Preparation method, intermediate and application of fenerenone

Abstract

The invention relates to a preparation method, an intermediate and application of fenerenone. The raw materials for synthesizing the key intermediate are easy to obtain; in the preparation process, a by-product of a deprotection reaction is p-nitrostyrene, and has ultraviolet absorption, so that the reaction is convenient to monitor; the compound is low in toxicity, not easy to volatilize and beneficial to large-scale production of the fenerenone.

Description

Preparation method of finerenone, its intermediates and uses Technical Field

[0001] The present invention relates to the technical field of organic synthesis, in particular to a preparation method of finerenone, an intermediate thereof and use thereof. Background Art

[0002] Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist used to treat type 2 diabetes mellitus associated with chronic kidney disease. The chemical structure of finerenone is shown in the following formula X′:

[0003] Patent US2018244668A1 discloses a synthetic route of finerenone, as shown below:

[0004] The carboxyl protecting group used in this preparation route is 2-cyanoethyl, and the byproduct after deprotection is acrylonitrile, which is highly toxic, a Class 2B carcinogen, and is flammable and explosive, posing risks to industrial production.

[0005] Summary of the Invention

[0006] In one aspect, the present invention provides a method for preparing a compound of formula X, comprising the following steps:

[0007] Step 6: reacting the compound of formula VIII in the presence of a base in a solvent to obtain a compound of formula IX;

[0008] Step 7: The compound of formula IX is further reacted to obtain the compound of formula X,

[0009] Another aspect of the present invention provides a method for preparing finerenone, comprising the following steps:

[0010] Step 6: The compound of formula VIII' reacts in the presence of a base in a solvent to obtain a compound of formula IX';

[0011] Step 7: The compound of formula IX′ is further reacted to obtain finerenone,

[0012] In some embodiments of the present invention, the base in step 6 is any one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and potassium trimethylsiliconate. Preferably, the base is any one or more of sodium hydroxide, sodium ethoxide, and potassium trimethylsiliconate.

[0013] In some embodiments of the present invention, the reaction temperature in step 6 is -10 to 50°C.

[0014] In some embodiments of the present invention, the solvent in step 6 is an organic solvent A or a mixed solvent thereof with water.

[0015] In some embodiments of the present invention, the organic solvent A in step 6 is any one or more combinations of alcohols, ethers, acetone, and acetonitrile; preferably, the organic solvent A is any one or more combinations of methanol, ethanol, dioxane, and acetonitrile; more preferably, the organic solvent A is any one or more combinations of ethanol and acetonitrile.

[0016] In some embodiments of the present invention, the base in step 6 is sodium hydroxide, the organic solvent A is ethanol, the reaction temperature is selected from 20 to 50° C., and the reaction time is selected from 2 to 8 hours;

[0017] In some embodiments of the present invention, the base in step 6 is sodium ethoxide, the organic solvent A is ethanol, the reaction temperature is selected from 20 to 30° C., and the reaction time is selected from 1 to 5 hours;

[0018] In some embodiments of the present invention, the base in step 6 is potassium trimethylsilanol, the organic solvent A is acetonitrile, the reaction temperature is selected from -10 to 10° C., and the reaction time is selected from 8 to 25 hours.

[0019] In some embodiments of the present invention, in step 6, potassium trimethylsilanol and acetonitrile are mixed at 20-30°C, and the compound of formula VIII' is added at 0-5°C (e.g., 0°C, 1°C, 2°C, 3°C, 4°C, 5°C or any value or range therebetween), and stirred at this temperature for 8-16 hours.

[0020] In some embodiments of the present invention, step 6 further includes post-treatment and crystallization steps.

[0021] In some embodiments of the present invention, in step 6, the post-treatment comprises adding water and methyl tert-butyl ether at 0-10° C. after the reaction, separating the liquids, and taking the aqueous phase for the subsequent crystallization step.

[0022] In some embodiments of the present invention, the crystallization process is performed in two stages to adjust the pH of the system. In the first stage, the pH is adjusted to 8.0-10.0 (e.g., 8.0, 8.5, 9.0, 9.5, or any value or range therebetween) using an acid (preferably 1-2 M hydrochloric acid). In the second stage, the pH is adjusted to 4-6 (e.g., 4.0, 4.5, 5.0, 5.5, 6.0, or any value or range therebetween). Seed crystals of Compound IX are optionally added between the two stages. Preferably, the pH of the system is adjusted at 0-10°C.

[0023] In some embodiments of the present invention, after the pH value of the system is adjusted, the temperature is returned to 20-30° C. (eg, 25° C.) and stirred, filtered, rinsed with water, and vacuum dried.

[0024] The use of potassium trimethylsilanol results in a milder reaction, which is more conducive to industrial process scale-up control.

