Finerenone intermediate, preparation method therefor and preparation method for finerenone

Abstract

The present application belongs to the technical field of drug synthesis, and particularly relates to a finerenone intermediate compound IV or compound V, a preparation method therefor and a preparation method for finerenone.

Description

Finerenone intermediate, preparation method thereof and preparation method of finerenone Technical Field

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

[0002] Finerenone, chemical name: (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, is a non-steroidal antagonist of mineralocorticoid receptors developed by Bayer. Finerenone is the first new mineralocorticoid receptor antagonist approved for the treatment of diabetes-related chronic kidney disease. This product was approved in China at the end of June 2022. Since 2021, finerenone has been approved for marketing in the United States, the European Union and other countries and regions. It was approved in China only 4 months after the EU approval, which is basically synchronized with the world, and can better meet the urgent clinical needs of my country for new drugs for the treatment of diabetes-related chronic kidney disease. Its structural formula is:

[0003]

[0004] Currently, there are multiple literature reports on the preparation methods of finerenone.

[0005] CN106795155 discloses the separation of isomers of a finerenone racemate using chiral HPLC. Although the finerenone prepared by this method has high optical purity, the total yield is only 34.3%, which is relatively low. Furthermore, the chiral separation is performed using expensive SMB (Chrialpak AS-V, 20-micron chromatographic column) equipment, which is expensive to purchase under GMP conditions. Currently, the industrialized price of this equipment ranges from several million to tens of millions of yuan. Furthermore, the separation uses expensive chromatographic-grade solvents, resulting in high costs. Furthermore, this separation method is complex to operate, making it unsuitable for industrial production.

[0006] CN114698375 and CN114667284 respectively report processes for splitting different intermediates, first obtaining a chiral intermediate and then continuing the reaction to prepare the finerenone product. However, the ee value of the diastereomers of the intermediates obtained after splitting is 65%-84%, and the isomers need to be further purified. The route is relatively cumbersome and costly.

[0007] CN115340539 also discloses a method for preparing finerenone, and the reaction steps are as follows:

[0008]

[0009] The main problems in the route of the present invention are: (1) the benzyl group is difficult to be removed by hydrogenation during the removal of the benzyl group, and the amount of palladium carbon used is large (the weight ratio of 10% palladium carbon to 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-ethoxy-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid 2-benzyl ester is 0.1:1), resulting in high reaction costs; (2) in actual repeated use of this scheme, a large amount of over-reduction impurities - dihydropyridine ring impurities - are generated during the hydrogenation reduction process, accounting for more than 15%, and the actual yield is less than 80%. This impurity is difficult to remove and affects the quality of the finished product. (3) The efficiency of tartaric acid in the resolution of this intermediate is low. After repeated verification, the ee value of the first resolution is only 75% to 85%, and multiple purifications are required to achieve an ee value of more than 99%, which seriously affects the yield and production efficiency. Summary of the Invention

[0010] In view of the deficiencies in the prior art, the present invention aims to provide a finerenone intermediate compound V, a preparation method thereof, and a preparation method of finerenone.

[0011] Finerenone intermediate compound V has the following structural formula:

[0012]

[0013] The preparation method of finerenone intermediate compound V comprises the following steps:

[0014] ,

[0015] 4-Cyano-2-methoxybenzaldehyde (raw material 2) and p-nitrobenzyl acetoacetate (raw material 1) were added to dichloromethane, followed by the addition of piperidine and glacial acetic acid. The mixture was heated and refluxed to separate the water. After the reaction was completed, the temperature was lowered, and the separated liquid was washed with purified water. The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness to obtain a yellow solid residue (Compound VI). 2-Butanol was added to the residue, followed by the addition of 4-amino-5-methyl-2-hydroxypyridine (raw material 3). The mixture was heated to reflux to react. After the reaction was completed, the temperature was lowered, the mixture was stirred for crystallization, and the filter cake was washed with isopropanol and dried with air to obtain Compound V.

[0016] In addition, the present invention protects a method for preparing finerenone via compound V, which is mainly achieved through two routes:

[0017] Route 1 is as follows:

[0018]

[0019] (1) Add compound V and triethyl orthoacetate to N-methylpyrrolidone, then add concentrated sulfuric acid dropwise. Turn on the heat, raise the temperature to react, cool down, add purified water dropwise, stir after the addition is complete, and then add purified water dropwise again. Cool down and stir, then continue to cool down and stir. Filter and air dry to obtain compound IV.

