Method for preparing fenerenone by recycling fenerenone enantiomer

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a method for preparing fenerenone by recycling a fenerenone enantiomer. A brand new reaction route is designed, an enantiomer is subjected to photochemical catalysis to obtain an aromatization product, then in the presence of a specific catalyst, the aromatization product is subjected to dihydropyridine reduction to obtain a finelrenone racemate, and the finelrenone racemate is subjected to resolution, dissociation and recrystallization to obtain the finelrenone. Compared with the prior art, the method has the advantages that the fennerenone enantiomer is recycled, the recycled fennerenone enantiomer is used for preparing the fennerenone, compared with the prior art, photochemical catalysis is realized under the action of the specific catalyst, the reaction condition is mild, the operation is simple, the requirement on equipment is low, and the method is suitable for industrial production. According to the method, the recycling of the enantiomer of the fenerenone can be realized for industrial production of the fenerenone, the commercialization cost of the fenerenone is reduced, large-scale industrial production can be carried out, repeated recycling is realized, and a direction is provided for process improvement of the fenerenone.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for preparing finerenone by recycling finerenone enantiomers. Background Art

[0002] Finerenone is the first novel oral selective nonsteroidal mineralocorticoid receptor antagonist (MRA) developed by Bayer, used to reduce the risk of hospitalization for sustained eGFR decline, end-stage renal disease, cardiovascular death, non-fatal myocardial infarction, and heart failure in patients with chronic kidney disease associated with type 2 diabetes. It was approved for marketing by the U.S. FDA on July 9, 2021, under the trade name Kerendia, mainly in the form of oral tablets.

[0003] The chemical structure of finerenone is as follows:

[0004]

[0005] Patent WO2008104306A2 discloses the synthetic route of finerenone:

[0006]

[0007] The process reaction is relatively mild and has a high yield, making it suitable for industrial production. However, it is inevitable that during the splitting process, the enantiomers are treated as waste liquid through the mother liquor and cannot be recycled.

[0008] Patent WO2017032678A1 discloses a method for recovering enantiomers, the main route is as follows:

[0009]

[0010] The process first oxidizes the enantiomers, then conducts high-temperature thermal racemization, and then conducts electrochemical reduction to obtain the key intermediate of finerenone, which can then be split to obtain the product. Although the patent provides a recovery method, the electrochemical method has harsh conditions, high economic costs, and severe electrode wear. Most factories are unable to use the electrochemical method for recovery in actual production, which is not conducive to industrial production. Summary of the invention

[0011] In the prior art production, the R configuration of compound 1 cannot be recycled. In order to overcome the shortcomings of the prior art, the purpose of the present invention is to provide a method for preparing finerenone by recycling finerenone enantiomers, which can recycle finerenone enantiomers to prepare finerenone, can carry out large-scale industrial production, realize repeated recycling, and reduce the production cost of finerenone.

[0012] The present invention provides a method for preparing finerenone by recycling finerenone enantiomers, comprising the following steps:

[0013] (1) Compound 1 is salified with D-(+)-dibenzoyltartaric acid, and crystallized to obtain a mixed solution of Compound 2 and Compound 3 and a solid Compound 4;

[0014] (2) The mixed solution of compound 2 and compound 3 is concentrated, diluted with a solvent, subjected to inorganic base freeing reaction, and crystallized to obtain compound 5;

[0015] (3) Compound 5 is added to a solvent, a photocatalyst is added, a photochemical reaction is carried out, crystallization is performed, and filtration is performed to obtain Compound 6;

[0016] (4) Compound 6 is subjected to reduction reaction in a solvent, a catalyst is added, and a reducing agent is added, and then post-treated and purified to obtain compound 1;

[0017] (5) Compound 4 obtained in step (1) is liberated by using an inorganic base to obtain finerenone.

[0018] The reaction equation is as follows:

[0019]

[0020] Finerenone is the S configuration of compound 1. In the prior art production, the R configuration of compound 1 cannot be recycled. The present invention mainly recycles the R configuration of compound 1 and reconverts it into finerenone.

