Synthetic method of fenerenone raceme

Abstract

The invention relates to a synthetic method of a finelrenone racemate, which comprises the following steps: carrying out Knoevenagel condensation, Hantzsch dihydropyridine synthesis, O-ethylation and deprotection four-step reaction, selecting a compound shown as a formula (2) and a compound shown as a formula (3) as initial raw materials, and carrying out Knoevenagel condensation reaction under the combined action of organic alkali and organic acid to synthesize a compound shown as a formula (4); carrying out Hantzsch reaction on the compound in the formula (4) and a compound in a formula (5) to synthesize a compound in a formula (6); carrying out O-ethylation reaction on the compound shown in the formula (6) and an ethylation reagent under the catalysis of acid to synthesize a compound shown in a formula (7); finally, 2, 4-dimethoxybenzyl is removed from the compound shown in the formula (7) under the promotion of acid to synthesize the finerenone racemate, the method is high in selectivity and simple in post-treatment, the yield and purity of the product are high, the HPLC purity can reach 99% or above, a new synthesis route and method are developed for synthesizing the finerenone racemate, and the method has good application potential and research value.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical compounds, and specifically refers to a method for synthesizing the racemate of finerenone. Background Art

[0002] Mineralocorticoid receptors are present in the epithelial cells of the distal convoluted tubules and collecting ducts of the kidney. When the mineralocorticoid receptors are over-activated by some endogenous hormones, it may lead to diseases such as hypertension, cardiovascular diseases, and chronic kidney diseases. Aldosterone, as the main mineralocorticoid, is produced in the glomerular zone of the adrenal cortex and is the product after the activation of the renin-angiotensin system. It can induce the activation of mineralocorticoid receptors to cope with hyperkalemia or sodium depletion. Aldosterone can promote the reabsorption of sodium and the excretion of potassium in the kidney, playing a role in regulating the balance of water and some electrolytes in the body. The excessive secretion of aldosterone will increase inflammation, fibrosis, and oxidative stress in the kidney, leading to various diseases, including chronic kidney disease, heart failure, coronary artery disease, and hypertension. Therefore, drugs that block the action of aldosterone on mineralocorticoid receptors have the effect of treating, for example, hypertension, heart failure, and chronic kidney diseases.

[0003] Mineralocorticoid receptor antagonists can be divided into steroidal and non-steroidal types according to their chemical structural characteristics. Spironolactone is the first-generation steroidal mineralocorticoid receptor antagonist. Due to its antagonistic effect with sex hormones, its non-specific binding to sex hormone receptors may cause gynecomastia and sexual dysfunction in men, and female patients may experience adverse reactions such as menstrual disorders or breast hyperplasia, which limits its use. Eplerenone is the second-generation steroidal mineralocorticoid receptor antagonist, which has higher selectivity than spironolactone, but has a weaker affinity for mineralocorticoid receptors and is prone to cause hyperkalemia. For the above reasons, the third-generation non-steroidal mineralocorticoid receptor antagonists with better efficacy have emerged. The representative drug is finerenone (Formula 8 below), developed by Bayer and approved by the US FDA for marketing on July 9, 2021, under the trade name Kerendia, for the treatment of adult chronic kidney disease caused by type 2 diabetes, and was approved for marketing in China in June 2022.

[0004]

[0005] The finerenone compound and its synthetic route were mainly developed by Bayer, and there are also reports on other new synthetic routes. According to the way of obtaining chiral compounds, it can be divided into the racemate resolution method and the asymmetric catalytic synthesis method. Based on cost and operability, the racemate resolution method is the preferred method, as follows:

[0006]

[0007] However, the current methods for synthesizing the racemate of finerenone have low selectivity and cumbersome operations, resulting in a long preparation time and low product yield. Therefore, the methods for synthesizing the racemate of finerenone need to be further improved. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to provide a method for synthesizing the racemate of finerenone with good selectivity, simple operation and high yield in view of the current situation of the prior art.

