Process for the preparation of finerenone and intermediates thereof

Abstract

The application provides a preparation method of finerenone and intermediates thereof. The application discloses a preparation method of a finerenone intermediate 5, which comprises the following steps: step 1: in an organic solvent, a resolution reaction is carried out between a finerenone intermediate 2 and D-tartaric acid diphenyl ester to obtain a resolution salt, then an acid-base reaction is carried out between the resolution salt and a base to obtain the finerenone intermediate 3; step 2: in an organic solvent, a nucleophilic substitution reaction is carried out between the finerenone intermediate 3 and triethyl orthoformate in the presence of an acid to obtain a finerenone intermediate 4; step 3: in a solvent, a hydrolysis reaction is carried out between the finerenone intermediate 4 to obtain the finerenone intermediate 5. The preparation method has the advantages of short reaction steps, high total reaction yield, simple and safe operation, simple post-treatment steps, high product purity, low production cost and suitability for industrial production.

Description

TECHNICAL FIELD

[0001] The present invention relates to a process for the preparation of finerenone and intermediates thereof. BACKGROUND

[0002] Finerenone, chemically (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4- dihydro-1,6-naphthyridine-3-carboxamide, as a non-steroidal antagonist of the mineralocorticoid receptor, can be used for the prevention and / or treatment of cardiovascular and renal diseases, such as heart failure and chronic kidney disease.

[0003]

[0004] ChemMedChem, 2012, 7, 1385 reported the preparation of finerenone from vanillin in 10 steps with a total yield of only 3.76%.

[0005] WO 2008 / 104306 also reported a process for the preparation of finerenone, but is not suitable for commercial production due to the low total yield (only 5%), the need for spectral purification of many intermediates and the large solvent consumption. In WO 2008 / 104306 a specially synthesized chiral phase (in-house preparation) was used for the resolution, which contains poly(N-methylacryloyl-D-leucine-dicyclopropylmethylamide) as chiral selector. According to Bayer, it is also possible to perform the separation on easily commercially available phases. It uses the phase Chiralpak AS-V, 20 pm. The eluent used is a mixture of methanol / acetonitrile 60:40. In this case, the chromatographic analysis can be carried out on a conventional chromatographic column, but preferably using techniques known to the person skilled in the art, such as SMB (simulated moving bed; G. Paredes, M. Mazotti, Journal of Chromatography A, 1142 (2007): 56-68) or Varicol (Computers and Chemical Engineering 27 (2003) 1883-1901).

[0006] CN112040318A reported the use of chiral substituted tartaric acid esters of general formula (IIIa) or (IIIb) as resolving agents for the resolution of the racemate to obtain finerenone with a resolution yield of 91.4%. However, the residual resolving agent is difficult to remove after resolution.

[0007] Therefore, there is a need to find a process for the preparation of finerenone that is industrially feasible, has a high total yield, is low in production costs and produces a product with high purity. SUMMARY

[0008] The technical problem solved by the present application is to provide a preparation method of finerenone and intermediates thereof to overcome the defects of long reaction steps, low total yield, complicated post-treatment steps, low purity of the prepared product, complicated resolution steps, high production cost and unsuitability for industrial production in the prior art.

[0009] The present application provides a preparation method of finerenone intermediate 3, which comprises the following steps: performing a resolution reaction on finerenone intermediate 2 and D-tartaric acid diphenyl ester in an organic solvent to obtain a resolution salt, and then performing an acid-base reaction on the resolution salt with a base to obtain the finerenone intermediate 3.

[0010]

[0011] In the present application, the preparation method of the finerenone intermediate 3 preferably adopts the following reaction conditions:

[0012] In the preparation method of the finerenone intermediate 3, the organic solvent is preferably a halogenated hydrocarbon solvent, and the halogenated hydrocarbon solvent is preferably dichloromethane.

[0013] In the preparation method of the finerenone intermediate 3, the volume / mass ratio of the organic solvent to the finerenone intermediate 2 is preferably 1 g / mL to 50 mL, and more preferably 20 g / mL to 40 mL, for example, 30 mL.

[0014] In the preparation method of the finerenone intermediate 3, the molar ratio of the D-tartaric acid diphenyl ester to the finerenone intermediate 2 is preferably 0.5 to 3.0, and more preferably 0.8 to 1.5, for example, 1.1.

[0015] In the preparation method of the finerenone intermediate 3, the temperature of the resolution reaction is preferably 10°C to 50°C, and more preferably 20°C to 40°C, for example, 30°C to 40°C or 20°C to 25°C.

