Preparation method of fenerenone impurity

Abstract

The invention provides a preparation method of a fenerenone impurity, and belongs to the technical field of medicine synthesis. The fenerenone impurity is prepared ingeniously through decarboxylation, oxidation, pyridine N-oxidation and Katada reaction according to the structural difference of the impurity and the intermediate, the operation is simple, the synthesis route is short, the target impurity can be synthesized directionally through three-step chemical reaction, purification means such as column chromatography or preparative liquid phase separation are not needed, and the method is suitable for industrial production. The high-purity fenerenone impurity can be obtained through crystallization after pH adjustment, and the method has high practicability.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing finerenone impurities. Background Art

[0002] Finerenone is the first non-steroidal selective mineralocorticoid receptor antagonist developed by Bayer Pharmaceuticals and can be used to treat diabetic nephropathy, chronic kidney disease and end-stage renal disease. The structure of finerenone is as follows:

[0003]

[0004] The preparation process of phenaretin disclosed in patent CN107849043B previously applied by the applicant is as follows:

[0005]

[0006] During the preparation of the finerenone intermediate, compound of formula III, we were concerned about an impurity, detected at concentrations between 0.2% and 0.6% in multiple batches. To ensure the safety of the finerenone API produced, we conducted qualitative analysis, structural confirmation, synthesis, and quantitative studies of this impurity. We established the required limit for this impurity in the finerenone intermediate, ensuring that qualified finerenone API could be consistently produced within this limit.

[0007] First, we used liquid chromatography-mass spectrometry (LC-MS) and preparative liquid chromatography (Prep-LC) to isolate and obtain a trace amount of an impurity reference substance. By analyzing the mass spectrometry, 1H-NMR, and 13C-NMR results of the unknown compound, we determined the structure of the impurity, as shown in Formula I:

[0008]

[0009] The acquisition of impurity reference materials is of great significance for quality research. It is necessary to qualitatively and quantitatively study the sources and destinations of impurities, analyze the principles and conditions of impurity generation from the structure of impurities, and then design scientific measures from the aspects of parameter control of production process.

[0010] The acquisition of impurity reference substances has the following positive significance:

[0011] (1) After obtaining the impurity reference substance, the actual detection of impurities in the sample can be quantitatively studied, the detection efficiency and accuracy can be improved, and the quality of the drug can be guaranteed to meet the requirements of the ICHQ3A guidelines and the national pharmacopoeia and other quality standards, thereby ensuring the safety of the patient's medication.

[0012] (2) After obtaining the impurity reference substance, the impurities can be accurately classified according to their structure, such as general impurities or mutagenic impurities, so as to design reasonable and scientific control basis and limits to ensure the safety of the raw materials.

[0013] (3) After obtaining the impurity reference substance, researchers can assist in designing a scientific drug production process supervision plan based on the intermediates, raw materials, and even the process of preparation and packaging and storage of the finished product to determine whether there is a possibility of degradation. Early acquisition can help identify potential risks and problems in each production link and take measures to reduce drug quality risks.

[0014] In summary, the acquisition and application of impurity reference substances play a vital role in ensuring the quality, safety and compliance of drugs, and are an indispensable part of process research, quality research, drug production and packaging, storage and transportation, and expiration date setting. Summary of the Invention

[0015] In view of this, the present invention aims to provide a method for preparing finerenone impurities. The preparation method provided by the present invention can obtain finerenone impurities in high yield and high purity, which is of great significance for ensuring the quality and safety of finerenone drugs.

[0016] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0017] The present invention provides a method for preparing a phenaretin impurity, wherein the phenaretin impurity has a structure shown in Formula I:

[0018]

[0019] The preparation method comprises the following steps:

[0020] Mixing a phenerenone intermediate having a structure represented by Formula III with a first alkaline aqueous solution and performing a decarboxylation reaction to obtain a compound having a structure represented by Formula INT;

[0021] The compound having the structure represented by formula INT is mixed with an oxidant and a halogenated alkane solvent to carry out an oxidation reaction to obtain a compound having the structure represented by formula II;

[0022] Under the action of trifluoroacetic anhydride, the compound having the structure represented by Formula II undergoes a pyridine 2-hydroxylation reaction with a second alkaline aqueous solution to obtain a phenerenone impurity having the structure represented by Formula I;

[0023]

[0024] Preferably, the alkaline substance in the first alkaline aqueous solution is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide;

[0025] The mass concentration of the first alkaline aqueous solution is 5-40%.

