Method for preparing finerenone by resolving the racemate with diastereomeric tartrates

Abstract

The present invention provides a method for preparing finerenone by resolving a racemate with diastereomeric tartrate esters, and also relates to diastereomeric salts (VIIa), (VIIb), (VIIc), and / or (VIId). The resolution method involves using chiral substituted tartrate esters of general formula (VIa) or (VIb) as resolving agents to resolve a racemate of formula (V) to obtain compounds of formula (Va) and / or (Vb). The racemate is added to a solvent mixture, first heated to dissolve, and then the resolving agent is added to obtain a homogeneous solution. The solution is then stirred to crystallize and resolve. The addition procedure is optimized to ensure sufficient salt formation and significantly reduce crystallization time. The base resolution process yields a crude product with very high chemical and enantiomeric purity in a single resolution. The content of the resolving agent, tartrate ester, is less than 0.05%, avoiding waste from multiple resolutions and significantly reducing production costs.

Description

[Technical Field]

[0001] This invention claims priority to patent application No. 202211374807.2, entitled "Method for preparing finerenone by resolving racemate with diastereomeric tartaric acid ester," filed with the State Intellectual Property Administration of China on November 4, 2022. The entire contents of the above prior application are incorporated herein by reference.

[0002] The present invention belongs to the technical field of medicine, and in particular relates to a method for preparing finerenone by resolving the racemate with diastereomeric tartrates, and also to the diastereomeric salts (VIIa), (VIIb), (VIIc) and / or (VIId). [Background technology]

[0003] "Finerenone" is the compound (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, i.e., the compound of formula (Va), and the compound of formula (V) is the racemic form of finerenone. TIFF2025537211000002.tif4589

[0004] The term "enantiomer of finerenone" or "enantiomer of compound of formula (V)" relates to compounds of formula (Va) and (Vb). TIFF2025537211000003.tif4588

[0005] Finerenone (Va) acts as a nonsteroidal antagonist of the mineralocorticoid receptor and can be used as a drug for preventing and / or treating cardiovascular and renal diseases such as heart failure and diabetic nephropathy. The compound of formula (V) or (Va) and its preparation method are described in WO2008 / 104306 and WO2016 / 016287A1, and Baerfacker L, Kuhl A, Hillisch A, et al. Discovery of BAY 94-8862: a nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiovascular diseases [J]. ChemMedChem, 2012, 7(8):1385-1403. To obtain an optically pure compound of formula (V), the racemic mixture of amides (V) must be separated into enantiomers (Va) and (Vb). TIFF2025537211000004.tif45137This is because only formula (Va) has activity. TIFF2025537211000005.tif4535

[0006] Chinese Patent Application CN112041318A describes the use of chiral substituted tartaric acid esters of general formula (IIIa) or (IIIb) to resolve racemic compounds of formula (V) into (Va) and / or (Vb). However, this patent only describes the use of D-dibenzoyltartaric acid as a resolving agent, and the actual recovery rate of the target isomer is only about 90%, resulting in significant resolution losses. Furthermore, the process of treating the diastereomeric salts with base usually requires multiple resolutions to reduce the content of chiral substituted tartaric acid esters in the resolving agent to less than 0.15%. Summary of the Invention [Means for solving the problem]

[0007] The present invention provides a method for resolving a racemate of formula (V) by using a chiral substituted tartaric acid ester of general formula (VIa) or (VIb) as a resolving agent to obtain compounds of formula (Va) and / or (Vb) by resolving the racemate of formula (V). TIFF2025537211000006.tif88138Here, Ar is, Selected from TIFF2025537211000007.tif171158, where * represents the binding site.

[0008] Another aspect of the present invention provides a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Va), in which a chiral substituted tartaric acid ester of formula (VIa) is used as a resolving agent to resolve the racemate of formula (V). TIFF2025537211000008.tif45123Here, Ar is, Selected from TIFF2025537211000009.tif171158, where * represents the binding site.

[0009] Preferably, Ar is Selected from TIFF2025537211000010.tif92157, where * represents the binding site.

[0010] In an embodiment of the present invention, the resolving agent is Selected from TIFF2025537211000011.tif115140.

[0011] Preferably, the resolving agent is Selected from TIFF2025537211000012.tif50105.

[0012] Particularly preferably, the resolving agent is The file is TIFF2025537211000013.tif4731.

[0013] Another aspect of the present invention provides diastereomeric salts of the formula: TIFF2025537211000014.tif83114Here, Ar is, Selected from TIFF2025537211000015.tif171158, where * represents the binding site.

