Preparation method of fenerenone key intermediate

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a fenerenone key intermediate, which comprises the following preparation steps: (1) carrying out dehydration reaction on 4-bromo-3-methoxybenzamide (I) to obtain 4-bromo-3-methoxybenzonitrile (II); and (2) carrying out reductive carbonyl insertion reaction on the 4-bromo-3-methoxybenzonitrile (II), so as to prepare the key intermediate 4-cyano-2-methoxybenzaldehyde (III) of the fenerenone. The synthetic route disclosed by the invention is short, the raw materials are easy to obtain, the reaction conditions are mild, and the method has the advantages of high yield, high product purity, safe and environment-friendly reaction materials and the like; the catalyst adopted in the invention is a catalyst containing heavy metal palladium, has a good catalytic effect, is easy to recover and reuse, and saves the cost.

Description

Technical Field

[0001] The present application belongs to the field of medical technology, and specifically relates to a method for preparing a key intermediate of finerenone. Background Art

[0002] 4-Cyano-2-methoxybenzaldehyde is a key intermediate of finerenone. As a key intermediate, its synthesis is relatively difficult.

[0003] The chemical structure of 4-cyano-2-methoxybenzaldehyde is as follows:

[0004] There are two main methods for preparing 4-cyano-2-methoxybenzaldehyde at present: ① Document US2018 / 244670 discloses that p-amino-o-hydroxybenzoic acid is used as a raw material, p-bromo-o-hydroxybenzoic acid is generated by diazotization, and then reacted with dimethyl sulfate to generate methyl p-bromo-o-methoxybenzoate, and then reduced by red aluminum to obtain p-bromo-o-methoxybenzaldehyde, and p-bromo-o-methoxybenzaldehyde is coupled with potassium hexacyanoferrate under the catalysis of palladium acetate to obtain the target compound 4-cyano-2-methoxybenzaldehyde. This route reaction requires the use of red aluminum, which is extremely flammable and has a high industrial production risk, making it difficult to produce industrially; ② Document CN115388272 discloses that 3-methoxy-4-methylbenzoic acid is used as a raw material, reacted with dichlorothionyl and then with ammonia water to obtain 3-methoxy-4-methylbenzamide, and 3-methoxy-4-methylbenzonitrile is generated in the presence of trifluoroacetic anhydride and N-methylmorpholine, followed by bromination with NBS to obtain 4-dibromomethyl-3-methoxybenzonitrile, and finally reacted with sodium iodide for hydrolysis to obtain 4-cyano-2-methoxybenzaldehyde. The bromination reaction in this route is difficult to completely convert the monobrominated product into the dibrominated product, and the solvent carbon tetrachloride used in the bromination reaction is highly toxic and is a 2B carcinogen, which is not suitable for industrial production. Summary of the invention

[0005] In order to solve the problems of the prior art, the present application provides a method for preparing a key intermediate of finerenone, which is achieved through the following scheme:

[0006] The synthesis method disclosed in the present application has readily available raw materials, avoids the use of hazardous chemicals, is simple to synthesize, has high efficiency, obtains products with high yield and purity, and is easy to industrialize.

[0007] The yield of 4-bromo-3-methoxybenzonitrile (II) prepared by the present application is as high as 92%, and the purity is as high as 99.6%. The yield of the intermediate 4-cyano-2-methoxybenzaldehyde (III) is as high as 90%, and the purity is as high as 99.5%.

[0008] The specific preparation process is as follows: (1) 4-bromo-3-methoxybenzamide (Ⅰ) undergoes a dehydration reaction to obtain 4-bromo-3-methoxybenzonitrile (Ⅱ); (2) 4-bromo-3-methoxybenzonitrile undergoes a reductive carbonylation reaction to obtain 4-cyano-2-methoxybenzaldehyde (Ⅲ), a key intermediate of finerenone.

[0009] Furthermore, a method for preparing a key intermediate of finerenone is provided, the preparation steps of which are as follows: (1) 4-bromo-3-methoxybenzamide (I) undergoes a dehydration reaction with a dehydrating agent in a solvent to obtain 4-bromo-3-methoxybenzonitrile (II); (2) 4-bromo-3-methoxybenzonitrile undergoes a reduction carbonylation reaction with hydrogen and carbon monoxide in a solvent in the presence of a catalyst, a ligand and an acid-binding agent to obtain a key intermediate of finerenone, 4-cyano-2-methoxybenzaldehyde (III).