[0016] In the preparation method of the finerenone intermediate 3, the resolution reaction is preferably performed for 1 hour to 24 hours, and more preferably for 18 hours to 20 hours.

[0017] In the preparation method of the finerenone intermediate 3, the base can be one or more of sodium phosphate, sodium carbonate and sodium bicarbonate.

[0018] In the preparation method of the finerenone intermediate 3, the pH of the acid-base reaction is preferably 7 to 9.

[0019] In the process for preparing the finasteride intermediate 3, the temperature of the acid-base reaction is preferably 20°C to 80°C, for example 50°C to 70°C.

[0020] In the process for preparing the finasteride intermediate 3, the time of the acid-base reaction is preferably 1 hour to 30 hours, further preferably 5 hours to 15 hours.

[0021] The process for preparing the finasteride intermediate 3 according to the present application further comprises a process for preparing the finasteride intermediate 2, which comprises the following step: subjecting the finasteride intermediate 1 to a cyclization reaction with 4-amino-5-methyl-2-hydroxypyridine in an organic solvent to obtain the finasteride intermediate 2;

[0022]

[0023] The process for preparing the finasteride intermediate 2 can employ the conventional conditions for such cyclization reactions in the art, and the following reaction conditions are preferred in the present application:

[0024] In the process for preparing the finasteride intermediate 2, the organic solvent is preferably an alcohol solvent; and the alcohol solvent is preferably 2-butanol (sec-butanol) and / or 1-butanol (n-butanol).

[0025] In the process for preparing the finasteride intermediate 2, the volume / mass ratio of the organic solvent to the finasteride intermediate 1 is preferably 1 mL / g to 30 mL / g; further preferably 1 mL / g to 5 mL / g, for example 2 mL / g.

[0026] In the process for preparing the finasteride intermediate 2, the mass ratio of the finasteride intermediate 1 to the 4-amino-5-methyl-2-hydroxypyridine is preferably 1.0 to 5.0, further preferably 2.0 to 3.0, for example 2.6.

[0027] In the process for preparing the finasteride intermediate 2, the temperature of the cyclization reaction is preferably 80°C to 150°C, further preferably 90°C to 140°C, for example 120°C.

[0028] In the process for preparing the finasteride intermediate 2, the time of the cyclization reaction is monitored by using the conventional detection methods in the art (for example HPLC, NMR or TLC), and the reaction is generally terminated when the finasteride intermediate 1 disappears, preferably 1 hour to 24 hours, further preferably 10 hours to 20 hours, for example 16 hours.

[0029] The preparation method of the finerenone intermediate 2 preferably adopts the following post-processing steps: after the reaction is completed, cooling, crystallization, and beating to obtain the finerenone intermediate 2. The cooling is preferably to a temperature of 40-50 DEG C. The crystallization temperature is preferably 0-10 DEG C. The crystallization time is preferably 1-10 hours, for example, 2-3 hours. The beating preferably uses a citric acid aqueous solution. The concentration of the citric acid aqueous solution is preferably 1-10%, for example, 5%, and the concentration refers to the mass percentage of citric acid in the total mass of the citric acid aqueous solution.

[0030] The preparation method of the finerenone intermediate 3 further comprises the preparation method of the finerenone intermediate 1, which comprises the following steps: condensation reaction of 4-bromo-2-methoxybenzaldehyde and 2-cyanoacetic acid ethyl ester in an organic solvent in the presence of an acid and a catalyst to obtain the finerenone intermediate 1.

[0031]

[0032] The preparation method of the finerenone intermediate 1 can adopt the conventional method for such condensation reaction in the art, and the following reaction conditions are particularly preferred in the present application:

[0033] In the preparation method of the finerenone intermediate 1, the organic solvent is preferably an alcohol solvent; and the alcohol solvent is preferably isopropyl alcohol.

[0034] In the preparation method of the finerenone intermediate 1, the volume-mass ratio of the organic solvent to the 4-bromo-2-methoxybenzaldehyde is preferably 1.0 mL / g-30.0 mL / g, further preferably 2.0 mL / g-10.0 mL / g, for example, 3.3 mL / g.

[0035] In the preparation method of the finerenone intermediate 1, the mass ratio of the 2-cyanoacetic acid ethyl ester to the 4-bromo-2-methoxybenzaldehyde is preferably 1.0-5.0, further preferably 1.0-2.0, for example, 1.0.

[0036] In the preparation method of the finerenone intermediate 1, the acid is preferably an organic acid; and the organic acid is preferably acetic acid.

[0037] In the preparation method of the finerenone intermediate 1, the molar ratio of the acid to the 4-bromo-2-methoxybenzaldehyde is preferably 0.01-1, further preferably 0.10-0.30, for example, 0.15.

