described in detail below in conjunction with the embodiments, but they should not be understood as limiting the scope of protection of the present application.

[0056] If no specific experimental steps or conditions are described in the following examples, the procedures can be carried out according to conventional experimental methods described in the open texts in this field. The reagents or equipment used without indicating the manufacturer are all conventional products that can be purchased commercially.

[0057] Example 1

[0058] Preparation of (R)-4-ethoxy-4-oxobutan-2-yl-2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate (structure as follows):

[0059] 50 g of 4-cyano-2-methoxybenzaldehyde was added to 500 ml of isopropanol, and 1 g of acetic acid and 1.4 g of piperidine were added. The temperature was controlled at 30°C, and 75 g of (R)-4-ethoxy-4-oxobutan-2-yl-3-oxobutyrate was slowly added dropwise. The reaction was kept warm until completion, and the solvent was concentrated to obtain 110.9 g of the title compound in a yield of 99.5%.

[0060] Example 2

[0061] Preparation of (R)-4-ethoxy-4-oxobutan-2-yl-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (structure as follows):

[0062] To 600 ml of sec-butanol were added 110.9 g of (R)-4-ethoxy-4-oxobutan-2-yl-2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate and 35 g of the compound of formula 4 (4-amino-5-methylpyridone), followed by the addition of 30 g of (S)-(+)-binaphthol phosphate. The mixture was stirred and refluxed for 24 hours, cooled to room temperature, filtered, and dried to obtain 123.6 g of the title compound (S:R ratio of 85:15, the desired configuration is S-type) in a yield of 94.1% (based on 4-amino-5-methylpyridone).

[0063] Example 3

[0064] Preparation of (R)-4-ethoxy-4-oxobutan-2-yl-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (structure as follows):

[0065] To 450 ml of N,N-dimethylacetamide were added 123.6 g of (R)-4-ethoxy-4-oxobutan-2-yl-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate obtained in Example 2 and 350 g of triethyl orthoformate. The temperature was controlled at 100° C., and 11 g of sulfuric acid (98% by mass) was slowly added. The reaction was kept warm until the raw material was completely converted. The temperature was then lowered, the mixture was precipitated, filtered, and dried to give 123.5 g of the title compound (S:R ratio of 85:15, the desired configuration is S-type) in a yield of 94.2%.

[0066] Example 4

[0067] Preparation of (R)-4-ethoxy-4-oxobutan-2-yl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (structure as follows):

[0068] 100 g of (R)-4-ethoxy-4-oxobutan-2-yl-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate obtained in Example 3 and 75 g of dibenzoyl-D-tartaric acid were added to 600 ml of ethyl acetate and 600 ml of methanol, and the mixture was stirred at 70° C. for 2 hours, cooled to 20° C., stirred for 8 hours, and filtered. The resulting solid was added to 1200 ml of 20% (isopropanol volume percentage) aqueous isopropanol solution, the pH was adjusted to 7.5 with sodium phosphate aqueous solution, filtered, and dried to give 84.5 g of the title compound (ee value was 99.3%), in a yield of 84.5%.

[0069] Example 5

[0070] Preparation of (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (structure as follows):

[0071] 84.5 g of (R)-4-ethoxy-4-oxobutan-2-yl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate obtained in Example 4 was added to 350 ml of methanol and 350 ml of dichloromethane. The temperature was controlled at 5°C, 25 g of potassium hydroxide was added, and the reaction was stirred until the conversion was complete. The reaction was neutralized with hydrochloric acid, precipitated, filtered, and dried to obtain 63.3 g of the title compound in a yield of 97.4%.

[0072] Example 6

[0073] Preparation of (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (structure as follows):

[0074] 63.3 g of (S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid and 35 g of N,N-carbonyldiimidazole were added to 270 ml of N,N-dimethylformamide. After stirring at room temperature for 2 hours, 3.5 g of 4-dimethylaminopyridine and 270 g of aqueous ammonia (28 wt%) were added. The reaction was stirred at 80° C. until completion. The mixture was cooled, precipitated, and filtered. The wet product was purified with isopropanol. The specific purification process was as follows: the wet product was dissolved in 1000 ml of isopropanol by heating, and the solvent was removed by concentration to obtain about 200 ml of concentrated solution; the concentrated solution was cooled from 60° C. to 5° C. at a cooling rate of 2° C. / min, and filtered directly without insulation treatment. The solid product was dried to obtain 57.5 g of finerenone (ee value 100%, HPLC purity 99.9%), with a yield of 90.9%.

