Preparation method of fenerenone racemate

Abstract

The invention provides a preparation method of a finerenone racemate, and belongs to the technical field of synthesis of drug intermediates. According to the method, 4-cyano-2-methoxybenzaldehyde and methyl acetoacetate which is low in price and easy to obtain serve as starting raw materials, the finerenone raceme can be obtained through the four chemical reactions of the Knoevenagel reaction, the cyclization reaction, the condensation reaction and the ammonolysis reaction in sequence, the synthetic route is short, the raw material cost is low, and the obtained finerenone raceme is high in total yield, high in purity and suitable for industrial production. The method is suitable for industrial batch production.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for preparing a finerenone racemate. 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, has a structure as shown in formula (I). Finerenone is a third-generation mineralocorticoid receptor antagonist. The U.S. Food and Drug Administration (FDA) has approved finerenone for marketing in the United States for the treatment of patients with type 2 diabetes with chronic kidney disease (CKD). The Phase III clinical trial of finerenone (FIDELIO-DKD) confirmed that finerenone can bring dual benefits to the heart and kidneys for patients with type 2 diabetic nephropathy and has good safety. Based on this, my country has recommended finerenone as a therapeutic drug for reducing urinary albumin and cardiovascular complications in patients with diabetic nephropathy in the "Chinese Guidelines for Clinical Diagnosis and Treatment of Diabetic Kidney Disease" issued in 2021.

[0003]

[0004] The finerenone racemate, whose structure is shown in formula (II), is an important intermediate for preparing finerenone. At present, the complete preparation process of finerenone mainly refers to the report of the original research company's patent WO2008104306: 4-cyano-2-methoxybenzaldehyde and 2-cyanoethyl acetoacetate are used as starting materials to obtain the finerenone racemate through 5 steps of chemical reaction. The finerenone racemate is finally subjected to chiral separation to obtain finerenone, and the reaction process is as follows:

[0005]

[0006] The disadvantages of this preparation process are that the steps are too long and the process is complicated. Five chemical reactions are required to prepare the finerenone racemate, resulting in very low production efficiency. In addition, the starting material 2-cyanoacetoacetic acid ethyl ester used is an unconventional material and is expensive, resulting in high material costs. In short, this route is not suitable for industrial production. Summary of the invention

[0007] In view of this, the object of the present invention is to provide a method for preparing a finerenone racemate. The preparation method provided by the present invention has a short synthetic route, a simple process, and readily available raw materials. The obtained finerenone racemate has a high yield and purity.

[0008] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0009] The present invention provides a method for preparing a finerenone racemate, comprising the following steps:

[0010] 4-cyano-2-methoxybenzaldehyde, methyl acetoacetate, an organic solvent and a catalyst are mixed and subjected to a Novegrin reaction to obtain methyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate having a structure shown in formula a;

[0011]

[0012] 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoic acid methyl ester having a structure shown in formula a, 4-amino-5-methylpyridone and an organic solvent are mixed and subjected to a ring-forming reaction to obtain 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula b;

[0013]

[0014] 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula b, triethyl orthoformate, sulfuric acid and an organic solvent are mixed and subjected to an oxyalkylation reaction to obtain 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula c;

[0015]

[0016] 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula C is mixed with ammonia water and a solvent, and an aminolysis reaction is carried out to obtain a finerenone racemate.

[0017] Preferably, the molar ratio of 4-cyano-2-methoxybenzaldehyde to methyl acetoacetate is 1:(1-1.5);

[0018] The molar ratio of the 4-cyano-2-methoxybenzaldehyde to morpholine is 10:(1-2).

[0019] Preferably, the temperature of the Novoweng reaction is 40-60°C and the time is 6-10 hours.

[0020] Preferably, the molar ratio of 4-amino-5-methylpyridone to 4-cyano-2-methoxybenzaldehyde is 0.22:0.25.

[0021] Preferably, the temperature of the cyclization reaction is 95-99° C. and the time is 16 h.

[0022] Preferably, the molar ratio of 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester to triethyl orthoformate is 1:(5-6);

[0023] The mass ratio of the 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester to sulfuric acid is 14:1.

[0024] Preferably, the condensation reaction temperature is 120-130° C. and the reaction time is 2 h.

[0025] Preferably, the volume ratio of the amount of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid methyl ester to ammonia water is 0.026 mol:10 mL.

[0026] Preferably, the temperature of the aminolysis reaction is reflux temperature, and the time is 12 to 18 hours.