[0038] In the preparation method of the finerenone intermediate 1, the catalyst is preferably piperidine.

[0039] In the process for preparing the non-steroidal glucocorticoid receptor antagonist non-steroidal glucocorticoid receptor antagonist intermediate 1, the molar ratio of the catalyst to the 4-bromo-2-methoxybenzaldehyde is preferably 0.01 to 1, further preferably 0.10 to 0.30, for example 0.15.

[0040] In the process for preparing the non-steroidal glucocorticoid receptor antagonist non-steroidal glucocorticoid receptor antagonist intermediate 1, the temperature of the condensation reaction is preferably 10°C to 60°C, further preferably 20°C to 50°C, for example 30°C to 40°C.

[0041] In the process for preparing the non-steroidal glucocorticoid receptor antagonist non-steroidal glucocorticoid receptor antagonist intermediate 1, the time of the condensation reaction can be monitored by using conventional detection methods in the art (e.g. HPLC, TLC or NMR), generally the end of the reaction is determined by the disappearance of the 4-bromo-2-methoxybenzaldehyde, in the present application the time is preferably 1 hour to 24 hours, for example 3 hours to 4 hours.

[0042] The process for preparing the non-steroidal glucocorticoid receptor antagonist non-steroidal glucocorticoid receptor antagonist intermediate 1 preferably comprises the following post-treatment steps: after the reaction is completed, the non-steroidal glucocorticoid receptor antagonist intermediate 1 is obtained by crystallization, filtration and washing. The temperature of the crystallization is preferably 10°C to 20°C. The time of the crystallization is preferably 1 hour to 24 hours, for example 16 hours. The washing is preferably performed by using an alcohol solvent; the alcohol solvent is preferably methanol.

[0043] The present application also provides a process for preparing the non-steroidal glucocorticoid receptor antagonist non-steroidal glucocorticoid receptor antagonist intermediate 4, which comprises the following steps: after the non-steroidal glucocorticoid receptor antagonist intermediate 3 is prepared according to the above method, the non-steroidal glucocorticoid receptor antagonist intermediate 3 is subjected to a nucleophilic substitution reaction with triethyl orthoformate in the presence of an acid in an organic solvent to obtain the non-steroidal glucocorticoid receptor antagonist intermediate 4.

[0044]

[0045] The process for preparing the non-steroidal glucocorticoid receptor antagonist non-steroidal glucocorticoid receptor antagonist intermediate 4 can use conventional conditions for such nucleophilic substitution reactions in the art, in the present application the following reaction conditions are particularly preferred:

[0046] In the process for preparing the non-steroidal glucocorticoid receptor antagonist non-steroidal glucocorticoid receptor antagonist intermediate 4, the organic solvent is preferably an amide solvent; the amide solvent is preferably N,N-dimethylacetamide and / or N,N-dimethylformamide.

[0047] In the process for preparing the non-steroidal glucocorticoid receptor antagonist non-steroidal glucocorticoid receptor antagonist intermediate 4, the volume / mass ratio of the organic solvent to the non-steroidal glucocorticoid receptor antagonist intermediate 3 is preferably 1 mL / g to 100 mL / g, further preferably 2 mL / g to 10 mL / g, for example 5.7 mL / g.

[0048] In the process for preparing the non-steroidal glucocorticoid receptor antagonist non-steroidal glucocorticoid receptor antagonist intermediate 4, the mass ratio of the triethyl orthoformate to the non-steroidal glucocorticoid receptor antagonist intermediate 3 is preferably 1 to 5, further preferably 1.1 to 2.0, for example 1.4.

[0049] In the preparation method of the finerenone intermediate 4, the acid is preferably an inorganic acid, and the inorganic acid is preferably concentrated sulfuric acid. The concentrated sulfuric acid can be a conventional commercially available concentrated sulfuric acid reagent. The concentration of the concentrated sulfuric acid can be 98%, and the concentration refers to the percentage of the mass of sulfuric acid in the total mass of the concentrated sulfuric acid aqueous solution.

[0050] In the preparation method of the finerenone intermediate 4, the molar ratio of the acid to the finerenone intermediate 3 is preferably 0.10-0.50, further preferably 0.20-0.45, for example 0.38.

[0051] In the preparation method of the finerenone intermediate 4, the temperature of the nucleophilic substitution reaction is preferably 100-150°C, further preferably 110-140°C, for example 115-125°C.