[0014] The diastereomeric salts (VIIa to VIId) are prepared as follows. TIFF2025537211000016.tif55148, TIFF2025537211000017.tif164154 When a racemic mixture of Formula (V) reacts with a chiral substituted tartaric acid ester of Formula (VIa) or (VIb), four diastereomeric salts are formed (VIIa, VIIb, VIIc, and VIId). When a racemic mixture of Formula (V) reacts with a chiral substituted tartaric acid ester of Formula (VIa), a diastereomeric salt of Formula (VIIa) is obtained, in which the S-configuration enantiomer predominates in salt formation. The diastereomeric salt of Formula (VIIa) precipitates almost quantitatively from solution and can be separated from the solution, for example, by filtration, while the R-configuration enantiomer remains in solution. The enantiomeric salt of Formula (VIIb) is prepared by reacting a racemic mixture of Formula (V) with a chiral substituted tartaric acid ester of Formula (VIb), in which the R-configuration enantiomer predominates in salt formation. The precipitated diastereomeric salts can be separated almost quantitatively, with the S-enantiomer remaining in solution.

[0015] The stoichiometric ratio of (V) to (VIa) / (VIb) and the choice of solvent can optimize the yield and enantiomeric purity.

[0016] Finerenone (Va) has the S configuration. The tartrate ester of S,S configuration is preferably used for the resolution of the racemate, preferably forming the diastereomeric salt of the S-enantiomer.

[0017] The chiral substituted tartaric acid ester of formula (VIa) or (VIb) is used as a resolving agent for optical resolution in an amount of 0.5 to 3.0 equivalents, preferably 0.5 to 1.5 equivalents, more preferably 0.5 to 1.0 equivalents, and most preferably 0.55 equivalents.

[0018] The diastereomeric salts are formed in organic solvents or solvent mixtures consisting of water and water-miscible organic solvents.

[0019] Suitable organic solvents include, for example, ethanol, methanol, isopropanol, n-propanol, dichloromethane, tetrahydrofuran, acetonitrile, methyl t-butyl ether, or acetone, with ethanol being preferred. Furthermore, the following solvents are used: methanol / water 3:1, methanol / acetonitrile 1:1, isopropanol / water 3:1, tetrahydrofuran / water 3:1, and acetonitrile / water 3:1. Here, the solvent ratio refers to the volume-to-volume ratio (v / v). For example, a 3:1 ethanol / water mixture contains 60 mL of ethanol and 20 mL of water. Therefore, the volume is based on the total volume of the solvent.

[0020] The optical resolution is preferably carried out in ethanol / water, with the mixing ratio (v / v) of ethanol:water ranging from 1:1 to 9:1. A preferred mixture is ethanol:water = 3:1 to 9:1. A particularly preferred mixture is ethanol:water = 3:1. The mixture can be prepared in advance or on-site after all components are placed in a container. The solvent mixture may be used in a 5- to 30-fold excess relative to the racemate of formula (V), i.e., 5-30 L of solvent mixture per 1 kg of racemate. A 5- to 15-fold excess is preferred.

[0021] Optical resolution is typically performed as follows: First, the racemate of formula (V) is added to a solvent mixture at room temperature, then heated to 0-78°C, preferably 70-78°C, and stirred at 70-78°C, most preferably 75°C, until dissolution occurs. Next, a resolving agent is added to the above system and stirred at 70-78°C for 0.5-3 hours, preferably 0.5-1 hour. The mixture is then cooled to 0-30°C, preferably 15-25°C, within 3-15 hours, preferably 3-5 hours. Stirring is then continued at 15-25°C for 12-24 hours, preferably 12-18 hours, and most preferably 12-14 hours. In the present invention, the racemate is first added to a solvent mixture and dissolved by heating. Then, a resolving agent is added to obtain a homogeneous system, followed by stirring to crystallize and resolve the system. By optimizing the addition procedure, sufficient salt formation is ensured and the crystallization time is significantly reduced.

[0022] The precipitated diastereomeric salts (VIIa), (VIIb), (VIIc) and / or (VIId) are then separated.

[0023] The separation is carried out by methods known to those skilled in the art, for example, by filtration or by using a centrifuge. The filter cake thus obtained can be washed one or more times with a solvent or a solvent mixture, and then dried under reduced pressure (45-65°C, preferably 55°C).

[0024] Using the above process, diastereomeric salts can be prepared with very high chemical purity, and the enantiomeric excess of the diastereomeric salts is typically less than 97.0% ee.

[0025] The diastereomeric salt does not necessarily have to be dried, and the wet diastereomeric salt may be used in the next step.

[0026] In the next step, the diastereomeric salt is treated with a base: To prepare the chiral compounds (Va) and (Vb), it is necessary to treat the diastereomeric salt of formula (VIIa), (VIIb), (VIIc) or (VIId) with a base, with the corresponding tartrate of formula (VIa) or (VIb) remaining in solution in the form of a salt.

[0027] TIFF2025537211000018.tif163116

[0028] In the present invention, suitable bases are inorganic or organic bases.As inorganic bases, ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, ammonium phosphate, sodium phosphate, or potassium phosphate can be used.Preferably, sodium hydroxide, sodium phosphate, or potassium phosphate is used.Particularly preferably, sodium phosphate or potassium phosphate is used.It is important that the inorganic base is used in the form of anhydrous or its hydrate.For example, sodium phosphate anhydrous and sodium phosphate hydrate can be used. Examples of the organic base include aliphatic or aromatic bases such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, isopropylamine, 1,3-propylenediamine, 1,2-propylenediamine, tripropylamine, cyclohexylamine, dicyclohexylamine, N,N-diisopropylethylamine, aniline, diphenylamine, triphenylamine, monoethanolamine, diethanolamine, triethanolamine, N-methylmorpholine, pyridine, sodium t-butoxide, potassium t-butoxide, sodium ethoxide, and sodium methoxide. Preferred are triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, and aniline.

