Preparation method of fenerenone racemate and preparation method of fenerenone

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of a finerenone racemate and a preparation method of finerenone. The preparation method of the finerenone racemate comprises the following steps: contacting a compound as shown in a formula I with a condensing agent, a solvent, a nitrogen source and organic alkali to obtain a compound as shown in a formula II; wherein the solvent comprises at least one of toluene and xylene; the organic base comprises at least one of triethylamine and N, N-diisopropylethylamine. The preparation method of the finerenone racemate can effectively reduce the generation amount of three wastes, reduce the production cost of a solvent, shorten the reaction period and obtain the finerenone racemate with relatively high purity, so that the product quality of the finerenone is further improved, and the production cost is reduced.

Description

Technical Field

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

[0002] Finerenone is a drug that can be used to treat adult patients with chronic kidney disease associated with type 2 diabetes. Due to its unique mechanism of action, finerenone can reduce fibrosis and inflammation by blocking mineralocorticoid receptor (MR)-mediated sodium reabsorption and MR overactivation, and is believed to slow or prevent the development of diabetic nephropathy. In addition, finerenone has been used to treat refractory hypertension, demonstrating good efficacy and safety. Because the drug has lower lipophilicity, higher polarity, does not penetrate the blood-brain barrier, has no active metabolites, and has a short half-life, it can reduce the risk of hyperkalemia in patients.

[0003] The preparation method currently disclosed by the original research manufacturer of finerenone (Bayer Pharmaceuticals AG, Germany) is as follows: Wherein step 5 generally adopts the following two reaction systems: System 1, CDI / tetrahydrofuran / DMAP / HMDS system, which is a commonly used system at present. It uses tetrahydrofuran (THF) or acetonitrile as solvent, CDI (N,N'-carbonyldiimidazole) to activate the carboxyl group of compound 7, HMDS (hexamethyldisilazane) provides nitrogen source, and DMAP (4-dimethylaminopyridine) is used as catalyst. When using this system, there are the following problems: (1) Effective quenching is required, otherwise compound 8 will contain a large amount of imidazole and unreacted CDI, resulting in an artificially high yield and the product is highly hygroscopic; (2) Because THF is miscible with water, the mother liquor after solid-liquid separation in this system cannot be treated by conventional distillation methods, otherwise it will result in a high water content (water content ≥3%). At the same time, because CDI is sensitive to water, the recovered solvent cannot be directly used, which also leads to the introduction of more three wastes in this step; (3) Due to the presence of potential peroxides in THF, it is easy to generate decarboxylation impurities M ( ) and impurity N ( ), which requires multiple post-processing to remove, affecting the yield; (4) When using this system, the reaction time is long, generally more than 20 hours, resulting in a long production cycle; System 2 uses an aprotic polar solvent such as DMF (N,N-dimethylformamide) or acetonitrile, aqueous ammonia or ammonia gas as the ammonia source, and DMAP catalysis followed by carboxylic acid amidation to prepare compound 8. This system requires a significant excess of aqueous ammonia, low reaction temperatures, and prolonged reaction times; it also requires demanding production equipment and places high demands on production. Furthermore, due to the high volatility of ammonia, effective control of its effective concentration is difficult, and post-processing can generate large amounts of waste liquid or odorous exhaust gas. Furthermore, the resulting compound 8 is difficult to separate from the intermediate, and the solvent DMF cannot be reused after conventional recycling, resulting in a large amount of alkaline waste liquid. Therefore, the utilization rate of this system is relatively low.

[0004] Therefore, there is an urgent need to provide a method for preparing finerenone to solve the above problems. Summary of the Invention

[0005] The present invention aims to at least partially address one of the technical problems in the related art. To this end, the present invention provides a method for preparing a finerenone racemate and a method for preparing finerenone. This method for preparing a finerenone racemate can effectively reduce the generation of three wastes, lower solvent production costs, shorten the reaction cycle, and obtain a high-purity finerenone racemate, thereby improving the product quality of finerenone and reducing production costs.

[0006] To this end, the first aspect of the present invention provides a method for preparing a finerenone racemate, comprising the following steps: contacting the compound represented by formula I with a condensing agent, a solvent, a nitrogen source, and an organic base to obtain a compound represented by formula II; Wherein, the solvent includes at least one of toluene and xylene; The organic base includes at least one of triethylamine (TEA) and N,N-diisopropylethylamine (DIPEA); .