[0020] (2) Compound IV is added to an organic solvent, followed by addition of L-di-p-methylbenzoyltartaric acid, the temperature is raised, the mixture is reacted, the temperature is lowered, the mixture is kept warm and stirred, the mixture is filtered, the filter cake is washed with ethyl acetate, and the mixture is dried to obtain compound IIIa;

[0021] (3) Preparation of finerenone

[0022] Add dichloromethane to compound IIIa, adjust the base with 3% sodium bicarbonate aqueous solution, extract, separate and distill, add tetrahydrofuran to the distillation residue, add 5% palladium on carbon, hydrogenate and filter to obtain a tetrahydrofuran solution of compound II, continue to add N-dimethylaminopyridine and N,N'-carbonyldiimidazole, react, then add ammonia water to react, crystallize, filter, recrystallize from anhydrous ethanol, filter and dry to obtain finerenone;

[0023] The molar ratio of compound IV to L-di-p-methylbenzoyltartaric acid in step (2) is 1:0.5-1.3;

[0024] The organic solvent in step (2) is one or more of ethyl acetate, methanol, ethanol, isopropanol, and dichloromethane;

[0025] The weight ratio of palladium carbon to S-configuration compound IV in step (3) is 0.2% to 2.5%:1

[0026] Route 2 is as follows:

[0027] ,

[0028] (1) Compound V is split into compound IVa

[0029] Compound V is added to an organic solvent, L-di-p-methylbenzoyltartaric acid is added to the organic solution, the temperature is raised, the reaction is carried out, the temperature is lowered, the mixture is kept warm and stirred, and the mixture is filtered. The filter cake is washed with ethyl acetate and dried to obtain the resolved salt compound IVa;

[0030] (2) Preparation of finerenone

[0031] Add dichloromethane to IVa, adjust the base with 3% sodium bicarbonate aqueous solution, extract, separate, and concentrate to obtain a residue. Add N-methylpyrrolidone, triethyl orthoacetate, and concentrated sulfuric acid to the residue to react to obtain S-configuration compound IV. Then add tetrahydrofuran and 5% palladium on carbon, hydrogenate, and filter to obtain a tetrahydrofuran solution of compound II. Continue to add N-dimethylaminopyridine and N,N'-carbonyldiimidazole, react, then add ammonia water to react, crystallize, filter, recrystallize from anhydrous ethanol, and filter and dry to obtain phenerenone.

[0032] The molar ratio of compound V described in step (1) to L-di-p-methylbenzoyltartaric acid is 1:0.5-1.3;

[0033] The organic solvent in step (1) is one or more of ethyl acetate, methanol, ethanol, isopropanol, and dichloromethane;

[0034] The weight ratio of palladium carbon to S-configuration compound IV in step (2) is 0.2%~2.5%:1. Beneficial effects of the present invention:

[0035] (1) We creatively invented a key intermediate of finerenone (Compound V). During the course of multiple experiments and explorations, we found that Compound V is an advantageous intermediate with stable and controllable quality, which is more conducive to controlling the quality and cost of finerenone. By adding a nitro substituent, Compound V increases the molecular polarity, making it easier for the product to form a cocrystal with L-di-p-methylbenzoyltartaric acid, which is more conducive to separation. The ee value of the intermediate after separation can reach more than 99%, and the separation yield calculated based on the racemic form reaches 45%. The obtained intermediate has high purity and can be directly used in the next reaction. However, the study found that when the benzene ring is chlorinated, the molecular polarity does not change much, and the cocrystal formed with L-di-p-methylbenzoyltartaric acid has better solubility, resulting in poor intermediate separation effect, with an ee value of only 80% to 85%.

[0036] (2) Route 2 of the present invention has an earlier splitting step, and then reacts with triethyl orthoacetate after splitting, which has good atom economy.

[0037] (3) The present invention adopts a one-pot reaction to directly obtain the target product in the preparation of the finerenone finished product, which reduces the post-processing purification and the generation of three wastes, simplifies the reaction operation, is more conducive to scale-up production, and reduces production costs.

[0038] (4) The present invention creatively discovered that the hydrogenation reaction of S-configuration compound IV can make the entire molecular structure electron-deficient through the strong electron-withdrawing property of the nitro group, thereby fundamentally solving the problem of excessive reduction of the dihydropyridine ring in the product under hydrogenation conditions. At the same time, the amount of 5% palladium carbon catalyst used is 0.2% to 2.5% of the amount of S-configuration compound IV, thereby improving product quality and significantly reducing production costs.

[0039] (5) The preparation method of phenaretin of the present application can obtain phenaretin with a purity of 99.9% and an ee value of 99.9%. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 is the 1H-NMR spectrum of compound V

[0041] Figure 2 is the MS spectrum of compound V DETAILED DESCRIPTION

[0042] The present application will be further described below in conjunction with the accompanying drawings and specific implementation methods so that those skilled in the art can better understand the present application, but the present invention is not limited thereto. Example 1: Preparation of Compound V

[0043]

[0044] To a reaction flask, add 400 ml of dichloromethane, followed by 4-cyano-2-methoxybenzaldehyde (40 g, 248 mmol) and p-nitrobenzyl acetoacetate (70.6 g, 296 mmol). Then, add piperidine (2.0 g) and glacial acetic acid (1.4 g). Heat and reflux for 6 hours. After completion, cool the reaction, wash twice with 100 ml of purified water, dry over anhydrous sodium sulfate, and filter. The filtrate is concentrated to yield a yellow solid. Then, add 600 ml of 2-butanol and 4-amino-5-methyl-2-hydroxypyridine (27.8 g, 224 mmol). Heat to reflux for 20 hours, cool to 0°C, stir to crystallize for 2 hours, filter, wash with 20 ml of isopropanol, and air-dry at 50°C to obtain 90.4 g of Compound V with a purity of 98.5% and a yield of 83.0% (based on 4-amino-5-methyl-2-hydroxypyridine).