[0052] In the preparation method of the finerenone intermediate 4, the time of the nucleophilic substitution reaction is monitored by using conventional detection methods in the art (such as TLC, HPLC or NMR), and the disappearance of the finerenone intermediate 3 is generally used as the end point of the reaction. The time of the nucleophilic substitution reaction is preferably 1-10 hours, for example 2-3 hours.

[0053] The preparation method of the finerenone intermediate 4 preferably comprises the following post-treatment steps: after the reaction is completed, cooling, adding water, and crystallization to obtain the finerenone intermediate 4. The cooling can be to 50-60°C. The crystallization preferably comprises adding crystal seeds and stirring for crystallization. The temperature of the crystallization is preferably 0-10°C. The time of the crystallization is preferably 2-3 hours.

[0054] The present application also provides a synthesis method of the finerenone intermediate 5, which comprises the following steps: after the finerenone intermediate 4 is prepared according to the above method, the finerenone intermediate 4 is subjected to a hydrolysis reaction in a solvent to obtain the finerenone intermediate 5.

[0055]

[0056] The preparation method of the finerenone intermediate 5 can use conventional conditions for such hydrolysis reactions in the art, and the following reaction conditions are particularly preferred in the present application:

[0057] In the preparation method of the finerenone intermediate 5, the organic solvent is preferably an ether solvent, and the ether solvent is preferably tetrahydrofuran (THF).

[0058] In the preparation method of the finerenone intermediate 5, the volume-to-mass ratio of the organic solvent to the finerenone intermediate 4 is preferably 1-100 mL / g, further preferably 2-10 mL / g, for example 5.3 mL / g.

[0059] In the preparation method of the finerenone intermediate 5, the base is preferably an inorganic base, and the inorganic base is preferably sodium hydroxide. The sodium hydroxide can be used in the form of an aqueous solution. The concentration of the sodium hydroxide aqueous solution can be 1% to 50%, for example, 7.3%, and the percentage refers to the mass percentage of sodium hydroxide in the total mass of the sodium hydroxide aqueous solution.

[0060] In the preparation method of the finerenone intermediate 5, the molar ratio of the base to the finerenone intermediate 4 is preferably 1 to 5, and further preferably 1.1 to 3.0, for example, 2.0.

[0061] In the preparation method of the finerenone intermediate 5, the temperature of the hydrolysis reaction is preferably -10°C to 20°C, and further preferably -5°C to 10°C, for example, -5°C to 5°C.

[0062] In the preparation method of the finerenone intermediate 5, the time of the hydrolysis reaction is monitored by using a conventional detection method in the art (for example, TLC, HPLC or NMR), and the end of the reaction is generally when the finerenone intermediate 4 disappears. The time of the hydrolysis reaction is preferably 1 hour to 10 hours, for example, 4 hours to 5 hours.

[0063] The preparation method of the finerenone intermediate 5 preferably comprises the following post-processing steps: after the reaction is completed, extraction, pH adjustment to about 3, filtration, and washing to obtain the finerenone intermediate 5. The extraction is preferably performed by using toluene. The pH adjustment can be performed by using hydrochloric acid, and the concentration of the hydrochloric acid can be 5% to 15%, for example, 10%, and the percentage refers to the mass percentage of hydrogen chloride in the total mass of the hydrochloric acid aqueous solution. The washing is preferably performed by using water and toluene in sequence, and the number of washing is preferably 1 to 3 times, for example, 2 times.

[0064] The application also provides a preparation method of the finerenone intermediate 6, which comprises the following steps: after the finerenone intermediate 5 is prepared according to the above method, the finerenone intermediate 5 is subjected to a condensation reaction with hexamethyl disilazane in the presence of an organic solvent, a catalyst and a condensing agent to obtain the finerenone intermediate 6.

[0065]

[0066] The preparation method of the finerenone intermediate 6 can use conventional methods and conditions for such condensation reactions in the art, and the following reaction conditions are particularly preferred in the application:

[0067] In the preparation method of the finerenone intermediate 6, the organic solvent is preferably an ether solvent, and the ether solvent is preferably tetrahydrofuran (THF).

[0068] In the process for preparing the finasteride intermediate 6, the volume / mass ratio of the organic solvent to the finasteride intermediate 5 is preferably 1 mL / g to 30 mL / g, further preferably 2 mL / g to 10 mL / g, for example 5.2 mL / g.

[0069] In the process for preparing the finasteride intermediate 6, the catalyst is preferably 4-dimethylaminopyridine (DMAP).

[0070] In the process for preparing the finasteride intermediate 6, the mole ratio of the catalyst to the finasteride intermediate 5 is preferably 0.01 to 2, further preferably 0.05 to 0.2, for example 0.1.