[0010] Furthermore, the dehydration reagent in step (1) is one or more of thionyl chloride, phosphine oxychloride, phosphorus pentachloride, Burgess reagent (methyl N-(triethylammoniumsulfonyl)carbamate), and trifluoroacetic anhydride.

[0011] Furthermore, in the step (1), the molar ratio of 4-bromo-3-methoxybenzamide (I) to the dehydrating agent is 1:1.0-6.0; preferably, the molar ratio of 4-bromo-3-methoxybenzamide (I) to the dehydrating agent is 1:3.0; and the temperature of the dehydration reaction is 50-110°C, preferably 90-100°C.

[0012] Furthermore, the solvent used in step (1) is one or more of toluene, xylene, chlorobenzene, N,N-dimethylformamide, N-methylpyrrolidone, and n-butanol; the solvent used in step (2) is one or more of toluene, xylene, chlorobenzene, N,N-dimethylformamide, N-methylpyrrolidone, and n-butanol.

[0013] Furthermore, the solvents used in step (1) and step (2) are the same or different.

[0014] Furthermore, the catalyst in step (2) is a heavy metal catalyst; preferably, the catalyst is a catalyst containing heavy metal palladium; more preferably, the catalyst is one or more of triphenylphosphine palladium dichloride, bis(triphenylphosphine)palladium dichloride, DPPF palladium dichloride, palladium dichloride, and palladium acetate.

[0015] Furthermore, the ligand in step (2) is a phosphine ligand; preferably, the ligand is one or more of 1,3-bis(diphenylphosphino)propane, di-tert-butylphosphine chloride, n-butyldi(1-adamantyl)phosphine, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, tert-butyldicyclohexylphosphine tetrafluoroborate, tri-tert-butylphosphine tetrafluoroborate, tri(2-tolyl)phosphine; more preferably, n-butyldi(1-adamantyl)phosphine and tri-tert-butylphosphine tetrafluoroborate.

[0016] Furthermore, the acid binding agent used in step (2) is one or more of triethylamine, N,N-diisopropylamine, and tetramethylethylenediamine.

[0017] Furthermore, in the step (2), the molar ratio of 4-bromo-3-methoxybenzonitrile (II), catalyst, ligand and acid-binding agent is 1:0.001-0.01:0.01-0.1:1-3; the preferred molar ratio is 1:0.005:0.05:2.0.

[0018] Furthermore, in step (2), the volume ratio of hydrogen to carbon monoxide is 1:1-10; preferably the volume ratio is 1:1-5; the pressure of the reduction carbonylation reaction is 0.2-3 MPa, preferably 0.5-0.7 MPa; the temperature of the reduction carbonylation reaction is 60-120°C, preferably 100-110°C.

[0019] Furthermore, the 4-cyano-2-methoxybenzaldehyde (III) obtained in step (2) can be purified by pulping with an organic solvent; the organic solvent used for pulping is petroleum ether or ethyl acetate or a mixture of the two. DETAILED DESCRIPTION

[0020] In order to make the objectives, technical solutions and advantages of the present application clearer, the implementation methods of the present application will be further described in detail below. Example 1

[0021] Step 1. Synthesis of 4-bromo-3-methoxybenzonitrile (II) 150 g (0.652 mol) of 4-bromo-3-methoxybenzamide (I), 600 ml of toluene and 232.7 g (1.956 mol) of thionyl chloride were placed in a reaction device, heated to 100°C for reaction for 5 h, and the reaction was complete when detected by HPLC. The temperature was then lowered to 40°C; toluene and excess thionyl chloride were recovered at 40-70°C and reduced pressure of -0.08-0.1 MPa, 300 ml of petroleum ether was added for slurrying for 2 h, and then filtered. The filter cake was washed with petroleum ether and dried at 50°C to obtain 131 g of 4-bromo-3-methoxybenzonitrile (II) with a yield of 94.8% and a purity of 99.6%.