[0025] In some embodiments of the present invention, step 7 is carried out in tetrahydrofuran in the presence of N,N'-carbonyldiimidazole and hexamethyldisilazane, and the reaction may be optionally carried out in the presence of a catalyst, wherein the catalyst is selected from any one or more combinations of pyridine, diethylamine, triethylamine, quinoline, N,N-dimethylaniline, 4-dimethylaminopyridine and 4-pyrrolidinylpyridine; preferably, the catalyst is selected from 4-dimethylaminopyridine or 4-pyrrolidinylpyridine; more preferably, the catalyst is 4-pyrrolidinylpyridine.

[0026] In some embodiments of the present invention, the method for preparing the compound of formula X further comprises the following steps:

[0027] Step 4: The compound of formula VII undergoes alkylation reaction to obtain the compound of formula VIII.

[0028] In some embodiments of the present invention, the method for preparing the compound of formula X further comprises the following steps:

[0029] Step 3: The compound of formula V reacts with the compound of formula VI to obtain the compound of formula VII.

[0030] In some embodiments of the present invention, the method for preparing the compound of formula X further comprises the following steps:

[0031] Step 2: The compound of formula III reacts with the compound of formula IV to obtain the compound of formula V.

[0032] In some embodiments of the present invention, the method for preparing the compound of formula X further comprises the following steps:

[0033] Step 1: reacting a compound of formula I with a compound of formula II to prepare a compound of formula III.

[0034] In another aspect, the present invention provides a compound as shown in any of the following structural formulas:

[0035] Another aspect of the present invention provides a method for preparing a compound of formula VIII, comprising the following steps:

[0036] Step 4: Alkylation of the compound of formula VII to obtain the compound of formula VIII,

[0037] In some embodiments of the present invention, the alkylation reaction in step 4 is: the compound of formula VII is alkylated with an orthoformate compound in an organic solvent B, optionally in the presence of an acid.

[0038] In some embodiments of the present invention, the orthoformate compound in step 4 is any one of triethyl orthoformate or triethyl orthoacetate.

[0039] In some embodiments of the present invention, the inorganic acid in step 4 is any one of sulfuric acid and phosphoric acid, or a combination of the two.

[0040] In some embodiments of the present invention, the organic solvent B in step 4 is selected from any one or more combinations of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0041] In some embodiments of the present invention, the reaction temperature in step 4 is 20°C to 150°C.

[0042] In another aspect, the present invention provides a method for preparing the compound of formula VII, comprising the following steps:

[0043] Step 3: The compound of formula V reacts with the compound of formula VI to obtain the compound of formula VII.

[0044] In some embodiments of the present invention, in step 3, the compound of formula V reacts with the compound of formula VI in an organic solvent C, optionally in the presence of a catalyst.

[0045] In some embodiments of the present invention, the catalyst in step 3 is any one or more combinations of acids and bases; preferably, it is any one or more combinations of acetic acid, trifluoroacetic acid, triethylamine, and 1,8-diazabicycloundec-7-ene.

[0046] In some embodiments of the present invention, the organic solvent C in step 3 is any one or more combinations of alcohols, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and tetrahydrofuran.

[0047] In another aspect, the present invention provides a method for preparing the compound of formula V, comprising the following steps:

[0048] Step 2: The compound of formula III reacts with the compound of formula IV to obtain the compound of formula V.

[0049] In some embodiments of the present invention, in step 2, the compound of formula III reacts with the compound of formula IV in an organic solvent D in the presence of a catalyst.

[0050] In some embodiments of the present invention, the organic solvent D in step 2 is any one or more combinations of alcohols, chlorinated hydrocarbons, acetonitrile, tetrahydrofuran, dioxane, toluene, chlorobenzene, pyridine, and glacial acetic acid; preferably, it is any one or more combinations of ethanol, isopropanol, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, and toluene; further preferably, it is any one or two combinations of dichloromethane, toluene, and ethanol.

[0051] In some embodiments of the present invention, the catalyst in step 2 is any one of an acid, an acid-base combination, an acid and a dehydrating agent, or an acid-base and a dehydrating agent; preferably, the acid is a combination of any one or more of acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid, and the base is any one or a combination of two of piperidine or pyridine; further preferably, the catalyst is a combination of acetic acid and piperidine.

[0052] In another aspect, the present invention provides use of the compound of formula VIII, the compound of formula VII, the compound of formula V, the compound of formula VII', and the compound represented by formula VIII' in the preparation of finerenone.

[0053] The compound of formula VII' can be obtained by resolving the compound of formula VII.

[0054] The compound represented by formula VIII' can be obtained by resolving the compound represented by formula VIII, or directly prepared from the compound represented by formula VII'.