[0026] Preferably, the temperature of the decarboxylation reaction is -10 to 60°C.

[0027] Preferably, the oxidant is urea peroxide and / or m-chloroperbenzoic acid;

[0028] The molar ratio of the oxidant to the finerenone intermediate having the structure shown in formula III is 1.5 to 3.5:1.

[0029] Preferably, the halogenated alkane solvent is a C1-C2 halogenated alkane solvent.

[0030] Preferably, the temperature of the oxidation reaction is -20 to 30°C.

[0031] Preferably, the alkaline substance in the second alkaline aqueous solution is one or more of sodium hydroxide, lithium hydroxide and potassium hydroxide;

[0032] The mass concentration of the second alkaline aqueous solution is 3-15%.

[0033] Preferably, the molar ratio of the trifluoroacetic anhydride to the phenerenone intermediate having the structure represented by Formula III is 1 to 3:1.

[0034] Preferably, the temperature of the pyridine 2-hydroxylation reaction is 20-120°C.

[0035] Preferably, after the 2-hydroxylation reaction of pyridine, the obtained 2-hydroxylation reaction liquid of pyridine is subjected to post-treatment, and the post-treatment comprises the following steps:

[0036] The pH value of the pyridine 2-hydroxylation reaction solution is adjusted to 7-8, and cooling crystallization, solid-liquid separation and drying are performed in sequence to obtain a pure phenerenone impurity product having a structure shown in Formula I.

[0037] The present invention provides a method for preparing a finerenone impurity. The method uses a commercially produced finerenone intermediate as a raw material, decarboxylates and oxidizes the compound of formula II, and then prepares the impurity of formula I based on the basic principle of pyridine 2-hydroxylation reaction (Katada reaction). The synthetic route is as follows: Figure 1 shown.

[0038] The beneficial effects of the present invention are as follows:

[0039] (1) The method for preparing the phenaretin impurity of the present invention is simple and convenient. The target impurity can be obtained by directed synthesis through three-step chemical reactions. No purification methods such as column chromatography or preparative liquid phase separation are required. The phenaretin impurity can be obtained in high purity by crystallization after pH adjustment, which has high practicality.

[0040] (2) The present invention cleverly prepares the finerenone impurity through decarboxylation, oxidation, pyridine N-oxidation and Katada reaction based on the structural differences between the impurity and the intermediate. The operation is simple and the synthetic route is short.

[0041] (3) The preparation method provided by the present invention does not require high temperature, high pressure, deep cooling and other conditions, the reaction is mild, the raw materials used are cheap and easily available, the post-treatment is simple and easy to operate, and there is no introduction of purification methods such as column chromatography and preparative liquid phase, which has high work efficiency and greatly reduces the difficulty for enterprises to obtain finerenone impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 The figure is a flow chart for the preparation of finerenone impurities;

[0043] Figure 2 HPLC spectrum of the finerenone impurity obtained in Example 1;

[0044] Figure 3 The impurities of finerenone obtained in Example 1 1 H-NMR spectrum;

[0045] Figure 4 The impurities of finerenone obtained in Example 1 13 C-NMR spectrum;

[0046] Figure 5 This is the MS spectrum of the finerenone impurity obtained in Example 1. DETAILED DESCRIPTION

[0047] The present invention provides a method for preparing a phenaretin impurity, wherein the phenaretin impurity has a structure shown in Formula I:

[0048]

[0049] The preparation method comprises the following steps:

[0050] Mixing a phenerenone intermediate having a structure represented by Formula III with a first alkaline aqueous solution and performing a decarboxylation reaction to obtain a compound having a structure represented by Formula INT;

[0051] The compound having the structure represented by Formula INT is mixed with an oxidant and a halogenated alkane solvent to carry out an oxidation reaction to obtain a reaction solution containing a compound having the structure represented by Formula II;