[0022] Step 2: Synthesis of 4-cyano-2-methoxybenzaldehyde (III) Place 120 g (0.566 mol) of 4-bromo-3-methoxybenzonitrile (II), 3.178 g (4.527 mmol) of bis(triphenylphosphine)palladium dichloride, 11.67 g (28.296 mmol) of 1,3-bis(diphenylphosphine)propane, 114.5 g (1.132 mol) of triethylamine, and 1000 ml of toluene into an autoclave. Replace the air in the autoclave with nitrogen three times while the autoclave is sealed. Then, introduce carbon monoxide into the autoclave until the pressure in the autoclave is 0.5 MPa. Continue to introduce hydrogen until the pressure in the autoclave is 0.6 MPa. Raise the temperature to 100°C, maintain the pressure for 18 hours, and complete the reaction after HPLC detection. Cool down to 20-30°C, filter, and reduce the pressure of the filtrate by -0.08~ at a temperature of 40-70°C. -0.1MPa concentration, slurrying with 300ml petroleum ether for 2h, suction filtration, washing with petroleum ether, and drying at 50℃ to obtain 84.2g of 4-cyano-2-methoxybenzaldehyde (III) with a yield of 92.3% and a purity of 99.5%.

[0023] 1H-NMR (300 MHz, DMSO-d6): δ=3.98 (s, 3H), 7.53 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H), 10.37 (s, 1H). Example 2

[0024] Step 1. Synthesis of 4-bromo-3-methoxybenzonitrile (II) 150 g (0.652 mol) of 4-bromo-3-methoxybenzamide (I) and 600 ml of xylene were placed in a reaction device. The temperature in the reaction device was controlled at 25°C and 233 g (0.978 mol) of Burgess reagent was added in portions. The reaction was kept at 25°C for 5 hours. The reaction was complete after HPLC detection. The reaction was washed once with 150 ml of saturated brine. The xylene was recovered at a temperature of 50 to 80°C under reduced pressure of -0.08 to -0.1 MPa. 300 ml of petroleum ether was added for slurrying for 1 hour. The filter cake was washed with petroleum ether and dried at 50°C to obtain 127.2 g of 4-bromo-3-methoxybenzonitrile (II) with a yield of 92% and a purity of 99.3%.

[0025] Step 2: Synthesis of 4-cyano-2-methoxybenzaldehyde (III) Place 120 g (0.566 mol) of 4-bromo-3-methoxybenzonitrile (II), 1 g (5.659 mmol) of palladium dichloride, 11.14 g (28.296 mmol) of 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl, 219.4 g (1.697 mol) of N,N-diisopropylamine, and 1000 ml of xylene in an autoclave. Replace the air in the autoclave with nitrogen three times while the autoclave is sealed. Then, introduce carbon monoxide into the autoclave until the pressure in the autoclave is 1 MPa. Continue to introduce hydrogen until the pressure in the autoclave is 1.2 MPa. Raise the temperature to 90°C, maintain the pressure for 18 h, cool to 20-30°C, filter, and reduce the pressure of the filtrate by -0.08~ at a temperature of 50-80°C. -0.1MPa concentration, slurrying with 300ml petroleum ether for 2h, suction filtration, washing with petroleum ether, and drying at 50℃ to obtain 83g of 4-cyano-2-methoxybenzaldehyde (III) with a yield of 91% and a purity of 99.3%. Example 3

[0026] Step 1. Synthesis of 4-bromo-3-methoxybenzonitrile (II) 100 g (0.435 mol) of 4-bromo-3-methoxybenzamide (I) and 600 ml of trichlorophosphine were placed in the reaction device, heated to 90°C for reaction for 8 h, and the reaction was complete when detected by HPLC. The temperature was lowered to 40°C, and the excess trichlorophosphine was recovered under reduced pressure of -0.08 to -0.1 MPa within the temperature range of 40 to 80°C. Attention was paid to the protection of equipment and personnel. 200 ml of ethyl acetate was added for beating for 2 h, filtered, and the filter cake was washed with ethyl acetate and dried at 50°C to obtain 83 g of 4-bromo-3-methoxybenzonitrile (II) with a yield of 90% and a purity of 98.5%.