[0029] In one embodiment of the present invention, the pH of the system is adjusted to 6.9 to 9.5 by adding an inorganic base at a temperature of 0 to 60°C.

[0030] In one embodiment of the present invention, 1.5 to 6.0 equivalents of an organic base are added at a temperature of 0 to 60°C.

[0031] The target compound (Va) or (Vb) is released into a mixture of water and a water-miscible organic solvent (e.g., ethanol, isopropanol, methanol, or acetone), preferably ethanol. It has been found advantageous to use a mixture of water and ethanol in a v / v ratio of 1:20 to 1:3. However, it is preferred to use a 1:19 ethanol:water mixture. The mixture can be prepared in advance or extemporaneously after all components are placed in a container. The amount of mixture used can be 8 to 35 times the amount of diastereomeric salt (VIIa, VIIb, VIIc, or VIId) used, i.e., for example, 8 to 35 L of mixture per 1 kg. It is preferred to use 15 to 35 times the amount of mixture, more preferably 25 to 35 times the amount of mixture, and most preferably 30 times the amount of mixture.

[0032] The target compound (Va) or (Vb) is released in the following steps. First, the diastereomeric salt (VIIa, VIIb, VIIc, or VIId) is added to a mixed solvent at 0°C to 80°C, preferably 20°C to 55°C, and an organic or inorganic base (in solid form or solution, preferably in water) is added to adjust the pH to 6.9 to 9.5, preferably 7.1 to 8.0, and particularly preferably 7.5. The base can be added very quickly (within a few minutes) or very slowly (within a few hours) (e.g., within 3 minutes to 2 hours). In either case, more rapid addition is preferred. Measurement within 3 to 30 minutes is preferred. This can be achieved by a pH meter installed in the reactor, which is used for adjustment and control, gradually metering the added base. After the pH is established, it has been found advantageous to resume stirring at 10°C to 80°C, preferably 20°C to 65°C, and preferably 45°C to 55°C. Stirring is continued for 1 to 20 hours, preferably 2 to 6 hours, and more preferably 2 to 3 hours. The mixture may then be cooled to 20°C to 30°C and stirred again for 1 to 40 hours, preferably 3 to 24 hours, and more preferably 10 to 18 hours.

[0033] The separation is carried out by methods known to those skilled in the art, for example by filtration or by using a centrifuge. The filter cake thus obtained can be washed one or more times with a solvent or a solvent mixture. Drying is then carried out under reduced pressure (preferably <100 mbar) and at a temperature (50-80°C, preferably 55°C).

[0034] The above process allows the preparation of crude products with very high chemical purity. The enantiomeric excess of crude products (Va) and (Vb) is usually 97% ee or more, preferably 99% ee or more. The content of the resolving agent tartaric acid ester is less than 0.05%.

[0035] In a method that is particularly preferred, especially for implementation on an industrial scale, D-di-o-methylbenzoyltartaric acid (VI-1) is used as the resolving agent. TIFF2025537211000019.tif53160

[0036] The resolution of the racemate is preferably carried out in an ethanol / water mixture, followed by the release of (Va) using sodium phosphate or sodium hydroxide as a base, preferably in an ethanol / water mixture. TIFF2025537211000020.tif56156

[0037] The present invention also allows for the separation of the target enantiomer from the mother liquor. Herein, the appropriate diastereomeric salt (VIa), (VIb), (VIc), or (VId) is prepared from formula (Va) or (Vb) and separated by filtration. The pH of the mother liquor containing the corresponding other diastereomer is then adjusted to pH > 7, preferably pH = 7.5, by adding a base, such as ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, or ammonium phosphate, preferably sodium hydroxide, sodium phosphate, or potassium phosphate, and particularly preferably sodium phosphate or potassium phosphate. The organic solvent, preferably ethanol, is then distilled at atmospheric pressure or, more gently, under reduced pressure, thereby precipitating the corresponding other enantiomer. The product is filtered, washed with water or a water / organic solvent mixture, and dried. [Effects of the Invention]

[0038] In the present invention, the racemate is added to a solvent mixture, heated to dissolve, and then a resolving agent is added to obtain a homogeneous system, followed by stirring to crystallize and resolve. By optimizing the addition procedure, sufficient salt formation is ensured, and the crystallization time is significantly reduced. Furthermore, the diastereomeric salt of the present invention can be obtained in a single base decomposition step to obtain a crude product with very high chemical purity and enantiomeric purity. The content of the resolving agent, tartaric acid ester, is less than 0.05%, which avoids waste generated by multiple decompositions and significantly reduces production costs. [Brief explanation of the drawings]

[0039] [Figure 1] 1 is an X-ray powder diffraction (XRPD) spectrum of the compound of formula (VII-1). DETAILED DESCRIPTION OF THE INVENTION

[0040] Reagent abbreviations and acronyms are as follows:

[0041] Ethanol (EtOH), dimethyl sulfoxide (DMSO), (yield) theoretical value (of th.), high-performance liquid chromatography (HPLC), 1H nuclear magnetic resonance spectroscopy (1H-NMR), room temperature (RT), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), time (h), volume (vol).