[0052] Under the action of trifluoroacetic anhydride, the compound having the structure represented by Formula II undergoes a pyridine 2-hydroxylation reaction with a second alkaline aqueous solution to obtain a phenerenone impurity having the structure represented by Formula I;

[0053]

[0054] In the present invention, a finerenone intermediate having the structure represented by Formula III is mixed with a first alkaline aqueous solution and subjected to a decarboxylation reaction to obtain a compound having the structure represented by Formula INT. In the present invention, the finerenone intermediate having the structure represented by Formula III is preferably prepared in-house. As a specific embodiment of the present invention, the finerenone intermediate having the structure represented by Formula III is prepared according to the method disclosed in Patent CN106795155A and preferably has a purity of 99%.

[0055] In the present invention, the alkaline substance in the first alkaline aqueous solution is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide, more preferably lithium hydroxide. In the present invention, the mass concentration of the first alkaline aqueous solution is preferably 5 to 40%, more preferably 10 to 40%. As a specific embodiment of the present invention, the mass concentration of the first alkaline aqueous solution is 5%, 10%, 20%, 30% or 40%. The present invention is beneficial to improving the conversion rate of the compound having the structure shown in formula INT and reducing the amount of impurities generated by controlling the type and concentration of the first alkaline aqueous solution.

[0056] The present invention has no special requirements for the mixing method, and any mixing method well known in the art can be used, such as stirring mixing.

[0057] In the present invention, the temperature of the decarboxylation reaction is preferably -10 to 60° C., more preferably 0 to 40° C.; as a specific embodiment of the present invention, the temperature of the decarboxylation reaction is -10° C., 0° C., 10° C., 20° C., 30° C., 40° C., 50° C. or 60° C. In the present invention, the time of the decarboxylation reaction is preferably 0.5 to 5 hours, more preferably 3 to 4 hours.

[0058] After the decarboxylation reaction, the present invention preferably performs solid-liquid separation on the obtained decarboxylation reaction liquid, and the obtained solid is washed with water to obtain a compound having a structure shown in Formula INT. In the present invention, the solid-liquid separation method is preferably suction filtration. After the washing, the present invention does not need to dry the obtained compound having a structure shown in Formula INT and can be directly used in the next reaction.

[0059] The present invention mixes the compound having the structure represented by Formula INT with an oxidant and a halogenated alkane solvent, and conducts an oxidation reaction to obtain a compound having the structure represented by Formula II. In the present invention, the oxidant is preferably urea peroxide (UHP) and / or m-chloroperbenzoic acid (m-CPBA), and the molar ratio of the oxidant to the finerenone intermediate having the structure represented by Formula III is preferably 1.5 to 3.5:1, more preferably 2 to 3:1. As a specific embodiment of the present invention, the molar ratio of the oxidant to the finerenone intermediate having the structure represented by Formula III is 1.5:1, 2:1, 2.5:1, 3:1, or 3.5:1.

[0060] In the present invention, the halogenated alkane solvent is preferably a C1-C2 halogenated alkane solvent, more preferably one of dichloromethane, chloroform, or 1,2-dichloroethane. In the present invention, the ratio of the compound having the structure represented by Formula INT to the halogenated alkane solvent is preferably 1 g: 3-30 mL, more preferably 1 g: 10-20 mL.

[0061] In the present invention, the temperature of the oxidation reaction is preferably -20 to 30° C., more preferably 0 to 10° C.; as a specific embodiment of the present invention, the temperature of the oxidation reaction is -20° C., -10° C., 0° C., 10° C., 20° C. or 30° C. In the present invention, the time of the oxidation reaction is preferably 2 to 10 hours, more preferably 3 to 5 hours.

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

[0063] The oxidation reaction liquid is washed, and the washed organic phase is dried and then used for the next reaction.

[0064] In the present invention, the washing liquid used in the washing is preferably an aqueous sodium metabisulfite solution, preferably having a mass concentration of 6 to 20 g / L. The present invention uses the aqueous sodium metabisulfite solution for washing to remove unreacted oxidant from the oxidation reaction solution. The present invention preferably separates the washed oxidation reaction solution to obtain an organic phase. The present invention preferably uses anhydrous sodium sulfate to dry the organic phase.

