Preparation method of finalidone key intermediate

Abstract

The invention relates to a preparation method of a finalidone key intermediate, which comprises the following steps: (1) synthesis of 2, 8-dimethyl-5-oxo-5, 6-dihydro-1, 6-naphthylpyridine-3-nitrile, and (2) synthesis of 2, 8-dimethyl-5-oxo-5, 6-dihydro-1, 6-naphthylpyridine-3-nitrile; (2) synthesis of the 4-(4-cyano-2-methoxyphenyl)-2, 8-dimethyl-5-oxo-5, 6-dihydro-1, 6-naphthyridine-3-nitrile, (3) synthesis of the 4-(4-cyano-2-methoxyphenyl)-2, 8-dimethyl-5-oxo-5, 6-dihydro-1, 6-naphthyridine-3-nitrile, (4) synthesis of the 4-(4- (3) synthesis of the 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-nitrile, and (4) synthesis of the 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-nitrile. (4) synthesis of the 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxylic acid, and (5) synthesis of the 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxylic acid. The method provided by the invention solves the problems existing in the process route of the original research company, has the advantages of mild reaction conditions and high yield, greatly saves the organic waste liquid treatment cost, and is an environment-friendly production process.

Description

Technical Field

[0001] The present invention relates to a preparation method of a key intermediate of finerenone, namely 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid. Background Art

[0002] Finerenone is the first new oral selective non-steroidal mineralocorticoid receptor antagonist developed by Bayer, and was approved by the US FDA for marketing on July 9, 2021; it was launched in China on June 29, 2022. The dosage is 10 mg and 20 mg, and it is used to treat adult patients with chronic kidney disease related to type II diabetes. A key intermediate 4-(4-cyano-2-methoxyphenyl)-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (hereinafter referred to as Compound D) is used in the synthesis of its active pharmaceutical ingredient.

[0003] Patents WO2008104306A, CN106795155A and CN107849043A reported the main methods for synthesizing Compound D, and the routes are as follows:

[0004]

[0005] The disadvantages of this route are as follows: the synthetic route basically adopts column chromatography separation operation, the processing operation is complex, and more three wastes are generated, which is not conducive to cost reduction.

[0006] Due to the large indication of this variety, the demand for the active pharmaceutical ingredient and the intermediate is large. Therefore, it is very necessary to develop an industrial production route with high efficiency, low cost and less pollution. Summary of the Invention

[0007] The purpose of the present invention is to provide a preparation method that is efficient, low-cost, less polluting, and can solve the technical problems existing in the preparation method of the existing key intermediate of finerenone, namely 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid.

[0008] The purpose of the present invention is achieved through the following technical solutions:

[0009] A preparation method of a finerenone intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, which comprises the following steps:

[0010] (1) Synthesis of 2,8-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carbonitrile (hereinafter referred to as Compound A): Compound SM1 and Compound SM2 react to obtain Compound A. The structural formulas of Compound SM1, Compound SM2, and Compound A are as follows:

[0011]

[0012] (2) Synthesis of 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carbonitrile (hereinafter referred to as Compound B): Compound A and Compound SM3 undergo a metal-catalyzed C-H activation cross-coupling reaction to form Compound B. The structural formulas of Compound SM3 and Compound B are as follows:

[0013]

[0014] (3) Synthesis of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbonitrile (hereinafter referred to as Compound C): Compound B reacts with triethyl orthoacetate to obtain Compound C. The structural formula of Compound C is as follows:

[0015]

[0016] (4) Synthesis of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (hereinafter referred to as Compound D): Compound C is hydrolyzed under strong alkaline conditions to obtain Compound D. The structural formula of Compound D is as follows:

[0017]

[0018] The specific reaction route for the synthesis of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid in the present invention is as follows:

[0019]

[0020] Compared with the prior art, the advantages of the present invention are as follows:

[0021] 1. The solvents and reagents used in the present invention are all commercially available products. The material prices are low, and the yield of each step of the reaction is high, greatly improving the economic efficiency.