[0055] In another aspect, the present invention provides a method for preparing a compound of formula VIII', comprising the following steps:

[0056] Step 5: The compound of formula VIII is salified in a solvent in the presence of a resolving agent, and treated with a base to obtain a compound of formula VIII', wherein the resolving agent is a compound of formula XI, and R is an optionally substituted aryl group, wherein the substitution refers to substitution with an alkyl group, an alkoxy group, a hydroxyl group, a halogen group, a nitro group, or a cyano group;

[0057] In some embodiments of the present invention, R is one of the following formulae:

[0058] Preferably, R is one of the following formulae:

[0059] More preferably, said R is

[0060] In some embodiments of the present invention, the solvent in step 5 is any one or more of acetone, 2-butanone, isopropanol, ethyl acetate, methanol or methyl tert-butyl ether, preferably any one or a combination of acetone and 2-butanone; the base in step 5 is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide, preferably any one or a combination of sodium bicarbonate and potassium bicarbonate.

[0061] In some embodiments of the present invention, the temperature of step 5 is 10 to 50°C, preferably 20 to 30°C;

[0062] The ratio of the compound of formula VIII to the solvent is 1:5 to 1:20 g / ml, preferably 1:12 to 1:14 g / ml.

[0063] In another aspect, the present invention provides a method for preparing finerenone, comprising the following steps:

[0064] Step 2: The compound of formula III reacts with the compound of formula IV to obtain the compound of formula V.

[0065] Step 3: The compound of formula V reacts with the compound of formula VI to obtain the compound of formula VII.

[0066] Step 4: Alkylation of the compound of formula VII to obtain the compound of formula VIII,

[0067] Step 5: The compound of formula VIII is salified in a solvent in the presence of a resolving agent, and treated with a base to obtain a compound of formula VIII', wherein the resolving agent is a compound of formula XI, wherein R is p-toluenemethyl;

[0068] Step 6: The compound of formula VIII' reacts in the presence of a base in a solvent to obtain a compound of formula IX';

[0069] Step 7: The compound of formula IX′ is further reacted to obtain finerenone,

[0070] Some implementations of steps 2 to 7 are as described above.

[0071] The beneficial technical effects of the present invention are:

[0072] 1. The technical solution of the present invention uses a carboxyl protecting group, p-nitrophenethyl, which has UV absorption. During the production of Compound V, its content in the reaction solution can be directly monitored by HPLC to monitor the progress of the reaction. Furthermore, during the preparation of Compound IX, the p-nitrophenethyl group is removed as p-nitrostyrene, and the reaction progress can also be determined by monitoring the p-nitrostyrene content. The in-process control method is simple, the reaction progress is easily controlled, and it is conducive to online automated production control.

[0073] 2. The product of the deprotection of p-nitrophenylethyl in the technical solution of the present invention is p-nitrostyrene, which is less toxic, less volatile, green and environmentally friendly, and suitable for large-scale industrial production.

[0074] 3. The yield of the technical solution of the present invention is significantly improved compared with the original synthetic route, especially in the step of hydrolyzing compound VIII or VIII' to compound IX or IX'. The reaction is stable, impurities are easily controlled, and the cost is low, which is conducive to the large-scale production of finerenone. DETAILED DESCRIPTION

[0075] Unless otherwise specified, the terms in this invention have the following meanings:

[0076] In the present invention, the term "eq" is an abbreviation of "equivalent", which refers to equivalent, and is a term used for the ratio of the amounts of substances when substances interact with each other.

[0077] In the present invention, the terms "organic solvent A", "organic solvent B", "organic solvent C" and "organic solvent D" actually refer to organic solvents, and A, B, C and D are only used to distinguish them as organic solvents used in different reactions.

[0078] In the present invention, the term "optionally" refers to both "in the presence" and "in the absence". For example, in step 4, the compound of formula VII is optionally in organic solvent B, which means that the compound of formula VII may be in organic solvent B or not. For another example, in step 3, the reaction is optionally in the presence of a catalyst, which means that the reaction may be in the presence of a catalyst or not.

[0079] In the present invention, "g / ml" refers to the ratio of the mass (g) of the reaction material to the volume (ml) of the reaction solvent.

[0080] In the present invention, "v / w" refers to the ratio of the volume (ml) of the reaction solvent to the weight (g) of the reaction raw materials.

[0081] In the present invention, "ee value" refers to the optical purity of a chiral compound, which is calculated as (the content of S isomer-the content of R isomer) / (the content of S isomer+the content of R isomer)×100%.