[0071] In the process for preparing the finasteride intermediate 6, the condensing agent is preferably N,N'-carbonyldiimidazole (CDI).

[0072] In the process for preparing the finasteride intermediate 6, the mole ratio of the condensing agent to the finasteride intermediate 5 is preferably 1.0 to 5.0, further preferably 1.1 to 2.0, for example 1.4.

[0073] In the process for preparing the finasteride intermediate 6, the mole ratio of the hexamethyldisilazane to the finasteride intermediate 5 is preferably 1.0 to 10.0, further preferably 2.0 to 6.0, for example 4.4.

[0074] In the process for preparing the finasteride intermediate 6, the temperature of the condensation reaction is preferably 20°C to 100°C, further preferably 65°C to 75°C, for example 70°C.

[0075] In the process for preparing the finasteride intermediate 6, the time of the condensation reaction is monitored by using the conventional detection methods in the art (e.g. TLC, HPLC or NMR), and the end of the reaction is generally determined by the disappearance of the finasteride intermediate 5, and the time of the condensation reaction is preferably 5 hours to 25 hours, further preferably 10 hours to 20 hours, for example 16 hours.

[0076] The process for preparing the finasteride intermediate 6 preferably comprises the following post-treatment steps: after the reaction is completed, adding an aqueous tetrahydrofuran solution, refluxing, cooling, filtering, and washing to obtain the finasteride intermediate 6. The volume ratio of tetrahydrofuran to water in the aqueous tetrahydrofuran solution is preferably 0.5 to 5, for example 1.4. The temperature of the refluxing is preferably 70°C to 80°C. The cooling is preferably to about 0°C. The rate of the cooling is preferably 14°C / hour to 27°C / hour. The washing is preferably with tetrahydrofuran and water in sequence; the number of washing is preferably 1 to 3 times, for example 2 times.

[0077] The present application also provides a preparation method of finerenone, which comprises the following steps: after obtaining the finerenone intermediate 6 by the above method, performing a nucleophilic substitution reaction on the finerenone intermediate 6 and zinc cyanide in an organic solvent in the presence of a catalyst to obtain the finerenone.

[0078]

[0079] The preparation method of the finerenone can adopt conventional methods and conditions for such nucleophilic substitution reactions in the art, and the following reaction conditions are particularly preferred in the present application:

[0080] In the preparation method of the finerenone, the organic solvent is preferably an amide solvent; and the amide solvent is preferably N,N-dimethylformamide (DMF).

[0081] In the preparation method of the finerenone, the volume / mass ratio of the organic solvent to the finerenone intermediate 6 is preferably 1 mL / g to 30 mL / g, further preferably 2 mL / g to 20 mL / g, for example 10 mL / g.

[0082] In the preparation method of the finerenone, the molar ratio of the zinc cyanide to the finerenone intermediate 6 is preferably 0.5 to 3, further preferably 1.0 to 2.0, for example 1.5.

[0083] In the preparation method of the finerenone, the catalyst is preferably 1,1'-bis(diphenylphosphino)ferrocene and / or Pd2(dba) 3， tetraphenylphosphine palladium.

[0084] In the preparation method of the finerenone, the molar ratio of the catalyst to the finerenone intermediate 6 is preferably 0.001 to 1.0, further preferably 0.05 to 0.2, for example 0.10.

[0085] In the preparation method of the finerenone, the temperature of the nucleophilic substitution reaction is preferably 60°C to 150°C, further preferably 90°C to 140°C, for example 100°C.

[0086] In the preparation method of the finerenone, the time of the nucleophilic substitution reaction can be monitored by using conventional detection methods in the art (for example HPLC, TLC or NMR), and the reaction is generally terminated when the finerenone intermediate 6 disappears; in the present application, the time is preferably 1 hour to 30 hours, further preferably 5 hours to 25 hours, for example 15 hours to 20 hours.

[0087] The preparation method of finerenone preferably comprises the following post-processing steps: after the reaction is completed, cooling, extraction, washing, and drying to obtain crude finerenone. The crude finerenone is preferably recrystallized to obtain finerenone. The solvent used in the recrystallization is preferably an alcohol solvent; and the alcohol solvent is preferably ethanol.

[0088] The preparation method of finerenone provided by the application preferably adopts the following synthesis route:

[0089]

[0090] The application further provides a preparation method of finerenone intermediate 1, which comprises the following steps: condensation reaction of 4-bromo-2-methoxybenzaldehyde and 2-cyanoacetic acid ethyl ester in an organic solvent in the presence of an acid and a catalyst to obtain the finerenone intermediate 1.

[0091]

[0092] In the above reactions, the reaction conditions are the same as described above.