[0075] The H-NMR spectrum of phenarenalone prepared in Example 6 is shown in FIG1 ; the C-NMR spectrum of phenarenalone prepared in Example 6 is shown in FIG2 ; and the HPLC chromatogram of phenarenalone prepared in Example 6 is shown in FIG3 .

[0076] Example 7

[0077] The preparation process of finerenone and intermediates in this embodiment is as follows:

[0078] Step 1: 50 g of 4-cyano-2-methoxybenzaldehyde was added to 250 ml of isopropanol, followed by 1.2 g of acetic acid and 1.69 g of piperidine. The temperature was controlled at 20°C, and 65 g of (3-ethoxy-3-oxypropyl) 3-oxobutyrate was slowly added dropwise. The reaction was kept warm until completion, and the solvent was concentrated to obtain 105.3 g of compound (B) with a yield of 98.4%.

[0079] Step 2: To 1000 ml of sec-butanol were added 105.3 g of compound (B) obtained in step 1 and 37 g of 4-amino-5-methylpyridone, followed by 25 g of (S)-(+)-binaphthol phosphate. The mixture was stirred and refluxed for 24 hours, cooled to room temperature, filtered, and dried to obtain 124.1 g of compound (C) (S:R configuration ratio of 75:25), with a yield of 92.1%.

[0080] Step 3: To 600 ml of N,N-dimethylacetamide were added 124.1 g of compound (C) obtained in step 2 and 180 g of triethyl orthoformate. The temperature was controlled at 80°C, and 9.2 g of sulfuric acid (98% by mass) was slowly added. The reaction was kept warm until the raw materials were completely converted. The temperature was then lowered, the mixture was eluted, filtered, and dried to obtain 123.3 g of compound (D) (S:R ratio of 75:25), with a yield of 93.5%.

[0081] Step 4: 100 g of compound (D) obtained in step 3 and 80 g of L-di(p-methylbenzoyl)tartaric acid were added to 1200 ml of n-propyl acetate, stirred at 60° C. for 4 hours, cooled to 0° C. and stirred for 12 hours, filtered, and the resulting solid was added to 1200 ml of 30% (ethanol volume percentage) aqueous ethanol solution, adjusted to pH 7.5 with aqueous potassium carbonate solution, filtered, and dried to obtain 74.3 g of compound (E) (ee value 99.5%), with a yield of 74.3%.

[0082] Step 5: 74.3 g of compound (E) obtained in step 4 was added to 600 ml of methanol, the temperature was controlled at 15°C, 16 g of sodium hydroxide was added, and the reaction was stirred until the conversion was complete. The product was neutralized with concentrated hydrochloric acid, precipitated with water, filtered, and dried to obtain 57.3 g of compound (8) with a yield of 97.4%.

[0083] Step 6: 57.3 g of compound (8) obtained in step 5 and 34 g of N,N-carbonyldiimidazole were added to 200 ml of tetrahydrofuran, stirred at room temperature for 2 hours, and then 4 g of 4-dimethylaminopyridine and 200 g of

[0084] Ammonia (28 wt%) was stirred at 70°C to complete the reaction, cooled, precipitated, and filtered to obtain a wet product which was purified with ethanol. The specific purification process was as follows: the wet product obtained above was dissolved in 900 ml of ethanol by heating, and the solvent was removed by concentration to obtain about 150 ml of concentrated solution; the concentrated solution was cooled from 55°C to 0°C at a cooling rate of 3°C / min, and filtered directly without insulation treatment. The obtained solid product was dried to obtain 51.7 g of phenerenone (ee value 100%, HPLC purity 99.7%), with a yield of 90.2%.

[0085] Example 8

[0086] The preparation process of finerenone and intermediates in this embodiment is as follows:

[0087] Step 1: 50 g of 4-cyano-2-methoxybenzaldehyde was added to 350 ml of anhydrous ethanol, followed by 1.5 g of acetic acid and 1.8 g of pyrrolidine. The temperature was controlled at 40°C, and 75 g of methyl 4-chloro-3-(3-oxobutanoyloxy)butyrate was slowly added dropwise. The reaction was maintained at this temperature until completion, and the solvent was concentrated to obtain 119.3 g of compound (F) with a yield of 97.7%.

