A kind of preparation method of finerenone impurity

Abstract

The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing a phenolic hydroxy impurity of finerenone. The present invention provides a novel method for preparing a phenolic hydroxy impurity of finerenone, and obtains a method for preparing a directional synthesis of a phenolic hydroxy impurity of finerenone by screening different routes and process conditions. The preparation method provided by the present invention has the advantages of simple and efficient process, no need for cumbersome purification steps such as column chromatography purification or liquid phase preparation, high yield, good purity, etc., and provides a more effective guarantee for the controllable quality and safety of drugs.

Description

Technical Field

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

[0002] Finerenone is the world's first and only new nonsteroidal mineralocorticoid receptor antagonist for the treatment of chronic kidney disease associated with type 2 diabetes. S )-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, the structural formula is as follows:

[0003] Finerenone tablets were approved by NMPA for listing in China in 2022 and officially entered the Chinese market, bringing good news to the majority of diabetic nephropathy patients. The structure of finerenone contains a 1,4-dihydropyridine structure. Based on the technical common sense in this field, the 1,4-dihydropyridine structure is sensitive to light and oxidation, and it is very easy to degrade and produce aromatized impurities during storage and transportation. However, during the research process, the applicant was surprised to discover another new oxidative degradation impurity of finerenone-finerenone phenolic hydroxyl impurity (structure shown in Formula 1 below). This impurity is bound to bring great risks to the quality of drugs during storage and transportation, thereby increasing the risk of drug safety. As we all know, impurities are the main factors affecting the safety of drugs, and degradation impurities are important factors affecting the stability and shelf life of drugs during storage and transportation. Therefore, in order to improve the controllability of drug quality and effectively ensure the safety of drugs, research on this impurity is essential in the process of finerenone quality research: .

[0004] The prior art WO2017032678A1 discloses the oxidation results of finerenone, which is oxidized by using a variety of oxidants such as DDQ, manganese dioxide, tetrachlorobenzoquinone, potassium permanganate, manganese acetate, or nitric acid, and the products are all high-proportion aromatization products. The prior art cannot provide any technical inspiration for the method of directly synthesizing finerenone phenolic hydroxyl impurities by oxidation: .

[0005] In addition, no literature reports on the direct synthesis of phenolic hydroxy impurities of phenerenone have been retrieved in the prior art. Therefore, inventing a method for preparing phenolic hydroxy impurities of phenerenone with simple and efficient directional synthesis to meet the needs of drug quality research is of great practical significance in improving the controllability of drug quality and ensuring the safety of drugs. Summary of the invention

[0006] The present invention provides a method for preparing a phenolic hydroxy impurity of finerenone, and a method for preparing a phenolic hydroxy impurity of finerenone by directed synthesis is obtained by screening different routes and process conditions. The preparation method provided by the present invention has the advantages of simple and efficient process, no need for cumbersome purification steps such as column chromatography purification or liquid phase preparation, high yield, good purity, etc., and provides more effective guarantee for drug quality control and safety.

[0007] The present invention provides a method for preparing phenerenol phenolic hydroxyl impurities, comprising the following steps: (1) Add finerenone to chloroform, heat and stir until dissolved, add glacial acetic acid and 30% hydrogen peroxide, and keep warm for reaction; (2) The reaction solution is cooled to room temperature, filtered, the filter cake is washed with chloroform, and the filter cake is dried to obtain phenerenol phenolic hydroxyl impurity; the reaction formula is as follows: The reaction temperature in step (1) is 20-70°C, preferably 50-70°C; The reaction time in step (1) is 1 to 18 hours, preferably 10 to 18 hours. The amount of 30% hydrogen peroxide in step (1) is 0.45-0.90 (30% hydrogen peroxide / phenerenone, mass ratio).

[0008] The method for preparing phenerenol phenolic hydroxy impurities provided by the present invention has the following advantages: By screening various routes and process conditions, the applicant has provided a method for the directed synthesis of phenolic hydroxyl impurities of phenerenol, which has the advantages of efficient and simple process, no need for tedious purification steps such as column chromatography purification or liquid phase preparation, high yield, good purity, etc., providing more effective guarantee for the controllable quality and safety of drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 Example 1 Liquid phase purity spectrum of phenolic hydroxyl impurities of phenerenone.

[0010] Figure 2 Example 1 Phenolic hydroxy impurities of finerenone and the system suitability of finerenone.

[0011] Figure 3 Example 1 Mass spectrum of phenolic hydroxyl impurity of phenerenone.