[0021] Furthermore, the step (2) is: concentrating the mixed solution of the compound 2 and the compound 3 under reduced pressure, adding a solvent to dilute, adding an inorganic base to adjust the pH to 7.5-7.6, heating to 50-52° C. for reaction for 3 hours, cooling to 20-25° C., keeping warm for crystallization, filtering, washing the filter cake with purified water, and drying to obtain compound 5;

[0022] The inorganic base in step (2) is one or more of sodium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, preferably sodium phosphate and sodium bicarbonate;

[0023] The solvent in step (2) is one or more of methanol, ethanol, isopropanol, and acetone, preferably ethanol or methanol;

[0024] The temperature of the free reaction is 40-70°C, preferably 60-70°C.

[0025] Furthermore, the solvent in step (3) is one or more of methanol, ethanol, acetone, tetrahydrofuran, N,N-dimethylformamide, and N-methylpyrrolidone, preferably methanol and ethanol; the light source used in the photochemical reaction is an LED light source; the photocatalyst is dichlorobis(2,2'-bipyridyl)ruthenium, 9-trimethyl-10-phenylacridine tetrafluoroborate, tris(2,2'-bipyridyl)ruthenium di(hexafluorophosphate), (lr[dF(CF 3 )ppy] 2 (dtbpy))PF 6 ,[lr(dtbbpy)(ppy) 2 ]PF 6 One or more of the above, the amount of the photocatalyst is 0.1% to 0.5% by mass of the compound 5; preferably 0.2% by mass. The difficulty of preparing compound 6 from compound 5 is the reaction. The preparation process of compound 6 of the present invention not only uses photocatalysis, but also adds the above-mentioned specific photocatalyst, so that the effect is far better than that of simple photocatalysis, and the reaction speed is faster, the impurities are less, and the yield is higher.

[0026] The photocatalyst is more preferably one or two of dichlorobis(2,2'-bipyridine)ruthenium and tris(2,2'-bipyridine)ruthenium di(hexafluorophosphate). The present invention has found through research that the catalytic effect of using these two photocatalysts in this reaction is the best, and the obtained product has very good color and quality, and high yield and purity.

[0027] Furthermore, the photochemical reaction temperature in step (3) is in the range of 40 to 100°C.

[0028] Furthermore, the catalysts in step (4) are catalyst 1 and catalyst 2, and the structural formula of catalyst 1 is:

[0029] Wherein R1 and R2 are phenyl, naphthyl, and derivatives of phenyl and naphthyl;

[0030] The catalyst 2 is one or both of 4A molecular sieve and 3A molecular sieve, preferably 4A molecular sieve.

[0031] The amount of the catalyst 1 added is 0.02 to 0.05 times the mass of the compound 6, preferably 0.03 times the mass, the amount of the catalyst 2 added is 0.01 to 0.04 times the mass of the compound 6, preferably 0.02 times the mass, and the mass ratio of the catalyst 1 to the catalyst 2 is 3-4:2.

[0032] Furthermore, the catalyst 1 is preferably one of the following compounds:

[0033]

[0034] Furthermore, compounds d to k are racemates or single chiral isomers, preferably S configuration. The present invention has found that using S configuration can produce more S configuration target products of compound 1 with higher purity than using R configuration.

[0035] Furthermore, the reducing agent in step (4) is one of the following:

[0036]

[0037] The present invention has been found through research that the best effect is achieved when the reducing agent is compound a or compound b. Compared with compound c, the product obtained by using compound a or compound b as the reducing agent has a higher proportion of s configuration, higher purity, and significantly better product quality and S configuration conversion rate.

[0038] Furthermore, the amount of the reducing agent added is 1.5 to 3.0 times the equivalent of compound 6, preferably 1.8 times the equivalent.

[0039] The solvent for the reaction in step (4) is one or more of tetrahydrofuran, toluene, chlorobenzene, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide, preferably toluene and tetrahydrofuran; the reaction temperature in step (4) is 60 to 100° C., preferably 80 to 100° C.;

[0040] The solvent used for the refining in step (4) is one or more of methanol, ethanol, isopropanol, acetone and water, preferably methanol / water.