[0082] In the present invention Compounds containing double bonds can be either Z-type or It can also be E type

[0083] In the present invention, "alcohols" refer to compounds containing a hydroxyl group bonded to a hydrocarbon group or a carbon on a benzene ring side chain, such as methanol, ethanol, benzyl alcohol, etc.

[0084] In the present invention, "aryl" refers to a monocyclic or bicyclic aromatic group, such as phenyl or naphthyl.

[0085] In the present invention, "room temperature" refers to 15 to 25°C.

[0086] In the present invention, unless otherwise specified, the compound of formula VII, the compound of formula VIII, the compound of formula IX and the compound of formula X may be in the form of the R enantiomer, the S enantiomer, a mixture of any R enantiomer or S enantiomer, or a racemic mixture. For example, the compound of formula VII may be a compound represented by formula VII′, a compound represented by formula VII″, a mixture thereof, or a racemic mixture thereof; the compound of formula VIII may be a compound represented by formula VIII′, a compound represented by formula VIII″, a mixture thereof, or a racemic mixture thereof; the compound of formula IX may be a compound represented by formula IX′, a compound represented by formula IX″, a mixture thereof, or a racemic mixture thereof; and the compound of formula X may be a compound represented by formula X′, a compound represented by formula X″, a mixture thereof, or a racemic mixture thereof.

[0087] In the present invention, compounds of formula VII, VIII, IX, and X can be chirally resolved by conventional techniques in the art to obtain finerenone directly or indirectly. Preferably, finerenone is obtained by chirally resolving compound VIII to obtain compound VIII', and then performing steps 6 and 7 to obtain finerenone.

[0088] In order to make the technical problems, technical solutions and beneficial effects solved by the present invention more clearly understood, the present invention is further described below in conjunction with specific embodiments. However, it should be understood that the embodiments do not limit the scope of this application.

[0089] The reagents and solvents used in this application were purchased from commercial sources and, unless otherwise specified, were used directly without further treatment.

[0090] The HPLC method used to determine the content of the compound of formula IX' of the present invention is as follows:

[0091] Chromatographic instruments: High performance liquid chromatography equipped with UV detector and automatic sample injector;

[0092] Chromatographic column: ACE-EXCEL C18-PFP 4.6*150mm 3.0μm; column temperature: 40℃;

[0093] Buffer: Accurately weigh 1.742 g of potassium hydrogen phosphate (KHPO) and dissolve it in 1000 mL of water. Adjust the pH to 6.5 with phosphoric acid. Filter and ultrasonicate. Mobile phase A: Buffer: acetonitrile = 95:5 (% V / V).

[0094] Mobile phase B: acetonitrile; flow rate: 1.0 mL / min; injection volume: 10 μL; detection wavelength: 244 nm.

[0095] The method for detecting the ee value of the compound of formula XII of the present invention is as follows:

[0096] Chromatographic instruments: High performance liquid chromatography equipped with UV detector and automatic sample injector;

[0097] Column: DAICEL OD-H 250*4.6mm, 5μm; column temperature: 30℃;

[0098] Mobile phase: n-hexane:ethanol:diethylamine = 88:12:0.1 (% V / V / V);

[0099] Flow rate: 1.0 mL / min; injection volume: 10 μL; detection wavelength: 254 nm.

[0100] Preparation of compound of formula III:

[0101] 22.32 g (1.05 eq) of 2,2,6-trimethyl-4H-1,3-dioxin-4-one, 25.00 g (1.0 eq) of p-nitrophenylethanol, and 75 mL of toluene were stirred at 90-100°C for 5 h. The reaction mixture was concentrated to dryness under reduced pressure by rotary evaporation. 25 mL of methyl tert-butyl ether was added to the residue and stirred at 20-30°C for 30 min. The mixture was then cooled to 0-5°C and stirred for 30 min. The mixture was filtered and the filter cake was dried to obtain 36.5 g of the title compound.

[0102] MS (EIpos): m / z=252[M+H] + .

[0103] 1 H NMR (600MHz, DMSO-d6): δ8.16(d,J=8.7Hz,2H), 7.56(d,J=8.6Hz,2H), 4.34(t,J=6.5Hz,2H), 3.57(s,2H), 3.05(t,J=6.5Hz,2H), 2.12(s,3H).

[0104] Example 1: Preparation of compound of formula V

[0105] 5.04 g (1.0 eq) of 4-cyano-2-methoxybenzaldehyde (compound IV), 9.42 g (1.2 eq) of 4-nitrophenylethyl 3-oxobutanoate (compound III), 0.40 g (0.15 eq) of piperidine, 0.28 g (0.15 eq) of acetic acid, and 100 mL of dichloromethane were stirred under reflux for 4 h. The reaction solution was washed three times with 100 mL of water, and the organic phase was concentrated to dryness. 9 mL of isopropanol was added to the residue, and the mixture was stirred at 40-50°C for 1 h. The mixture was cooled to 20-25°C and stirred for 1 h. The mixture was filtered and the filter cake was dried to obtain 11.80 g of the title compound.