[0009] The technical solution adopted by the present invention to solve the above technical problems is as follows:

[0010] A method for synthesizing the racemate of finerenone, comprising the following steps:

[0011] (1) Knoevenagel condensation reaction:

[0012] In an organic solvent, under the combined action of an organic base and an organic acid, the compound of formula (2) and the compound of formula (3) undergo a Knoevenagel condensation reaction to synthesize the compound of formula (4); after the reaction is completed, the pure product of the compound of formula (4) is obtained through filtration, washing, filtering dry, and vacuum drying.

[0013]

[0014] (2) Hantzsch reaction:

[0015] The compound of formula (4) and the compound of formula (5) undergo a cyclization reaction in an organic solvent to synthesize the compound of formula (6); after the reaction is completed, the temperature is lowered and crystallization is carried out while maintaining the temperature; after crystallization is completed, filtration, rinsing, filtering dry, and vacuum drying are carried out to obtain the pure product of the compound of formula (6).

[0016]

[0017] (3) O-ethylation reaction:

[0018] In the presence of an acid catalyst, the compound of formula (6) and an ethylating agent are dissolved in an organic solvent to undergo an O-ethylation reaction to synthesize the compound of formula (7).

[0019]

[0020] After the reaction is completed, the temperature is lowered, crystallization is carried out, filtration, washing, filtering dry, and vacuum drying are carried out to obtain the pure product of the compound of formula (7).

[0021] (4) Deprotection reaction:

[0022] The compound of formula (7) is dissolved in an organic solvent and undergoes a deprotection reaction under the action of an acid to synthesize the compound of formula (1).

[0023]

[0024] After the reaction is completed, the temperature is lowered, an aqueous alkali solution is added to adjust the pH, crystallization occurs, filtration, washing, drying by filtration, and vacuum drying are carried out to obtain the pure product of the compound of formula (1), and the compound of formula (1) is the target product;

[0025] The described R′ and R″ are each independently a C1-C4 alkyl group.

[0026] Furthermore, the method for synthesizing the enzalutamide racemate includes the following steps:

[0027] (1) Knoevenagel condensation reaction:

[0028] In an organic solvent, under the combined action of an organic base and an organic acid, the compound of formula (2) and the compound of formula (3) undergo a Knoevenagel condensation reaction at 20-30 °C to synthesize the compound of formula (4); after the reaction is completed, filtration, washing with an organic solvent, drying by filtration, and vacuum drying at 40-50 °C are carried out to obtain the pure product of the compound of formula (4);

[0029] (2) Hantzsch reaction:

[0030] At 80-100 °C, the compound of formula (4) and the compound of formula (5) undergo a cyclization reaction in an organic solvent to synthesize the compound of formula (6); after the reaction is completed, the temperature is lowered to 20-30 °C, and crystallization is carried out while maintaining the temperature for 1-3 h; after crystallization is completed, filtration, washing with an appropriate amount of organic solvent, drying by filtration, and vacuum drying at 50-60 °C are carried out to obtain the pure product of the compound of formula (6);

[0031] (3) O-ethylation reaction:

[0032] The obtained compound of formula (6) and an ethylating agent are dissolved in an organic solvent, and an O-ethylation reaction is carried out at 100-120 °C in the presence of an acid catalyst to synthesize the compound of formula (7); after the reaction is completed, the temperature is lowered to 20-30 °C, a diluting solvent is added for crystallization, and crystallization is carried out while maintaining the temperature at 20-30 °C for 1-3 h, filtration, washing, drying by filtration, and vacuum drying at 50-60 °C are carried out to obtain the pure product of the compound of formula (7);

[0033] (4) Deprotection reaction:

[0034] The compound of formula (7) is dissolved in an organic solvent, and a deprotection reaction is carried out at 80-100 °C under the action of an acid to synthesize the compound of formula (1); after the reaction is completed, the temperature is lowered to 20-30 °C, an aqueous alkali solution is added to adjust the pH, and crystallization is carried out while maintaining the temperature at 20-30 °C for 1-3 h, filtration, washing, drying by filtration, and vacuum drying at 50-60 °C are carried out to obtain the pure product of the compound of formula (1);

[0035] R′ and R″ are each independently one of methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, 2-butyl, tert-butyl, and cyclobutyl.