[0041] In the present invention, the preparation of compound 1 from compound 6 is also a reaction difficulty. The present invention uses catalyst 1 as a chiral phosphoric acid catalyst, and adds a specific reducing agent as a Hantzsch pyridine catalyst. The chiral phosphoric acid catalyst and the Hantzsch pyridine catalyst are subjected to enantioselective hydrogenation to obtain compound 1, which has not only a high yield, but also a fast reaction speed, and milder reaction conditions, which is suitable for scale-up production, and makes compound 1 contain 80% of the S configuration (phenerenone), and the selective reduction effect is obvious.

[0042] Furthermore, step (5) is: adding the compound 4 obtained in step (1) to a solvent, adding an inorganic base to adjust the pH to 7.5-7.6, wherein the inorganic base is sodium phosphate or potassium phosphate, heating to 50-52° C. for reaction for 2.8-3 hours, cooling to 20-25° C., keeping warm for crystallization for 1.8-2 hours, filtering, and washing the filter cake with purified water; adding to a reaction bottle, adding 450 mL-500 mL of methanol, heating to reflux to dissolve, hot filtering, cooling the filtrate to 20-30° C., dripping 450 g-500 g of purified water, the dripping time is not less than 5 hours, and after the dripping is completed, keeping warm and stirring, filtering, and drying to obtain finerenone.

[0043] Furthermore, step (1) is: adding compound 1 to an ethanol toluene aqueous solution or an ethanol aqueous solution, adding D-(+)-dibenzoyltartaric acid, heating to 70-75°C, keeping the temperature for reaction for 2.8-3h, slowly cooling to 20-25°C, the cooling time is not less than 4h, keeping the temperature for reaction for 1-2h, filtering, washing the filter cake with an ethanol aqueous solution, collecting the mother liquor, i.e., a mixed solution of compound 2 and compound 3, for standby use; adding an acetone aqueous solution to the filter cake, stirring at 20-25°C, filtering, rinsing with an acetone aqueous solution, and drying to obtain a solid compound 4.

[0044] Step (1) uses ethanol toluene aqueous solution or ethanol aqueous solution as a solvent, has a higher yield, better resolution effect and purity, preferably uses ethanol toluene aqueous solution, and the mass ratio of toluene, ethanol and water in the ethanol toluene aqueous solution is preferably 55:790-800:650-660. Using the ethanol toluene aqueous solution as a solvent has a higher yield, better resolution effect and higher purity.

[0045] Step (1) adds D-(+)-dibenzoyltartaric acid, raises the temperature to 70-75° C., keeps the temperature for reaction for 2.8-3 hours, slowly cools the temperature to 20-25° C., the cooling time is not less than 4 hours, keeps the temperature for crystallization for 1-2 hours, and filters. Slow cooling has better reaction effect, higher yield and purity. If there is no further keeping temperature for reaction after cooling to 20-25° C., the yield and purity will be reduced.

[0046] The preparation method of compound 1 is as follows: using 4-cyano-2-methoxybenzaldehyde (compound 7) and ethyl 2-cyanoacetoacetate (compound 8) as starting materials, performing Knoevenagel condensation to obtain compound 9, then performing ring closure with 4-amino-5-methyl-2-hydroxypyridine (compound 10) to obtain compound 11, selectively performing O-alkylation with triethyl orthoacetate to obtain compound 12, then hydrolyzing the ester group to obtain compound 13, and preparing primary amide through carbonyldiimidazole and hexamethyldisilazane to obtain racemic compound 1.

[0047] Compared with the prior art, the present invention has the following beneficial effects:

[0048] The present invention designs a completely new reaction route, wherein enantiomers are subjected to photochemical catalysis to obtain aromatization products, and then, under a specific catalyst, dihydropyridine reduction is performed to obtain a finerenone racemate, and then finerenone is obtained through splitting, freeing, and recrystallization. The present invention realizes the recycling of finerenone enantiomers, and uses the recovered finerenone enantiomers to prepare finerenone. Compared with the existing process, the present invention realizes photochemical catalysis under a specific catalyst, and the reaction conditions are mild, the operation is simple, and the requirements for workshop equipment are low. The recycling of finerenone enantiomers can be realized for the industrial production of finerenone, so that the commercial cost of finerenone is further reduced, large-scale industrial production can be carried out, and repeated recycling can be realized, which provides a direction for the process improvement of finerenone. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 : The liquid phase purity of the finerenone product prepared in Example 1;