[0106] MS (EIpos): m / z=395[M+H] + .

[0107] 1 H NMR (600MHz, DMSO-d6): δ8.06(d,J=8.6Hz,2H),7.76(s,1H),7.52(s,1H),7.38(d,J=8.6Hz,2H),7.33(dd,J=7 .9, 1.0Hz, 1H), 7.25 (d, J = 7.9Hz, 1H), 4.40 (t, J = 6.3Hz, 2H), 3.86 (s, 3H), 2.98 (t, J = 6.3Hz, 2H), 2.38 (s, 3H).

[0108] Example 2: Preparation of compound of formula V

[0109] 70.00 g (1.0 eq) of 4-cyano-2-methoxybenzaldehyde (compound of formula IV), 130.95 g (1.2 eq) of 4-nitrophenylethyl 3-oxobutyrate (compound of formula III), 2.22 g (0.06 eq) of piperidine, 1.56 g (0.06 eq) of acetic acid, and 1400 mL of ethanol were stirred at 20-25°C for 19.5 h, filtered, and the filter cake was dried to obtain 159.95 g of the title compound.

[0110] Example 3: Preparation of compound of formula VII

[0111] 11.80 g (1.0 eq) of 4-nitrophenylethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate (compound of formula V), 3.71 g (1.0 eq) of 4-amino-5-methylpyridin-2(1H)-one (compound of formula VI), and 55 mL of N,N-dimethylformamide were stirred at 110°C for 7 h. The mixture was cooled to 20-30°C, 110 mL of water was added dropwise, and the mixture was filtered. The filter cake was dried to obtain 13.3 g of the title compound.

[0112] MS (EIpos): m / z=501[M+H]+ .

[0113] 1 H NMR (600MHz, DMSO-d6): δ10.74(s,1H),8.12(d,J=8.7Hz,2H),8.09(s,1H),7.45(d,J=8.6Hz,2H),7.28(d,J=1.1Hz,1H),7.17(dd ,J=7.8,1.3Hz,1H),7.13(d,J=7.8Hz,1H),6.93(s,1H),5.15(s,1H),4.31–4.07(m,2H),3.70(s,3H),3.10–2.85(m,2H),2.24(s, 3H),2.00(s,3H).

[0114] Example 4: Preparation of the compound of formula VIII

[0115] 18.8 g (1.0 eq) of 4-nitrophenylethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (Formula VII), 30.62 g (5.5 eq) of triethyl orthoformate, 1.88 g (10% w / w) of concentrated sulfuric acid, and 188 mL of N,N-dimethylformamide were stirred at 110°C for 2 h. The system was cooled to 20-30°C, 360 mL of water was added, and the solution was basified to pH 8 with sodium bicarbonate solution. The solution was extracted three times with 200 mL of ethyl acetate. The combined organic phases were washed once with 200 mL of saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to a residue of approximately 30 mL. The residue was stirred at 0-10°C for 2 h, filtered, and the filter cake dried to afford 16.10 g of the title compound.

[0116] MS (EIpos): m / z=529[M+H] + .

[0117] 1 H NMR (600MHz, DMSO-d6): δ8.29(s,1H),8.13(d,J=8.7Hz,2H),7.57(s,1H),7 .46(d,J=8.6Hz,2H),7.25(d,J=1.2Hz,1H),7.18(dd,J=7.8,1.4Hz,1H),7.0 5(d,J=7.8Hz,1H),5.24(s,1H),4.28–4.12(m,2H),4.11–3.93(m,2H),3.71 (s,3H),3.09–2.90(m,2H),2.32(s,3H),2.13(s,3H),1.08(t,J=7.0Hz,3H).

[0118] Example 5: Preparation of the compound of formula IX

[0119] 50 mL of ethanol and 12.87 g (10.0 eq) of sodium ethoxide were stirred and dissolved at room temperature. 10.00 g (1.0 eq) of 4-nitrophenylethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (Formula VIII) was then added and stirred at 20-30°C for 2 h. 210 mL of water was added to the mixture, and the mixture was extracted twice with 150 mL of dichloromethane. The aqueous phase was adjusted to pH 5-6 with 6N hydrochloric acid, filtered, and the filter cake was dried to obtain 5.63 g of the title compound.

[0120] MS (EIpos): m / z=380[M+H] + .

[0121] 1 H NMR (600MHz, DMSO-d6): δ11.42(s,1H),8.14(s,1H),7.57(s,1H),7.31(s,1H),7.29–7.19(m,2H ),5.33(s,1H),4.17–3.92(m,2H),3.73(s,3H),2.37(s,3H),2.14(s,3H),1.11(t,J=7.0Hz,3H).