[0088] Step 2: To 800 ml of isopropanol were added 119.3 g of compound (F) obtained in step 1 and 37 g of 4-amino-5-methylpyridone, followed by 45 g of D(+)-10-camphorsulfonic acid. The mixture was stirred and refluxed for 24 hours. The mixture was cooled to room temperature, filtered, and dried to obtain 135 g of compound (G) (S:R configuration ratio of 78:22), with a yield of 90.5%.

[0089] Step 3: To 500 ml of N,N-dimethylacetamide were added 135 g of compound (G) obtained in step 2 and 225 g of triethyl orthoformate. The temperature was controlled at 100°C, and 12.9 g of sulfuric acid (98% by mass) was slowly added. The reaction was kept warm until the raw material conversion was complete. The temperature was then lowered, the mixture was eluted, filtered, and dried to obtain 128.5 g of compound (H) (S:R configuration ratio of 78:22), with a yield of 90.1%.

[0090] Step 4: 100 g of compound (H) obtained in step 3 and 90 g of L-di(p-methylbenzoyl)tartaric acid were added to 1500 ml of isopropyl acetate, stirred at 70° C. for 4 hours, cooled to 0° C. and stirred for 12 hours, filtered, and the resulting solid was added to 1500 ml of 25% (methanol volume percentage) methanol aqueous solution, adjusted to pH 7.5 with sodium bicarbonate aqueous solution, filtered, and dried to obtain 76.5 g of compound (J) (ee value 99.1%), with a yield of 76.5%.

[0091] Step 5: 76.5 g of compound (E) obtained in step 4 was added to 850 ml of ethanol, the temperature was controlled at 5°C, 15 g of potassium hydroxide was added, and the reaction was stirred until the conversion was complete. The product was neutralized with formic acid, precipitated with water, filtered, and dried to obtain 52.2 g of compound (8), with a yield of 95.0%.

[0092] Step 6: 52.2 g of compound (8) obtained in step 5 and 35 g of N,N-carbonyldiimidazole were added to 250 ml of N-methylpyrrolidone. After stirring at room temperature for 2 hours, 5 g of 4-dimethylaminopyridine and 200 g of aqueous ammonia (28 wt%) were added. The temperature was controlled at 100° C. and stirred until the reaction was complete. The mixture was cooled, precipitated, and filtered. The wet product was purified with 95 wt % aqueous ethanol. The specific purification process was as follows: the wet product obtained above was dissolved in 1200 ml of 95 wt % aqueous ethanol, concentrated to remove the solvent, and obtained about 180 ml of concentrated solution; the concentrated solution was cooled from 60° C. to -5° C. at a cooling rate of 1° C. / min, and filtered directly without insulation treatment. The obtained solid product was dried to obtain 46.9 g of phenerenone (ee value 100%, HPLC purity 99.8%), with a yield of 90.0%.

[0093] Example 9

[0094] The preparation process of finerenone and intermediates in this embodiment is as follows:

[0095] Step 1: Referring to the experimental method of Example 1, (R)-4-ethoxy-4-oxobutan-2-yl-3-oxobutanoate was replaced with d-4-ethoxy-4-oxobutan-2-yl-3-oxobutanoate. The yield of the target product, compound ①, was 99.0%.

[0096] Step 2: Referring to the experimental method of Example 2, the target product compound ② (S:R ratio is 80:20) has a yield of 93.5%.

[0097] Step 3: Referring to the experimental method of Example 3, the target product compound ③ (S:R ratio is 80:20) has a yield of 94.5%.

[0098] Step 4: Referring to the experimental method of Example 4, the ee value of the target product compound ④ was 99.5%, and the yield was 79.5%.

[0099] Step 5: Referring to the experimental method of Example 5, the yield of the target product, compound ⑤, was 97.5%.

[0100] Step 6: Referring to the experimental method of Example 6, finerenone (ee value 100%, HPLC purity 99.6%) was obtained in a yield of 90.3%.

[0101] Comparative Example 1

[0102] The original research routes for the preparation of finerenone and its intermediates provided in this comparative example are as follows:

[0103] Step 1: 50 g of 4-cyano-2-methoxybenzaldehyde was added to 223 ml of isopropanol, followed by 1.86 ml of acetic acid and 2.64 g of piperidine. The temperature was controlled at 30°C, and 65 g of 2-cyanoethyl 3-oxobutyrate dissolved in 25 ml of isopropanol was slowly added dropwise. The mixture was kept warm for 1 hour, then cooled to 0°C, filtered, and dried to obtain 89.7 g of compound (K) with a yield of 96.8%.