[0045] 1H-NMR (400MHz, DMSO-d6) δ=2.034 (s, 3H), δ=2.365 (s, 3H), δ=3.673 (s, 3H), δ=5.136 (s, 2H), δ=5.266 (s, 1H), δ=6.956 (s, 1H), δ=7.186-7.231 (m, 2H), δ=7.308 (s, 1H), δ=7.401 (s, 1H), δ=7.423 (s, 1H), δ=8.172 (s, 1H), δ=8.194 (s, 2H), δ=10.780 (s, 1H).

[0046] MS (ESI): m / z=487.2[M+H] + . Example 2:

[0047] Route 1: Preparation of finerenone

[0048]

[0049] To the reaction flask, add 68 ml of N-methylpyrrolidone, followed by Compound V (45 g, 92 mmol) and triethyl orthoacetate (45.0 g, 277 mmol), followed by the dropwise addition of 2.7 g of concentrated sulfuric acid. Heat to 115°C for 2 h, then cool to 50°C and dropwise add 68 ml of purified water. After the addition is complete, stir for 0.5 h, followed by another 68 ml of purified water. Cool to 0°C and stir for 1 h to allow crystallization. Filter, and dry the filter cake at 50°C with air to yield 43.2 g of Compound IV, a 90.8% yield and 98.8% purity.

[0050] 1 H-NMR (400MHz, DMSO-d6) δ=1.162-1.197 (t, 3H), δ=1.602 (s, 3H), δ=2.151 (s, 3H), δ=3.640 (s, 3H), δ=4.095-4.183 (m, 2H), δ=5.132 (s, 2H), δ=5. 525 (s, 1H), δ = 5.992 (s, 1H), δ = 6.972 (s, 1H), δ = 7.086-7.108 (dd, 1H), δ =7.263 (s, 1H), δ = 7.291-7.320 (m, 3H), δ = 8.154 (s, 1H), δ = 8.175 (s, 1H).

[0051] MS (ESI): m / z=515.2[M+H] + .

[0052]

[0053] 800 ml of ethyl acetate was added to the reaction flask, followed by compound IV (40 g, 78 mmol) and L-di-p-methylbenzoyltartaric acid (15 g, 39 mmol). The mixture was heated to 70 °C and stirred for 1 h. The mixture was cooled to 30 °C and stirred for 2 h. The mixture was filtered and the filter cake was washed with 40 ml of ethyl acetate and dried at 50 °C to obtain 32.7 g of compound IIIa with a resolution yield of 46.7% and an ee value of 99.9%.

[0054] 1H-NMR (400MHz, DMSO-d6) δ=1.162-1.197 (t, 3H), δ=1.602 (s, 3H), δ=2.151 (s, 3H), δ=2.409 (s, 6H), δ =3.640 (s, 3H), δ = 4.095-4.183 (m, 2H), δ = 5.132 (s, 2H), δ = 5.525 (s, 1H), δ = 5.829 (s, 2H), δ = 5.992 (s, 1 H), δ=6.972 (s, 1H), δ=7.086-7.108 (dd, 1H), δ=7.263 (s, 1H), δ=7.291-7.320 (m, 3H), δ=7.396 (s, 2H) , δ=7.417 (s, 2H), δ=7.895 (s, 2H), δ=7.915 (s, 2H), δ=8.154 (s, 1H), δ=8.175 (s, 1H), δ=13.885 (s, 2H).

[0055]

[0056] Add 250 ml of dichloromethane to the reaction flask, followed by compound IIIa (25 g, 27.7 mmol). Adjust the pH to 7-8 with 3% sodium carbonate solution. Once the solution is clear, separate the organic layer, wash with 100 ml of purified water, dry over anhydrous sodium sulfate, and concentrate to obtain a residue. Add 150 ml of tetrahydrofuran and stir to dissolve the residue, followed by 0.36 g of 5% palladium on carbon. After three hydrogen substitutions, stir at 10°C for 1 h, filter, and then add 4-dimethylaminopyridine (0.32 g, 2.6 mmol). Add N,N'-carbonyldiimidazole (6.0 g, 37 mmol) with stirring, and stir at room temperature for 3 h. Then, 30 ml of ammonia water was slowly added, and the mixture was stirred at 50 ° C for 8 h. After the reaction was completed, the temperature was lowered to 20 ° C, 150 ml of purified water was added dropwise, and then the temperature was slowly lowered to 0 ° C, stirred and crystallized for 1 h, filtered, and the filter cake was added to 150 ml of anhydrous ethanol, heated to 75 ° C and stirred for 1 h, then slowly cooled to 20 ° C, stirred and crystallized for 1 h, filtered, and the filter cake was dried to obtain 9.7 g of finerenone finished product with a yield of 92.4%, a purity of 99.9%, and an ee value of 99.9%.