[0122] Example 6: Preparation of compound of formula IX'

[0123] At 20-30°C, potassium trimethylsilanol (16.38 g) and acetonitrile (450.00 mL) were added to the reaction flask, stirred, and the temperature was controlled at 3°C. The compound of formula VIII' (45.00 g) was added and stirred at this temperature for 16 h. The temperature was controlled below 10°C. Pure water (135.00 mL) and methyl tert-butyl ether (1350.00 mL) were added and stirred for separation. Water (90.00 mL) was added to the organic phase and stirred for separation. Water (45.00 mL) was added to the organic phase and stirred for separation. The mixture was stirred for 10 min, and the pH of the solution was adjusted to 5.5 with 1 mol / L hydrochloric acid. The mixture was warmed to 25°C and stirred for 1 h. The mixture was filtered, washed with pure water (45.00 mL), and dried in vacuo at 25°C to give 26.56 g of an off-white solid with a yield of 81.42% and a purity of 91.54%.

[0124] When the reaction of this step is carried out for a certain period of time, the reaction liquid is taken for detection, and it is found that decarboxylation impurity Z is easily produced in the reaction of this step. When under inappropriate reaction conditions, the decarboxylation impurity Z is the main product of the reaction of this step or the reaction does not proceed. The structural formula of the decarboxylation impurity is shown below:

[0125] Table 1: Product IX', decarboxylation impurity Z content in the reaction solution and purity of raw materials under different reaction conditions

[0126] Example 7: Preparation of Compound X

[0127] 6.98 g (1.0 eq) of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid and 4.18 g (1.4 eq) of carbonyldiimidazole were added to 69.8 mL of tetrahydrofuran, followed by 0.22 g (0.1 eq) of 4-dimethylaminopyridine. The mixture was stirred at 20-30°C, then heated to 50°C and stirred for 3 h. 13.36 g (4.5 eq) of hexamethyldisilazane was then added, and the mixture was stirred at 50-60°C for 4 h. The reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was added with 70 mL of ethyl acetate and 70 mL of water, stirred and separated. The organic phase was concentrated under reduced pressure. The residue was added with 20 mL of ethanol, heated to 70-80°C, stirred at this temperature for 1 h, cooled to 20-30°C, stirred at this temperature for 1 h, filtered, and the filter cake was dried to obtain the title compound.

[0128] MS (EIpos): m / z=379[M+H] + .

[0129] Example 8:

[0130] At 20-30°C, add the compound of formula VIII (2.00 g) and acetone (24.00 mL) to the reaction flask, stir to dissolve, then add the compound of formula XI-1 (1.46 g), stir at 20-30°C for 14 h, filter, rinse the filter cake with acetone, and dry the solid at 45-50°C to obtain 1.65 g of a white solid with a yield of 95.38% and an ee value of 97.21%.

[0131] Example 9:

[0132] At 20-30°C, add the compound of formula VIII (2.00 g) and ethyl acetate (40.00 mL) to the reaction flask, stir to dissolve, then add the compound of formula XI-2 (1.44 g), stir at 20-30°C for 14 h, filter, rinse the filter cake with ethyl acetate, and dry the solid at 45-50°C to obtain 1.52 g of a white solid with a yield of 88.4% and an ee value of 95.54%.

[0133] Example 10:

[0134] At 20-30°C, add the compound of formula VIII (2.00 g) and acetone (24.00 mL) to the reaction flask, stir to dissolve, then add the compound of formula XI-3 (1.52 g), stir at 20-30°C for 14 h, filter, rinse the filter cake with ethyl acetate, and dry the solid at 45-50°C to obtain 1.61 g of a white solid with a yield of 91.48% and an ee value of 95.89%.

[0135] Example 11:

[0136] At 20-30°C, the compound of formula XII-1 (2.00 g), ethanol (10.00 mL) and 2.5% sodium bicarbonate (20.00 mL) were added to the reaction flask and stirred. The temperature was raised to 50°C, stirred at 50°C for 1 h, stirred at 25°C for 1 h, filtered, and the filter cake was rinsed with pure water (2 mL). Ethanol (10.00 mL) and 0.5% sodium bicarbonate (20.00 mL) were added to the filter cake, the temperature was raised to 50°C, stirred at 50°C for 1 h, stirred at 25°C for 1 h, filtered, rinsed with pure water (3 mL), and dried in vacuo at 65°C to obtain 1.72 g of a white solid with a yield of 99.19%.