[0065] In the present invention, the compound having the structure represented by Formula II undergoes a pyridine-2-hydroxylation reaction with a second alkaline aqueous solution under the action of trifluoroacetic anhydride to produce a phenerenone impurity having the structure represented by Formula I. In the present invention, the alkaline substance in the second alkaline aqueous solution is preferably one or more of sodium hydroxide, lithium hydroxide, and potassium hydroxide; the mass concentration of the second alkaline aqueous solution is preferably 3-15%, more preferably 5-10%. In specific embodiments of the present invention, the mass concentration of the second alkaline aqueous solution is 3%, 5%, 8%, 10%, 12%, or 15%.

[0066] In the present invention, the molar ratio of the trifluoroacetic anhydride to the finerenone intermediate having the structure represented by Formula III is preferably 1 to 3:1. As a specific embodiment of the present invention, the molar ratio of the trifluoroacetic anhydride to the finerenone intermediate having the structure represented by Formula III is 1:1, 2:1 or 3:1.

[0067] The present invention preferably first pre-reacts trifluoroacetic anhydride with a phenerenone intermediate having the structure represented by Formula III to produce a pre-reaction solution. In the present invention, the pre-reaction is preferably carried out in an organic solvent, preferably the halogenated alkane solvent used in the oxidation reaction. During the pre-reaction, trifluoroacetic anhydride reacts with the phenerenone intermediate having the structure represented by Formula III to form a trifluoroacetic acid amide salt. In the present invention, the pre-reaction temperature is preferably reflux temperature, and the reaction time is preferably 0.5 to 1.5 hours, more preferably 1 hour. Following the pre-reaction, the present invention removes the organic solvent from the pre-reaction solution, and the resulting product is mixed with a second alkaline aqueous solution to carry out a hydroxylation reaction at the 2-position of pyridine.

[0068] In the present invention, the method of removing the organic solvent is preferably evaporation concentration.

[0069] In the present invention, the temperature of the pyridine 2-hydroxylation reaction is preferably 20 to 120° C., more preferably 40 to 100° C.; as a specific embodiment of the present invention, the temperature of the pyridine 2-hydroxylation reaction is 20° C., 30° C., 40° C., 50° C., 60° C., 70° C., 80° C., 90° C., 100° C., 110° C., or 120° C. In the present invention, the time of the pyridine 2-hydroxylation reaction is preferably 1.5 to 2.5 hours, more preferably 2 hours.

[0070] In the present invention, after the 2-hydroxylation reaction of pyridine, the obtained 2-hydroxylation reaction liquid of pyridine is preferably subjected to post-treatment, and the post-treatment comprises the following steps:

[0071] The pH value of the pyridine 2-hydroxylation reaction solution is adjusted to 7-8, and cooling crystallization, solid-liquid separation and drying are performed in sequence to obtain a pure phenerenone impurity product having a structure shown in Formula I.

[0072] In the present invention, the reagent used to adjust the pH value is preferably a hydrochloric acid aqueous solution, and the concentration of the hydrochloric acid aqueous solution is preferably 3 mol / L.

[0073] In the present invention, the temperature of the cooling crystallization is preferably 0-10°C, and the time is preferably 1.5-2.5 hours, more preferably 2 hours.

[0074] In the present invention, the solid-liquid separation method is preferably suction filtration. The present invention has no special requirements for the drying method, and any drying method well known to those skilled in the art can be used.

[0075] In the present invention, the preparation flow chart of the finerenone impurity is as follows: Figure 1 shown.

[0076] The preparation method of finerenone impurities provided by the present invention is described in detail below with reference to the examples, but they should not be construed as limiting the scope of protection of the present invention.

[0077] The phenerenone intermediate compound of formula III in the following examples was prepared according to the method disclosed in patent CN106795155A and had a purity of 99%.