[0036] Preferably, the organic solvent in the Knoevenagel condensation reaction is one or more of methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, and polyethylene glycol (300 - 400); the organic base in the Knoevenagel condensation reaction is one of piperidine, pyrrolidine, morpholine, piperazine, and N-methylpiperazine; the organic acid in the Knoevenagel condensation reaction is one of formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, trifluoroacetic acid, and citric acid; the combination of the organic base and the organic acid is any combination, with a molar ratio of 1:1, and the amounts used are 0.1 - 1.0 eq of the molar amount of the compound of formula (3).

[0037] Preferably, the organic solvent in the Hantzsch reaction is one or more of methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, polyethylene glycol (300 - 400), 1,4-dioxane, diethylene glycol dimethyl ether, DMF, DMAc, DMSO, NMP, toluene, and xylene.

[0038] Preferably, the organic solvent in the O-ethylation reaction is one or more of methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, polyethylene glycol (300 - 400), 1,4-dioxane, diethylene glycol dimethyl ether, DMF, DMAc, DMSO, NMP, toluene, and xylene.

[0039] Preferably, the ethylating agent in the O-ethylation reaction is one or more of ethyl bromide, ethyl iodide, ethyl methanesulfonate, diethyl sulfate, diethyl carbonate, triethyl orthoformate, triethyl orthoacetate, and triethyloxonium tetrafluoroborate.

[0040] Preferably, the acid catalyst in the O-ethylation reaction is one of sulfuric acid, phosphoric acid, perchloric acid, acetic acid, trichloroacetic acid, and trifluoroacetic acid, and the amount used is 0.1 - 1.0 eq of the molar amount of the compound of formula (6).

[0041] Preferably, the organic solvent in the deprotection reaction is one or more of ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, polyethylene glycol (300 - 400), 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, DMF, DMAc, DMSO, NMP, toluene, xylene, and 1,2-dichloroethane.

[0042] Preferably, the acid in the deprotection reaction is one of trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, methanesulfonic acid, and p-toluenesulfonic acid, and the dosage is 0.1-2.0 eq of the molar amount of the compound of formula (7).

[0043] Preferably, the aqueous alkali solution in the deprotection reaction is one of sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, sodium bicarbonate solution, potassium carbonate solution, and ammonia water, and the pH is adjusted to 8-10.

[0044] Compared with the prior art, the advantages of the present invention are as follows: The synthesis method of the present invention includes four steps of Knoevenagel condensation, Hantzsch dihydropyridine synthesis, O-ethylation, and deprotection. The compounds of formula (2) and formula (3) are selected as the starting materials, and the Knoevenagel condensation reaction occurs under the combined action of an organic base and an organic acid to synthesize the compound of formula (4); the compound of formula (4) and the compound of formula (5) undergo a Hantzsch reaction to synthesize the compound of formula (6); the compound of formula (6) undergoes an O-ethylation reaction with an ethylating reagent under acid catalysis to synthesize the compound of formula (7); finally, the compound of formula (7) removes 2,4-dimethoxybenzyl under acid promotion to synthesize the racemate of finerenone. This method has high selectivity, simple post-treatment, high yield and purity of the product, and the HPLC purity can reach more than 99%. It has opened up a new synthetic route and method for synthesizing the racemate of finerenone, and has good application potential and research value. Specific Embodiments

[0045] The present invention will be further described in detail below with reference to the embodiments.