[0022] 2. The process route of the present invention avoids the problems of cumbersome operation and high production cost caused by the large use of column chromatography purification and separation steps in the preparation process of the original process route.

[0023] 3. The problems existing in the process route of the original research company are solved. The reaction conditions are mild, the yield is high, and the cost of treating organic waste liquid is greatly saved. It is an environment-friendly production process. Detailed implementation mode

[0024] A preparation method of the finerenone intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, which comprises the following steps:

[0025] (1) Synthesis of 2,8-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carbonitrile (hereinafter referred to as compound A): Compound SM1 and compound SM2 undergo a reaction similar to the Hantzzsch reaction to obtain compound A. The structural formulas of compound SM1, compound SM2, and compound A are as follows:

[0026]

[0027] (2) Synthesis of 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carbonitrile (hereinafter referred to as compound B): Compound A and compound SM3 generate compound B through a metal-catalyzed C-H activation cross-coupling reaction. The structural formulas of compound SM3 and compound B are as follows:

[0028]

[0029] (3) Synthesis of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbonitrile (hereinafter referred to as compound C): Compound B reacts with triethyl orthoacetate to obtain compound C. The structural formula of compound C is as follows:

[0030]

[0031] (4) Synthesis of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (hereinafter referred to as compound D): Compound C is hydrolyzed under strong alkaline conditions to obtain compound D. The structural formula of compound D is as follows:

[0032]

[0033] The specific operation method of step (1) is as follows: In a three-necked flask, add compound SM1, compound SM2, organic solvent A, K2CO3 and CuBr. Heat up to 80 - 90 °C and react at this temperature for 10 - 20 h (preferably 16 - 18 h), then cool to room temperature, add water, stir for 30 min, and filter. Add ethyl acetate to the filtrate for extraction and liquid separation. Wash the organic layer twice with saturated brine. Then concentrate the organic layer to obtain compound A.

[0034] Among them, the molar ratio of compound SM1, compound SM2 and CuBr during the reaction is 1:1 - 3:0.5 - 3, and more preferably 1:1.2:0.8.

[0035] The organic solvent A is one or a mixture of several of NMP, DMF, DMSO, and more preferably DMF.

[0036] The specific operation method of step (2) is as follows: Under nitrogen protection, add organic solvent B, compound A and compound SM3 to a three-necked flask. After stirring and dissolving, add a base and Pd(OAc)2, heat up to 60 - 120 °C, and react at this temperature for 5 - 24 h (preferably 16 - 18 h). Cool to room temperature, add hydrochloric acid aqueous solution to adjust the pH to 6 - 7, filter, add ethyl acetate to the filtrate for extraction and liquid separation, and concentrate the organic layer to obtain compound B.

[0037] Among them, the molar ratio of compound A, compound SM3, base, and Pd(OAc)2 is 1:1.0 - 2.0:0.1 - 0.5:0.01 - 0.1.

[0038] The organic solvent B is one or a mixture of several of DMSO, DMA, DMF, DMAP, DMAc, t-BuOH, THF, dioxane, and more preferably DMF.

[0039] The base is one of Cs2CO3, KF, NaOAc, Na2CO3, K2CO3, K2HPO4, and more preferably Cs2CO3.

[0040] The specific operation method of step (3) is as follows: Under nitrogen protection, add organic solvent C, compound B and triethyl orthoacetate to a three-necked flask. After stirring and dissolving, add a catalytic amount of acid. Heat up to 50 - 60 °C and react at this temperature for 4 - 8 h (preferably 5 - 6 h). Cool to room temperature, add 5% NaOH aqueous solution at this temperature to adjust the pH to 6 - 7, separate the liquid, extract the organic layer twice with ethyl acetate. Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate the organic layer to obtain compound C.

[0041] Among them, the molar ratio of compound B, triethyl orthoacetate and acid during the reaction is 1:1 to 2:0.01 - 0.1, more preferably 1:1.1:0.05.

[0042] The organic solvent C is one or a mixture of several of DMF, NMP, DMSO, and DMAc, more preferably DMAc.