[0104] Step 2: To 1078 ml of isopropanol were added 89.7 g of compound (K) obtained in Step 1 and 36.5 g of 4-amino-5-methylpyridone. The mixture was stirred and refluxed at an internal temperature of 100°C under a pressure of 1.4 bar for 24 hours. The temperature was then lowered to 0°C, filtered, and dried to obtain 104.8 g of compound (L) (S / R configuration ratio of 1:1) in a yield of 88.0%.

[0105] Step 3: Dissolve 104.8 g of compound (L) and 229.8 g of triethyl orthoacetate in 594 ml of dimethylacetamide, and add 7.7 g of concentrated sulfuric acid (98 wt%). Heat the mixture at 115°C for 1.5 hours and then cool to 50°C. Add 1188 ml of water dropwise at 50°C over 30 minutes. Cool the mixture to 0°C (gradient, 2 hours) and stir at 0°C for 2 hours. The product is filtered, washed twice with 375 ml of water each time, and dried under vacuum at 50°C to obtain 103.4 g of compound (M) (the ratio of desired configuration to undesired configuration is 1:1), with a yield of 92.2%.

[0106] Step 4: 100 g of Compound (M) was dissolved in 600 ml of tetrahydrofuran and 300 ml of water and cooled to 0°C. Aqueous sodium hydroxide (prepared from 41 g of a 45% aqueous NaOH solution and 211 ml of water) was added dropwise over 15 minutes, and the mixture was stirred at 0°C for 1.5 hours. The mixture was extracted twice with 240 ml of methyl tert-butyl ether each time and once with 240 ml of ethyl acetate. The aqueous solution was adjusted to pH 7 at 0°C with dilute hydrochloric acid (prepared from 18.5 g of 37% hydrochloric acid and 75.5 ml of water). The solution was warmed to 20°C, and an aqueous solution of 102.5 g of ammonium chloride in 277 ml of water was added. The solution was stirred at 20°C for 1 hour. The product was filtered, washed twice with 75 ml of water each time and once with 200 ml of acetonitrile, and dried at 40°C. 86.8 g of Compound (N) were obtained, with a yield of 99%.

[0107] Step 5: 80 g of compound (N) and 47.9 g of 1,1-carbonyldiimidazole were added to 400 ml of tetrahydrofuran, and 2.55 g of 4-dimethylaminopyridine was added at 20°C. The mixture was stirred at 20°C for 1 hour and then heated to 50°C for 2.5 hours. 148.6 g of hexamethyldisilazane was added to the solution and boiled under reflux for 2 hours. 90 ml of tetrahydrofuran was added and the mixture was cooled to 5°C. A mixture of 58.5 ml of tetrahydrofuran and 42 g of water was added over 3 hours, maintaining the temperature between 5 and 20°C. The mixture was then boiled under reflux for 1 hour, then cooled to 0°C via a gradient (3 hours) and stirred at this temperature for 1 hour. The product was filtered off and washed twice with 120 ml of tetrahydrofuran each time and twice with 160 ml of water each time. The mixture was dried under vacuum at 70°C. 75 g of compound (O) was obtained with a yield of 94%.

[0108] Step 6: 75 g of compound (O) was dissolved in 1.5 L of a mixture of methanol / acetonitrile 60:40 and chromatographed by SMB. After concentration of the product-containing fractions, 36 g of a solution of fenareline in acetonitrile / methanol 40:60 was obtained. Yield: 48%.

[0109] Comparative Example 2

[0110] Preparation of (R)-4-ethoxy-4-oxobutan-2-yl-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (structure as follows):

[0111] Referring to the experimental method of Example 2, the chiral catalyst was replaced with an equal amount of glacial acetic acid to obtain the title compound (S:R ratio is 58:42) with a yield of 90.0%

[0112] Comparative Example 3

[0113] 2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (structure shown below) was synthesized using a chiral catalyst:

[0114] Referring to the experimental method of Example 2, 2-cyanoethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate was reacted with the compound of formula 4 in the presence of (S)-(+)-binaphthol phosphate to obtain the title compound (S:R ratio of 50:50) with a yield of 87.0%.