[0042] Example 1

[0043] Example 1a

[0044] Preparation of diastereomeric salt (VII-1) TIFF2025537211000021.tif52160; 100 g (0.2642 mol) of racemic finerenone (V) was suspended in a mixture of 900 mL of ethanol and 300 mL of water and heated to 75°C with stirring to dissolve. 56.15 g (0.1453 mol) of D-di-o-methylbenzenebenzoyltartaric acid was added via a solid glass funnel and crystallized at 75°C with stirring for 1.0 h. The mixture was then cooled to 25°C over 3 h and stirred at this temperature for 16 h. The precipitated crystals were filtered and washed twice with 200 mL of ethanol / water (3:1, v / v). The product was dried under reduced pressure at 55°C.

[0045] The yield is 100.2 g (99.2% of theory) of an off-white crystalline powder.

[0046] Analysis results: The enantiomeric purity (ee%) is 97.2%ee. 1H-NMR(400MHz,DMSO-d6):δ=7.90-7.85(m,2H),7.70(s,1H),7.58-7.52(m, 3H),7.42-7.35(m,5H),7.29(dd,J=7.9,1.5Hz,1H),7.16(d,J=7.9Hz,1H),6 .73(d,J=33.4Hz,2H),5.88(s,2H),5.38(s,1H),4.01(qt,J=6.7,3.4Hz,2H) ,3.83(s,3H),2.55(s,6H),2.19(s,3H),2.13(s,3H),1.05(t,J=7.0Hz,3H).

[0047] The off-white crystalline powder (VII-1) obtained by Example 1a was characterized by X-ray powder diffraction at room temperature, and the results are shown in FIG.

[0048] TIFF2025537211000022.tif183162

[0049] Example 1b

[0050] Preparation of crude product (Va) TIFF2025537211000023.tif411111100 g of compound (VII-1) prepared in Example 1a was suspended in a mixture of 150 mL of ethanol and 2850 mL of water. Subsequently, 356.5 g of aqueous sodium phosphate solution (100 g of sodium phosphate dissolved in 1000 mL of water) was added linearly and uniformly within 1 h to adjust the pH to pH = 7.5. The mixture was heated to an internal temperature of 55 °C within 1 h and stirred at this temperature for 3.0 h. The mixture was cooled to 20 °C within 1 h and stirred at this temperature for an additional 1 h. The precipitated crystals were filtered and washed twice with 200 mL of ethanol / water (5:95, v / v). The product was dried under reduced pressure at 55 °C. The yield was 47.0 g (95.0% of theoretical) of an off-white crystalline powder.

[0051] Analysis results: The enantiomeric purity (ee%) is 97.0%ee; The content of D-di-o-methylbenzenebenzoyltartaric acid is 0.04%; 1H-NMR (400MHz, DMSO-d6): δ=7.69(s,1H),7.56(s,1H),7.37(d,J=1.5Hz,1H),7.28(dd,J=7.9,1.5Hz,1H),7.15(d,J=7.8Hz,1H) ),6.72(d,J=29.6Hz,2H),5.38(s,1H),4.02(qt,J=7.0,3.2Hz,2H),3.83(s,3H),2.16(d,J=25.7Hz,6H),1.05(t,J=7.0Hz,3H). Example 2 Example 2a

[0052] Preparation of diastereomeric salt (VII-2) TIFF2025537211000024.tif51153 100 g (0.2642 mol) of racemic finerenone (V) was suspended in a mixture of 900 mL of ethanol and 300 mL of water, heated to 75 °C, and dissolved with stirring. 52.07 g (0.1453 mol) of D-dibenzoyltartaric acid was added via a solid glass funnel and crystallized at 75 °C for 3.0 h with stirring. The mixture was then cooled to 25 °C over 3 h and stirred at this temperature for 16 h. The precipitated crystals were filtered and washed twice with 200 mL of ethanol / water (3:1, v / v). The product was dried under reduced pressure at 55 °C.

[0053] The yield is 100.0 g (100.0% of theory) of an off-white crystalline powder.

[0054] Analysis results: The enantiomeric purity (ee%) is 96.7%ee.