[0093] The application further provides a preparation method of finerenone intermediate 2, which comprises the following steps: cyclization reaction of the finerenone intermediate 1 and 4-amino-5-methyl-2-hydroxypyridine in an organic solvent to obtain the finerenone intermediate 2.

[0094]

[0095] In the above reactions, the reaction conditions are the same as described above.

[0096] The application further provides a preparation method of finerenone intermediate 4, which comprises the following steps: nucleophilic substitution reaction of the finerenone intermediate 3 and triethyl orthoformate in an organic solvent in the presence of an acid to obtain the finerenone intermediate 4.

[0097]

[0098] In the above reactions, the reaction conditions are the same as described above.

[0099] The application further provides a preparation method of finerenone intermediate 5, which comprises the following steps: hydrolysis reaction of the finerenone intermediate 4 in a solvent to obtain the finerenone intermediate 5.

[0100]

[0101] In the above reactions, the reaction conditions are the same as described above.

[0102] The application further provides a preparation method of finerenone intermediate 6, which comprises the following steps: performing a condensation reaction on finerenone intermediate 5 and hexamethyl disilazane in an organic solvent in the presence of a catalyst and a condensing agent to obtain the finerenone intermediate 6.

[0103]

[0104] The reaction conditions are the same as described above.

[0105] The application further provides a preparation method of finerenone, which comprises the following steps: performing a nucleophilic substitution reaction on finerenone intermediate 6 and zinc cyanide in an organic solvent in the presence of a catalyst to obtain the finerenone.

[0106]

[0107] The reaction conditions are the same as described above.

[0108] The raw materials or reagents in the application are commercially available, except for special instructions.

[0109] In the application, the room temperature refers to the ambient temperature, which is 10-35°C.

[0110] The positive progress effect of the application is that the preparation method has short reaction steps, high total reaction yield, simple and safe operation, simple post-treatment steps, high product purity, low production cost and suitability for industrial production. DETAILED DESCRIPTION

[0111] The application will be further described by means of examples, but the application is not limited in the scope of the examples. The experimental methods in the following examples without specific conditions are selected according to conventional methods and conditions or according to the instructions of the goods.

[0112] Example 1: Preparation of finerenone intermediate 1

[0113] Into a reaction bottle, 150 g of p-4-bromo-2-methoxybenzaldehyde (0.698 mol), 500 ml of isopropyl alcohol, 9.1 g of piperidine (0.107 mol) and 6.4 g of acetic acid (0.107 mol) were added, and stirred uniformly, and heated to 30-40°C. Then, 146 g of ethyl 2-cyanoacetoacetate in 50 ml of isopropyl alcohol was added dropwise into the reaction solution. After the dropwise addition was completed, the reaction was carried out at 30-40°C for 3-4 hours. After cooling to 10-20°C, the stirring was carried out for 16 hours. Then, the filter cake was washed with 100 ml of methanol, and dried to obtain 170 g of solid (finerenone intermediate 1). The HPLC purity was 92.50%, and the yield was 82.1%.

[0114] Example 2: Preparation of finerenone intermediate 2

[0115] 150g of phenelzine intermediate 1, 57g of 4-amino-5-methyl-2-hydroxypyridine, and 300ml of 2-butanol were added to an autoclave. The reaction was carried out at 120℃ for 16 hours, then cooled to 40-50℃, and then gradually cooled to 0-10℃. The mixture was stirred for 2-3 hours, filtered, and the filter cake was slurried with 600ml of 5% citric acid aqueous solution (the percentage refers to the mass of citric acid to the total mass of the citric acid aqueous solution). The mixture was filtered again, and the filter cake was washed with 300ml of water and dried to obtain 148.5g of solid (phenelzine intermediate 2). The HPLC purity was 98.08%, and the yield was 73.1%.

[0116] Example 3 Preparation of phenelzine intermediate 3

[0117] Add 35g of phenelzine intermediate 2 (0.076mol), dichloromethane solution (1050mL), and 31g of D-diphenyl tartrate to the reaction flask. 0.086 mol), the reaction solution was heated to 30-40℃ and stirred for 2-4 hours, then cooled to 20-25℃ and stirred for 16 hours, filtered, and dried to obtain 31.5 g of the decomposed salt. Add the sample to a bottle, add 60 ml of ethanol and 250 ml of water, heat to 50°C, add 100 ml of 9.1% sodium phosphate aqueous solution dropwise (the percentage refers to the mass of sodium phosphate to the total mass of the sodium phosphate aqueous solution), adjust the pH to 7-8, stir at 50°C for 1-2 hours, then gradually cool to 20-25°C, stir overnight, filter, wash with 25 ml of 25% ethanol, dry to obtain 14.1 g of solid, add 120 ml of ethanol and 60 ml of water, heat to 70°C and stir for 30 minutes, add 7 g of 1.6% sodium phosphate to the reaction solution, adjust the pH to about 9, stir at 70°C overnight after the addition is complete, cool to 40°C, concentrate until almost no distillate, add 180 ml of water, stir at room temperature for 1-2 hours, filter, dry the filter cake to obtain 13.3 g of solid (fenelone intermediate 3). HPLC purity 98.9%, chiral purity 99.5%, yield 38.0%.