[0078] Example 1

[0079] In a 250 mL three-necked flask, 100 mL of 10% sodium hydroxide aqueous solution was added, and the compound of formula III (5 g, 13.18 mmol, batch number: 24032201) was added. The temperature was controlled at 10-20 ° C. The reaction was kept warm for 4 hours. After the reaction was completed, the mixture was stirred for 1 hour and filtered. The filter cake was rinsed with purified water until neutral.

[0080] In a 250 mL three-necked flask, 50 mL of dichloromethane was added, the filter cake was cooled to control the temperature at -10 to 0 ° C, urea peroxide (1.86 g, 19.77 mmol) was added, the reaction solution was controlled, and the reaction was completed in 3 hours. The reaction solution was washed with sodium metabisulfite aqueous solution (50 mL / time, 2 times) and separated. The organic phase was dried over anhydrous sodium sulfate and used for subsequent reactions.

[0081] The organic phase was transferred to a 250 mL three-necked flask, trifluoroacetic anhydride (2.77 g, 13.18 mmol) was added, and the mixture was heated to reflux and kept warm for 1 hour. After the reaction was completed, the dichloromethane was evaporated and concentrated, and a 3% aqueous sodium hydroxide solution (44 mL, 32.95 mmol) was added. The mixture was reacted at 30-40° C. for 2 hours. After the reaction was completed, the temperature was lowered to 0-10° C. and the pH was adjusted to 7-8 with a 3 mol / L aqueous hydrochloric acid solution. The mixture was crystallized at this temperature for 2 hours, filtered, and dried to obtain 2.42 g of an off-white powder (i.e., a phenerenone impurity having the structure shown in Formula I), with a yield of 52.6% and a purity of 99.5%.

[0082] The HPLC spectrum of the obtained finerenone impurity is as follows: Figure 2 shown.

[0083] The obtained finerenone impurities 1 H-NMR spectrum Figure 3 The hydrogen spectrum data are as follows:

[0084] 1 H-NMR(DMSO): 21H, 0.6983ppm, CH 3， t; 16H, 2.4652ppm, -CH3, d; 1H, 2.6425ppm, -CH 3， s; 19H, 3.6849ppm, CH3, s; 20H, 3.9403ppm, -CH2, m; 7H, 7.2440ppm, Ar-H, d; 6H, 7.45 43ppm, Ar-H, d; 3H, 7.5371ppm, Ar-H, s, 9H, 7.8159, Ar-H, s; 18H, 9.0077ppm, -OH, s.

[0085]

[0086] The obtained finerenone impurities 13 C-NMR spectrum Figure 4 shown.

[0087] The MS spectrum of the obtained finerenone impurity is as follows: Figure 5 shown.

[0088] Example 2

[0089] In a 250 mL three-necked flask, 100 mL of 5% potassium hydroxide aqueous solution was added, and the compound of formula III (5 g, 13.18 mmol, batch number: 24032201) was added. The mixture was kept at 50-60 ° C for 0.5 h. After the reaction was completed, the temperature was lowered to 10-25 ° C, stirred for 1 h, filtered, and the filter cake was rinsed with purified water until neutral.

[0090] In a 100 mL three-necked flask, 30 mL of chloroform and the filter cake were added, the temperature was cooled to -10 ~ 0 ° C, m-chloroperbenzoic acid (3.41 g, 19.77 mmol) was added in batches, the reaction liquid was controlled, the reaction was completed in 4 hours, the reaction solution was washed with sodium metabisulfite aqueous solution (50 mL / time, 2 times), the liquid was separated, and the organic phase was dried over anhydrous sodium sulfate and used for subsequent reactions.

[0091] Trifluoroacetic anhydride (2.77 g, 13.18 mmol) was added to the organic phase, heated to 30-40°C, and the reaction was maintained at this temperature for 1 hour. After the reaction was completed, the chloroform was evaporated and concentrated, and a 10% aqueous potassium hydroxide solution was added, and the reaction was carried out at 50-60°C for 2 hours. After the reaction was completed, the temperature was lowered to 0-10°C, and the pH was adjusted to 7-8 with a 3 mol / L aqueous hydrochloric acid solution. Crystallization was carried out at this temperature for 2 hours, filtered, and dried to obtain 1.8 g of an off-white powder (i.e., a phenerenone impurity having the structure represented by Formula I), with a yield of 40.0% and a purity of 98.1%.