[0012] Figure 4 Example 1: H NMR spectrum of phenolic hydroxyl impurity of phenerenone.

[0013] Figure 5 Example 3 Mass spectrum of phenolic hydroxyl impurity of phenerenone.

[0014] Figure 6Example 3: H NMR spectrum of phenolic hydroxyl impurity of phenerenone. DETAILED DESCRIPTION

[0015] Example 1 Preparation of phenerenol hydroxy impurity Add finerenone (3.00g) to chloroform (30ml), stir and heat to about 60~70℃, add glacial acetic acid (3ml) and 30% hydrogen peroxide (1.35g) after the reaction is clear, the reaction liquid is light yellow, keep warm for 12.5 hours, cool to room temperature, the reaction liquid is a yellow suspension, filter, wash the filter cake with chloroform, dry the filter cake in a 50℃ vacuum drying oven, and obtain 1.75g ​​of off-white solid, with a yield of 63.18%. The product was confirmed to be finerenone phenolic hydroxyl impurity by mass spectrometry and nuclear magnetic hydrogen spectrum, and the data are as follows: HPLC purity: 98.361% (phenolic hydroxy impurities of finerenone can be effectively separated from finerenone in this liquid phase system); TLC: developing solvent: dichloromethane / methanol = 1 ml / 1 drop, Rf value 0.3; MS (ES-): m / z = 348.23 [MH] - ;MS (ES+): m / z=350.19[M+H] + ; 1 H-NMR (DMSO- d 6 , 600M) Chemical shift: 0.694~0.717 (t, 3H); 2.473 (s, 3H); 2.648 (s, 3H); 3.690 (s, 3H); 3.893~4.003 (m, 2H); 7.242~7.255 (d, 1H); 7.460~7.475 (dd, 1H); 7.537~7.539 (d, 1H); 7.824 (s, 1H); 8.999 (s, 1H).

[0016] Example 2 Preparation of phenerenol hydroxy impurity Add finerenone (3.00 g) into chloroform (30 ml), stir and heat to about 50-60°C. After the reaction is clear, add glacial acetic acid (3 ml) and 30% hydrogen peroxide (2.70 g). The reaction liquid is light yellow. Keep the temperature for 18 hours and cool to room temperature. The reaction liquid is a yellow suspension. Filter and wash the filter cake with chloroform. Dry the filter cake in a vacuum drying oven at 50°C to obtain 1.63 g of an off-white solid with a yield of 58.85%. TLC confirmed that it was finerenone phenolic hydroxyl impurity.

[0017] TLC: developing solvent: dichloromethane / methanol = 1 ml / 1 drop, Rf value: 0.3, which is completely consistent with Example 1.

[0018] Example 3 Preparation of phenerenol hydroxy impurity Step 1: Add compound 2 (400 g) and ethanol / isopropanol mixed solution (2.2 L) into a reaction bottle, start stirring, add piperidine (21.13 g) and glacial acetic acid (14.91 g), add dropwise a solution of compound 1 (462 g) in ethanol / isopropanol (200 ml), keep warm at 20-30 °C for reaction, cool to 10-20 °C after the reaction is completed, crystallize for 1 hour, filter, rinse the filter cake with isopropanol, and dry under reduced pressure at 50 °C to obtain compound 4; Step 2: Add compound 4 (300 g) and 2-butanol (3 L) into a reaction bottle, start stirring, add compound 3 (124 g), raise the temperature to reflux, cool to 20-30 ° C after the reaction is completed, crystallize for 1 hour, filter, rinse the filter cake with isopropanol, and dry under reduced pressure at 55 ° C to obtain compound 5; Step 3: Add compound 5 (470 g, 2 batches combined) and NMP (0.94 L) to a reaction bottle, start stirring, add TEOA (0.66 kg), add concentrated sulfuric acid dropwise, raise the temperature to 100-110 °C for reaction, add water for crystallization after the reaction, cool to 20-30 °C, crystallize for 1 hour, filter, rinse the filter cake with isopropanol, and dry under reduced pressure at 55 °C to obtain compound 6; Step 4: Add compound 6 (350 g) and tetrahydrofuran / water solution (3.15 L) to the reaction bottle, start stirring, add 8% sodium hydroxide solution at 0~10°C, complete the addition, keep warm for reaction, and after the reaction, use ethyl acetate and methyl tert-butyl ether for back extraction, adjust the acidity of the aqueous phase for crystallization, filter, wash the filter cake with purified water, and rinse the filter cake with acetonitrile. Take the acetonitrile filtrate, concentrate to dryness under reduced pressure, and purify the residue by column chromatography, using the eluent petroleum ether: ethyl acetate = 25 / 1~1 / 1, and elute to obtain 0.47 g of off-white solid. The product was confirmed to be phenerenone phenolic hydroxyl impurity by mass spectrometry and nuclear magnetic hydrogen spectrum, and the data are as follows: HPLC purity: 96.839%; MS (ES-): m / z = 348.30 [MH] - ;MS (ES+): m / z=350.25[M+H] + ; 1 H-NMR (DMSO- d 6, 600M) Chemical shift: 0.689~0.712 (t, 3H); 2.471 (s, 3H); 2.645 (s, 3H); 3.687 (s, 3H); 3.888~3.917 (m, 1H); 3.970~3.999 (m, 1H); 7.242~7.254 (d, 1H); 7.462~7.477 (dd, 1H); 7.540~7.542 (d, 1H); 7.823~7.824 (d, 1H); 9.024 (s, 1H).