[0007] To address the shortcomings of the prior art, the present invention utilizes a condensing agent / solvent / nitrogen source / organic base system, using toluene and / or xylene as solvents. The carboxyl groups of the compound represented by Formula I are activated by the condensing agent. Under the catalytic action of the nitrogen source and the organic base, the carboxylic acid in the compound represented by Formula I is amidated to synthesize the compound represented by Formula II (the phenerenone racemate). The resulting phenerenone racemate is of high purity, avoiding the formation of decarboxylation impurities M and pyridine-like impurities N. Furthermore, this method has a short synthesis cycle, simple and easy post-processing, and the solvent is recyclable, effectively reducing the generation of the three wastes and production costs.

[0008] According to an embodiment of the present invention, the condensing agent includes N,N'-carbonyldiimidazole; And / or, the nitrogen source includes hexamethyldisilazane.

[0009] According to an embodiment of the present invention, the concentration of the solvent is 3 mL / g to 10 mL / g, preferably 5 mL / g.

[0010] According to an embodiment of the present invention, the molar ratio of the condensing agent to the compound represented by formula I is (1-3):1, preferably 1.4:1; And / or, the molar ratio of the nitrogen source to the compound represented by formula I is (2-6):1, preferably 4:1; And / or, the molar ratio of the organic base to the compound represented by formula I is (0.1-2):1, preferably 0.2:1.

[0011] According to an embodiment of the present invention, the preparation method further comprises: contacting the compound represented by Formula I with a condensing agent and a solvent to obtain a reaction product; The reaction product is contacted with a nitrogen source and an organic base for a second time to obtain a compound represented by formula II.

[0012] According to an embodiment of the present invention, the temperature of the second contact is 90°C to 130°C, preferably 100°C; And / or, the second contact time is 0.5 to 24 hours, preferably 1 hour.

[0013] According to an embodiment of the present invention, the preparation method further comprises: The compound represented by Formula I is contacted with a condensing agent, a solvent, a nitrogen source, and an organic base to obtain a product containing the compound represented by Formula II. The temperature of the product is adjusted to 20°C to 30°C, water is added to the product for crystallization, and the compound represented by Formula II is obtained through separation.

[0014] According to an embodiment of the present invention, the mass ratio of the volume of water to the compound represented by Formula I is (0.2-15) mL:1 g, preferably 5 mL:1 g; And / or, the temperature of the crystallization treatment is -10°C to 60°C, preferably 25°C.

[0015] According to an embodiment of the present invention, the preparation method further comprises: The liquid obtained by the separation treatment is subjected to extraction treatment and distillation treatment, and the obtained fraction is used as the solvent in the preparation method of the compound represented by formula II.

[0016] A second aspect of the present invention provides a method for preparing finerenone, comprising the following steps: The finerenone racemate is prepared by the preparation method described in the first aspect; The finerenone racemate is resolved to obtain finerenone.

[0017] Thus, the purity of finerenone can be improved, the production cycle of finerenone can be shortened, and the production cost can be reduced.

[0018] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. DETAILED DESCRIPTION

[0019] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0020] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the number of the technical features indicated. Therefore, features defined as "first" or "second" may explicitly or implicitly include one or more of such features. Furthermore, in the description of the present invention, unless otherwise specified, "plurality" means two or more.

[0021] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0022] In order to make the present invention more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meaning commonly understood by those skilled in the art to which the present invention belongs.

[0023] In this document, the terms “include” or “comprising” are open expressions, that is, including the contents specified in the present invention, but not excluding other contents.

[0024] According to an embodiment of the present invention, a first aspect of the present invention provides a method for preparing a finerenone racemate, comprising the following steps: contacting the compound represented by formula I with a condensing agent, a solvent, a nitrogen source, and an organic base to obtain a compound represented by formula II; Wherein, the solvent includes at least one of toluene and xylene; The organic base includes at least one of triethylamine and N,N-diisopropylethylamine; .

[0025] The present invention uses toluene and / or xylene as solvents. The carboxyl groups of the compound represented by Formula I are activated with a condensing agent. Under the catalytic action of a nitrogen source and an organic base, the carboxylic acid in the compound represented by Formula I is amidated to form the compound represented by Formula II. The use of toluene / xylene as solvents in the present invention has a boiling point approximately 45°C higher than that of tetrahydrofuran. Therefore, at relatively high reaction temperatures, both the condensing agent activation time and the amidation reaction time are relatively short. Furthermore, post-processing is relatively simple, significantly shortening the overall production cycle for the preparation of the finerenone racemate. Compared to tetrahydrofuran or acetonitrile systems, the production of a single batch of finerenone racemate can save approximately 18 hours. Furthermore, by avoiding the use of tetrahydrofuran, peroxides are not generated or introduced, and the resulting compound represented by Formula II does not contain the decarboxylation impurity M or the pyridine-like impurity N.