[0092] Example 3

[0093] In a 250 mL three-necked flask, 100 mL of 40% lithium hydroxide aqueous solution was added, and the compound of formula III (5 g, 13.18 mmol, batch number: 24032201) was added. The mixture was kept at 20-35 ° C for 3 hours. After the reaction was completed, the temperature was lowered to 10-25 ° C, stirred for 1 hour, filtered, and the filter cake was rinsed with purified water until neutral.

[0094] In a 100 mL three-necked flask, 30 mL of 1,2-dichloroethane and the filter cake were added, the temperature was cooled to -10 to 0 ° C, urea peroxide (1.86 g, 19.77 mmol) was added, the reaction liquid was controlled, the reaction was completed in 2 hours, and sodium metabisulfite aqueous solution was added to the reaction liquid for washing (50 mL / time, 2 times), and the liquid was separated. The organic phase was dried over anhydrous sodium sulfate and used for subsequent reactions.

[0095] Trifluoroacetic anhydride (2.77 g, 13.18 mmol) was added to the organic phase, heated to 50-60°C, and the reaction was maintained at this temperature for 0.5 hour. After the reaction was completed, the 1,2-dichloroethane was evaporated and concentrated. A 15% aqueous lithium hydroxide solution was added and the reaction was carried out at 60-70°C for 2 hours. After the reaction was completed, the temperature was lowered to 0-10°C, and the pH was adjusted to 7-8 with a 3 mol / L aqueous hydrochloric acid solution. Crystallization was carried out at this temperature for 2 hours, filtered, and dried to obtain 2.3 g of an off-white powder (i.e., a phenerenone impurity having the structure shown in Formula I), with a yield of 51.1% and a purity of 98.1%.

[0096] Comparative Example 1

[0097] In a 250 mL three-necked flask, 100 mL of 10% sodium hydroxide aqueous solution was added, and the compound of formula III (5 g, 13.18 mmol, batch number: 24032201) was reacted at 10-20°C for 4 hours. After the intermediate control reaction was completed, the mixture was stirred for 1 hour, filtered, and the filter cake was rinsed with purified water until neutral.

[0098] In a 100 mL three-necked flask, 30 mL of tetrahydrofuran was added, the filter cake was cooled to control the temperature at -10 to 0 ° C, m-chloroperbenzoic acid (3.41 g, 19.77 mmol) was added, the reaction solution was controlled, and the reaction was completed after 6 hours. An aqueous solution of sodium metabisulfite was added to the reaction solution and stirred for 1 hour. Tetrahydrofuran was evaporated under reduced pressure, dichloromethane was added, the aqueous phase was extracted with dichloromethane, washed again with water, dried over anhydrous sodium sulfate, and the organic phase was dried over anhydrous sodium sulfate and used for subsequent reactions.

[0099] Trifluoroacetic anhydride (2.77 g, 13.18 mmol) was added to the organic phase, heated to 30-40°C, and the reaction was maintained at this temperature for 1 hour. After the reaction was completed, the dichloromethane was evaporated and concentrated, and a 15% aqueous lithium hydroxide solution was added. The reaction was continued at 60-70°C for 2 hours. After the reaction was completed, the temperature was lowered to 0-10°C, and the pH was adjusted to 7-8 with a 3 mol / L aqueous hydrochloric acid solution. Crystallization was carried out at this temperature for 2 hours, filtered, and dried to obtain 0.7 g of an off-white powder (i.e., a phenerenone impurity having the structure shown in Formula I), with a yield of 15.6% and a purity of 97.5%.

[0100] Comparative Example 2

[0101] In a 100 mL three-necked flask, 20 mL of saturated potassium carbonate aqueous solution was added, and compound III (0.5 g, 1.32 mmol, batch number: 24032201) was added. The mixture was kept at 70-80°C for 5 hours. The mid-control reaction had obvious impurities and was abandoned without further treatment.