[0019] Comparative Example 1 Prior Art WO2017032678A1 Finerenone (20.00 g) was added to n-butanol (200 ml), stirred until it did not dissolve, and concentrated nitric acid (7.69 g) was added dropwise. After the addition was completed, the temperature was raised to 90-100°C, and a white suspension was obtained. The reaction was kept warm for 1 hour, and the temperature was slightly lowered for vacuum concentration to precipitate a large amount of yellow solid. Petroleum ether (100 ml) was added to the residue, stirred for 15 minutes, filtered, and the filter cake was washed with a mixed solution of petroleum ether and methyl tert-butyl ether (60 ml, 2:1 volume ratio). The filter cake was placed in a vacuum drying oven at 55°C and dried to obtain 16.12 g of yellow solid with a yield of 81.03%. The product was confirmed to be the aromatization product of finerenone by mass spectrometry and nuclear magnetic hydrogen spectrum, and the data are as follows: HPLC purity: 95.524%; MS (ES-): m / z = 375.22 [MH] - ;MS (ES+): m / z=377.25[M+H] + ; 1 H-NMR (DMSO- d 6 , 400M) Chemical shift: 0.692~0.727 (t, 3H); 2.505 (s, 3H); 2.706 (s, 3H); 3.656 (s, 3H); 3.920~4.057 (m, 2H); 7.305~7.324 (d, 1H); 7.450~7.472 (dd, 1H); 7.510 (s, 2H); 7.710 (s, 1H); 8.042~8.044 (d, 1H).

[0020] Combined with the test results of Comparative Example 1, it can be seen that the product of the oxidation of phenarenin using concentrated nitric acid in the prior art WO2017032678A1 by the applicant is a high proportion of phenarenin aromatization product, with a yield of >80%, and it is impossible to directly and easily obtain a high proportion of phenarenin phenolic hydroxyl impurities through the prior art. Therefore, the applicant has provided two methods for preparing phenarenin phenolic hydroxyl impurities through a large number of experimental explorations. Although Example 3 obtains the target phenarenin phenolic hydroxyl impurities, the method has a long route, and column chromatography purification technology is used for enrichment and purification during the period, which is cumbersome and has a very low total yield. The method provided in Examples 1 to 2 uses a mixed system of hydrogen peroxide and peracetic acid to directly oxidize phenarenin, and the post-treatment is extremely simple, and phenarenin phenolic hydroxyl impurities with good purity and high yield can be obtained without cumbersome purification methods such as column chromatography or liquid phase preparation. This method makes it easier to obtain a phenarenin phenolic hydroxyl impurity reference substance, which is of great practical significance in improving the controllability of drug quality and ensuring the safety of drugs.

Claims

1. A method for preparing phenerenol phenolic hydroxyl impurities, characterized in that: The following steps are involved: (1) Add finerenone to chloroform, heat and stir until dissolved, add glacial acetic acid and 30% hydrogen peroxide, and keep warm for reaction; (2) The reaction solution is cooled to room temperature, filtered, the filter cake is washed with chloroform, and the filter cake is dried to obtain phenerenol phenolic hydroxyl impurities.

2. The method according to claim 1, characterized in that The reaction temperature of step (1) is 20-70°C, more preferably 50-70°C.

3. The method according to claim 1, characterized in that The reaction time of step (1) is 1 to 18 hours, more preferably 10 to 18°C.

4. The method according to claim 1, characterized in that: The amount of 30% hydrogen peroxide used in step (1) is 0.45-0.90 (30% hydrogen peroxide / phenerenone, mass ratio).

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