[0046] Example 1:

[0047] The synthesis method of the finerenone racemate in this example includes the following steps:

[0048] (1) Knoevenagel condensation reaction:

[0049] After nitrogen replacement, N-acetylaceto-2,4-dimethoxybenzylamine (81.10 g, 322.66 mmol), the compound of formula (3) (40.00 g, 248.20 mmol), piperidine (2.11 g, 24.82 mmol), acetic acid (1.49 g, 24.82 mmol) and isopropanol (400 mL) were successively added to a clean reaction flask. Stirring was started, and the reaction was carried out at 20 - 30 °C for 24 h; Sampling and detection were carried out. When the content of the compound of formula (3) in the reaction solution detected by HPLC was ≤1%, the reaction ended. Otherwise, the reaction was continued with heat preservation, and detection was carried out every 2 h until qualified; After the reaction ended, filtration was carried out, and the filter cake was washed with an appropriate amount of isopropanol, drained, and vacuum dried at 40 - 50 °C to obtain the pure product of the compound of formula (4) (light yellow solid, 86.3 g, 88%, HPLC purity > 98.5%).

[0050] (2) Hantzsch reaction: After nitrogen replacement, the compound of formula (4) (69.90 g, 177.21 mmol), the compound of formula (5) (20.00 g, 161.10 mmol) and n-butanol (200 mL) were successively added to a clean reaction flask. Stirring was started, and the temperature was raised to 80 - 100 °C, and the reaction was carried out with heat preservation for 48 h; Sampling and detection were carried out. When the content of the compound of formula (5) in the reaction solution detected by HPLC was ≤1%, the reaction ended. Otherwise, the reaction was continued with heat preservation, and detection was carried out every 2 h until qualified; After the reaction ended, the temperature was lowered to 20 - 30 °C, and heat preservation and crystallization were carried out for 1 - 3 h; After crystallization was completed, filtration was carried out, and the filter cake was washed with an appropriate amount of isopropanol, drained, and vacuum dried at 50 - 60 °C to obtain the pure product of the compound of formula (6) (yellow solid, 66.2 g, 82%, HPLC purity > 98.5%).

[0051] (3) O-ethylation reaction: After nitrogen replacement, the compound of formula (6) (65.00 g, 129.86 mmol), triethyl orthoformate (96.22 g, 649.28 mmol), DMF (650 mL) and perchloric acid (3.73 g, 70%, 25.97 mmol) were successively added to a clean reaction flask. Stirring was started, and the temperature was raised to 100 - 120 °C, and the reaction was carried out with heat preservation for 6 h; Sampling and detection were carried out. When the content of the compound of formula (6) in the reaction solution detected by HPLC was ≤1%, the reaction ended. Otherwise, the reaction was continued with heat preservation, and detection was carried out every 2 h until qualified; After the reaction ended, the temperature was lowered to 20 - 30 °C, and purified water (300 mL) was added for crystallization. Heat preservation and crystallization were carried out at 20 - 30 °C for 1 - 3 h, filtration was carried out, and the filter cake was washed with an appropriate amount of purified water and isopropanol, drained, and vacuum dried at 50 - 60 °C to obtain the pure product of the compound of formula (7) (light yellow solid, 57.60 g, 84%, HPLC purity > 99%).

[0052] (4) Deprotection reaction: After purging with nitrogen, add the compound of formula (7) (55.00 g, 104.05 mmol), 1,2-dichloroethane (550 mL) and methanesulfonic acid (10.00 g, 104.05 mmol) to a clean reaction flask in sequence. Start stirring and heat up to 80 - 100 °C, and keep the reaction at this temperature for 16 h. Take a sample for detection. When the content of the compound of formula (7) in the reaction solution detected by HPLC is ≤ 0.5%, the reaction ends; otherwise, continue the reaction while keeping the temperature, and detect every 2 h until it is qualified. After the reaction ends, cool down to 20 - 30 °C, add 10% aqueous sodium carbonate solution to adjust the pH to 8 - 10, keep the temperature at 20 - 30 °C for 1 - 3 h for crystallization, filter, wash with an appropriate amount of purified water and dichloromethane, drain, and dry in vacuum at 50 - 60 °C to obtain the pure product of the compound of formula (1) (white solid, 35.20 g, 89%, HPLC purity > 99%).

[0053] Examples 2 - 7 were respectively carried out in the same manner as Example 1, except that isopropanol was replaced with the following solvents respectively. The solvents used, the yields and purities of the corresponding products are shown in the following table.