[0055] Example 2b

[0056] Preparation of crude product (Va) TIFF2025537211000025.tif40110 100 g of the compound prepared in Example 2a was suspended in a mixture of 100 mL of ethanol and 900 mL of water. Subsequently, 367.2 g of aqueous sodium phosphate solution (100 g of sodium phosphate dissolved in 1000 mL of water) was added linearly and uniformly within 1 hour to adjust the pH to pH = 7.5. The mixture was heated to an internal temperature of 55°C within 1 hour and stirred at this temperature for 3.0 hours. The mixture was cooled to 20°C within 1 hour and stirred at this temperature for an additional 1 hour. The precipitated crystals were filtered and washed twice with 200 mL of ethanol / water (10:90, v / v). The product was dried under reduced pressure at 55°C. The yield was 45.0 g (87.6% of theoretical) of an off-white crystalline powder.

[0057] Analysis results: The enantiomeric purity (ee%) is 96.5%ee; The content of D-dibenzoyltartaric acid is 0.50%.

[0058] Example 3

[0059] The residual content of the resolving agent was detected for the crude products obtained after decomposition of salts of different resolving agents in Example 1b and Example 2b. When D-di-o-methylbenzoyltartaric acid was used as the resolving agent, the content of the resolving agent after decomposition was less than 0.10%, 0.04%. When D-dibenzoyltartaric acid was used as the resolving agent, the content of the resolving agent after decomposition was 0.50%, and more than two decompositions were required.

[0060] Example 4

[0061] The resolution effects of Example 1a, Example 2a, and (+)-O,O-di-p-anisyl-D-tartaric acid disclosed in Patent CN112041318A were compared, and the enantiomeric excess values ​​of different (Va) were determined and summarized in Table 2.

[0062] TIFF2025537211000026.tif42166

[0063] As can be seen from the above table, the resolving agent of the present invention, D-di-o-methylbenzenebenzoyltartaric acid, has the best resolving effect, which is superior to the resolving effects of D-dibenzoyltartaric acid and (+)-O,O-di-p-anisoyl-D-tartaric acid.

[0064] Example 5

[0065] Example 5a

[0066] Preparation of diastereomeric salt (VII-1) TIFF2025537211000027.tif57157 100 g (0.2642 mol) of racemic finerenone (V) was suspended in a mixture of 900 mL of ethanol and 300 mL of water and heated to 75 °C with stirring. 56.15 g (0.1453 mol) of D-di-o-methylbenzenebenzoyltartaric acid was added via a solid glass funnel and crystallized at 75 °C with stirring for 1.0 h. The mixture was then cooled to 25 °C over 3 h and stirred at this temperature for 16 h. The precipitated crystals were filtered and washed twice with 200 mL of ethanol / water (3:1, v / v). The product was dried under reduced pressure at 55 °C. The yield was 100.3 g (99.3% of theoretical) of an off-white crystalline powder.

[0067] Analysis results: The enantiomeric purity (ee%) is 97.0%ee.

[0068] Example 5b

[0069] Preparation of crude product (Va) TIFF2025537211000028.tif62158

[0070] 100 g of compound (VII-1) prepared in Example 5a was suspended in 500 mL of ethanol, and 2.0 equivalents (33.80 g, 0.2615 mol) of N,N-diisopropylethylamine was gradually metered in at 40°C, and the mixture was stirred at this temperature for 1 hour. After cooling to 5°C, the mixture was stirred at this temperature for 1 hour. The precipitated solid was filtered. The product was dried under reduced pressure at 40°C. The yield was 42.1 g (85.1% of theoretical) of a white crystalline powder.

[0071] Analysis results: The enantiomeric purity (ee%) is 99.3%ee; The content of D-di-o-methylbenzenebenzoyltartaric acid is 0.08%.

[0072] Example 5c

[0073] Preparation of crude product (Va) TIFF2025537211000029.tif41110

[0074] Another batch of 100 g of racemic finerenone (V) and diastereomeric salt (VII-1) was prepared according to Example 5a. 100 g of diastereomeric salt (VII-1) was suspended in 3000 mL of water. Subsequently, 88.8 g of aqueous sodium hydroxide (8.8 g of sodium hydroxide dissolved in 80 g of water) was added linearly and uniformly within 10 minutes to adjust the pH to pH = 7.5. The mixture was heated to an internal temperature of 55°C within 1 hour and stirred at this temperature for 3.0 hours. The mixture was cooled to 23°C within 1 hour and stirred at this temperature for another 1 hour. The precipitated crystals were filtered and washed with 100 g of water. The wet product was then slurried in 100 g of purified water at 50°C for 1 hour, cooled to 23°C, and stirred for 1 hour. The solid was filtered, rinsed with 100 g of purified water, and dried under reduced pressure at 55°C to obtain the final product. The yield is 45.8 g (92.6% of theory) of an off-white crystalline powder.

[0075] Analysis results: The enantiomeric purity (ee%) is 98.0%ee. The content of D-di-o-methylbenzenebenzoyltartaric acid was not detected.