[0026] Furthermore, the system is simple and easy to post-process. After the reaction is completed, the compound represented by Formula II can be directly obtained by quenching with water and cooling to crystallize. Specifically, because toluene and xylene have low polarity and are immiscible with water, the solubility of the compound represented by Formula II in these solvents and water is low. This allows for effective control of the reaction conversion rate while allowing the solvent to be post-processed for recovery and reuse, effectively reducing the generation of three wastes and minimizing solvent production costs.

[0027] According to a specific embodiment of the present invention, the condensing agent includes N,N'-carbonyldiimidazole, thereby activating the carboxyl group in the compound represented by Formula I.

[0028] According to a specific embodiment of the present invention, the nitrogen source includes hexamethyldisilazane, thereby achieving amidation.

[0029] According to a specific embodiment of the present invention, the concentration of the solvent is not particularly limited, and those skilled in the art can make a reasonable selection according to the circumstances. As some specific examples, the concentration of the solvent can be 3 mL / g to 10 mL / g, such as 3 mL / g, 4 mL / g, 5 mL / g, 6 mL / g, 7 mL / g, 8 mL / g, 9 mL / g, 10 mL / g, etc., preferably 5 mL / g.

[0030] Specifically, "solvent concentration" should be understood as the ratio of the volume of the solvent to the mass of the compound represented by Formula I.

[0031] According to a specific embodiment of the present invention, the molar ratio of the condensing agent to the compound represented by Formula I is not particularly limited. Those skilled in the art can make a reasonable selection according to the circumstances. As some specific examples, the molar ratio of the condensing agent to the compound represented by Formula I can be (1-3):1, for example, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 3:1, etc., preferably 1.4:1.

[0032] According to a specific embodiment of the present invention, the molar ratio of the nitrogen source to the compound represented by Formula I is not particularly limited, and those skilled in the art can make a reasonable selection according to the circumstances. As some specific examples, the molar ratio of the nitrogen source to the compound represented by Formula I is (2-6):1, for example, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, etc., preferably 4:1.

[0033] According to a specific embodiment of the present invention, the molar ratio of the organic base to the compound represented by formula I is not particularly limited. Those skilled in the art can make a reasonable selection according to the circumstances. As some specific examples, the molar ratio of the organic base to the compound represented by formula I can be (0.1~2):1, for example, 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.5:1, 2:1, etc., preferably 0.2:1.

[0034] According to a specific embodiment of the present invention, the preparation method further comprises: contacting the compound represented by Formula I with a condensing agent and a solvent to obtain a reaction product; The reaction product is contacted with a nitrogen source and an organic base for a second time to obtain a compound represented by formula II.

[0035] Specifically, the first contacting can activate the carboxyl group in the compound represented by Formula I. The temperature and time of the first contacting are not particularly limited and can be reasonably selected by those skilled in the art according to the circumstances. As some specific examples, the temperature of the first contacting can be 20° C. to 50° C. and the time of the first contacting can be 1 hour to 8 hours.

[0036] Specifically, the second contacting can achieve amidation to obtain the compound represented by Formula II. The temperature and time of the second contacting are not particularly limited and can be reasonably selected by those skilled in the art according to the circumstances. As some specific examples, the temperature of the second contacting is 90°C to 130°C, preferably 100°C, and the time of the second contacting can be 0.5h to 24h, preferably 1h.

[0037] Specifically, the preparation method further comprises: contacting the compound represented by Formula I with a condensing agent, a solvent, a nitrogen source, and an organic base to obtain a product containing the compound represented by Formula II; regulating the temperature of the product to 20°C to 30°C; adding water to the product for crystallization; and separating to obtain the compound represented by Formula II. The compound represented by Formula II can thus be obtained through simple post-treatment (i.e., water quenching, crystallization, and solid-liquid separation).

[0038] Specifically, the mass ratio of the volume of the water to the compound represented by Formula I is not particularly limited. Those skilled in the art can make a reasonable selection according to the circumstances. As some specific examples, the mass ratio of the volume of water to the compound represented by Formula I can be (0.2~15) mL:1 g, for example, 0.2 mL:1 g, 1 mL:1 g, 2 mL:1 g, 3 mL:1 g, 4 mL:1 g, 5 mL:1 g, 6 mL:1 g, 7 mL:1 g, 8 mL:1 g, 9 mL:1 g, 10 mL:1 g, 11 mL:1 g, 12 mL:1 g, 13 mL:1 g, 14 mL:1 g, 15 mL:1 g, etc., preferably 5 mL:1 g.