[0102] Comparative Example 3

[0103] In a 100 mL three-necked flask, 20 mL of triethylamine was added, and compound III (0.1 g, 0.26 mmol, batch number: 24032201) was added. The reaction was kept at 65-72 ° C for 12 hours. No target intermediate was generated in the mid-control reaction, so it was abandoned. Triethylamine was not suitable for this reaction.

[0104] Based on the above examples and comparative examples, the present invention investigated the reaction raw materials and reaction conditions, which are as follows:

[0105] (1) Investigation of the preparation of intermediate INT reaction base

[0106] The present invention investigates the alkaline aqueous solution in the decarboxylation step, including hydroxides, carbonates and organic bases. The investigation results are shown in Table 1.

[0107] The specific method for preparing the intermediate INT is:

[0108] To a 250 mL three-necked flask, add 100 mL of alkaline aqueous solution and compound III (5 g, 13.18 mmol, batch number: 24032201) for decarboxylation. After completion, maintain the temperature at 10-25°C, stir for 1 hour, filter, and rinse the filter cake with purified water until neutral. The type of alkaline aqueous solution, decarboxylation reaction temperature, and time are shown in Table 1.

[0109] As shown in Table 1, the concentration of aqueous hydroxide (lithium, sodium, potassium) solution, reaction temperature, carbonate, and inorganic base have a significant impact on the conversion rate of compound III to intermediate INT and the generation of impurities.

[0110] Table 1 Effect of different alkaline solutions on the conversion rate and purity of the intermediate INT

[0111] Alkaline aqueous solution Reaction temperature Reaction time Conversion rate Unknown single impurity 5% potassium hydroxide solution 50～60℃ 0.5 hours 96.4％ 1.2％ 10% sodium hydroxide aqueous solution 10～20℃ 4 hours 97.8％ 0.65％ 40% lithium hydroxide aqueous solution 20～35℃ 3 hours 98.2％ 0.76％ Saturated potassium carbonate aqueous solution 70～80℃ 5 hours 88.4％ 6.5％ Triethylamine 65～72℃ 12 hours 0 -

[0112] (2) Investigation of the oxides used to prepare the compound represented by Formula II and the preparation conditions

[0113] The preparation conditions of the compound of formula II were investigated, and the oxidant, reaction solvent, reaction time, yield, difficulty of post-treatment and yield were investigated and evaluated. The comparative investigation data are shown in Table 2.

[0114] The specific method for preparing the compound shown in formula II is:

[0115] In a 100 mL three-necked flask, add 30 mL of organic solvent and the wet product of the intermediate INT obtained in (1) above. The temperature is lowered to control the oxidation reaction temperature to -10 to 0°C. An oxidant is added and the oxidation reaction is carried out at -10 to 0°C. After the reaction is completed, the reaction solution is washed with sodium metabisulfite aqueous solution (50 mL / time, twice), separated, and the organic phase is dried over anhydrous sodium sulfate. The type of organic solvent, type and amount of oxidant, and reaction time are shown in Table 2.

[0116] Table 2 Preparation of the compound represented by formula II using oxides and preparation conditions

[0117] Reaction solvent oxidants Oxidant equivalent Reaction time Yield Experimental phenomenon dichloromethane UHP 1.5 3 hours 92.1％ homogeneous 1,2-Dichloroethane UHP 1.5 5 hours 88.6％ homogeneous Chloroform m-CPBA 1.5 2 hours 87.9％ homogeneous Tetrahydrofuran m-CPBA 2.0 6 hours 65.2％ homogeneous dichloromethane <![CDATA[H2O2]]> 2.0 24 hours - Heterogeneous dichloromethane m-CPBA 3.5 10 hours 89.5％ Heterogeneous DMF m-CPBA 1.5 4 hours 38％ homogeneous DMSO m-CPBA 1.5 4 hours 35％ homogeneous purified water m-CPBA 1.5 24 hours - Heterogeneous

[0118] (3) Investigation of Preparation Conditions of Compounds of Formula I

[0119] The present invention investigated the reaction conditions of the compound of formula I. Based on the mechanism of the reaction, the concentration of the pyridine 2-hydroxylation base (the second alkaline aqueous solution) and the reaction temperature were investigated. The purity and yield of the compound of formula I were compared. The comparative investigation data are shown in Table 3.