[0027] Phosphine oxychloride is both a solvent and a dehydrating agent, serving two purposes at once. After the reaction is completed, the recovery step is reduced.

[0028] Step 2: Synthesis of 4-cyano-2-methoxybenzaldehyde (III) Place 100 g (0.472 mol) of 4-bromo-3-methoxybenzonitrile (II), 1.725 g (2.360 mmol) of DPPF palladium dichloride, 8.519 g (47.159 mmol) of di-tert-butylphosphine chloride, 54.8 g (0.472 mol) of tetramethylethylenediamine, and 800 ml of chlorobenzene in an autoclave. Replace the air in the autoclave with nitrogen three times while the autoclave is sealed. Then, introduce carbon monoxide into the autoclave until the pressure in the autoclave is 0.1 MPa. Continue to introduce hydrogen until the pressure in the autoclave is 0.2 MPa. Raise the temperature to 120°C and maintain the pressure for 20 hours. HPLC detects that the reaction is complete. Cool down to 20-30°C, filter, and decompress the filtrate at 50-80°C under reduced pressure of -0.08~ -0.1MPa concentration, slurrying with 300ml petroleum ether for 2h, suction filtration, washing with petroleum ether, and drying at 50℃ to obtain 69.17g of 4-cyano-2-methoxybenzaldehyde (III) with a yield of 91% and a purity of 98.9%. Example 4

[0029] Step 1. Synthesis of 4-bromo-3-methoxybenzonitrile (II) 200g (0.87mol) 4-bromo-3-methoxybenzamide (Ⅰ), 400ml NN-dimethylformamide and 220g (1.056mol) of phosphorus pentachloride were placed in the reaction device, heated to 50℃ for reaction for 3h, and the reaction was complete when detected by HPLC. The temperature was lowered to 0~10℃, 1400ml of purified water was added dropwise, and the mixture was stirred at room temperature for 1h. The mixture was filtered and washed with 50ml of saturated sodium bicarbonate solution, and dried at 50℃ to obtain 169.8g of 4-bromo-3-methoxybenzonitrile (Ⅱ), with a yield of 92% and a purity of 98.4%. Purified water was added dropwise to quench the remaining phosphorus pentachloride.

[0030] Step 2: Synthesis of 4-cyano-2-methoxybenzaldehyde (III) Place 100 g (0.472 mol) of 4-bromo-3-methoxybenzonitrile (II), 1.07 g (4.724 mmol) of palladium acetate, 8.454 g (23.579 mmol) of n-butyldi(1-adamantyl)phosphine, 95.44 g (0.943 mol) of triethylamine, and 800 ml of NN-dimethylformamide into an autoclave. Replace the air in the autoclave with nitrogen three times while the autoclave is sealed. Then, introduce carbon monoxide into the autoclave until the pressure in the autoclave is 1.2 MPa. Continue to introduce hydrogen until the pressure in the autoclave is 1.5 MPa. Raise the temperature to 70°C and maintain the pressure for 18 hours. HPLC detects that the reaction is complete. Cool down to 20-30°C, filter, and decompress the filtrate at 40-80°C under reduced pressure of -0.08~ -0.1MPa concentration, slurrying with 300ml petroleum ether for 2h, suction filtration, washing with petroleum ether, and drying at 50℃ to obtain 70.69g of 4-cyano-2-methoxybenzaldehyde (III) with a yield of 93% and a purity of 99.1%. Example 5

[0031] Step 1. Synthesis of 4-bromo-3-methoxybenzonitrile (II) 100 g (0.435 mol) of 4-bromo-3-methoxybenzamide (Ⅰ), 400 ml of chlorobenzene and 133 g (1.305 mol) of triethylamine were placed in a reaction device, and 164.43 g (0.783 mol) of trifluoroacetic anhydride was slowly added. The mixture was kept at 25°C for 3 h. The reaction was complete as detected by HPLC. The mixture was washed with 200 ml of saturated brine and 200 ml of purified water in sequence, concentrated under reduced pressure of -0.08 to -0.1 MPa, added with 200 ml of petroleum ether, stirred for 1 h, filtered, washed with 20 ml of petroleum ether, and dried at 50°C to obtain 84.9 g of 4-bromo-3-methoxybenzonitrile (Ⅱ) with a yield of 92% and a purity of 98.7%.