[0043] The acid is one of H2SO4, H3PO4, and HCl, more preferably H2SO 4.

[0044] The specific operation method of step (4) is as follows: Under nitrogen protection, add organic solvent D, compound C and strong base into a three-necked flask, stir, and heat to 50 - 60 °C. React at this temperature for 1 - 8 h (preferably 2 - 3 h), then cool to room temperature, add hydrochloric acid aqueous solution to adjust the pH to 6 - 7, then add water, a large amount of solid will precipitate, filter the solid, and dry to obtain compound D.

[0045] Among them, the molar ratio of compound C to strong base during the reaction is 1:1 to 5, more preferably 1:3.

[0046] The organic solvent D is one or a mixture of several of THF, acetone, DMF, NMP, DMSO, and CH3CN, more preferably THF.

[0047] The strong base is NaOH or KOH.

[0048] The content of the present invention will be described in detail below in conjunction with examples:

[0049] Example 1:

[0050] Example 1

[0051] 1.1 Synthesis of Compound A

[0052] In a 500 ml three-necked flask, add 12.4 g of compound SM1 (0.1 mol), 11.4 g of compound SM2 (0.12 mol), 200 ml of DMF, 13.8 g of K2CO3 (0.1 mol) and 11.5 g of CuBr (0.08 mol). Heat to 80 - 90 °C, react at this temperature for 16 - 18 h, then cool to room temperature, add 100 ml of water, stir for 30 min, and filter. Add 200 ml of ethyl acetate to the filtrate for extraction and liquid separation. The organic layer is washed twice with 100 ml of saturated brine. Then the organic layer is concentrated to obtain 17.2 g of compound A, and the yield is 86.4%.

[0053] NMR analysis:

[0054] 1H-NMR (300 MHz, DMSO): 11.82 (1H, s), 8.79 (1H, s), 7.31 (1H, m), 2.68 (3H, s),

[0055] 2.28 (3H, s)

[0056] Synthesis of Compound B

[0057] Under nitrogen protection, 200 ml of DMF, 19.9 g of Compound A (0.1 mol) and 25.4 g of Compound SM3 (0.12 mol) were added to a three-necked flask. After stirring and dissolving, 9.7 g (0.03 mol) of Cs2CO3 and 1.2 g (0.005 mol) of Pd(OAc)2 were added. The temperature was raised to 90 - 100 °C and the reaction was carried out at this temperature for 16 - 18 h. After cooling to room temperature, 100 ml of (10%) hydrochloric acid aqueous solution was added to adjust the pH to 6 - 7. After filtration, 150 ml of ethyl acetate was added to the filtrate for extraction and liquid separation. The organic layer was concentrated to obtain 27.3 g of Compound B, and the yield was 82.5%.

[0058] NMR analysis:

[0059] 1H-NMR (300 MHz, DMSO):

[0060] 10.76 (1H, s), 7.62 - 7.66 (2H, m), 7.45 (1H, m), 7.35 (1H, m),

[0061] 3.84 (3H, s), 2.72 (3H, s), 2.30 (3H, s).

[0062] Synthesis of Compound C

[0063] Under nitrogen protection, 200 ml of DMAc, 33.0 g of Compound B (0.1 mol) and 17.8 g of triethyl orthoacetate (0.11 mol) were added to a three-necked flask. After stirring the solvent, 0.5 g of concentrated sulfuric acid (0.005 mol) was slowly added. The temperature was raised to 50 - 60 °C and the reaction was carried out at this temperature for 5 - 6 h. After cooling to room temperature, 150 ml of NaOH (5%) aqueous solution was added at this temperature to adjust the pH to 6 - 7. After liquid separation, the organic layer was extracted twice with 150 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated to obtain 30.7 g of Compound C, and the yield was 85.4%.