[0057] 1 H-NMR (400MHz, DMSO-d6): δ=1.032-1.067 (t, 3H), δ=2.122 (s, 3H), δ=2.188 (s, 3H), δ=3.825 (s, 3H), δ=3.958-4.035 (m, 2H), δ=,6.6 61-6.749 (d, 2H), δ = 2.122 (s, 3H), δ = 7.142-7.161 (d, 1H), δ = 7.2, 1-7.290 (d, 1H), δ = 7.371 (s, 1H), δ = 7.554 (s, 1H), δ = 7.685 (s, 1H).

[0058] MS (ESI): m / z=379.1[M+H] + . Example 3:

[0059] Route 2: Preparation of finerenone

[0060]

[0061] 800 ml of dichloromethane was added to the reaction flask, followed by compound V (40 g, 82 mmol) and L-di-p-methylbenzoyltartaric acid (41.3 g, 107 mmol). The mixture was heated to 35 °C and stirred for 1 h. The mixture was cooled to 20 °C and stirred for 2 h. The mixture was filtered and the filter cake was washed with 40 ml of ethyl acetate and dried at 50 °C to obtain 31.5 g of compound IVa with a resolution yield of 43.9% and an ee value of 99.9%.

[0062]

[0063] Add 250 ml of dichloromethane to the reaction flask, followed by compound IVa (30 g, 34 mmol). Adjust the pH to 7-8 with 3% sodium carbonate solution. Once the solution is clear, separate the organic layer, wash with 100 ml of purified water, dry over anhydrous sodium sulfate, and concentrate to obtain a residue. Add 75 ml of N-methylpyrrolidone to the residue, followed by triethyl orthoacetate (16.5 g, 102 mmol), and then dropwise add 1 g of concentrated sulfuric acid. Heat to 115°C for 2 h, then cool to 50°C. Add 25 ml of purified water dropwise, stir for 0.5 h, and then add another 75 ml of purified water dropwise. Continue cooling to 0°C and stir for 1 h to allow crystallization. Filter, and dry the filter cake at 50°C with air to obtain 15.8 g of compound IV with S configuration, in an 89.3% yield and 98.8% purity.

[0064] 1H-NMR (400MHz, DMSO-d6) δ=1.162-1.197 (t, 3H), δ=1.602 (s, 3H), δ=2.151 (s, 3H), δ=3.640 (s, 3H), δ=4.095-4.183 (m, 2H), δ=5.132 (s, 2H), δ=5. 525 (s, 1H), δ = 5.992 (s, 1H), δ = 6.972 (s, 1H), δ = 7.086-7.108 (dd, 1H), δ =7.263 (s, 1H), δ = 7.291-7.320 (m, 3H), δ = 8.154 (s, 1H), δ = 8.175 (s, 1H).

[0065] MS (ESI): m / z=515.2[M+H] + .

[0066]

[0067] To a reaction flask, add 150 ml of tetrahydrofuran, then add the S-configuration compound (15 g, 29.1 mmol) and stir to dissolve. Then, add 30 mg of 5% palladium on carbon. After three hydrogen substitutions, stir at 10°C for 1 hour, filter, and then add 4-dimethylaminopyridine (0.32 g, 2.6 mmol). Add N,N'-carbonyldiimidazole (6 g, 37.0 mmol) with stirring, and stir at room temperature for 3 hours. Then, slowly add 30 ml of aqueous ammonia, stir at 50°C for 8 hours. After completion of the reaction, cool to 20°C, add 150 ml of purified water dropwise, then slowly cool to 0°C, stir to crystallize for 1 hour, filter, and add the filter cake to 150 ml of anhydrous ethanol. Heat to 75°C and stir for 1 hour, then slowly cool to 20°C, stir to crystallize for 1 hour, filter, and dry the filter cake to yield 10.1 g of finerenone (91.6% yield, 99.8% purity, and 99.9% ee).

[0068] 1 H-NMR (400MHz, DMSO-d6): δ=1.032-1.067 (t, 3H), δ=2.122 (s, 3H), δ=2.188 (s, 3H), δ=3.825 (s, 3H), δ=3.958-4.035 (m, 2H), δ=,6.6 61-6.749 (d, 2H), δ = 2.122 (s, 3H), δ = 7.142-7.161 (d, 1H), δ = 7.2, 1-7.290 (d, 1H), δ = 7.371 (s, 1H), δ = 7.554 (s, 1H), δ = 7.685 (s, 1H).