[0027] The invention provides a method for preparing a finerenone racemate. The method uses 4-cyano-2-methoxybenzaldehyde and cheap and readily available methyl acetoacetate as starting materials, performs a Novenge reaction to obtain a compound 2-(4-cyano-2-methoxybenzylidene)-3-oxobutyric acid methyl ester, and then forms a ring with 4-amino-5-methylpyridone to obtain a compound 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester. Then, the compound reacts with triethyl orthoformate to obtain a compound 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid methyl ester, and finally undergoes aminolysis to obtain a final product finerenone racemate. The invention uses 4-cyano-2-methoxybenzaldehyde and cheap and easily available methyl acetoacetate as starting materials, and sequentially undergoes four chemical reactions of Novoweng reaction, cyclization reaction, condensation reaction and aminolysis reaction to obtain the finerenone racemate. The invention has a short synthetic route, low raw material cost, high total yield of the obtained finerenone racemate, high purity and is suitable for industrial mass production. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The synthetic route of the racemate of finerenone is shown in FIG. DETAILED DESCRIPTION

[0029] The present invention provides a method for preparing a finerenone racemate, comprising the following steps:

[0030] 4-cyano-2-methoxybenzaldehyde, methyl acetoacetate, an organic solvent and a catalyst are mixed and subjected to a Novegrin reaction to obtain methyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate having a structure shown in formula a;

[0031]

[0032] 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoic acid methyl ester having a structure shown in formula a, 4-amino-5-methylpyridone and an organic solvent are mixed and subjected to a ring-forming reaction to obtain 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula b;

[0033]

[0034] 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula b, triethyl orthoformate, sulfuric acid and an organic solvent are mixed and subjected to an oxyalkylation reaction to obtain 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula c;

[0035]

[0036] 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula C is mixed with ammonia water and a solvent, and subjected to an aminolysis reaction to obtain a finerenone racemate.

[0037] The invention mixes 4-cyano-2-methoxybenzaldehyde, methyl acetoacetate, an organic solvent and a catalyst, and performs a Novegrin reaction to obtain methyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate having a structure shown in formula a.

[0038] In the present invention, the molar ratio of 4-cyano-2-methoxybenzaldehyde to methyl acetoacetate is preferably 1:(1-1.5), more preferably 1:(1-1.3), and most preferably 1:1.

[0039] In the present invention, the organic solvent is preferably dichloromethane and / or n-hexane, more preferably dichloromethane; when the organic solvent is dichloromethane and n-hexane, the present invention has no special limitation on the ratio of dichloromethane and n-hexane, and they can be mixed in any ratio.

[0040] In the present invention, the catalyst preferably includes morpholine and glacial acetic acid; the molar ratio of the 4-cyano-2-methoxybenzaldehyde to morpholine is preferably 10:(1-2), more preferably 10:1, and the mass ratio of the amount of the 4-cyano-2-methoxybenzaldehyde to glacial acetic acid is preferably 0.25 mol:1.52 g.

[0041] In the present invention, the mixing method is preferably: firstly, 4-cyano-2-methoxybenzaldehyde, methyl acetoacetate and an organic solvent are stirred and mixed, and then the catalyst is added.

[0042] In the present invention, the Novoweng reaction is preferably carried out under reflux conditions, the temperature of the Novoweng reaction is preferably 40 to 60° C., and the time is preferably 6 to 10 hours.

[0043] After the Novoweng reaction, the present invention performs post-treatment on the obtained Novoweng reaction solution, and the post-treatment preferably includes the following steps:

[0044] The Naowenge reaction solution is separated from water and distilled under reduced pressure until there is substantially no fraction left, and the obtained residue is methyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate having a structure shown in formula a.

[0045] In the present invention, the temperature of the reduced pressure distillation is preferably 40°C.

[0046] The present invention mixes 2-(4-cyano-2-methoxybenzylidene)-3-oxobutyric acid methyl ester having a structure shown in formula a, 4-amino-5-methylpyridone and an organic solvent, and performs a ring-forming reaction to obtain 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula b. In the present invention, the molar ratio of the 4-amino-5-methylpyridone to the 4-cyano-2-methoxybenzaldehyde is preferably 0.22:0.25.

[0047] In the present invention, the organic solvent is preferably sec-butanol and / or n-propanol, more preferably sec-butanol; when the organic solvent is sec-butanol and n-propanol, the present invention has no special limitation on the ratio of the sec-butanol and n-propanol, and they can be mixed in any ratio.