[0064] NMR analysis:

[0065] 1H-NMR (300 MHz, DMSO): 8.17 (1H, s), 7.53 (1H, s), 7.36

[0066] (1H, s), 7.26(2H, m), 5.31(1H, s), 4.08(2H, m), 3.76(3H, s), 2.32(3H, s), 2.16(3H, s),

[0067] 1.18(3H, t)

[0068] Synthesis of Compound D

[0069] Under nitrogen protection, 200 ml of THF, 36.0 g of Compound C (0.1 mol) and 12 g of NaOH (0.3 mol) were added to a three-necked flask, stirred, and heated to 50 - 60 °C. Reacted at this temperature for 2 - 3 h, then cooled to room temperature, and the pH was adjusted to 6 - 7 with hydrochloric acid aqueous solution. Then water was added, a large amount of solid was precipitated, the solid was filtered and dried to obtain 33.5 g of Compound D. The yield was 88.2%.

[0070] NMR analysis:

[0071] 1H-NMR(300 MHz, DMSO): 11.43(1H, s), 8.16(1H, s), 7.57(1H, s), 7.30

[0072] (1H, s), 7.24(2H, m), 5.33(1H, s), 4.04(2H, m), 3.74(3H, s), 2.37(3H, s), 2.15(3H, s),

[0073] 1.14(3H, t)

[0074] Example 2:

[0075] Synthesis of Compound A

[0076] In a 100 ml three-necked flask, 12.4 g of Compound SM1 (0.1 mol), 14.3 g of Compound SM2 (0.15 mol), 200 ml of DMSO, 13.8 g of K2CO3 (0.1 mol) and 14.3 g of CuBr (0.1 mol) were added. Heated to 80 - 90 °C, reacted at this temperature for 14 - 16 h, then cooled to room temperature, 100 ml of water was added, stirred for 30 min, and filtered. 200 ml of ethyl acetate was added to the filtrate for extraction and liquid separation. The organic layer was washed twice with 100 ml of saturated brine. Then the organic layer was concentrated to obtain 14.4 g of Compound A, and the yield was 72.2%.

[0077] Synthesis of Compound B

[0078] Under nitrogen protection, 200 ml of DMSO, 19.9 g of compound A (0.1 mol) and 31.8 g of compound SM3 (0.15 mol) were added to a three-necked flask. After stirring and dissolving, 1.7 g (0.03 mol) of KF and 1.8 g (0.008 mol) of Pd(OAc)2 were added. The temperature was raised to 85 - 95 °C, and the reaction was carried out at this temperature for 14 - 16 h. After cooling to room temperature, 80 ml of (10%) hydrochloric acid aqueous solution was added to adjust the pH to 6 - 7. After filtration, 150 ml of ethyl acetate was added to the filtrate for extraction and liquid separation. The organic layer was concentrated to obtain 23.8 g of compound B, and the yield was 72.1%.

[0079] 2.3 Synthesis of Compound C

[0080] Under nitrogen protection, 200 ml of DMF, 33.0 g of compound B (0.1 mol) and 24.3 g of triethyl orthoacetate (0.15 mol) were added to a three-necked flask. After stirring the solvent, 0.78 g of phosphoric acid (0.008 mol) was slowly added. The temperature was raised to 50 - 60 °C, and the reaction was carried out at this temperature for 4 - 5 h. After cooling to room temperature, 150 ml of NaOH (5%) aqueous solution was added at this temperature to adjust the pH to 6 - 7. After liquid separation, the organic layer was extracted twice with 150 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the organic layer was concentrated to obtain 28.3 g of compound C, and the yield was 78.5%.

[0081] 2.4 Synthesis of Compound D

[0082] Under nitrogen protection, 200 ml of DMF, 36.0 g of compound C (0.1 mol) and 8 g of NaOH (0.2 mol) were added to a three-necked flask, stirred, and the temperature was raised to 50 - 60 °C. The reaction was carried out at this temperature for 4 - 6 h, then cooled to room temperature, and hydrochloric acid aqueous solution was added to adjust the pH to 6 - 7. Then water was added, and a large amount of solid was precipitated. The solid was filtered and dried to obtain 28.6 g of compound D. The yield was 75.3%.