[0069] MS (ESI): m / z=379.1[M+H] + . Example 4: Preparation of Compound V

[0070]

[0071] To a reactor, add 40 L of dichloromethane, followed by 4-cyano-2-methoxybenzaldehyde (4 kg, 24.8 mol) and p-nitrobenzyl acetoacetate (7.1 kg, 29.9 mol). Then, add piperidine (200 g) and glacial acetic acid (140 g). Heat and reflux the reaction mixture for 6 hours. After completion, cool the reaction mixture and wash the mixture twice with 10 L of purified water. Dry the mixture over anhydrous sodium sulfate and filter the mixture. The filtrate is concentrated to yield a yellow solid. Then, add 60 L of 2-butanol and 4-amino-5-methyl-2-hydroxypyridine (2.8 kg, 22.6 mol). Heat the mixture to reflux for 20 hours, cool the mixture to 0°C, stir the mixture to allow crystallization for 2 hours, filter the mixture, wash the mixture with 2 L of isopropanol, and air-dry the mixture at 50°C. This yields 9.2 kg of Compound V with a purity of 98.7% and a yield of 83.8% (based on 4-amino-5-methyl-2-hydroxypyridine).

[0072] MS (ESI): m / z=487.2[M+H] + . Example 5:

[0073] Route 1: Preparation of finerenone

[0074]

[0075] To the reactor, add 6.8 L of N-methylpyrrolidone, followed by Compound V (4.5 kg, 9.3 mol) and triethyl orthoacetate (4.5 kg, 27.7 mol), and then dropwise add 270 g of concentrated sulfuric acid. Heat to 115°C for 2 h, then cool to 50°C and dropwise add 6.8 L of purified water. After the addition is complete, stir for 0.5 h, and then add another 6.8 L of purified water. Cool to 0°C and stir for 1 h to allow crystallization. Filter, and dry the filter cake at 50°C with air to yield 4.41 kg of Compound IV, a 92.7% yield and 98.9% purity.

[0076] MS (ESI): m / z=515.2[M+H] +

[0077]

[0078] 80 L of dichloromethane was added to the reactor, followed by compound IV (4 kg, 7.8 mol) and L-di-p-methylbenzoyltartaric acid (3.9 kg, 10.1 mol). The heating was turned on, the temperature was raised to 35 ° C for dissolution and stirring for 1 h, the temperature was slowly lowered to 20 ° C, stirred for 2 h, filtered, and the filter cake was washed with 4 L of ethyl acetate and dried with air at 50 ° C to obtain 3.3 kg of compound IIIa with a resolution yield of 47.1% and an ee value of 99.9%.

[0079]

[0080] Add 25 L of dichloromethane to the reactor, followed by compound IIIa (2.5 kg, 2.8 mol). Adjust the pH to 7-8 with 3% sodium carbonate solution. Once the solution is clear, separate the organic layer, wash with 10 L of purified water, dry over anhydrous sodium sulfate, and concentrate to obtain a residue. Add 15 L of tetrahydrofuran and stir to dissolve the residue, followed by 2.9 g of 5% palladium on carbon. After three hydrogen substitutions, stir at 10°C for 1 h, filter, and then add 4-dimethylaminopyridine (32 g, 0.26 mol). Add N,N'-carbonyldiimidazole (600 g, 3.7 mol) with stirring, and stir at room temperature for 3 h. Then, 3 L of ammonia water was slowly added, and the mixture was stirred at 50 ° C for 8 h. After the reaction was completed, the temperature was lowered to 20 ° C, 15 L of purified water was added dropwise, and then the temperature was slowly lowered to 0 ° C, stirred and crystallized for 1 h, filtered, and the filter cake was added to 15 L of anhydrous ethanol, heated to 75 ° C and stirred for 1 h, then slowly cooled to 20 ° C, stirred and crystallized for 1 h, filtered, and the filter cake was dried to obtain 0.96 kg of finerenone finished product with a yield of 91.4%, a purity of 99.9%, and an ee value of 99.9%.

[0081] MS (ESI): m / z=379.1[M+H] + . Example 6:

[0082] Route 2: Preparation of finerenone

[0083]

[0084] 80 L of ethanol was added to the reactor, followed by compound V (4 kg, 8.2 mol) and L-di-p-methylbenzoyltartaric acid (1.6 kg, 4.1 mol). The reaction mixture was heated to 75 °C and stirred for 1 h. The mixture was cooled to 30 °C and stirred for 2 h. The mixture was filtered and the filter cake was washed with 4 L of ethyl acetate and dried at 50 °C to obtain 3.1 kg of compound IVa with a resolution yield of 43.2% and an ee value of 99.9%.

[0085]

[0086] Add 25 L of dichloromethane to the reactor, followed by Compound IVa (3 kg, 3.4 mol). Adjust the pH to 7-8 with 3% sodium carbonate solution. Once the solution is clear, separate the organic layer, wash with 10 L of purified water, dry over anhydrous sodium sulfate, and concentrate to obtain a residue. Add 7.5 L of N-methylpyrrolidone to the residue, followed by triethyl orthoacetate (1.6 kg, 9.9 mol), and then dropwise add 100 g of concentrated sulfuric acid. Heat to 115°C for 2 h, then cool to 50°C. Add 2.5 L of purified water dropwise. Stir for 0.5 h, then add another 7.5 L of purified water dropwise. Continue cooling to 0°C and stir for 1 h to allow crystallization. Filter, and dry the filter cake at 50°C with air to obtain 1.6 kg of S-configuration Compound IV, with a yield of 90.5% and a purity of 99.0%.