[0032] Step 2: Synthesis of 4-cyano-2-methoxybenzaldehyde (III) Place 100 g (0.472 mol) of 4-bromo-3-methoxybenzonitrile (II), 0.995 g (2.264 mmol) of triphenylphosphine palladium dichloride, 7.725 g (22.64 mmol) of tert-butyl dicyclohexylphosphine tetrafluoroborate, 219.4 g (1.697 mol) of N,N-diisopropylamine, and 800 ml of N,N-dimethylformamide into an autoclave. Replace the air in the autoclave with nitrogen three times while the autoclave is sealed. Then, introduce carbon monoxide into the autoclave until the pressure in the autoclave is 2.0 MPa. Continue to introduce hydrogen until the pressure in the autoclave is 2.2 MPa. Raise the temperature to 60°C and maintain the pressure for 24 hours. HPLC detects that the reaction is complete. Cool down to 20-30°C, filter, and reduce the pressure of the filtrate by -0.08~ at a temperature of 40-60°C. -0.1MPa concentration, slurrying with 300ml petroleum ether for 2h, suction filtration, washing with petroleum ether, and drying to obtain 63.1g of 4-cyano-2-methoxybenzaldehyde (III) with a yield of 83% and a purity of 98.4%. Example 6

[0033] Step 2: Synthesis of 4-cyano-2-methoxybenzaldehyde (III) 100 g (0.472 mol) of 4-bromo-3-methoxybenzonitrile (II), 0.167 g (0.944 mmol) of palladium dichloride, 2.73 g (4.72 mmol) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 95.44 g (0.943 mol) of triethylamine, and 800 ml of n-butanol were placed in an autoclave. The air in the autoclave was replaced with nitrogen three times while the autoclave was sealed. Carbon monoxide was then introduced into the autoclave until the pressure in the autoclave reached 2.5 MPa. Hydrogen was then introduced until the pressure in the autoclave reached 3 MPa. The temperature was raised to 120°C, and the pressure was maintained for 24 h. The reaction was complete when detected by HPLC. The temperature was lowered, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The mixture was then slurried with 300 ml of petroleum ether for 2 h, filtered, and the filter cake was washed with petroleum ether and dried to obtain 63.1 g of 4-cyano-2-methoxybenzaldehyde (III) with a yield of 83% and a purity of 98.4%. Example 7

[0034] Step 2: Synthesis of 4-cyano-2-methoxybenzaldehyde (III) Place 100 g (0.472 mol) of 4-bromo-3-methoxybenzonitrile (II), 0.835 g (4.72 mmol) of palladium dichloride, 22.5 g (47.2 mmol) of 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 95.44 g (0.943 mol) of triethylamine, and 1000 ml of N-methylpyrrolidone into an autoclave. Replace the air in the autoclave with nitrogen three times while the autoclave is sealed. Then, introduce carbon monoxide into the autoclave until the pressure in the autoclave is 0.5 MPa. Continue to introduce hydrogen until the pressure in the autoclave is 0.6 MPa. Raise the temperature to 80°C and maintain the pressure for 18 hours. HPLC detects that the reaction is complete. Cool down to 20-30°C, filter, and decompress the filtrate at 40-90°C under reduced pressure of -0.08~ -0.1MPa concentration, slurrying with 300ml petroleum ether for 2h, suction filtration, washing with petroleum ether, and drying at 50℃ to obtain 69.6g of 4-cyano-2-methoxybenzaldehyde (III) with a yield of 91.6% and a purity of 99.1%. Example 8