[0083] Example 3:

[0084] 3.1 Synthesis of Compound A

[0085] In a 1000 ml three-necked flask, add 12.4 g of compound SM1 (0.1 mol), 19.0 g of compound SM2 (0.2 mol), 200 ml of NMP, 13.8 g of K2CO3 (0.1 mol) and 21.5 g of CuBr (0.15 mol). Heat up to 80 - 90 °C and react for 10 - 12 h under this temperature condition. Then cool to room temperature, add 100 ml of water, stir for 30 min, and filter. Add 300 ml of ethyl acetate to the filtrate for extraction and liquid separation. Wash the organic layer twice with 200 ml of saturated brine. Then concentrate the organic layer to obtain 13.2 g of compound A, with a yield of 66.5%.

[0086] 3.2 Synthesis of Compound B

[0087] Under nitrogen protection, add 200 ml of DMSO, 19.9 g of compound A (0.1 mol) and 38.2 g of compound SM3 (0.18 mol) to a three-necked flask. After stirring and dissolving, add 5.5 g (0.04 mol) of K2CO3 and 1.8 g (0.008 mol) of Pd(OAc)2. Heat up to 80 - 90 °C and react for 12 - 14 h under this temperature condition. Cool to room temperature, add 80 ml (10%) hydrochloric acid aqueous solution to adjust the pH to 6 - 7, filter, add 150 ml of ethyl acetate to the filtrate for extraction and liquid separation, and concentrate the organic layer to obtain 21.6 g of compound B, with a yield of 65.5%.

[0088] 3.3 Synthesis of Compound C

[0089] Under nitrogen protection, add 200 ml of DMSO, 33.0 g of compound B (0.1 mol) and 21.1 g of triethyl orthoacetate (0.13 mol) to a three-necked flask. After stirring the solvent, slowly add 0.5 g of phosphoric acid (0.005 mol). Heat up to 50 - 60 °C and react for 6 - 7 h under this temperature condition. Cool to room temperature, add 200 ml of NaOH (5%) aqueous solution under this temperature condition to adjust the pH to 6 - 7, separate the liquid, and extract the organic layer twice with 150 ml of ethyl acetate. Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate the organic layer to obtain 26.2 g of compound C, with a yield of 72.6%.

[0090] 3.4 Synthesis of Compound D

[0091] Under nitrogen protection, add 200 ml of NMP, 36.0 g of compound C (0.1 mol) and 16 g of NaOH (0.4 mol) to a three-necked flask, stir, and heat up to 50 - 60 °C. React for 5 - 7 h under this temperature condition, then cool to room temperature, add hydrochloric acid aqueous solution to adjust the pH to 6 - 7. Then add water, a large amount of solid precipitates, filter the solid, and dry to obtain 26.7 g of compound D. The yield is 70.4%.

[0092] The upper and lower limits and interval values of the raw materials of the present invention can all implement the present invention, and the listed raw materials can all implement the present invention. Examples are not listed one by one here. The NMR analysis data of the compounds in Example 2 and Example 3 of the present invention are basically the same as those of the corresponding compounds in Example 1. Therefore, the present invention does not provide the NMR analysis data of the compounds in Example 2 and Example 3.

[0093] It should be noted that all the documents or patents mentioned in the present invention are cited as references in this application, just as if each article or patent is cited separately for reference. In addition, it should be understood that the above are specific embodiments and technical principles of the present invention. After reading the above content of the present invention, those skilled in the art can make various improvements and modifications to the present invention without departing from the scope of the present invention, and these equivalent forms also fall within the scope of the present invention.