[0048] In the present invention, the cyclization reaction is preferably carried out under reflux conditions, the temperature of the cyclization reaction is preferably 95-99° C., and the time is preferably 16 h.

[0049] After the reflux reaction, the present invention preferably performs post-treatment on the obtained cyclization reaction solution, and the post-treatment preferably comprises the following steps:

[0050] The cyclization reaction solution was cooled to 5° C., stirred and solid-liquid separated, and the obtained solid was washed with water and dried to obtain pure 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester.

[0051] In the present invention, the solid-liquid separation method is preferably suction filtration; the drying is preferably forced air drying, and the drying temperature is preferably 50°C.

[0052] In the present invention, 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula b, triethyl orthoformate, sulfuric acid and an organic solvent are mixed and subjected to an oxyalkylation reaction to obtain 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula c. In the present invention, the molar ratio of the 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester to triethyl orthoformate is preferably 1:(5-6), more preferably 1:5.

[0053] In the present invention, the sulfuric acid is preferably concentrated sulfuric acid; the mass ratio of the 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester to sulfuric acid is preferably 14:1.

[0054] In the present invention, the organic solvent is preferably N,N-dimethylacetamide and / or N-methylpyrrolidone, more preferably N,N-dimethylacetamide; when the organic solvent is N,N-dimethylacetamide and N-methylpyrrolidone, the present invention has no special limitation on the ratio of N,N-dimethylacetamide and N-methylpyrrolidone, and they can be mixed in any ratio.

[0055] In the present invention, the oxyalkylation reaction is preferably carried out under stirring conditions, the temperature of the oxyalkylation reaction is preferably 120-130° C., and the time is preferably 2 hours.

[0056] After the oxyalkylation reaction, the present invention preferably performs post-treatment on the obtained oxyalkylation reaction liquid, and the post-treatment preferably comprises the following steps:

[0057] The oxyalkylation reaction liquid is cooled to 15-20° C., water is added to precipitate solid, solid-liquid separation is performed, and the obtained solid is dried to obtain 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid methyl ester.

[0058] In the present invention, the solid-liquid separation is preferably suction filtration; the drying is preferably forced air drying, and the drying temperature is preferably 50°C.

[0059] In the present invention, 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula C is mixed with ammonia water and a solvent, and an aminolysis reaction is performed to obtain a racemic form of phenelenone. In the present invention, the volume ratio of the amount of the substance of the 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid methyl ester to the ammonia water is preferably 0.026 mol:10 mL.

[0060] In the present invention, the solvent is preferably methanol.

[0061] In the present invention, the ammonolysis reaction is preferably carried out under reflux conditions, the temperature of the ammonolysis reaction is preferably 65 to 80° C., and the time is preferably 12 to 16 hours.

[0062] After the ammonolysis reaction, the present invention preferably performs post-treatment on the obtained ammonolysis reaction solution, and the post-treatment preferably comprises the following steps:

[0063] The aminolysis reaction liquid is cooled to 5° C., stirred and solid-liquid separated, and the obtained solid is washed and dried to obtain a pure product of the finerenone racemate.

[0064] In the present invention, the solid-liquid separation is preferably suction filtration; the detergent used in the washing is preferably methanol. In the present invention, the drying is preferably forced air drying, and the drying temperature is preferably 50°C.

[0065] As a specific embodiment of the present invention, the synthetic route of the finerenone racemate is as follows Figure 1 shown.

[0066] The preparation method of the finerenone racemate provided by the present invention is described in detail below in conjunction with the examples, but they should not be construed as limiting the scope of protection of the present invention.

[0067] Example 1

[0068] according to Figure 1 The route shown is to synthesize the racemate of finerenone as follows:

[0069] (1) Preparation of methyl 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (Compound 5)

[0070] Add 4-cyano-2-methoxybenzaldehyde (40.00g, 0.25mol), methyl acetoacetate (29.00g, 0.25mol) and dichloromethane (600mL) to a 1L three-necked reaction bottle, stir to completely dissolve, add morpholine (2.16g, 0.025mol), and 1.52g of glacial acetic acid, and heat to 40°C. React for 10h, and use a water separator to separate water. The reaction solution is distilled under reduced pressure at 40°C until there is basically no fraction, and then cooled to room temperature to obtain a yellow residue (compound 3). Add 250mL of sec-butyl alcohol and 4-amino-5-methylpyridone (27.68g, 0.22mol) to the residue, heat to 99°C, and react for 16h. The mixture was cooled to 5°C, stirred for 2 h and then filtered. The filter cake was washed with 40 mL of purified water and dried under air at 50°C to obtain 58.2 g of a yellow solid with a yield of 90.0% and a HPLC purity of 98.3%. 1 HNMR(400MHz,DMSO-d6)δ10.75(s,1H),8.08(s,1H),7.17-7.32(m,3H),6. 95(s,1H),5.24(s,1H),3.75(s,1H),350(s,1H),2.30(s,1H),2.02(s,1H).