[0054]

[0055] Examples 8 - 15 were respectively carried out in the same manner as Example 1, except that piperidine and acetic acid were replaced with the following organic bases and organic acids respectively. The organic bases, organic acids used, and the yields and purities of the corresponding products are shown in the following table.

[0056]

[0057]

[0058] Example 16:

[0059] The difference in the synthesis method of the fenofibrate racemate in this example from that in Example 1 is the Hantzsch reaction:

[0060] After purging with nitrogen, add the compound of formula (4) (69.90 g, 177.21 mmol), the compound of formula (5) (20.00 g, 161.10 mmol) and n-butanol (200 mL) to a clean reaction flask in sequence. Start stirring and heat up to 80 - 100 °C, and keep the reaction at this temperature for 48 h. Take a sample for detection. When the content of the compound of formula (5) in the reaction solution detected by HPLC is ≤ 1%, the reaction ends; otherwise, continue the reaction while keeping the temperature, and detect every 2 h until it is qualified. After the reaction ends, cool down to 20 - 30 °C, and keep the temperature for 1 - 3 h for crystallization. After crystallization is completed, filter, wash with an appropriate amount of isopropanol, drain, and dry in vacuum at 50 - 60 °C to obtain the pure product of the compound of formula (6) (yellow solid, 66.2 g, 82%, HPLC purity > 98.5%).

[0061] Examples 17 to 23 were carried out in the same manner as Example 16, except that the n-butanol therein was replaced with the following solvents respectively. The solvents used and the yields and purities of the corresponding products are shown in the following table.

[0062]

[0063] Example 24:

[0064] The difference in the O-ethylation reaction between the synthesis method of the finerenone racemate in this example and that in Example 1 is as follows:

[0065] After purging with nitrogen, compound (65.00 g, 129.86 mmol) of formula (6), triethyl orthoformate (96.22 g, 649.28 mmol), DMF (650 mL) and perchloric acid (3.73 g, 70%, 25.97 mmol) were successively added to a clean reaction flask. Stirring was started, and the temperature was raised to 100 - 120 °C, and the reaction was maintained for 6 h. Sampling was carried out for detection. When the content of the compound of formula (6) in the reaction solution detected by HPLC was ≤ 1%, the reaction was ended; otherwise, the reaction was continued to be maintained, and detection was carried out every 2 h until it was qualified. After the reaction was completed, the temperature was lowered to 20 - 30 °C, and purified water (325 mL) was added for crystallization. Crystallization was carried out at 20 - 30 °C for 1 - 3 h, filtered, washed with an appropriate amount of purified water and isopropanol, dried by filtration, and vacuum dried at 50 - 60 °C to obtain the pure product of the compound of formula (7) (light yellow solid, 57.60 g, 84%, HPLC purity > 99%).

[0066] Examples 25 to 30 were carried out in the same manner as Example 24, except that the n-butanol therein was replaced with the following solvents respectively. The solvents used and the yields and purities of the corresponding products are shown in the following table.

[0067]

[0068] Examples 31 to 36 were carried out in the same manner as Example 24, except that the triethyl orthoformate therein was replaced with the following ethylating reagents respectively. The ethylating reagents used and the yields and purities of the corresponding products are shown in the following table.

[0069]

[0070] Examples 37 to 41 were carried out in the same manner as Example 24, except that the sulfuric acid therein was replaced with the following acids respectively. The acids used and the yields and purities of the corresponding products are shown in the following table.

[0071]

[0072] Example 42:

[0073] The difference in the synthesis method of the non-nalidixic acid racemate in this example from that in Example 1 lies in the deprotection reaction:

[0074] After purging with nitrogen, successively add the compound of formula (7) (55.00 g, 104.05 mmol), 1,2-dichloroethane (550 mL), and methanesulfonic acid (10.00 g, 104.05 mmol) to a clean reaction flask. Start stirring and heat up to 80 - 100 °C, and keep the reaction at this temperature for 16 h; take a sample for detection. When the content of the compound of formula (7) in the reaction solution detected by HPLC is ≤ 0.5%, the reaction ends. Otherwise, continue the reaction while keeping the temperature, and detect every 2 h until it is qualified; after the reaction ends, cool down to 20 - 30 °C, add 10% aqueous sodium carbonate solution to adjust the pH to 8 - 10, keep it at 20 - 30 °C for crystallization for 1 - 3 h, filter, wash with an appropriate amount of purified water and dichloromethane, drain, and dry in vacuo at 50 - 60 °C to obtain the pure product of the compound of formula (1) (white solid, 35.20 g, 89%, HPLC purity > 99%).