[0118] Example 4 Preparation of phenelzine intermediate 4

[0119] Into a reaction flask, add 140 g of the nonaline intermediate 3 (0.305 mol), 800 ml of N,N-dimethylacetamide, heat to 100°C, stir for 10-20 minutes, add 191 g of triethyl orthoformate, 11.5 g of concentrated sulfuric acid (0.115 mol), heat to 115-125°C and stir for 2-3 hours, cool to 50-60°C, add 800 ml of water dropwise, add seed crystals to crystallize, add another 800 ml of water, cool to 0-10°C, stir for 2-3 hours, filter, wash the filter cake with 150 ml of water, and dry to obtain 143.9 g of the nonaline intermediate 4 in powder form. The HPLC purity is 97.30%, the chiral purity is 99.8%, and the yield is 93.9%.

[0120] Example 5 Preparation of the nonaline intermediate 5

[0121] Into a reaction flask, add the nonaline intermediate 4 (175.5 g, 0.361 mol), THF (936 mL), water (468 mL), and cool to -5-5°C, and then add a solution of sodium hydroxide (28.9 g, 0.7225 mol) in water (365 mL) dropwise. After the dropwise addition, maintain the temperature for 4-5 hours, add toluene (390 mL) and sodium acetate (30 g) to the reaction solution, and stir for 30 minutes, separate the phases, and extract the aqueous phase with toluene (390 mL) once. Reserve the aqueous phase, and adjust the pH to about 3 with 10% hydrochloric acid. Stir for 1 hour, filter, wash the filter cake with water (300 mL x 2) and toluene (50 mL x 2). Collect the filter cake, and dry at 50°C to obtain 165.3 g of the nonaline intermediate 5. The HPLC purity is 96.08%, the chiral purity is 99.9%, and the yield is 99%.

[0122] Example 6 Preparation of the nonaline intermediate 6

[0123] N, N'-carbonyldiimidazole (CDI, 22.7 g, 0.14 mol) was dissolved in THF (227 ml), 4-dimethylaminopyridine (DMAP, 1.22 g, 0.01 mol) was added, and the reaction was carried out at 20-25 °C for 1-2 hours, and then heated to about 50 °C for 2-3 hours. Hexamethyldisilazane (HMDS, 70.4 g, 0.44 mol) was added to the reaction solution, and the reaction was carried out at a slow heating to about 70 °C for 16 hours. THF (45 ml) was added to the reaction solution, and the temperature was lowered to 0-5 °C. Then a mixture of THF (28 ml) and water (20 ml) was slowly added dropwise to the reaction solution, and the reaction was carried out at a heating to 70-80 °C for 1-2 hours. The temperature was lowered to about 0 °C (3-5 hours) in a gradient, and then stirred for 1-2 hours. Filtration was performed, and the filter cake was washed with THF (50 ml) x 2 and water (80 ml) x 2. The filter cake was dried at 70 °C overnight to obtain 40.6 g of a white solid powder (non- narinex intermediate 6) with a HPLC purity of 100%, a chiral purity of 100%, and a yield of 94.1%.

[0124] Example 7 Preparation of non-narinex

[0125] Non-narinex intermediate 6 (30 g, 0.0694 mol) and zinc cyanide (12.2 g, 0.104 mol) were added to N, N-dimethylformamide (DMF, 300 ml), and tetrakis triphenylphosphine palladium (8.02 g, 0.00694 mol) was added to the reaction bottle. Nitrogen was replaced three times, and the temperature was raised to 100 °C. The reaction was carried out for 15-20 hours. The reaction was completed. The temperature was lowered to 20-25 °C. Water (50 ml) and dichloromethane (DCM, 150 ml) were added to the reaction solution, and the mixture was stirred for 30 min. The mixture was separated, and the water phase was extracted with dichloromethane (DCM, 150 ml) three times. The organic phase was combined, washed with saturated brine (100 ml) three times, dried over anhydrous sodium sulfate, and concentrated. Ethanol was added for recrystallization to obtain 20 g of non-narinex with a HPLC purity of 99%, a chiral purity of 100%, and a yield of 76%.