[0087] MS (ESI): m / z=515.2[M+H] +

[0088]

[0089] A reactor was charged with 15 L of tetrahydrofuran, followed by the S-configuration compound (1.5 kg, 2.9 mol) and stirred to dissolve. Then, 37.5 g of 5% palladium on carbon was added. After three hydrogen substitutions, the reaction was stirred at 10°C for 1 hour and filtered. 4-Dimethylaminopyridine (32 g, 0.26 mol) was then added, followed by N,N'-carbonyldiimidazole (600 g, 3.7 mol) with stirring, and the reaction was stirred at room temperature for 3 hours. Then, 3 L of aqueous ammonia was slowly added, and the reaction was stirred at 50°C for 8 hours. After the reaction was complete, the temperature was cooled to 20°C, 15 L of purified water was added dropwise, and the temperature was slowly cooled to 0°C. The mixture was stirred for 1 hour to allow crystallization, and filtered. The filter cake was added to 15 L of anhydrous ethanol, heated to 75°C and stirred for 1 hour, then slowly cooled to 20°C, stirred for 1 hour to allow crystallization, filtered, and the filter cake was dried to yield 1.0 kg of finerenone, with a yield of 90.6%, a purity of 99.9%, and an ee of 99.9%.

[0090] MS (ESI): m / z=379.1[M+H] + . Comparative Example 1

[0091]

[0092] To the reaction flask, add 40 ml of dichloromethane, followed by 4-cyano-2-methoxybenzaldehyde (4.0 g, 24 mmol) and p-chlorobenzyl acetoacetate (6.8 g, 30 mmol). Then, add piperidine (0.2 g) and glacial acetic acid (0.14 g). Heat and reflux for 6 h. After completion, cool the reaction, wash twice with 10 ml of purified water, dry over anhydrous sodium sulfate, and filter. The filtrate is concentrated to yield a yellow solid. Then, add 60 ml of 2-butanol and 4-amino-5-methyl-2-hydroxypyridine (2.8 g, 22 mmol). Heat to reflux for 20 h, cool to 0°C, stir to crystallize for 2 h, filter, wash with 10 ml of isopropanol, and air-dry at 50°C to yield 8.2 g of compound V-2 with a purity of 98.2% and a yield of 76.4% (based on 4-amino-5-methyl-2-hydroxypyridine).

[0093] 1 H-NMR (400MHz, DMSO-d6) δ=2.032 (s, 3H), δ=2.361 (s, 3H), δ=3.672 (s, 3H), δ=5.135 (s, 2H), δ=5.265 (s, 1H), δ=6.904 (s, 1H), δ=7.086-7.130 (m, 2H), δ=7.201 (s, 1H), δ=7.305 (s, 1H), δ=7.420 (s, 1H), δ=8.160 (s, 1H), δ=8.181 (s, 2H), δ=10.782 (s, 1H).

[0094] Route 1:

[0095]

[0096] To the reaction flask, add 6 ml of N-methylpyrrolidone, followed by Compound V-2 (4 g, 8.4 mmol) and triethyl orthoacetate (4.1 g, 25 mmol), and then dropwise add 0.2 g of concentrated sulfuric acid. Heat to 115°C for 2 h, then cool to 50°C and dropwise add 6 ml of purified water. After addition is complete, stir for 0.5 h, and then add another 6 ml of purified water. Cool to 0°C and stir for 1 h to allow crystallization. Filter, and dry the filter cake at 50°C with air to yield 3.8 g of Compound IV-2, with a yield of 89.8% and a purity of 98.5%.

[0097]

[0098] Add 40 ml of ethyl acetate to the reaction flask, then add compound IV-2 (2 g, 3.9 mmol), and then add L-di-p-methylbenzoyltartaric acid (1.5 g, 3.9 mmol). Turn on the heating, raise the temperature to 70 ° C and dissolve and stir for 1 hour, cool naturally to 25 ° C, stir for 2 hours, filter, wash the filter cake with 2 ml of ethanol, and dry it with air at 50 ° C to obtain 1.28 g of compound IIIa-2, with a resolution yield of 36.2% and an ee value of 83.1%.