Claims

1. Preparation method of finerenone key intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid, characterized in that: It includes the following steps: (1) Synthesis of compound A, 2,8-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carbonitrile: Compound SM1 reacts with compound SM2 to obtain compound A. The structural formulas of compound SM1, compound SM2, and compound A are as follows: (2) Synthesis of compound B, 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carbonitrile: Compound A and compound SM3 undergo a metal-catalyzed C-H activation cross-coupling reaction to form compound B. The structural formulas of compound SM3 and compound B are as follows: (3) Synthesis of compound C, 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbonitrile: Compound B reacts with triethyl orthoacetate to obtain compound C. The structural formula of compound C is as follows: (4) Synthesis of the target compound D, 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid: Compound C is hydrolyzed under strong alkaline conditions to obtain compound D. The structural formula of compound D is as follows:

2. The preparation method of finerenone key intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid according to claim 1, characterized in that: The specific operation method of step (1) is as follows: In a three-necked flask, add compound SM1, SM2, organic solvent A, K2CO3, and CuBr. Heat to 80 - 90 °C and react at this temperature for 10 - 20 h. Then cool to room temperature, add water, stir for 30 min, and filter; add ethyl acetate to the filtrate for extraction and separation; wash the organic layer twice with saturated brine; then concentrate the organic layer to obtain compound A; Among them, the molar ratio of compound SM1, compound SM2, and CuBr during the reaction is 1:1 - 3:0.5 - 3.

3. The preparation method of finerenone key intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid according to claim 2, characterized in that: The organic solvent A is one or a mixture of several of NMP, DMF, and DMSO.

4. The preparation method of finerenone key intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid according to claim 1, characterized in that: The specific operation method of step (2) is as follows: Under nitrogen protection, add organic solvent B, compound A, and compound SM3 to a three-necked flask. After stirring and dissolving, add a base and Pd(OAc)2. Heat to 60 - 120 °C and react at this temperature for 5 - 24 h. Cool to room temperature, add hydrochloric acid aqueous solution to adjust the pH to 6 - 7, filter, add ethyl acetate to the filtrate for extraction and separation, and concentrate the organic layer to obtain compound B; Among them, the molar ratio of compound A, compound SM3, the base, and Pd(OAc)2 is 1:1.0 - 2.0:0.1 - 0.5:0.01 - 0.

1.

5. The preparation method of finerenone key intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid according to claim 4, characterized in that: The organic solvent B is one or a mixture of several of DMSO, DMA, DMF, DMAP, DMAc, t-BuOH, THF, and dioxane.

6. The preparation method of finerenone key intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid according to claim 4, characterized in that: The base is one of Cs2CO3, KF, NaOAc, Na2CO3, K2CO3, and K2HPO4. ​7. The preparation method of the finerenone key intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid according to claim 1, characterized in that: The specific operation method of step (3) is as follows: Under nitrogen protection, add organic solvent C, compound B, and triethyl orthoacetate to a three-necked flask. After stirring and dissolving, add a catalytic amount of acid; Heat to 50 - 60 °C, react for 4 - 8 h under this temperature condition, cool to room temperature, add 5% NaOH aqueous solution under this temperature condition, adjust the pH to 6 - 7, separate the layers, and extract the organic layer with ethyl acetate twice; dry the organic layer with anhydrous sodium sulfate, filter, and concentrate the organic layer to obtain compound C; Among them, the molar ratio of compound B, triethyl orthoacetate and acid during the reaction is 1:1 - 2:0.01 - 0.

1.

8. The preparation method of the finerenone key intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid according to claim 7, characterized in that: The organic solvent C is one or a mixture of several of DMF, NMP, DMSO, and DMAc; The acid is one of H2SO4, H3PO4, and HCl.

9. The preparation method of the finerenone key intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid according to claim 1, characterized in that: The specific operation method of step (4) is: under nitrogen protection, add organic solvent D, compound C and a strong base to a three-necked flask, stir, heat to 50 - 60 °C, react for 1 - 8 h under this temperature condition, then cool to room temperature, add hydrochloric acid aqueous solution to adjust the pH to 6 - 7, then add water, a large amount of solid will precipitate, filter the solid, and dry to obtain compound D; Among them, the molar ratio of compound C to the strong base during the reaction is 1:1 - 5.

10. The preparation method of the finerenone key intermediate 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid according to claim 9, characterized in that: The organic solvent D is one or a mixture of several of THF, acetone, DMF, NMP, DMSO, and CH3CN.

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