Claims

1. A process for the preparation of a non-nalirximab intermediate 5 characterized by The method comprises the following steps: Into a reaction flask was added 35 g, 0.076 mol of the nonaline intermediate 2 in 1050 mL of dichloromethane, 31 g, 0.086 mol of The reaction solution was heated to 30-40°C and stirred for 2-4 hours, then cooled to 20-25°C and stirred for 16 hours, filtered, and dried to obtain 31.5 g of the resolution salt; which was added to a flask, 60 ml of ethanol and 250 ml of water were added, heated to 50°C, 100 ml of 9.1% sodium phosphate aqueous solution was added dropwise, the percentage refers to the mass of sodium phosphate accounting for the percentage of the total mass of sodium phosphate aqueous solution, the pH was adjusted to 7-8, 50°C was stirred for 1-2 hours, then gradient cooling to 20-25°C, stirring overnight, filtering, washing with 25 ml 25% ethanol, drying to obtain 14.1 g of solid, 120 ml of ethanol and 60 ml of water were added, heated to 70°C and stirred for 30 minutes, 7 g of 1.6% sodium phosphate was added to the reaction solution, the pH was adjusted to about 9, after adding, 70°C was stirred overnight, cooled to 40°C, concentrated to substantially no fraction, added 180 ml of water, stirred at room temperature for 1-2 hours, filtered, and the filter cake was dried to obtain 13.3 g of solid nonaline intermediate 3; HPLC purity 98.9%, chiral purity 99.5%, yield 38.0%; The reaction bottle is added with 140 g, 0.305 mol of the nonaline intermediate 3, 800 ml of N,N-dimethylacetamide, and heated to 100 DEG C and stirred for 10-20 min, then 191 g of triethyl orthoformate and 11.5 g, 0.115 mol of concentrated sulfuric acid are added, and heated to 115-125 DEG C and stirred for 2-3 h, then cooled to 50-60 DEG C, 800 ml of water is added dropwise, and crystallization is carried out by adding seed crystals, then 800 ml of water is added, and cooled to 0-10 DEG C and stirred for 2-3 h, then filtered, the filter cake is washed with 150 ml of water, and dried to obtain 143.9 g of the nonaline intermediate 4 in powder form; the HPLC purity is 97.30%, the chiral purity is 99.8%, and the yield is 93.9%; The reaction bottle is added with 175.5 g, 0.361 mol of the nonaline intermediate 4, 936 ml of THF, and 468 ml of water, and cooled to -5~5 DEG C, then 28.9 g, 0.7225 mol of sodium hydroxide in 365 ml of water is added dropwise; after dropwise addition, the reaction is kept for 4~5 h, then 390 ml of toluene and 30 g of sodium acetate are added to the reaction solution, and stirred for 30 min; the liquid is separated, the water phase is extracted with 390 ml of toluene once, then the water phase is reserved, and the pH is adjusted to 3 by using 10% hydrochloric acid; stirred for 1 h, filtered, the filter cake is washed with 300 ml of water twice, and washed with 50 ml of toluene twice; the filter cake is collected, and dried at 50 DEG C to obtain the nonaline intermediate 5; the structures of the nonaline intermediates 2, 3, 4 and 5 are shown in the following respectively: 。 2. A process for the preparation of a non-nalerixone intermediate 6, characterized by The method comprises the following steps: The reaction bottle is added with 43.3 g, 0.10 mol of the nonaline intermediate 5, 22.7 g, 0.14 mol of N,N'-carbonyldiimidazole, and 227 ml of THF, then 1.22 g, 0.01 mol of 4-dimethylaminopyridine is added, and reacted at 20~25 DEG C for 1~2 h, then heated to about 50 DEG C and reacted for 2~3 h, then 70.4 g, 0.44 mol of hexamethyldisilazane is added to the reaction solution, and slowly heated to about 70 DEG C and reacted for 16 h, then 45 ml of THF is added to the reaction solution, and cooled to 0~5 DEG C, then a mixture of 28 ml of THF and 20 ml of water is slowly added dropwise to the reaction solution, then heated to 70~80 DEG C and refluxed for 1~2 h, then gradiently cooled to about 0 DEG C for 3~5 h, and then stirred for 1~2 h; filtered, washed with 50 ml of THF twice, washed with 80 ml of water twice, and the filter cake is collected and dried at 70 DEG C overnight to obtain 40.6 g of the nonaline intermediate 6 in white solid powder form; the structure of the nonaline intermediate 6 is shown in the following: 。

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