[0137] Example 12: Preparation of Finerenone

[0138] At 20-30°C, tetrahydrofuran (100 mL), compound of formula IX' (20.00 g) and 4-pyrrolidinylpyridine (0.78 g) were added to the reaction bottle, and N, N-carbonyldiimidazole (17.10 g) was added in batches. The mixture was stirred at 25°C for 1 h, hexamethyldisilazane (34.03 g) was added, and the mixture was stirred at 62°C for 17 h. Water (10 mL) was added dropwise at 0-10°C, and the mixture was stirred at 20-30°C for 1 h. The mixture was added at 40°C. The mixture was concentrated by vacuum distillation to a remaining 60 mL, 40 mL of ethanol was added, and the mixture was further concentrated to a remaining 60 mL. Water (200 mL) was added, and the mixture was stirred at 20-30°C for 1 h. The mixture was filtered and dried. Ethanol (300 mL) was added to the solid, and the mixture was distilled under reduced pressure at 90°C to 60 mL. The mixture was stirred at 0-5°C for 2 h, and the mixture was rinsed with 10 mL of ice ethanol. The mixture was filtered and dried to obtain 9.67 g of an off-white solid with a purity of 99.54%, an ee value of 99.84%, and a yield of 48.47%.

[0139] 1 H NMR (600MHz, DMSO) δ7.69(s,1H),7.55(s,1H),7.37(s,1H),7.28(dd,J=7.9,1.2Hz,1H),7.15(d,J=7.9Hz,1H),6.7 3(d,J=62.7Hz,2H),5.37(s,1H),4.18-3.96(m,2H),3.82(s,3H),2.18(s,3H),2.12(s,3H),1.05(t,J=7.0Hz,3H).

[0140] The present invention has been described in detail above. It will be apparent to those skilled in the art that the present invention can be practiced over a wide range of parameters, concentrations, and conditions without departing from the spirit and scope of the present invention and without unnecessary experimentation. Although specific embodiments have been given herein, it should be understood that further modifications may be made to the present invention. In short, according to the principles of the present invention, this application is intended to include any variations, uses, or improvements to the present invention, including changes made by conventional techniques known in the art that depart from the scope disclosed herein. Applications of some of the basic features may be made within the scope of the following claims.

Claims

1. A method for preparing a compound of formula X, characterized in that: The following steps are involved: Step 6: The compound of formula VIII reacts in the presence of a base in a solvent to obtain a compound of formula IX; Step 7: The compound of formula IX is further reacted to obtain a compound of formula X, 2. A method for preparing finerenone, characterized in that: The following steps are involved: Step 6: The compound of formula VIII′ reacts in the presence of a base in a solvent to obtain a compound of formula IX′; Step 7: The compound of formula IX′ is further reacted to obtain finerenone, 3. The method according to claim 1 or 2, characterized in that: The base in step 6 is any one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and potassium trimethylsiliconate. Preferably, the base is any one or more of sodium hydroxide, sodium ethoxide, and potassium trimethylsiliconate; or The solvent in step 6 is organic solvent A or a mixed solvent thereof with water; or In step 6, the organic solvent A is any one or more combinations of alcohols, ethers, acetone, and acetonitrile; preferably, the organic solvent A is any one or more combinations of methanol, ethanol, dioxane, and acetonitrile; more preferably, the organic solvent A is any one or more combinations of ethanol and acetonitrile.

4. The method according to claim 3, characterized in that: The base is sodium hydroxide, the organic solvent A is ethanol, the reaction temperature is selected from 20 to 50° C., and the reaction time is selected from 2 to 8 hours; or The base is sodium ethoxide, the organic solvent A is ethanol, the reaction temperature is selected from 20 to 30° C., and the reaction time is selected from 1 to 5 hours; or The base is potassium trimethylsilanol, the organic solvent A is acetonitrile, the reaction temperature is selected from -10 to 10° C., and the reaction time is selected from 8 to 25 hours.

5. The method according to claim 1 or 2, characterized in that: Step 7: reacting in tetrahydrofuran in the presence of N,N'-carbonyldiimidazole and hexamethyldisilazane, optionally in the presence of a catalyst, wherein the catalyst is selected from any one or more of pyridine, diethylamine, triethylamine, quinoline, N,N-dimethylaniline, 4-dimethylaminopyridine, and 4-pyrrolidinylpyridine; preferably, the catalyst is selected from 4-dimethylaminopyridine and 4-pyrrolidinylpyridine; more preferably, the catalyst is 4-pyrrolidinylpyridine.