[0039] Specifically, the temperature of the crystallization treatment is not particularly limited, and those skilled in the art can make a reasonable selection according to the circumstances. As some specific examples, the temperature of the crystallization treatment can be -10°C to 60°C, such as -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, etc., preferably 25°C.

[0040] Specifically, the preparation method further includes: subjecting the liquid obtained by the separation process to extraction and distillation, and the resulting fraction is used as the solvent in the preparation method of the compound represented by Formula II. This treatment can achieve solvent recovery and achieve a solvent water content of less than 0.1%, thereby being used for the subsequent preparation of the compound represented by Formula II.

[0041] According to an embodiment of the present invention, a second aspect of the present invention provides a method for preparing finerenone, comprising the following steps: The finerenone racemate is prepared by the preparation method described in the first aspect; The finerenone racemate is resolved to obtain finerenone.

[0042] According to a specific embodiment of the present invention, the resolution method is not particularly limited and conventional resolution methods in the art can be used, such as salifying the finerenone racemate with an acidic resolving agent and then freeing the finerenone with alkaline treatment.

[0043] Specifically, the type of the acidic resolving agent is not particularly limited, and those skilled in the art may make a reasonable selection according to the circumstances. As some specific examples, the acidic resolving agent may include dibenzoyltartaric acid.

[0044] Specifically, the alkaline dissociation method is not particularly limited, and those skilled in the art can make a reasonable choice according to the circumstances. As some specific examples, the alkaline dissociation can be achieved by adjusting the pH value of the system to 7-8.

[0045] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0046] In the following examples, "eq" refers to molar equivalent.

[0047] Example 1 This embodiment provides a method for preparing a racemate of finerenone, which is as follows: At room temperature (25°C), the compound of Formula I (1.0 eq), toluene (5 mL / g), and CDI (1.4 eq) were added sequentially to a reaction flask. After the addition was complete, the reaction was stirred for 1 h. HMDS (4.0 eq) and TEA (0.2 eq) were then added sequentially. The reaction system was heated to 100°C and kept at this temperature for 1 h.

[0048] After the reaction, the reaction system was cooled to 25°C, and drinking water (0.25 mL / g, the ratio of the volume of water to the mass of the compound represented by Formula I) was slowly added to the system. After the addition was completed, the mixture was stirred and crystallized for 1 hour. The solid-liquid separation was then carried out, and the wet product was dried to obtain the finerenone racemate with a yield of 94.7% and a purity of 99.57%. The decarboxylation impurity M and impurity N were not detected.

[0049] Example 2 This embodiment provides a method for preparing a racemate of finerenone, which is as follows: At room temperature (25°C), the compound of Formula I (1.0 eq), toluene (5 mL / g), and CDI (3.0 eq) were added sequentially to a reaction flask. After the additions were complete, the reaction was stirred for 1 h. HMDS (4.0 eq) and DIPEA (0.2 eq) were then added sequentially. The reaction system was heated to reflux and kept at this temperature for 1 h.

[0050] After the reaction, the reaction system was cooled to 25°C, and drinking water (0.25 mL / g) was slowly added to the system. After the addition was completed, the system was cooled to 5°C and stirred for crystallization for 1 hour. The solid-liquid separation was then carried out, and the wet product was dried to obtain the finerenone racemate with a yield of 97.5% and a purity of 99.84%. The decarboxylation impurity M and impurity N were not detected.

[0051] Example 3 This embodiment provides a method for preparing a racemate of finerenone, which is as follows: At room temperature (25°C), the compound of Formula I (1.0 eq), xylene (5 mL / g), and CDI (1.4 eq) were added sequentially to a reaction flask. After the additions were complete, the reaction was stirred for 1 h. HMDS (4.0 eq) and TEA (0.2 eq) were then added sequentially. The reaction system was heated to 100°C and kept warm for 1 h.

[0052] After the reaction, the reaction system was cooled to 25°C, and drinking water (5 mL / g) was slowly added to the system. After the addition was completed, the mixture was stirred and crystallized for 1 h. The solid-liquid separation was then carried out, and the wet product was dried to obtain the finerenone racemate with a yield of 91.6% and a purity of 99.52%. The decarboxylation impurity M and impurity N were not detected.