[0076] Example 5d

[0077] Preparation of pure product (Va) 40 g of the crude product prepared in Example 5b was suspended in 880 mL of ethanol and heated to reflux. Upon heating, the product dissolved. Stirring was continued at this temperature for 1 hour. The solution was filtered through a heated filter press (T = 75 °C). The solvent was then distilled to approximately four times the final volume (based on the material used: 40 g x 4 = 160 mL) (approximately 720 mL was distilled). The mixture was then cooled to an internal temperature of 23 °C (over approximately 1.5 to 2 hours). The mixture was then stirred at an internal temperature of 3 °C for 2 hours. The product was filtered and washed once with 80 mL of absolute ethanol. The wet product was dried under reduced pressure for 48 hours. The yield was 36.6 g (91.5% of theoretical) of a colorless crystalline powder.

[0078] Analysis results: The enantiomeric purity (ee%) is 100.0%ee.

[0079] Example 6

[0080] Separation of finerenone enantiomers (Vb) Example 6a

[0081] Preparation of L-di-o-methylbenzenebenzoyl tartrate 100 g (0.2642 mol) of racemic finerenone (V) was suspended in a mixture of 900 mL of ethanol and 300 mL of water and heated to 75°C with stirring. 56.15 g (0.1453 mol) of L-di-o-methylbenzenebenzoyltartaric acid was added via a solid glass funnel and crystallized at 75°C with stirring for 3.0 hours. The mixture was then cooled to 25°C over 3 hours and stirred at this temperature for 16 hours. The precipitated crystals were filtered and washed twice with 200 mL of ethanol / water (3:1, v / v). The product was dried under reduced pressure at 55°C. The yield was 100.7 g (99.7% of theoretical) of an off-white crystalline powder.

[0082] The enantiomeric purity (ee%) is 96.5%ee.

[0083] Example 6b

[0084] Separation of finerenone (Va) from mother liquor The combined mother liquor and washings from Example 6a were adjusted to pH 7.5 by adding aqueous sodium phosphate solution (100 g sodium phosphate dissolved in 1000 mL water) at room temperature. Vacuum distillation was then started to evaporate all the ethanol until the residual volume was approximately 0.4 L. The mixture was cooled to 25°C and stirred at 25°C for 3 hours. The product was filtered and washed four times with 200 mL water. The wet product was concentrated under reduced pressure (48 hours). The yield was 46.8 g (93.6% of theory) of a colorless crystalline powder.

[0085] Analysis results: The enantiomeric purity (ee%) is 98.1%ee.

[0086] The content of L-di-o-methylbenzenebenzoyltartaric acid is 0.51%.

[0087] This crude product can be used to prepare pure phenerenone (Va) in a similar manner as described in Example 5c.

[0088] Example 7

[0089] Example 7a

[0090] Preparation of diastereomeric salt (VII-3) TIFF2025537211000030.tif57162 10 g (0.02642 mol) of racemic finerenone (V) was suspended in a mixture of 90 mL of ethanol and 30 mL of water and heated to 75 °C with stirring to dissolve. 6.21 g (0.01454 mol) of D-di-o-chlorobenzenebenzoyltartaric acid was added via a solid glass funnel and crystallized at 75 °C with stirring for 3.0 h. The mixture was then cooled to 25 °C over 3 h and stirred at this temperature for 16 h. The precipitated crystals were filtered and washed twice with 20 mL of ethanol / water (3:1, v / v). The product was dried under reduced pressure at 55 °C.

[0091] The yield is 9.1 g (85.5% of theory) of an off-white crystalline powder.

[0092] Analysis results: The enantiomeric purity (ee%) is 90.7%ee.

[0093] Example 7b

[0094] Preparation of crude product (Va) 5 g of the compound prepared in Example 7a was suspended in a mixture of 5 mL of ethanol and 45 mL of water. Subsequently, 10.2 g of aqueous sodium phosphate (100 g of sodium phosphate dissolved in 1000 mL of water) was added linearly and uniformly within 1 h to adjust the pH to pH = 7.5. The mixture was heated to an internal temperature of 55 °C within 1 h and stirred at this temperature for 3.0 h. The mixture was cooled to 20 °C within 1 h and stirred at this temperature for an additional 1 h. The precipitated crystals were filtered and washed twice with 10 mL of ethanol / water (10:90, v / v). The product was dried under reduced pressure at 55 °C. The yield was 2.1 g (89.4% of theoretical) of an off-white crystalline powder.

[0095] Analysis results: The enantiomeric purity (ee%) is 90.5%ee. The content of D-di-o-chlorobenzenebenzoyltartaric acid is 0.63%.

[0096] Example 8

[0097] Example 8a

[0098] Preparation of diastereomeric salt (VII-4) TIFF2025537211000032.tif59162 10 g (0.02642 mol) of racemic finerenone (V) was suspended in a mixture of 90 mL of ethanol and 30 mL of water and heated to 75 °C with stirring. 6.21 g (0.01454 mol) of D-di-m-chlorobenzenebenzoyltartaric acid was added via a solid glass funnel and crystallized at 75 °C for 3.0 h with stirring. The mixture was then cooled to 25 °C over 3 h and stirred at this temperature for 16 h. The precipitated crystals were filtered and washed twice with 20 mL of ethanol / water (3:1, v / v). The product was dried under reduced pressure at 55 °C.

[0099] The yield is 9.2 g (86.4% of theory) of an off-white crystalline powder.