[0115] Through the implementation of the above embodiments and comparative examples, the comparison results are statistically summarized in Table 1.

[0116] Table 1 Comparison results of the embodiments and comparative examples

[0117] As can be seen from Table 1, the examples of the present application utilize the compound of formula 2 with a unique diester structure in combination with a chiral catalyst to induce the formation of a chiral center in the target product, resulting in a target product with an S:R configuration ratio of up to 85:15, which is significantly better than the comparative example.

[0118] Although the above embodiment provides a detailed description of the present application, it is only a part of the embodiments of the present application, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the scope of protection of the present application.

Claims

1. A method for preparing finerenone, characterized in that: The following steps are involved: 1) mixing a compound of the structure shown in Formula 1, a compound of the structure shown in Formula 2, an organic base, acetic acid, and a first organic solvent to carry out a condensation reaction to obtain a compound of the structure shown in Formula 3; II) mixing the compound represented by Formula 3, the compound represented by Formula 4, a chiral catalyst, and a second organic solvent to carry out a cyclization reaction to obtain a compound represented by Formula 5; III) mixing the compound of formula 5, triethyl orthoformate, concentrated sulfuric acid, and a third organic solvent to perform an etherification reaction to obtain a compound of formula 6; IV) mixing the compound of Formula 6, a tartaric acid derivative, and a fourth organic solvent, performing a first incubation at a first temperature, then cooling to a second temperature and performing a second incubation to obtain a salt of the tartaric acid derivative; mixing the salt of the tartaric acid derivative, water, and a fifth organic solvent, and adjusting the pH to 7.5 to 9.5 with an alkaline pH adjuster to obtain a compound of Formula 7; V) mixing the compound of formula 7, a sixth organic solvent, and a basic compound to perform a hydrolysis reaction to obtain a compound of formula 8; VI) mixing the compound represented by Formula 8, N,N′-carbonyldiimidazole, a seventh organic solvent, 4-dimethylaminopyridine and aqueous ammonia to carry out an amidation reaction to obtain the finerenone; In Formula 2, Formula 3, Formula 5, Formula 6 and Formula 7: R1 is selected from C1-10 alkyl; R2 is selected from hydrogen, C1-10 alkyl, halogen-substituted C1-10 alkyl or cyano-substituted C1-10 alkyl.

2. The preparation method according to claim 1, characterized in that In step I), the organic base includes one or more of piperidine, morpholine and pyrrolidine; the first organic solvent includes one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol and sec-butanol; the mass ratio of the compound with the structure represented by Formula 1, the organic base, acetic acid and the compound with the structure represented by Formula 2 is 1:(0.03-0.2):(0.02-0.2):(1.0-2.0); the temperature of the condensation reaction is 20-50°C.

3. The preparation method according to claim 1 or 2, characterized in that The ratio of the volume of the first organic solvent to the mass of the compound having the structure represented by Formula 1 is (5-20) mL:1 g.

4. The preparation method according to claim 1, characterized in that In step II), the chiral catalyst includes D(+)-10-camphorsulfonic acid or (S)-(+)-binaphthol phosphate; the second organic solvent includes one or more of isopropanol, tert-butanol, sec-butanol, and sec-pentanol; the mass ratio of the compound represented by the structure of Formula 3, the compound represented by the structure of Formula 4, and the chiral catalyst is 1:(0.2-1.2):(0.2-2.0); and the temperature of the cyclization reaction is 70-120°C.

5. The preparation method according to claim 1 or 4, characterized in that The ratio of the volume of the second organic solvent to the mass of the compound having the structure represented by Formula 3 is (5-20) mL:1 g.

6. The preparation method according to claim 1, characterized in that In step III), the third organic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; the mass ratio of triethyl orthoformate to the compound represented by Formula 5 is (1 to 5):1; the mass percentage of concentrated sulfuric acid is 98%, and the mass ratio of the compound represented by Formula 5 to concentrated sulfuric acid is 1:(0.02 to 0.3); and the temperature of the etherification reaction is 80 to 130°C.

7. The preparation method according to claim 1 or 6, characterized in that The ratio of the volume of the third organic solvent to the mass of the compound having the structure represented by Formula 5 is (2-10) mL:1 g.