[0050] Figure 2 : Mass spectrum of the finerenone product prepared in Example 1;

[0051] Figure 3 : Hydrogen spectrum of the finerenone product prepared in Example 1;

[0052] Figure 4 : The carbon spectrum of the finerenone product prepared in Example 1;

[0053] Figure 5 : XRD pattern of the finerenone product prepared in Example 1. DETAILED DESCRIPTION

[0054] The present invention is further described below by means of specific examples. The examples described in the present invention are only used to illustrate the present invention and do not limit the scope of the present invention.

[0055] The sources of the main raw materials are as follows:

[0056] reducing agent:

[0057]

[0058] Compound a: purchased from Aladdin Biochemical Technology Co., Ltd.;

[0059] Compound b: purchased from Aladdin Biochemical Technology Co., Ltd.;

[0060] Compound c: purchased from Aladdin Biochemical Technology Co., Ltd.;

[0061] Compound e (S configuration): purchased from Shanghai MacLean Biochemical Technology Co., Ltd.;

[0062] Compound e (R configuration): purchased from Shanghai MacLean Biochemical Technology Co., Ltd.;

[0063] Compound d (S configuration): purchased from Shanghai MacLean Biochemical Technology Co., Ltd.

[0064] Example 1

[0065] A method for preparing finerenone by recycling finerenone enantiomers comprises the following steps:

[0066] (1) Preparation of Compound 1:

[0067] 9 kg of isopropanol, 2.4 kg of 4-cyano-2-methoxybenzaldehyde (compound 7), 120 g of benzylamine, and 90 g of acetic acid were added to the reaction kettle. 2.55 kg of ethyl 2-cyanoacetoacetate (compound 8) was added dropwise at 20-30°C. After the addition was completed, the mixture was reacted for 6 hours, filtered, and dried to obtain 4.35 kg of compound 9.

[0068] Add 6 kg of sec-butanol, 1 kg of compound 9, and 0.37 kg of 4-amino-5-methyl-2-hydroxypyridine (compound 10) to the reactor, raise the temperature to reflux for reaction for 20 h, cool to 0-10° C., filter, and dry to obtain 1.2 kg of compound 11.

[0069] Add 1.5 kg NMP, 1 kg compound 11, 1 kg triethyl orthoacetate, and 50 g sulfuric acid to the reactor, heat to 105 °C and react for 1.5 h, cool to 50 °C, add 1.5 kg purified water for crystallization, then continue to add 1.5 kg purified water, cool to 10 °C for crystallization, filter, and obtain 1 kg compound 12.

[0070] To the reactor, 5.5 kg of tetrahydrofuran, 2.6 kg of purified water, and 1 kg of compound 12 were added, and the temperature was lowered to 0-5°C. 0.55 kg of sodium hydroxide solution (27% content) was added dropwise. After the addition was completed, the reaction was continued for 2 h. 3 kg of toluene was added for washing. The liquids were separated, the aqueous phase was collected, the pH was adjusted to 6.5 with hydrochloric acid, and 0.9 kg of compound 13 was obtained after filtering and drying.

[0071] Add 4 kg of tetrahydrofuran, 1 kg of compound 13, 30 g of DMAP, and 600 g of CDI to the reactor, heat to 40 ° C and react for 3 h, add 1.5 kg of hexamethyldisilazane, heat to reflux and react for 8 h, cool to room temperature, add 0.5 kg of purified water dropwise, heat to 70 ° C and react for 3 h, cool to 10 ° C and crystallize for 2 h, filter to obtain 0.95 kg of compound 1.

[0072] The reaction equation for the preparation process of compound 1 is as follows:

[0073]

[0074] (2) Preparation of Compound 4

[0075] Add 1500 g of ethanol toluene aqueous solution (containing 55 g toluene, 795 g ethanol, and 650 g water) to a reaction flask, add 100 g of compound 1 prepared in step (1), add 55 g of D-(+)-dibenzoyltartaric acid in batches, heat to 70-75° C., keep warm for 3 h, slowly cool to 20-25° C. for not less than 4 h, keep warm for 1 h, filter, wash the filter cake with 50 g of ethanol aqueous solution, collect the mother liquor, which is a mixed solution of compound 2 and compound 3, and set aside; add the filter cake to a reaction flask, add 1000 g of acetone aqueous solution (containing 400 g of purified water), stir at 20-25° C. for 15 h, filter, rinse with 50 g of acetone aqueous solution, and dry at 50° C. to obtain 92 g of compound 4 with a yield of 47.25% and a purity of 99.5%.