[0100] Analysis results: The enantiomeric purity (ee%) is 88.1%ee.

[0101] Example 8b

[0102] Preparation of crude product (Va) 5 g of the compound prepared in Example 8a was suspended in a mixture of 5 mL of ethanol and 45 mL of water. Subsequently, 10.2 g of aqueous sodium phosphate (100 g of sodium phosphate dissolved in 1000 mL of water) was added linearly and uniformly within 1 h to adjust the pH to pH = 7.5. The mixture was heated to an internal temperature of 55 °C within 1 h and stirred at this temperature for 3.0 h. The mixture was cooled to 20 °C within 1 h and stirred at this temperature for an additional 1 h. The precipitated crystals were filtered and washed twice with 10 mL of ethanol / water (10:90, v / v). The product was dried under reduced pressure at 55 °C. The yield was 2.0 g (85.2% of theoretical) of an off-white crystalline powder.

[0103] Analysis results: The enantiomeric purity (ee%) is 88.0%ee. The content of D-di-m-chlorobenzenebenzoyltartaric acid is 0.65%.

[0104] Example 9

[0105] Example 9a

[0106] Preparation of diastereomeric salt (VII-5) TIFF2025537211000034.tif59165 10 g (0.02642 mol) of racemic finerenone (V) was suspended in a mixture of 90 mL of ethanol and 30 mL of water and heated to 75 °C with stirring. 7.50 g (0.01454 mol) of D-di-o-bromobenzenebenzoyltartaric acid was added via a solid glass funnel and crystallized at 75 °C for 3.0 h with stirring. The mixture was then cooled to 25 °C over 3 h and stirred at this temperature for 16 h. The precipitated crystals were filtered and washed twice with 20 mL of ethanol / water (3:1, v / v). The product was dried under reduced pressure at 55 °C.

[0107] The yield is 10.3 g (87.1% of theory) of an off-white crystalline powder.

[0108] Analysis results: The enantiomeric purity (ee%) is 93.1%ee.

[0109] Example 9b

[0110] Preparation of crude product (Va) 5 g of the compound prepared in Example 9a was suspended in a mixture of 5 mL of ethanol and 45 mL of water. Subsequently, 10.1 g of aqueous sodium phosphate (100 g of sodium phosphate dissolved in 1000 mL of water) was added linearly and uniformly within 1 h to adjust the pH to pH = 7.5. The mixture was heated to an internal temperature of 55 °C within 1 h and stirred at this temperature for 3.0 h. The mixture was cooled to 20 °C within 1 h and stirred at this temperature for an additional 1 h. The precipitated crystals were filtered and washed twice with 10 mL of ethanol / water (10:90, v / v). The product was dried under reduced pressure at 55 °C. The yield was 1.9 g (89.8% of theoretical) of an off-white crystalline powder.

[0111] Analysis results: The enantiomeric purity (ee%) is 93.3%ee. The content of D-di-o-bromobenzenebenzoyltartaric acid is 0.35%.

[0112] Example 10

[0113] Example 10a

[0114] Preparation of diastereomeric salt (VII-6) TIFF2025537211000036.tif58163 10 g (0.02642 mol) of racemic finerenone (V) was suspended in a mixture of 90 mL of ethanol and 30 mL of water and heated to 75 °C with stirring. 6.08 g (0.01454 mol) of D-di-m-methoxybenzenebenzoyltartaric acid was added via a solid glass funnel and crystallized at 75 °C for 3.0 h with stirring. The mixture was then cooled to 25 °C over 3 h and stirred at this temperature for 16 h. The precipitated crystals were filtered and washed twice with 20 mL of ethanol / water (3:1, v / v). The product was dried under reduced pressure at 55 °C.

[0115] The yield is 9.9 g (94.0% of theory) of an off-white crystalline powder.

[0116] Analysis results: The enantiomeric purity (ee%) is 95.6%ee.

[0117] Example 10b

[0118] Preparation of crude product (Va) 5 g of the compound prepared in Example 10a was suspended in a mixture of 5 mL of ethanol and 45 mL of water. Subsequently, 10.3 g of aqueous sodium phosphate (100 g of sodium phosphate dissolved in 1000 mL of water) was added linearly and uniformly within 1 h to adjust the pH to pH = 7.5. The mixture was heated to an internal temperature of 55 °C within 1 h and stirred at this temperature for 3.0 h. The mixture was cooled to 20 °C within 1 h and stirred at this temperature for an additional 1 h. The precipitated crystals were filtered and washed twice with 10 mL of ethanol / water (10:90, v / v). The product was dried under reduced pressure at 55 °C. The yield was 2.2 g (92.6% of theoretical) of an off-white crystalline powder.

[0119] Analysis results: The enantiomeric purity (ee%) is 95.5%ee. The content of D-di-m-methoxybenzenebenzoyltartaric acid is 0.13%.