[0099]

[0100] To the reaction flask, add 15 ml of dichloromethane, followed by compound IIIa (1.5 g, 1.7 mmol). Adjust the pH to 7-8 with 3% sodium carbonate solution. Once the solution is clear, separate the organic layer, wash with 7 ml of purified water, dry over anhydrous sodium sulfate, and concentrate to obtain a residue. Add 10 ml of tetrahydrofuran to the residue, followed by 25 mg of 10% palladium on carbon. After three hydrogen substitutions, stir at 10°C for 1 h, filter, and then add 4-dimethylaminopyridine (21 mg, 0.2 mmol). Add N,N'-carbonyldiimidazole (0.4 g, 2.5 mmol) with stirring, and stir at room temperature for 3 h. Then, 2 ml of ammonia water was slowly added, and the reaction was stirred at 50 ° C for 8 h. After the reaction was completed, the temperature was lowered to 20 ° C, 10 ml of purified water was added dropwise, and then the temperature was slowly lowered to 0 ° C, stirred and crystallized for 1 h, filtered, and the filter cake was added to 5 ml of anhydrous ethanol, heated to 75 ° C and stirred for 1 h, then slowly cooled to 20 ° C, stirred and crystallized for 1 h, filtered, and the filter cake was dried to obtain 0.59 g of finerenone finished product with a yield of 94.6%, a purity of 92.5%, and an ee value of 83.5%.

[0101] MS (ESI): m / z=379.1[M+H] + . Comparative Example 2

[0102] Method 2

[0103]

[0104] Add 80 ml of dichloromethane to the reaction flask, then add compound V-2 (4 g, 8.4 mmol), then add L-di-p-methylbenzoyltartaric acid (4.2 g, 10.9 mmol), turn on the heating, raise the temperature to 75 ° C and dissolve and stir for 1 hour, cool naturally to 25 ° C, stir for 2 hours, filter, wash the filter cake with 4 ml of ethyl acetate, and dry it with air at 50 ° C to obtain 2.8 g of compound IVa-2, with a resolution yield of 38.6% and an ee value of 80.8%.

[0105]

[0106] To a reaction flask, add 20 ml of dichloromethane and compound IVa-2 (2 g, 2.3 mmol). Add 3% sodium carbonate solution to adjust the pH to 7-8. Once the solution is clear, separate the organic layer, wash with 10 ml of purified water, dry over anhydrous sodium sulfate, and concentrate to obtain a residue. Add 6 ml of N-methylpyrrolidone to the residue, followed by triethyl orthoacetate (1.1 g, 6.9 mmol), and then dropwise add 0.1 g of concentrated sulfuric acid. Heat to 115°C for 2 h, then cool to 50°C. Add 3 ml of purified water dropwise. Stir for 0.5 h, then add another 3 ml of purified water. Continue cooling to 0°C and stir for 1 h to allow crystallization. Filter the filter cake, and air dry it at 50°C to obtain 1.01 g of compound IV-S1, with a yield of 86.4% and a purity of 98.8%.

[0107]

[0108] 10 ml of tetrahydrofuran was added to a reaction flask, and IV-S (1.0 g) was added and stirred to dissolve. Then, 25 mg of 5% palladium on carbon was added. After three hydrogen substitutions, the reaction was stirred at 10°C for 1 hour and filtered. 4-Dimethylaminopyridine (21 mg, 0.2 mmol) was then added, followed by N,N'-carbonyldiimidazole (0.4 g, 2.5 mmol) with stirring, and the reaction was stirred at room temperature for 3 hours. Then, 2 ml of aqueous ammonia was slowly added, and the reaction was stirred at 50°C for 8 hours. After the reaction was complete, the temperature was cooled to 20°C, 10 ml of purified water was added dropwise, and the temperature was slowly cooled to 0°C. The mixture was stirred for 1 hour to allow crystallization, and filtered. The filter cake was added to 5 ml of anhydrous ethanol, heated to 75°C and stirred for 1 hour, then slowly cooled to 20°C, stirred for 1 hour to allow crystallization, filtered, and the filter cake was dried to obtain 0.71 g of finerenone (94.6% yield, 88.5% purity, and 81.0% ee).

[0109] 1 H-NMR (400MHz, DMSO-d6): δ=1.032-1.067 (t, 3H), δ=2.122 (s, 3H), δ=2.188 (s, 3H), δ=3.825 (s, 3H), δ=3.958-4.035 (m, 2H), δ=,6.6 61-6.749 (d, 2H), δ = 2.122 (s, 3H), δ = 7.142-7.161 (d, 1H), δ = 7.2, 1-7.290 (d, 1H), δ = 7.371 (s, 1H), δ = 7.554 (s, 1H), δ = 7.685 (s, 1H).

[0110] MS (ESI): m / z=379.1[M+H] + . Comparative Example 3

[0111] Compound II was prepared according to patent CN115340539

[0112]

[0113] At room temperature (approximately 20°C), compound IV-3 (10 g, 21.2 mmol), L-di-p-methylbenzoyltartaric acid (8.2 g, 21.2 mmol), and methyl isobutyl ketone (150 ml) were added to a reaction flask, which was then heated to an internal temperature of 70°C to dissolve and stirred for 3 h. Subsequently, the mixture was cooled to 20°C over 5 h, stirred at this temperature for 15 h, filtered, and the solid was rinsed with methyl isobutyl ketone (5 ml) and dried in vacuo at 45°C to obtain 9.8 g of compound IIIa-3 as a white solid with an ee value of 83.1%.