8. The preparation method according to claim 1, characterized in that In step IV), the tartaric acid derivative includes dibenzoyl-L-tartaric acid, L-di(p-methylbenzoyl)tartaric acid, dibenzoyl-D-tartaric acid, or D-di(p-methylbenzoyl)tartaric acid; the mass ratio of the compound represented by Formula 6 to the tartaric acid derivative is 1:(0.4-1.2); the fourth organic solvent includes one or more of methanol, ethanol, isopropanol, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, acetone, and butanone; the first temperature is 30-80° C., and the first insulation treatment time is 1-5 hours; the second temperature is 0-25° C., and the second insulation treatment time is 1-24 hours; The fifth organic solvent includes one or more of ethanol, methanol, isopropanol, n-butanol and sec-butanol; the volume ratio of the fifth organic solvent to water is 1:(3-10); the alkaline pH regulator includes one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium phosphate and potassium phosphate.

9. The preparation method according to claim 1 or 8, characterized in that The ratio of the volume of the fourth organic solvent to the mass of the compound of the structure represented by Formula 6 is (10-30) mL:1 g; The ratio of the volume of the fifth organic solvent to the mass of the compound having the structure represented by Formula 6 is (10-30) mL:1 g.

10. The preparation method according to claim 1, characterized in that In step V), the alkaline compound includes sodium hydroxide and / or potassium hydroxide, and the mass ratio of the alkaline compound to the compound having the structure shown in Formula 7 is (0.2 to 2.0):1; the sixth organic solvent includes one or more of methanol, ethanol, dichloromethane and ethylene glycol dimethyl ether; and the temperature of the hydrolysis reaction is 0 to 30°C.

11. The preparation method according to claim 1 or 10, characterized in that: The ratio of the volume of the sixth organic solvent to the mass of the compound having the structure represented by Formula 7 is (5-30) mL:1 g.

12. The preparation method according to claim 1, characterized in that In step VI), the seventh organic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and tetrahydrofuran; the mass percentage of the ammonia water is 25-28%; the mass ratio of the compound represented by the structure of Formula 8, N,N′-carbonyldiimidazole, 4-dimethylaminopyridine and ammonia water is 1:(0.3-1.5):(0.02-0.2):(3-10); and the temperature of the amidation reaction is 70-120°C.

13. The preparation method according to claim 1 or 12, characterized in that: The ratio of the volume of the seventh organic solvent to the mass of the compound having the structure represented by Formula 8 is (3-10) mL:1 g.

14. The preparation method according to claim 1, 8 or 10, characterized in that: In step VI), the amidation reaction produces an amidation reaction solution, further comprising: subjecting the amidation reaction solution to water precipitation to obtain a crude product; and refining the crude product with an alcohol solvent to obtain pure fenarenon; wherein the alcohol solvent comprises one or more of methanol, an aqueous ethanol solution, and isopropanol, wherein the ethanol content in the aqueous ethanol solution is 95-100% by weight; In step V), the hydrolysis reaction obtains a hydrolysis reaction liquid, further comprising: neutralizing the hydrolysis reaction liquid with an acid and then performing hydrolysis to obtain a compound with a structure shown in Formula 8; the acid comprises one or more of hydrochloric acid, sulfuric acid, acetic acid and formic acid.

15. The preparation method according to claim 14, characterized in that The specific implementation steps of the refining include: heating and dissolving the crude product with the alcohol solvent to obtain a crude product solution; sequentially concentrating, cooling and crystallizing the crude product solution, solid-liquid separation, and drying to obtain the pure finerenone; the volume ratio of the concentrated solution obtained by the concentration to the crude product solution is 1:(5-7); the initial temperature of the cooling and crystallization is 50-60°C, the terminal temperature of the cooling and crystallization is -5-5°C, and the cooling rate of the cooling and crystallization is 1-3°C / min.

16. Finerenone prepared by the method according to any one of claims 1 to 15, characterized in that: The ee value of finerenone is greater than 99.9%.

17. The finerenone intermediate prepared by the preparation method according to any one of claims 1 to 11, characterized in that: It has the structure shown in Formula 3, Formula 5, Formula 6 or Formula 7: In Formula 3, Formula 5, Formula 6 and Formula 7: R1 is selected from C1-10 alkyl; R2 is selected from hydrogen, C1-10 alkyl, halogen-substituted C1-10 alkyl or cyano-substituted C1-10 alkyl.

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