[0076] (3) Preparation of Compound 5

[0077] The mother liquor in step (2) was concentrated under reduced pressure, most of the solvent was evaporated, 50 g of ethanol was added, the pH was adjusted to 7.5 with 10% sodium phosphate solution, the temperature was raised to 50° C. for reaction for 3 h, the temperature was lowered to 20-25° C., the temperature was kept for crystallization for 2 h, and the filter cake was washed with 25 g of purified water and dried at 50° C. to obtain 46 g of a white solid with a purity of 98.5%.

[0078] (4) Preparation of Compound 6

[0079] Add 800 ml of methanol to the reaction bottle, add 100 g of compound 5, add 0.2 g of photocatalyst dichlorobis(2,2'-bipyridine)ruthenium, turn on the LED light source for irradiation, heat to reflux reaction for 16 hours, cool to 20-30°C, add 1000 ml of purified water dropwise for crystallization, keep stirring at 20-30°C for 2 hours, filter, and dry the filter cake at 50°C to obtain 86 g of white solid with a yield of 86.46% and a purity of 96.8%.

[0080] (5) Preparation of Compound 1

[0081] Add 1000 ml of tetrahydrofuran to the reaction bottle, add 100 g of compound 6, add 4 g of compound e (S configuration), add 2 g of 4A molecular sieve, add 130 g of reducing agent compound a, replace with nitrogen and protect with nitrogen throughout the process, heat to reflux for 30 hours, cool to 20-30°C, filter, and rinse the filter cake with 100 ml of tetrahydrofuran; add the filter cake to the reaction bottle, add 800 ml of methanol, heat to reflux, cool to 30-40°C, filter, collect the filtrate, add 600 ml of purified water dropwise to the filtrate, keep warm at 20-30°C for crystallization for 2 hours, filter, and dry at 50°C to obtain 83 g of white solid with a yield of 82.56% (S configuration accounts for more than 80%) and a purity of 98.6%.

[0082] (6) Compound 4 was prepared using compound 1 obtained in step (5). The preparation process was the same as step (2), except that the amount of D-(+)-dibenzoyltartaric acid added was 71.5 g. The yield was 70.20% and the purity was 99.5%.

[0083] (7) Synthesis of finerenone

[0084] Add 950g of ethanol aqueous solution (containing 760g of purified water) to the reaction flask, add 100g of compound 4, adjust pH to 7.5 with 10% sodium phosphate solution, heat to 50°C for reaction for 3h, cool to 20-25°C, keep warm for crystallization for 2h, filter, and wash the filter cake with 25g of purified water; add the wet sample to the reaction flask, add 450ml of methanol, heat to reflux to dissolve, filter hot, cool the filtrate to 20-30°C, slowly add 450g of purified water, the addition time is not less than 5h, after the addition is completed, keep warm and stir for 5h, filter, and dry at 50°C to obtain 46g of white solid, which is the finerenone product. The liquid phase purity of the prepared finerenone product is shown in Figure 1. Figure 1 , mass spectrum see Figure 2 , hydrogen spectrum see Figure 3 , carbon spectrum see Figure 4 , XRD pattern see Figure 5 , yield 89.49%, purity>99.5%, ee value>99.9%.

[0085] The raw material compound 1 used in step (2) of this embodiment is the compound 1 prepared in step (1), and the R / S configuration each accounts for 50%, so the maximum yield of step (2) does not exceed 50%; the compound 1 used in step (6) is obtained by the process of step (5), and the S configuration accounts for more than 80%, so the yield of the obtained product is high, reaching 70.20%.