[0114]

[0115] At room temperature (approximately 20°C), compound IIIa-3 (5.0 g) and water (50 ml) were added to a reaction flask and stirred for 30 minutes. Then, sodium phosphate solution (100 g sodium phosphate dissolved in 1000 ml water) was added dropwise to adjust the pH to 7-7.5. Stirring was continued for 3 hours. The mixture was filtered, the solid rinsed with 20 ml of water, and dried under vacuum at 45°C to obtain 2.5 g of compound IV-S2 as a white solid, with a yield of 93.6%, a purity of 97.9%, and an ee value of 83.1%.

[0116]

[0117] At room temperature (about 20°C), compound IV-S2 (2.5 g, 5.3 mmol), tetrahydrofuran (25 ml), and 10% palladium on carbon (0.25 g) were added to the reaction flask, replaced with nitrogen three times and then with hydrogen three times. The mixture was stirred at room temperature for 3 h, the palladium on carbon was filtered, and the organic phase was concentrated to obtain 1.85 g of white solid compound II with a purity of 75.79%.

[0118] Experiments conducted under the conditions described in this literature failed to replicate the reported purity of 99.7%. Instead, a 16.8% impurity was observed. Analysis revealed that this impurity was generated by the reduction of the dihydropyridine ring. This impurity affects product quality.

Claims

1. Finerenone intermediate compound V, the structural formula is as follows: 。 2. The method for preparing the finerenone intermediate compound V according to claim 1, characterized in that: The steps include: ， 4-cyano-2-methoxybenzaldehyde (raw material 2) and p-nitrobenzyl acetoacetate (raw material 1) were added to dichloromethane, followed by piperidine and glacial acetic acid. The mixture was heated and refluxed to react. After the reaction was completed, the temperature was lowered, purified water was added to wash the separated liquid, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a yellow solid residue (Compound VI). 2-Butanol was added to the residue, followed by 4-amino-5-methyl-2-hydroxypyridine (raw material 3), and the mixture was heated to reflux to react. After the reaction was completed, the temperature was lowered, stirred for crystallization, filtered, and the filter cake was washed with isopropanol and dried with air to obtain Compound V.

3. A method for preparing finerenone, characterized in that: The steps include: ， (1) Compound V, triethyl orthoacetate and concentrated sulfuric acid are added to N-methylpyrrolidone to react to prepare compound IV; (2) Compound IV is added to an organic solvent, and L-di-p-methylbenzoyltartaric acid is added to the solution to perform separation to obtain compound IIIa; (3) Preparation of finerenone Add dichloromethane to compound IIIa, adjust the base with sodium bicarbonate aqueous solution, extract, separate and distill, add tetrahydrofuran to the distillation residue, add 5% palladium on carbon, hydrogenate and filter to obtain a tetrahydrofuran solution of compound II, continue to add N-dimethylaminopyridine and N,N'-carbonyldiimidazole, react, then add ammonia water to react, crystallize, filter, recrystallize with anhydrous ethanol, filter and dry to obtain phenerenone.

4. The method for preparing finerenone according to claim 3, characterized in that: The molar ratio of compound IV to L-di-p-methylbenzoyltartaric acid in step (2) is 1:0.5-1.

3.

5. The method for preparing finerenone according to claim 3, characterized in that: The organic solvent described in step (2) is one or more of ethyl acetate, methanol, ethanol, isopropanol and dichloromethane.

6. The method for preparing finerenone according to claim 3, characterized in that: The weight ratio of palladium carbon to S-configuration compound IV in step (3) is 0.2%~2.5%:

1.

7. A method for preparing finerenone, characterized in that: The steps include: ， (1) Compound V is resolved into compound IVa Compound V is added to a solvent, and L-di-p-methylbenzoyltartaric acid is added to the organic solution to perform separation to obtain compound IVa; (2) Preparation of finerenone Add dichloromethane to IVa, adjust the base with sodium bicarbonate aqueous solution, extract, separate and concentrate to obtain a residue, add N-methylpyrrolidone, triethyl orthoacetate and concentrated sulfuric acid to the residue, react to obtain S-configuration compound IV, then add tetrahydrofuran, add 5% palladium on carbon, hydrogenate and filter to obtain a tetrahydrofuran solution of compound II, continue to add N-dimethylaminopyridine and N,N'-carbonyldiimidazole, react, then add ammonia water to react, crystallize, filter, recrystallize with anhydrous ethanol, filter and dry to obtain phenerenone.

8. The method for preparing finerenone according to claim 7, characterized in that: The molar ratio of compound V to L-di-p-methylbenzoyltartaric acid in step (1) is 1:0.5-1.

3.

9. The method for preparing finerenone according to claim 7, characterized in that: The organic solvent described in step (1) is one or more of ethyl acetate, methanol, ethanol, isopropanol and dichloromethane.

10. The method for preparing finerenone according to claim 7, characterized in that: The weight ratio of palladium carbon to S-configuration compound IV in step (2) is 0.2%~2.5%:1.

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