[0035] Step 2: Synthesis of 4-cyano-2-methoxybenzaldehyde (III) Place 100 g (0.472 mol) of 4-bromo-3-methoxybenzonitrile (II), 0.835 g (4.72 mmol) of palladium dichloride, 5.48 g (18.89 mmol) of tri-tert-butylphosphine tetrafluoroborate, 219.4 g (1.697 mol) of N,N-diisopropylamine, and 1000 ml of toluene in an autoclave. Replace the air in the autoclave with nitrogen three times while the autoclave is sealed. Then, introduce carbon monoxide into the autoclave until the pressure in the autoclave is 0.8 MPa. Continue to introduce hydrogen until the pressure in the autoclave is 1 MPa. Raise the temperature to 90°C and maintain the pressure for 18 hours. HPLC detects that the reaction is complete. Cool down to 20-30°C, filter, and decompress the filtrate at 40-70°C under reduced pressure of -0.08~ -0.1MPa concentration, slurrying with 300ml petroleum ether for 2h, suction filtration, washing with petroleum ether, and drying to obtain 68.4g of 4-cyano-2-methoxybenzaldehyde (III) with a yield of 90% and a purity of 99.1%. Example 9

[0036] Step 2: Synthesis of 4-cyano-2-methoxybenzaldehyde (III) Place 100 g (0.472 mol) of 4-bromo-3-methoxybenzonitrile (II), 0.835 g (4.72 mmol) of palladium dichloride, 5.75 g (18.89 mmol) of tri(2-methylphenyl)phosphine, 219.4 g (1.697 mol) of N,N-diisopropylamine, and 1000 ml of toluene in an autoclave. Replace the air in the autoclave with nitrogen three times while the autoclave is sealed. Then, introduce carbon monoxide into the autoclave until the pressure in the autoclave is 0.8 MPa. Continue to introduce hydrogen until the pressure in the autoclave is 1 MPa. Raise the temperature to 90°C and maintain the pressure for 18 hours. HPLC detects that the reaction is complete. Cool down to 20-30°C, filter, and decompress the filtrate at 40-70°C under reduced pressure of -0.08~ The mixture was concentrated at -0.1 MPa, slurried with 300 ml of petroleum ether for 2 h, filtered, washed with petroleum ether, and dried at 50 °C to obtain 68.1 g of 4-cyano-2-methoxybenzaldehyde (III) with a yield of 89.6% and a purity of 98.2%. Example 10

[0037] Step 2: Synthesis of 4-cyano-2-methoxybenzaldehyde (III) Place 120 g (0.566 mol) of 4-bromo-3-methoxybenzonitrile (II), 3.178 g (4.527 mmol) of bis(triphenylphosphine)palladium dichloride, 11.67 g (28.296 mmol) of 1,3-bis(diphenylphosphine)propane, 114.5 g (1.132 mol) of triethylamine, and 1000 ml of toluene into the autoclave, seal the autoclave, replace with nitrogen three times, pressurize to 0.6 MPa with carbon monoxide, heat to 100°C, and react under pressure for 10 hours. After HPLC detection of the complete reaction of the raw materials, add hydrogen to 0.8 MPa, and react under hydrogen pressure for 6 hours. After HPLC detection of the complete reaction, cool to 20-30°C, filter, and reduce the pressure of the filtrate to -0.08~ at a temperature of 40-70°C. The mixture was concentrated at -0.1 MPa, slurried with 300 ml of petroleum ether for 2 h, filtered, washed with petroleum ether, and dried at 50 °C to obtain 83.1 g of 4-cyano-2-methoxybenzaldehyde (III) with a yield of 91.1% and a purity of 99.1%. Embodiment 11

[0038] Step 2: Synthesis of 4-cyano-2-methoxybenzaldehyde (III) Place 120 g (0.566 mol) of 4-bromo-3-methoxybenzonitrile (II), 3.178 g (4.527 mmol) of bis(triphenyl)palladium dichloride, 11.67 g (28.296 mmol) of 1,3-bis(diphenylphosphino)propane, 114.5 g (1.132 mol) of triethylamine, and 1000 ml of toluene into the autoclave, seal the autoclave, replace with nitrogen three times, pressurize with carbon monoxide to 0.6 MPa, heat to 100°C, and react under pressure for 10 hours. After HPLC detection of the complete reaction of the raw materials, cool to 20-30°C, replace with hydrogen to 0.3 MPa, heat to 100°C, and react under hydrogen pressure for 8 hours. After HPLC detection of the complete reaction, cool to 20-30°C, filter, and reduce the pressure of the filtrate to -0.08~ at a temperature of 40-70°C. -0.1MPa concentration, slurrying with 300ml petroleum ether for 2h, suction filtration, washing with petroleum ether, and drying at 50℃ to obtain 83.6g of 4-cyano-2-methoxybenzaldehyde (III) with a yield of 91.6% and a purity of 99.0%.