[0053] Example 4 This embodiment provides a method for preparing a racemate of finerenone, which is as follows: At room temperature (25°C), the compound of Formula I (1.0 eq), xylene (5 mL / g), and CDI (1.4 eq) were added sequentially to a reaction flask. After addition, the mixture was stirred and reacted for 1 h. HMDS (4.0 eq) and DIPEA (0.3 eq) were then added sequentially. The reaction system was heated to 120°C and incubated for 1 h.

[0054] After the reaction, the reaction system was cooled to 25°C, and drinking water (5 mL / g) was slowly added to the system. After the addition was completed, the mixture was stirred and crystallized for 1 h. The solid-liquid separation was then carried out, and the wet product was dried to obtain the finerenone racemate with a yield of 93.4% and a purity of 99.39%. The decarboxylation impurity M and impurity N were not detected.

[0055] Example 5 This embodiment provides a method for preparing a racemate of finerenone, which is as follows: At room temperature (25°C), the compound of Formula I (1.0 eq), xylene (8 mL / g), and CDI (3.0 eq) were added sequentially to a reaction flask. After addition, the mixture was stirred and reacted for 1 h. HMDS (4.0 eq) and TEA (0.2 eq) were then added sequentially. The reaction system was heated to reflux and kept at this temperature for 1 h.

[0056] After the reaction, the reaction system was cooled to 25°C, and drinking water (0.5 mL / g) was slowly added to the system. After the addition was completed, the mixture was stirred and crystallized for 1 h. The solid-liquid separation was then carried out, and the wet product was dried to obtain the finerenone racemate with a yield of 93.5% and a purity of 99.21%. The decarboxylation impurity M and impurity N were not detected.

[0057] Comparative Example 1 This comparative example provides a method for preparing a racemate of finerenone, which is as follows: 16 g of the compound of Formula I and 9.58 g (59.1 mmol) of CDI were added to 80 mL of THF. 0.51 g (4.17 mmol) of DMAP was added at 20°C. The mixture was stirred at 20°C (gas evolution required) for 1 hour and then heated to 50°C for 2.5 hours. 29.73 g (184.2 mmol) of HMDS was added to this solution and boiled under reflux for 22 hours. An additional 18 mL of THF was added, and the mixture was cooled to 5°C. A mixture of 11.7 mL of THF and 8.35 g of water was added over 3 hours, maintaining the temperature below 20°C. The mixture was then boiled under reflux for 1 hour, then cooled to 0°C via a gradient (3 hours) and stirred at this temperature for 1 hour. The product was filtered and washed twice with 24 mL of THF and twice with 32 mL of water. The product was vacuum dried at 70° C. to obtain a compound represented by Formula II. The content of decarboxylation impurity M in the obtained compound represented by Formula II was 0.21%, and the content of impurity N was 0.36%.

[0058] Comparative Example 2 This comparative example provides a method for preparing a racemate of finerenone, which is as follows: The compound shown in Formula I (66 g, 0.17 mol), CDI (66 g, 0.4 mol) and DMAP (8.5 g, 0.07 mol) were dissolved in 1.15 L of THF and stirred at room temperature until carbon dioxide gas was generated. After 4 h of reaction at room temperature, 25% aqueous ammonia solution (0.45 L) was added and stirred at room temperature for three days until a white solid was gradually generated. After monitoring the reaction completion, the aqueous phase was neutralized with hydrochloric acid and discarded. The organic phase was washed with saturated aqueous ammonium chloride solution and 0.1% dilute hydrochloric acid solution until the DMAP was cleaned by TLC monitoring, washed with water, and the organic phase was dried and spin-dried to obtain the compound shown in Formula II. The decarboxylation impurity M content in the obtained compound shown in Formula II was 0.33%, and the impurity N content was 0.42%.

[0059] Test example: (1) Synthesis of finerenone To a reaction flask, 10.0 g of the compound of Formula II obtained in Example 1 (26.43 mmol, 1.0 eq), 4.83 g of D-dibenzoyltartaric acid (13.48 mmol, 0.55 eq), 100 mL of ethanol (10 mL / g, volume of ethanol to mass of the compound of Formula I), and 40 mL of water (4 mL / g) were added. The mixture was heated to 75°C with stirring and allowed to react for 3 h. The temperature was then slowly lowered to 25°C and stirred for 2 h. The mixture was filtered, and the filter cake was rinsed with an appropriate amount of an ethanol / water mixture (v / v = 1 / 8). The wet product was transferred to a reaction flask, and 120 mL of an ethanol / water mixture (H2O / EtOH) (v / v = 1 / 8) was added. Aqueous sodium phosphate solution was slowly added dropwise to the system until the pH reached 7-8. The mixture was heated to 50°C with stirring for 3 h, then cooled to 25°C and stirred for 1 h to crystallize. The filter cake was filtered and rinsed with an appropriate amount of ethanol / water mixed solvent (V / V = 1 / 8). The wet product was dried under vacuum at 70 °C to obtain finerenone.