[0071] (2) Preparation of methyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (Compound 6)

[0072] Compound 5 (14.00 g, 0.04 mol), triethyl orthoformate (29.6 g, 0.2 mol), N,N-dimethylacetamide (70 mL) and 1.0 g of concentrated sulfuric acid were added to a 500 mL three-necked reaction bottle in sequence, and the mixture was heated to 120°C and stirred for 2 h. The heating was stopped. The mixture was cooled to 15-20°C, and 125 mL of purified water was added dropwise. A large amount of solid precipitated. The mixture was stirred for 2 h and then filtered. The filter cake was dried with air at 50°C to obtain 14.1 g of a yellow solid with a yield of 93.1% and a HPLC purity of 98.9%. 1 H NMR(400MHz,DMSO-d6)δ:8.10(s,1H),7.18-7.34(m,3H),7.00(s,1H),5.26(s,1 H),4.39(q,2H),3.72(s,1H),3.53(s,1H),2.32(s,1H),1.96(s,1H),1.36(t,3H)

[0073] (3) Preparation of racemic form of phenerenone

[0074] Compound 6 (10.00 g, 0.026 mol), 200 mL of methanol and 10 mL of ammonia water were added to a 500 mL three-necked flask, and the mixture was heated to 65°C for 16 h. The mixture was cooled to 10°C and stirred for 1 h. The mixture was filtered and the filter cake was rinsed with 10 mL of methanol. The filter cake was dried at 50°C to obtain 8.9 g of a light yellow solid with a yield of 95.0% and a HPLC purity of 99.2%. 1 H NMR(400MHz,DMSO-d6)δ:7.98(s,1H),7.55(s,1H),7.15-7.37(m,5H),5.3 8(s,1H),4.46(m,2H),3.73(s,3H),2.25(s,3H),2.06(s,3H),1.32(t,3H)

[0075] Example 2

[0076] (1) Preparation of methyl 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (Compound 5)

[0077] Add 4-cyano-2-methoxybenzaldehyde (40.00g, 0.25mol), methyl acetoacetate (29.00g, 0.25mol) and n-hexane (600mL) to a 1L three-necked reaction bottle, stir to completely dissolve, add morpholine (2.16g, 0.025mol), and 1.52g of glacial acetic acid, and heat to 60°C. React for 6h, and use a water separator to separate water. The reaction solution is distilled under reduced pressure at 40°C until there is basically no fraction, and then cooled to room temperature to obtain a yellow residue (compound 3). Add 250mL of n-propanol and 4-amino-5-methylpyridone (27.68g, 0.22mol) to the residue, heat to 95°C, and react for 16h. The mixture was cooled to 5°C, stirred for 2 h and then filtered. The filter cake was washed with 40 mL of purified water and dried under air at 50°C to obtain 59.5 g of a yellow solid with a yield of 92.0% and a HPLC purity of 98.6%.

[0078] (2) Preparation of methyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (Compound 6)

[0079] Compound 5 (14.00 g, 0.04 mol), triethyl orthoformate (29.6 g, 0.2 mol), N-methylpyrrolidone (70 mL) and 1.0 g of concentrated sulfuric acid were added to a 500 mL three-necked reaction bottle in sequence, and the temperature was raised to 130°C and stirred for 2 h, and the heating was stopped. The temperature was lowered to 15-20°C, and 125 mL of purified water was added dropwise. A large amount of solid precipitated, and it was filtered after stirring for 2 h. The filter cake was dried with air at 50°C to obtain 14.4 g of a yellow solid, with a yield of 95% and a HPLC purity of 98.4%.

[0080] (3) Preparation of racemic form of phenerenone

[0081] Compound 6 (10.00 g, 0.026 mol) and 150 mL of 7M methanolic ammonia solution were added to a 500 mL high pressure reactor and heated to 80°C for 12 h. The mixture was cooled to 5°C and stirred for 2 h. The mixture was filtered and the filter cake was rinsed with 10 mL of methanol. The filter cake was dried at 50°C to obtain 8.8 g of a light yellow solid with a yield of 93.0% and a HPLC purity of 99.4%.