[0086] Example 2

[0087] A method for preparing finerenone by recycling finerenone enantiomers comprises the following steps:

[0088] (1) Preparation of Compound 4

[0089] 1500 g of ethanol aqueous solution (containing 700 g of ethanol and 800 g of purified water) was added to the reaction flask, 100 g of compound 1 prepared in step (1) of Example 1 was added, 55 g of D-(+)-dibenzoyltartaric acid was added in batches, the temperature was raised to 70-75° C., the reaction was kept warm for 3 h, the temperature was slowly lowered to 20-25° C., the cooling time was not less than 4 h, the reaction was kept warm for 2 h, and the filter cake was washed with 50 g of ethanol aqueous solution. The mother liquor was collected, which was a mixed solution of compound 2 and compound 3, and was set aside; the filter cake was added to the reaction flask, 1000 g of acetone aqueous solution (containing 300 g of purified water) was added, the mixture was stirred at 20-25° C. for 15 h, filtered, rinsed with 50 g of acetone aqueous solution, and dried at 50° C. to obtain 89 g of compound 4, with a yield of 45.71% and a purity of 99.2%.

[0090] (2) Preparation of Compound 5

[0091] The mother liquor in step (1) was concentrated under reduced pressure, most of the ethanol was evaporated, 20 g of methanol was added, the pH was adjusted to 7.5 with 8% sodium bicarbonate solution, the temperature was raised to 50° C. for reaction for 3 h, the temperature was lowered to 20-25° C., the temperature was kept for crystallization for 2 h, and the filter cake was washed with 25 g of purified water and dried at 50° C. to obtain 43 g of a white solid with a purity of 98.8%.

[0092] (3) Preparation of Compound 6

[0093] Add 1800 ml of ethanol to the reaction bottle, add 100 g of compound 5, add 0.2 g of photocatalyst tri(2,2'-bipyridine)ruthenium di(hexafluorophosphate), turn on the LED light source, heat to reflux reaction for 25 hours, cool to 40-60°C, distill under reduced pressure to 1 / 2 of the original solvent volume, continue to cool to 20-30°C, add 800 ml of purified water dropwise for crystallization, keep stirring at 20-30°C for 2 hours, filter, and dry the filter cake at 50°C to obtain 81 g of white solid with a yield of 81.43% and a purity of 96.2%.

[0094] (4) Preparation of Compound 1

[0095] Add 1000 ml of toluene to the reaction flask, add 100 g of compound 6, add 3 g of compound d (S configuration), add 2 g of 4A molecular sieve, add 121 g of reducing agent compound b, replace with nitrogen and protect with nitrogen throughout the process, heat to 100 ° C and react for 20 hours, cool to 20-30 ° C, filter, and rinse the filter cake with 100 ml of toluene; add the filter cake to the reaction flask, add 800 ml of methanol, heat to reflux, cool to 30-40 ° C, filter, collect the filtrate, add 500 ml of purified water dropwise to the filtrate, keep warm at 20-30 ° C for crystallization for 2 hours, filter, and dry at 50 ° C to obtain 76 g of white solid with a yield of 75.60% (S configuration accounts for more than 80%) and a purity of 99.0%.

[0096] (5) Compound 4 was prepared using compound 1 obtained in step (4). The preparation process was the same as step (1), except that the amount of D-(+)-dibenzoyltartaric acid added was 71.5 g. The yield was 65.8% and the purity was 99.5%;

[0097] (6) Synthesis of finerenone

[0098] Add 900g of ethanol aqueous solution (containing 700g of purified water) to the reaction bottle, add 100g of compound 4, adjust the pH to 7.5 with 10% sodium phosphate solution, heat to 50℃ for reaction for 3h, cool to 20-25℃, keep warm for crystallization for 2h, filter, and wash the filter cake with 25g of purified water; add the wet sample to the reaction bottle, add 500ml of methanol, heat to reflux to dissolve, filter hot, cool the filtrate to 20-30℃, slowly add 500g of purified water, the addition time is not less than 5h, keep warm and stir for 5h after the addition is completed, filter, and dry at 50℃ to obtain 44g of white solid with a yield of 85.60%, purity>99.5%, and ee value>99.9%.