[0075] Examples 43 - 48 were respectively carried out in the same manner as Example 42, except that 1,2-dichloroethane was replaced with the following solvents respectively. The solvents used and the yields and purities of the corresponding products are shown in the following table.

[0076]

[0077] Examples 49 - 53 were respectively carried out in the same manner as Example 42, except that methanesulfonic acid was replaced with the following acids respectively. The acids used and the yields and purities of the corresponding products are shown in the following table.

[0078]

[0079] Example 54:

[0080] The difference in the synthesis method of the non-nalidixic acid racemate in this example from that in Example 1 lies in the Knoevenagel condensation reaction:

[0081] After purging with nitrogen, successively add N-acetylaceto-2,4-dimethoxybenzylamine (2.43 kg), the compound of formula (3) (1.2 kg), piperidine (63.4 g), acetic acid (44.7 g), and isopropanol (12 L) to a clean glass reaction kettle. Start stirring and react at 20 - 30 °C for 24 h; take a sample for detection. When the content of the compound of formula (3) in the reaction solution detected by HPLC is ≤ 1%, the reaction ends. Otherwise, continue the reaction while keeping the temperature, and detect every 2 h until it is qualified; after the reaction ends, filter, wash with an appropriate amount of isopropanol, drain, and dry in vacuo at 40 - 50 °C to obtain the pure product of the compound of formula (4) (light yellow solid, 2.6 kg, 89%, HPLC purity > 98.5%).

[0082] Example 55:

[0083] The difference in the synthesis method of the canrenone racemate in this example from that in Example 1 lies in the Hantzsch reaction:

[0084] After purging with nitrogen, compound of formula (4) (2.45 kg), compound of formula (5) (0.70 kg) and n-butanol (7 L) were successively added to a clean reaction flask. Stirring was started, and the temperature was raised to 80 - 100 °C, and the reaction was carried out under insulation for 48 h; samples were taken for detection, and by HPLC, the content of the compound of formula (5) in the reaction solution was ≤1%, then the reaction ended, otherwise the reaction continued under insulation and was detected every 2 h until qualified; after the reaction ended, the temperature was lowered to 20 - 30 °C, and crystallization was carried out under insulation for 1 - 3 h; after crystallization was completed, filtration was carried out, and the filter cake was rinsed with an appropriate amount of isopropanol, dried by filtration, and vacuum dried at 50 - 60 °C to obtain the pure product of the compound of formula (6) (yellow solid, 2.4 kg, 85%, HPLC purity > 98.5%).

[0085] Example 56:

[0086] The difference in the synthesis method of the canrenone racemate in this example from that in Example 1 lies in the O-ethylation reaction:

[0087] After purging with nitrogen, compound of formula (6) (2.3 kg), triethyl orthoformate (3.4 kg), DMF (23 L) and perchloric acid (132.0 g) were successively added to a clean reaction flask. Stirring was started, and the temperature was raised to 100 - 120 °C, and the reaction was carried out under insulation for 6 h; samples were taken for detection, and by HPLC, the content of the compound of formula (6) in the reaction solution was ≤1%, then the reaction ended, otherwise the reaction continued under insulation and was detected every 2 h until qualified; after the reaction ended, the temperature was lowered to 20 - 30 °C, purified water (11.5 L) was added for crystallization, and crystallization was carried out under insulation at 20 - 30 °C for 1 - 3 h, filtration was carried out, and the filter cake was washed with an appropriate amount of purified water and isopropanol, dried by filtration, and vacuum dried at 50 - 60 °C to obtain the pure product of the compound of formula (7) (light yellow solid, 2.1 kg, 86%, HPLC purity > 99%).