[0060] (2) Recycling of solvent toluene After solid-liquid separation, the mother liquor from Example 1-4 was extracted and separated, retaining the organic layer. Concentrated sulfuric acid was slowly added to the organic phase (the amount of concentrated sulfuric acid added was 1%-5% of the mass of the organic phase). The organic phase was heated to reflux for 12 hours, and the fraction at 110.5°C was collected. The toluene test data obtained was collected as follows:

[0061] The recovered toluene was used to prepare the compound represented by Formula II using the synthesis process of Example 1, with a yield of 95.1% and a purity of 99.31%. The decarboxylation impurity M and impurity N were not detected.

[0062] (3) Recycling of solvent xylene After solid-liquid separation, the mother liquor from Example 5 was extracted and separated, retaining the organic layer. Concentrated sulfuric acid was slowly added to the organic phase (the amount of concentrated sulfuric acid added was 1%-5% of the mass of the organic phase). The organic phase was heated to reflux for 12 hours, and the 140°C fraction was collected. The resulting xylene analysis data was collected as follows:

[0063] The recovered xylene was used to prepare the compound represented by Formula II using the synthesis process of Example 5, with a yield of 93.5% and a purity of 99.26%. The decarboxylation impurity M and impurity N were not detected.

[0064] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0065] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A method for preparing a finerenone racemate, characterized in that: The following steps are involved: contacting the compound represented by formula I with a condensing agent, a solvent, a nitrogen source, and an organic base to obtain a compound represented by formula II; Wherein, the solvent includes at least one of toluene and xylene; The organic base includes at least one of triethylamine and N,N-diisopropylethylamine; 。 2. The preparation method according to claim 1, characterized in that The condensing agent includes N,N'-carbonyldiimidazole; And / or, the nitrogen source includes hexamethyldisilazane.

3. The preparation method according to claim 1 or 2, characterized in that The concentration of the solvent is 3 mL / g to 10 mL / g, preferably 5 mL / g.

4. The preparation method according to any one of claims 1 to 3, characterized in that The molar ratio of the condensing agent to the compound represented by formula I is (1-3):1, preferably 1.4:1; And / or, the molar ratio of the nitrogen source to the compound represented by formula I is (2-6):1, preferably 4:1; And / or, the molar ratio of the organic base to the compound represented by formula I is (0.1-2):1, preferably 0.2:

1.

5. The preparation method according to any one of claims 1 to 4, characterized in that The preparation method further comprises: contacting the compound represented by Formula I with a condensing agent and a solvent to obtain a reaction product; The reaction product is contacted with a nitrogen source and an organic base for a second time to obtain a compound represented by formula II.

6. The preparation method according to claim 5, wherein The second contact temperature is 90°C to 130°C, preferably 100°C; And / or, the second contact time is 0.5h~24h, preferably 1h.

7. The preparation method according to any one of claims 1 to 6, characterized in that The preparation method further comprises: The compound represented by Formula I is contacted with a condensing agent, a solvent, a nitrogen source, and an organic base to obtain a product containing the compound represented by Formula II. The temperature of the product is adjusted to 20°C to 30°C, water is added to the product for crystallization, and the compound represented by Formula II is obtained through separation.

8. The preparation method according to claim 7, wherein The mass ratio of the volume of the water to the compound represented by Formula I is (0.2-15) mL:1 g, preferably 5 mL:1 g; And / or, the temperature of the crystallization treatment is -10°C to 60°C, preferably 25°C.

9. The preparation method according to claim 7 or 8, characterized in that The preparation method further comprises: The liquid obtained by the separation treatment is subjected to extraction treatment and distillation treatment, and the obtained fraction is used as the solvent in the preparation method of the compound represented by formula II.

10. A method for preparing finerenone, characterized in that: The following steps are involved: The finerenone racemate is prepared by the preparation method according to any one of claims 1 to 9; The finerenone racemate is resolved to obtain finerenone.

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