[0099] The raw material compound 1 used in step (1) of this embodiment is the compound 1 prepared in step (1) of Example 1, and the R / S configuration each accounts for 50%, so the maximum yield of step (1) does not exceed 50%; the compound 1 used in step (5) is obtained by the process of step (4), and the S configuration accounts for more than 80%, so the yield of the obtained product is high, reaching 65.8%.

[0100] It can be seen from Examples 1 and 2 that the use of an ethanol-toluene aqueous solution containing toluene in step (2) of Example 1 has a higher yield and a better resolution effect than the use of an ethanol-toluene aqueous solution without toluene in Example 2.

[0101] Example 3

[0102] Step (2) of Example 3 is basically the same as that of Example 1, except that:

[0103] After adding D-(+)-dibenzoyltartaric acid in step (2) of Example 3, the temperature was raised to 70-75°C and kept for reaction for 6 hours. The temperature was quickly lowered to 20-25°C within 1 hour without continuing the heat preservation process and directly filtered. The post-treatment process was the same as that of Example 1.

[0104] Results: The yield of compound 4 obtained in step (2) was 44.02% and the purity was 99.0%.

[0105] Comparative Example 1

[0106] Step (4) of Comparative Example 1 is basically the same as that of Example 1, except that:

[0107] In step (4), the photocatalyst is 9-trimethyl-10-phenylacridine tetrafluoroborate.

[0108] The solid obtained in step (4) of this comparative example is off-white, with a yield of 80.5% and a purity of 87%. The color and quality of the product deteriorate.

[0109] Comparative Example 2

[0110] The step (4) of Comparative Example 2 is basically the same as that of Example 1, except that:

[0111] In step (4), no photocatalyst is added, and only LED light source is used for irradiation;

[0112] The result of step (4) of this comparative example: the experimental reflux reaction time was 25 hours, and the remaining raw material was 99%, and there was basically no reaction.

[0113] Comparative Example 3

[0114] The step (5) of comparative example 3 is basically the same as that of example 1, except that:

[0115] In step (5), compound e adopts the R configuration.

[0116] Results: The yield of step (5) was 75.25% (S configuration accounted for 20%), and the purity was 97.4%. The S configuration target product of compound 1 obtained was significantly less and had poor purity.

[0117] Comparative Example 4

[0118] The step (5) of comparative example 4 is basically the same as that of example 1, except that:

[0119] In step (5), the reducing agent compound a is replaced by compound c.

[0120] Results: The yield of step (5) was 75.62% (S configuration accounted for more than 60%), and the purity was 97.1%. The yield, quality and S configuration conversion rate were significantly worse than those in Example 1.

[0121] Comparative Example 5

[0122] Step (5) of Comparative Example 5 is basically the same as that of Example 1, except that:

[0123] In step (5), 4A molecular sieve is not added, and 4A molecular sieve is replaced with an equal amount of compound e (S configuration), i.e., 6 g of compound e (S configuration) is added;

[0124] Results: The reaction rate of step (5) was slow, and the reaction time was as long as 72 hours to complete the reaction; 72 g of white solid was obtained, with a yield of 71.62% (S configuration accounted for more than 80%) and a purity of 98.6%.

[0125] Comparative Example 6

[0126] Step (5) of Comparative Example 6 is basically the same as that of Example 1, except that:

[0127] In step (5), the reducing agent is

[0128] Result: Step (5) obtained 68 g of white solid with a yield of 71.40% (S configuration accounted for more than 70%) and a purity of 98.0%.

Claims

1. A method for preparing finerenone by recycling finerenone enantiomers, characterized in that: The following steps are involved: (1) Compound 1 is salified with D-(+)-dibenzoyltartaric acid, and crystallized to obtain a mixed solution of Compound 2 and Compound 3 and a solid Compound 4; (2) The mixed solution of compound 2 and compound 3 is concentrated, diluted with a solvent, subjected to inorganic base freeing reaction, and crystallized to obtain compound 5; (3) Compound 5 is added to a solvent, a photocatalyst is added, a photochemical reaction is carried out, crystallization is performed, and filtration is performed to obtain Compound 6; (4) Compound 6 is subjected to reduction reaction in a solvent, a catalyst is added, and a reducing agent is added, and then post-treated and purified to obtain compound 1; (5) The compound 4 obtained in step (1) is freed by an inorganic base to obtain finerenone; The reaction equation is as follows:

2. The method according to claim 1, characterized in that: The step (2) comprises: concentrating the mixed solution of the compound 2 and the compound 3 under reduced pressure, adding a solvent to dilute, adding an inorganic base to adjust the pH to 7.5-7.6, heating to 50-52° C. to react for 2.8-3 hours, cooling to 20-25° C., keeping the temperature for crystallization, filtering, washing the filter cake with purified water, and drying to obtain the compound 5; The inorganic base in step (2) is one or more of sodium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate; The solvent in step (2) is one or more of methanol, ethanol, isopropanol and acetone.

3. The method according to claim 1, characterized in that: The solvent in step (3) is one or more of methanol, ethanol, acetone, tetrahydrofuran, N,N-dimethylformamide, and N-methylpyrrolidone; The light source used for the photochemical reaction is an LED light source; The photocatalyst is one or more of dichlorobis(2,2'-bipyridine)ruthenium, 9-trimethyl-10-phenylacridine tetrafluoroborate, tris(2,2'-bipyridine)ruthenium di(hexafluorophosphate), (lr[dF(CF3)ppy]2(dtbpy))PF6, [lr(dtbbpy)(ppy)2]PF6; the amount of the photocatalyst used is 0.1% to 0.5% of the mass of compound 5.

4. The method according to claim 3, characterized in that: The photocatalyst is one or two of dichlorobis(2,2'-bipyridine)ruthenium and tris(2,2'-bipyridine)ruthenium di(hexafluorophosphate).

5. The method according to claim 1, characterized in that: The catalysts in step (4) are catalyst 1 and catalyst 2, and the structural formula of catalyst 1 is: Wherein R1 and R2 are phenyl, naphthyl, and derivatives of phenyl and naphthyl; The catalyst 2 is one or both of 4A molecular sieve and 3A molecular sieve; The amount of the catalyst 1 added is 0.02 to 0.05 times the mass of the compound 6, the amount of the catalyst 2 added is 0.01 to 0.04 times the mass of the compound 6, and the mass ratio of the catalyst 1 to the catalyst 2 is 3 to 4:

2.

6. The method according to claim 5, characterized in that: The catalyst 1 is one of the following compounds: Compounds d to k are of S configuration.

7. The method according to claim 1, characterized in that: The reducing agent in step (4) is one of the following:

8. The method according to claim 7, characterized in that: The reducing agent in step (4) is compound a or compound b; the solvent for the reduction reaction in step (4) is one or more of tetrahydrofuran, toluene, chlorobenzene, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide; the solvent used for the refining in step (4) is one or more of methanol, ethanol, isopropanol, acetone, and water.

9. The method according to claim 1, characterized in that: Step (5) is: adding the compound 4 obtained in step (1) to a solvent, adding an inorganic base to adjust the pH to 7.5-7.6, wherein the inorganic base is sodium phosphate or potassium phosphate, heating to 50-52° C. for reaction for 2.8-3 hours, cooling to 20-25° C., keeping warm for crystallization for 1.8-2 hours, filtering, and washing the filter cake with purified water; adding to a reaction bottle, adding 450 mL-500 mL of methanol, heating to reflux to dissolve, hot filtering, cooling the filtrate to 20-30° C., dripping 450 g-500 g of purified water, the dripping time is not less than 5 hours, and after the dripping is completed, keeping warm and stirring, filtering, and drying to obtain finerenone.

10. The method according to claim 1, characterized in that: Step (1) is: adding compound 1 to an ethanol toluene aqueous solution or an ethanol aqueous solution, adding D-(+)-dibenzoyltartaric acid, heating to 70-75° C., keeping the temperature for reaction for 2.8-3 hours, slowly cooling to 20-25° C., the cooling time is not less than 4 hours, keeping the temperature for reaction for 1-2 hours, filtering, washing the filter cake with an ethanol aqueous solution, collecting the mother liquor, i.e., a mixed solution of compound 2 and compound 3, for standby use; adding an acetone aqueous solution to the filter cake, stirring at 20-25° C., filtering, rinsing with an acetone aqueous solution, and drying to obtain a solid compound 4.

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