6. The method according to claim 1, characterized in that It also includes the following steps: Step 4: The compound of formula VII undergoes an alkylation reaction to obtain a compound of formula VIII, 7. The method according to claim 6, characterized in that It also includes the following steps: Step 3: The compound of formula V reacts with the compound of formula VI to obtain a compound of formula VII, 8. The method according to claim 7, characterized in that It also includes the following steps: Step 2: The compound of formula III reacts with the compound of formula IV to obtain the compound of formula V, 9. The method according to claim 8, characterized in that It also includes the following steps: Step 1: The compound of formula I reacts with the compound of formula II to prepare the compound of formula III.

10. A compound represented by any of the following structural formulas:

11. A method for preparing a compound of formula VIII, characterized in that: The following steps are involved: Step 4: Alkylation of the compound of formula VII to obtain the compound of formula VIII, Preferably, The alkylation reaction in step 4 is as follows: the compound of formula VII is optionally alkylated with an orthoformate compound in an organic solvent B in the presence of an acid; or The orthoformate compound in step 4 is any one of triethyl orthoformate or triethyl orthoacetate; or The inorganic acid in step 4 is any one of sulfuric acid and phosphoric acid or a combination of the two; or The organic solvent B in step 4 is selected from any one or more of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone; or The reaction temperature in step 4 is 20°C to 150°C.

12. A method for preparing a compound of formula VII, characterized in that: The following steps are involved: Step 3: The compound of formula V reacts with the compound of formula VI to obtain a compound of formula VII, Preferably, The reaction in step 3 is optionally carried out in an organic solvent C in the presence of a catalyst; or The catalyst in step 3 is any one or more combinations of acids and bases; preferably, any one or more combinations of acetic acid, trifluoroacetic acid, triethylamine, and 1,8-diazabicycloundec-7-ene; or The organic solvent C in step 3 is any one or more of alcohols, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and tetrahydrofuran.

13. A method for preparing a compound of formula V, characterized in that: The following steps are involved: Step 2: The compound of formula III reacts with the compound of formula IV to obtain the compound of formula V, Preferably, In step 2, the compound of formula III reacts with the compound of formula IV in an organic solvent D in the presence of a catalyst; or The organic solvent D in step 2 is any one or more of alcohols, chlorinated hydrocarbons, acetonitrile, tetrahydrofuran, dioxane, toluene, chlorobenzene, pyridine, and glacial acetic acid; preferably, any one or more of ethanol, isopropanol, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, and toluene; further preferably, any one or two of dichloromethane, toluene, and ethanol; or The catalyst in step 2 is any one of an acid, an acid-base combination, an acid and a dehydrating agent, or an acid-base and a dehydrating agent; preferably, the acid is any one or more of acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid, and the base is any one or a combination of two of piperidine or pyridine; further preferably, the catalyst is a combination of acetic acid and piperidine.

14. Use of the compound of formula VIII, the compound of formula VII, the compound of formula V, the compound of formula VII', and the compound of formula VIII' as claimed in claim 10 in the preparation of finerenone.

15. A method for preparing a compound of formula VIII′, characterized in that: The following steps are involved: Step 5: The compound of formula VIII is salified in a solvent in the presence of a resolving agent, and then treated with alkali to obtain a compound of formula VIII′. The resolving agent is a compound represented by formula XI, R is an optionally substituted aryl group, wherein the substitution refers to substitution by an alkyl group, an alkoxy group, a hydroxyl group, a halogen group, a nitro group or a cyano group; 16. The method according to claim 15, characterized in that The R is one of the following formulas: Preferably, R is one of the following formulae: More preferably, said R is 17. The method according to claim 15, characterized in that The solvent in step 5 is any one or more of acetone, 2-butanone, isopropanol, ethyl acetate, methanol or methyl tert-butyl ether, preferably any one of acetone and 2-butanone or a combination of both; the base in step 5 is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide, preferably any one of sodium bicarbonate and potassium bicarbonate or a combination of both.

18. The method according to claim 15, characterized in that The temperature of step 5 is 10-50°C, preferably 20-30°C; The ratio of the compound of formula VIII to the solvent is 1:5 to 1:20 g / ml, preferably 1:12 to 1:14 g / ml.

19. A method for preparing finerenone, characterized in that: The following steps are involved: Step 2: The compound of formula III reacts with the compound of formula IV to obtain the compound of formula V, Step 3: The compound of formula V reacts with the compound of formula VI to obtain a compound of formula VII, Step 4: Alkylation of the compound of formula VII to obtain the compound of formula VIII, Step 5: The compound of formula VIII is salified in a solvent in the presence of a resolving agent, and treated with a base to obtain a compound of formula VIII′, wherein the resolving agent is a compound of formula XI, wherein R is p-toluenemethyl; Step 6: The compound of formula VIII′ reacts in the presence of a base in a solvent to obtain a compound of formula IX′; Step 7: The compound of formula IX′ is further reacted to obtain finerenone,