[0120] The specific method for preparing the compound of formula I is:

[0121] Trifluoroacetic anhydride was added to the organic phase obtained in (2) above, with the molar ratio of trifluoroacetic anhydride to the starting material III compound being 1:1. A preliminary reaction was carried out under heating reflux conditions, and the reaction was kept warm for 1 hour. After the reaction was completed, the organic solvent was concentrated and evaporated, and an alkaline aqueous solution was added to carry out the 2-hydroxylation reaction of pyridine for 2 hours. After the reaction was completed, the temperature was lowered to 0-10°C, and the pH was adjusted to 7-8 with a 3 mol / L hydrochloric acid aqueous solution. Crystallization was carried out at this temperature for 2 hours, and the mixture was filtered and dried to obtain an off-white powder. The type of alkaline aqueous solution and the reaction temperature for the 2-hydroxylation of pyridine are shown in Table 3.

[0122] Table 3 Investigation of reaction conditions for introduction of 2-hydroxyl group into compound of formula I

[0123] Alkaline aqueous solution Reaction temperature Yield purity 3% sodium hydroxide water solution 80～90℃ 92.1％ 99.22％ 10% sodium hydroxide aqueous solution 50～60℃ 88.6％ 98.5％ 15% sodium hydroxide aqueous solution 30～40℃ 87.9％ 98.9％ 10% potassium hydroxide aqueous solution 50～60℃ 87.2％ 97.8％ 15% lithium hydroxide aqueous solution 60～70℃ 87.6％ 98.1％ Saturated potassium carbonate aqueous solution 80～90℃ - -

[0124] 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 principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing finerenone impurities, characterized in that: The phenerenone impurity has a structure shown in Formula I: The preparation method comprises the following steps: Mixing a phenerenone intermediate having a structure represented by Formula III with a first alkaline aqueous solution and performing a decarboxylation reaction to obtain a compound having a structure represented by Formula INT; The compound having the structure represented by formula INT is mixed with an oxidant and a halogenated alkane solvent to carry out an oxidation reaction to obtain a compound having the structure represented by formula II; Under the action of trifluoroacetic anhydride, the compound having the structure represented by Formula II undergoes a pyridine 2-hydroxylation reaction with a second alkaline aqueous solution to obtain a phenerenone impurity having the structure represented by Formula I; 2. The preparation method according to claim 1, characterized in that The alkaline substance in the first alkaline aqueous solution is one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; The mass concentration of the first alkaline aqueous solution is 5-40%.

3. The preparation method according to claim 1 or 2, characterized in that The temperature of the decarboxylation reaction is -10 to 60°C.

4. The preparation method according to claim 1, characterized in that The oxidant is urea peroxide and / or meta-chloroperbenzoic acid; The molar ratio of the oxidant to the finerenone intermediate having the structure shown in formula III is 1.5 to 3.5:

1.

5. The preparation method according to claim 1, characterized in that The halogenated alkane solvent is a C1-C2 halogenated alkane solvent.

6. The preparation method according to claim 1 or 4, characterized in that The temperature of the oxidation reaction is -20 to 30°C.

7. The preparation method according to claim 1, characterized in that The alkaline substance in the second alkaline aqueous solution is one or more of sodium hydroxide, lithium hydroxide and potassium hydroxide; The mass concentration of the second alkaline aqueous solution is 3-15%.

8. The preparation method according to claim 1, characterized in that The molar ratio of the trifluoroacetic anhydride to the finerenone intermediate having the structure shown in formula III is 1 to 3:

1.

9. The preparation method according to claim 1, 7 or 8, characterized in that: The temperature of the pyridine 2-hydroxylation reaction is 20-120°C.

10. The preparation method according to claim 1, characterized in that After the 2-hydroxylation reaction of pyridine, the obtained 2-hydroxylation reaction liquid of pyridine is subjected to post-treatment, and the post-treatment comprises the following steps: The pH value of the pyridine 2-hydroxylation reaction solution is adjusted to 7-8, and cooling crystallization, solid-liquid separation and drying are performed in sequence to obtain a pure phenerenone impurity product having a structure shown in Formula I.

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