[0039] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present application and are not intended to limit it. Although the present application has been described in detail with reference to the preferred embodiments, a person of ordinary skill in the art should understand that the technical solution of the present application can be modified or replaced by equivalents without departing from the purpose and scope of the technical solution of the present application, which should be included in the scope of the claims of the present application.

Claims

1. A method for preparing a key intermediate of finerenone, characterized in that: The preparation steps are as follows: (1) 4-bromo-3-methoxybenzamide (I) undergoes a dehydration reaction to obtain 4-bromo-3-methoxybenzonitrile (II); (2) 4-bromo-3-methoxybenzonitrile (II) undergoes a reduction carbonylation reaction to obtain 4-cyano-2-methoxybenzaldehyde (III), a key intermediate of finerenone; 2. The method for preparing a key intermediate of finerenone according to claim 1, characterized in that: The preparation steps are as follows: (1) 4-bromo-3-methoxybenzamide (I) undergoes a dehydration reaction with a dehydrating agent in a solvent to obtain 4-bromo-3-methoxybenzonitrile (II); (2) 4-bromo-3-methoxybenzonitrile (II) undergoes a reduction carbonylation reaction with hydrogen and carbon monoxide in a solvent in the presence of a catalyst, a ligand and an acid-binding agent to obtain 4-cyano-2-methoxybenzaldehyde (III), a key intermediate of finerenone.

3. The method for preparing a key intermediate of finerenone according to claim 2, characterized in that: The dehydration reagent in step (1) is one or more of thionyl chloride, phosphine oxychloride, phosphorus pentachloride, Burgess reagent (methyl N-(triethylammoniumsulfonyl)carbamate), and trifluoroacetic anhydride.

4. The method for preparing a key intermediate of finerenone according to claim 2, characterized in that: The catalyst in step (2) is a catalyst containing heavy metal palladium.

5. The method for preparing a key intermediate of finerenone according to claim 4, characterized in that: The catalyst is one or more of triphenylphosphine palladium dichloride, bis(triphenylphosphine)palladium dichloride, DPPF palladium dichloride, palladium dichloride and palladium acetate.

6. The method for preparing a key intermediate of finerenone according to claim 2, characterized in that: The ligand in step (2) is a phosphine ligand.

7. The method for preparing a key intermediate of finerenone according to claim 6, characterized in that: The ligand is one or more of 1,3-bis(diphenylphosphino)propane, di-tert-butylphosphine chloride, n-butyldi(1-adamantyl)phosphine, 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)-biphenyl, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl, tert-butyldicyclohexylphosphine tetrafluoroborate, tri-tert-butylphosphine tetrafluoroborate, and tri(2-tolyl)phosphine.

8. The method for preparing a key intermediate of finerenone according to claim 2, characterized in that: The acid binding agent used in step (2) is one or more of triethylamine, N,N-diisopropylamine, and tetramethylethylenediamine.

9. The method for preparing a key intermediate of finerenone according to claim 2, characterized in that: The solvent used in step (1) is one or more of toluene, xylene, chlorobenzene, N,N-dimethylformamide, N-methylpyrrolidone, and n-butanol; the solvent used in step (2) is one or more of toluene, xylene, chlorobenzene, N,N-dimethylformamide, N-methylpyrrolidone, and n-butanol; the solvents used in step (1) and step (2) are the same or different.

10. The method for preparing a key intermediate of finerenone according to claim 2, characterized in that: In the step (1), the molar ratio of 4-bromo-3-methoxybenzamide (I) to the dehydrating agent is 1:1.0-6.0; in the step (2), the molar ratio of 4-bromo-3-methoxybenzonitrile (II), the catalyst, the ligand, and the acid binding agent is 1:0.001-0.01:0.01-0.1:1-3; and the volume ratio of hydrogen to carbon monoxide is 1:1-10.

Images