[0082] Example 3

[0083] (1) Preparation of methyl 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (Compound 5)

[0084] Add 4-cyano-2-methoxybenzaldehyde (40.00g, 0.25mol), methyl acetoacetate (43.5g, 0.375mol) and dichloromethane (600mL) to a 1L three-necked reaction bottle, stir to completely dissolve, add morpholine (4.32g, 0.05mol), and 3.04g of glacial acetic acid, and heat to 40°C. React for 10h, and use a water separator to separate water. The reaction solution is distilled under reduced pressure at 40°C until there is basically no fraction, and then cooled to room temperature to obtain a yellow residue (compound 3). Add 250mL of sec-butyl alcohol and 4-amino-5-methylpyridone (27.68g, 0.22mol) to the residue, heat to 99°C, and react for 16h. The mixture was cooled to 5°C, stirred for 2 h and then filtered. The filter cake was washed with 40 ml of purified water and dried under air at 50°C to obtain 61.6 g of a yellow solid with a yield of 95.3% and a HPLC purity of 98.8%.

[0085] (2) Preparation of methyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (Compound 6)

[0086] Compound 5 (14.00 g, 0.04 mol), triethyl orthoformate (35.5 g, 0.24 mol), N,N-dimethylacetamide (70 mL) and 1.0 g of concentrated sulfuric acid were added to a 500 mL three-necked reaction bottle in sequence, and the mixture was heated to 130°C and stirred for 2 h. The heating was stopped. The mixture was cooled to 15-20°C, and 125 ml of purified water was added dropwise. A large amount of solid precipitated. The mixture was stirred for 2 h and then filtered. The filter cake was dried with air at 50°C to obtain 14.3 g of a yellow solid with a yield of 94.5% and a purity of 99.2% by HPLC.

[0087] (3) Preparation of racemic form of phenerenone

[0088] Compound 6 (10.00 g, 0.026 mol), 200 mL of methanol and 20 mL of ammonia water were added to a 500 mL three-necked flask, and the mixture was heated to 65°C for 18 h. The mixture was cooled to 10°C and stirred for 1 h. The mixture was filtered and the filter cake was rinsed with 10 mL of methanol. The filter cake was dried at 50°C to obtain 8.94 g of a light yellow solid with a yield of 95.4% and a HPLC purity of 99.5%.

[0089] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing a racemate of finerenone, comprising the following steps: 4-cyano-2-methoxybenzaldehyde, methyl acetoacetate, an organic solvent and a catalyst are mixed and subjected to a Novegrin reaction to obtain methyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate having a structure shown in formula a; 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoic acid methyl ester having a structure shown in formula a, 4-amino-5-methylpyridone and an organic solvent are mixed and subjected to a ring-forming reaction to obtain 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula b; 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula b, triethyl orthoformate, sulfuric acid and an organic solvent are mixed and subjected to an oxyalkylation reaction to obtain 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula c; 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid methyl ester having a structure shown in formula C is mixed with ammonia water and a solvent, and an aminolysis reaction is carried out to obtain a finerenone racemate.

2. The preparation method according to claim 1, characterized in that: The molar ratio of 4-cyano-2-methoxybenzaldehyde to methyl acetoacetate is 1:(1-1.5); The molar ratio of the 4-cyano-2-methoxybenzaldehyde to morpholine is 10:(1-2).

3. The preparation method according to claim 1 or 2, characterized in that: The temperature of the brain wenge reaction is 40 to 60° C., and the time is 6 to 10 hours.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the 4-amino-5-methylpyridone to 4-cyano-2-methoxybenzaldehyde is 0.22:0.

25.

5. The preparation method according to claim 1 or 4, characterized in that: The temperature of the cyclization reaction is 95-99° C. and the time is 16 hours.

6. The preparation method according to claim 1, characterized in that: The molar ratio of 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester to triethyl orthoformate is 1:(5-6); The mass ratio of the 4-(4-cyano-2-methoxyphenyl)-2-methyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylic acid methyl ester to sulfuric acid is 14:

1.

7. The preparation method according to claim 1 or 6, characterized in that: The temperature of the oxyalkylation reaction is 120-130° C. and the time is 2 hours.

8. The preparation method according to claim 1, characterized in that: The volume ratio of the amount of the 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid methyl ester to the ammonia water is 0.026 mol:10 mL.

9. The preparation method according to claim 1 or 8, characterized in that: The temperature of the aminolysis reaction is reflux temperature, and the time is 12 to 18 hours.

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