[0088] Example 57:

[0089] The difference between the synthesis method of the non-nalidixic acid racemate in this example and that in Example 1 lies in the deprotection reaction: After purging with nitrogen, sequentially add the compound of formula (7) (2.0 kg), 1,2-dichloroethane (20 L) and methanesulfonic acid (364.0 g) to a clean reaction flask, start stirring, heat up to 80 - 100 °C, and keep the reaction at this temperature for 16 h; take a sample for detection. When the content of the compound of formula (7) in the reaction solution detected by HPLC is ≤ 0.5%, the reaction ends. Otherwise, continue the reaction while keeping the temperature, and detect every 2 h until it is qualified; after the reaction ends, cool down to 20 - 30 °C, add 10% aqueous sodium carbonate solution to adjust the pH to 8 - 10, keep the temperature at 20 - 30 °C for crystallization for 1 - 3 h, filter, wash with an appropriate amount of purified water and dichloromethane, drain, and dry under vacuum at 50 - 60 °C to obtain the pure product of the compound of formula (1) (white solid, 1.3 kg, 91%, HPLC purity > 99%).

Claims

1. A method for synthesizing the racemate of finerenone, characterized in that It includes the following steps: (1) Knoevenagel condensation reaction: In an organic solvent, under the combined action of an organic base and an organic acid, the compound of formula (2) reacts with the compound of formula (3) to undergo a Knoevenagel condensation reaction to synthesize the compound of formula (4); after the reaction is completed, it is filtered, washed, dried by filtration, and vacuum dried to obtain the pure product of the compound of formula (4); (2) Hantzsch reaction: The compound of formula (4) and the compound of formula (5) undergo a cyclization reaction in an organic solvent to synthesize the compound of formula (6); after the reaction is completed, the temperature is lowered and crystallization is carried out while maintaining the temperature; After crystallization is completed, it is filtered, rinsed, dried by filtration, and vacuum dried to obtain the pure product of the compound of formula (6); (3) O-ethylation reaction: In the presence of an acid catalyst, the compound of formula (6) and an ethylating agent are dissolved in an organic solvent to undergo an O-ethylation reaction to synthesize the compound of formula (7); After the reaction is completed, the temperature is lowered, crystallization is carried out, it is filtered, washed, dried by filtration, and vacuum dried to obtain the pure product of the compound of formula (7); (4) Deprotection reaction: The compound of formula (7) is dissolved in an organic solvent and undergoes a deprotection reaction under the action of an acid to synthesize the compound of formula (1); After the reaction is completed, the temperature is lowered, an aqueous alkali solution is added to adjust the pH, crystallization is carried out, it is filtered, washed, dried by filtration, and vacuum dried to obtain the pure product of the compound of formula (1), and the compound of formula (1) is the target product; The described R′ and R″ are each independently a C1-C4 alkyl group.

2. The synthesis method of the non-nalidixic acid racemate according to claim 1, characterized in that It includes the following steps: (1) Knoevenagel condensation reaction: In an organic solvent, under the combined action of an organic base and an organic acid, the compound of formula (2) reacts with the compound of formula (3) at 20-30 °C to undergo a Knoevenagel condensation reaction to synthesize the compound of formula (4); after the reaction is completed, it is filtered, washed with an organic solvent, dried by filtration, and vacuum dried at 40-50 °C to obtain the pure product of the compound of formula (4); (2) Hantzsch reaction: At 80-100 °C, the compound of formula (4) and the compound of formula (5) undergo a cyclization reaction in an organic solvent to synthesize the compound of formula (6); after the reaction is completed, the temperature is lowered to 20-30 °C and crystallization is carried out while maintaining the temperature for 1-3 h; after crystallization is completed, it is filtered, washed with an appropriate amount of organic solvent, dried by filtration, and vacuum dried at 50-60 °C to obtain the pure product of the compound of formula (6); (3) O-ethylation reaction: The obtained compound of formula (6) and an ethylating agent are dissolved in an organic solvent and undergo an O-ethylation reaction at 100-120 °C in the presence of an acid catalyst to synthesize the compound of formula (7); after the reaction is completed, the temperature is lowered to 20-30 °C, a diluting solvent is added for crystallization, crystallization is carried out while maintaining the temperature at 20-30 °C for 1-3 h, it is filtered, washed, dried by filtration, and vacuum dried at 50-60 °C to obtain the pure product of the compound of formula (7); (4) Deprotection reaction: The compound of formula (7) is dissolved in an organic solvent and undergoes a deprotection reaction at 80-100 °C under the action of an acid to synthesize the compound of formula (1); after the reaction is completed, the temperature is lowered to 20-30 °C, an aqueous alkali solution is added to adjust the pH, crystallization is carried out while maintaining the temperature at 20-30 °C for 1-3 h, it is filtered, washed, dried by filtration, and vacuum dried at 50-60 °C to obtain the pure product of the compound of formula (1); R′ and R″ are each independently one of methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, 2-butyl, tert-butyl, and cyclobutyl.

3. The synthesis method of the finerenone racemate according to claim 2, wherein: The organic solvent in the Knoevenagel condensation reaction is one or more of methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, and polyethylene glycol; the organic base in the Knoevenagel condensation reaction is one of piperidine, pyrrolidine, morpholine, piperazine, and N-methylpiperazine; the organic acid in the Knoevenagel condensation reaction is one of formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, trifluoroacetic acid, and citric acid; the combination of the organic base and the organic acid is any combination, with a molar ratio of 1:1, and the amounts used are 0.1 - 1.0 eq of the molar amount of the compound of formula (3).

4. The synthesis method of the non-nalidixic acid racemate according to claim 2, characterized in that: The organic solvent in the Hantzsch reaction is one or more of methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, polyethylene glycol, 1,4-dioxane, diethylene glycol dimethyl ether, DMF, DMAc, DMSO, NMP, toluene, and xylene.

5. The synthesis method of the finerenone racemate according to claim 2, wherein: The organic solvent in the O-ethylation reaction is one or more of methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, polyethylene glycol, 1,4-dioxane, diethylene glycol dimethyl ether, DMF, DMAc, DMSO, NMP, toluene, and xylene.

6. The synthetic method of the non-nalidixic acid racemate according to claim 2, characterized in that: The ethylating agent in the O-ethylation reaction is one or more of ethyl bromide, ethyl iodide, ethyl methanesulfonate, diethyl sulfate, diethyl carbonate, triethyl orthoformate, triethyl orthoacetate, and triethyloxonium tetrafluoroborate.

7. The synthesis method of the non-nalidixic acid racemate according to claim 2, characterized in that: The acid catalyst in the O-ethylation reaction is one of sulfuric acid, phosphoric acid, perchloric acid, acetic acid, trichloroacetic acid, and trifluoroacetic acid, and the amount used is 0.1 - 1.0 eq of the molar amount of the compound of formula (6).

8. The synthesis method of the non-nalidixic acid racemate according to claim 2, characterized in that: The organic solvent in the deprotection reaction is one or more of ethanol, propanol, isopropanol, n-butanol, 2-butanol, ethylene glycol, diethylene glycol, polyethylene glycol, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, DMF, DMAc, DMSO, NMP, toluene, xylene, and 1,2-dichloroethane.

9. The synthesis method of the finerenone racemate according to claim 2, characterized in that: The acid in the deprotection reaction is one of trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulfuric acid, perchloric acid, phosphoric acid, methanesulfonic acid, and p-toluenesulfonic acid, and the amount used is 0.1 - 2.0 eq of the molar amount of the compound of formula (7).

10. The synthesis method of the canrenoate racemate according to claim 2, characterized in that: The aqueous base solution in the deprotection reaction is one of sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, sodium bicarbonate solution, potassium carbonate solution, and ammonia water, and the pH is adjusted to 8 - 10.

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