[0120] Example 11

[0121] Example 11a

[0122] Preparation of diastereomeric salt (VII-7) TIFF2025537211000038.tif81156 10 g (0.02642 mol) of racemic finerenone (V) was suspended in a mixture of 90 mL of ethanol and 30 mL of water and heated to 75°C with stirring. 6.84 g (0.01454 mol) of D-di-pt-butylbenzenebenzoyltartaric acid was added via a solid glass funnel and crystallized at 75°C for 3.0 h with stirring. The mixture was then cooled to 25°C over 3 h and stirred at this temperature for 16 h. The precipitated crystals were filtered and washed twice with 20 mL of ethanol / water (3:1, v / v). The product was dried under reduced pressure at 55°C.

[0123] The yield is 10.5 g (93.6% of theory) of an off-white crystalline powder.

[0124] Analysis results: The enantiomeric purity (ee%) is 92.7%ee.

[0125] Example 11b

[0126] Preparation of crude product (Va) 5 g of the compound prepared in Example 11a was suspended in a mixture of 5 mL of ethanol and 45 mL of water. Subsequently, 10.2 g of aqueous sodium phosphate solution (100 g of sodium phosphate dissolved in 1000 mL of water) was added linearly and uniformly within 1 h to adjust the pH to pH = 7.5. The mixture was heated to an internal temperature of 55 °C within 1 h and stirred at this temperature for 3.0 h. The mixture was cooled to 20 °C within 1 h and stirred at this temperature for an additional 1 h. The precipitated crystals were filtered and washed twice with 10 mL of ethanol / water (10:90, v / v). The product was dried under reduced pressure at 55 °C. The yield was 1.9 g (85.2% of theoretical) of an off-white crystalline powder.

[0127] Analysis results: The enantiomeric purity (ee%) is 92.7%ee. The content of D-di-pt-butylbenzenebenzoyltartaric acid is 0.45%.

[0128] Example 12

[0129] Example 12a Preparation of diastereomeric salt (VII-8) TIFF2025537211000040.tif57165 10 g (0.02642 mol) of racemic finerenone (V) was suspended in a mixture of 90 mL of ethanol and 30 mL of water, heated to 75 °C, and dissolved with stirring. 5.94 g (0.01454 mol) of D-di-o-cyanobenzenebenzoyltartaric acid was added via a solid glass funnel and crystallized at 75 °C for 3.0 h with stirring. The mixture was then cooled to 25 °C over 3 h and stirred at this temperature for 16 h. The precipitated crystals were filtered and washed twice with 20 mL of ethanol / water (3:1, v / v). The product was dried under reduced pressure at 55 °C.

[0130] The yield is 9.5 g (91.4% of theory) of an off-white crystalline powder.

[0131] Analysis results: The enantiomeric purity (ee%) is 92.9%ee.

[0132] Example 12b

[0133] Preparation of crude product (Va) 5 g of the compound prepared in Example 12a was suspended in a mixture of 5 mL of ethanol and 45 mL of water. Subsequently, 10.4 g of aqueous sodium phosphate (100 g of sodium phosphate dissolved in 1000 mL of water) was added linearly and uniformly within 1 h to adjust the pH to pH = 7.5. The mixture was heated to an internal temperature of 55 °C within 1 h and stirred at this temperature for 3.0 h. The mixture was cooled to 20 °C within 1 h and stirred at this temperature for an additional 1 h. The precipitated crystals were filtered and washed twice with 10 mL of ethanol / water (10:90, v / v). The product was dried under reduced pressure at 55 °C. The yield was 2.2 g (91.5% of theoretical) of an off-white crystalline powder.

[0134] Analysis results: The enantiomeric purity (ee%) is 92.6%ee. The content of D-di-o-cyanobenzenebenzoyltartaric acid is 0.15%.

Claims

1. A method for resolving a racemic compound of formula (V), which comprises using a chiral substituted tartaric acid ester of general formula (VIa) or (VIb) as a resolving agent to resolve the racemic compound of formula (V) to obtain compounds of formula (Va) and / or (Vb). is selected from Here, * represents a binding site.

2. A method for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Va), which comprises resolving the racemate of formula (V) using a chiral substituted tartaric acid ester of formula (VIa) as a resolving agent. is selected from Here, * represents a binding site.

3. 3. The process according to claim 1 or 2, characterized in that the resolution of the racemate is carried out in a binary solvent system of ethanol / water.

4. 4. The method according to claim 3, wherein the resolution of the racemate is carried out at a temperature ranging from 60 to 80°C.

5. The resolving agent is 5. The method of claim 4, wherein the compound is selected from the group consisting of:

6. The resolving agent is 6. The method of claim 5, wherein the compound is selected from the group consisting of:

7. 3. The process according to claim 1 or 2, characterized in that the precipitated diastereomeric salts (VIIa), (VIIb), (VIIc) and / or (VIId) are separated.

8. 8. The process according to claim 7, characterized in that the diastereomeric salt is treated with a base and the solvent is removed.

9. 9. The process according to claim 8, wherein the base is an inorganic base selected from ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, ammonium phosphate, sodium phosphate or potassium phosphate.

10. 9. The method of claim 8, wherein the base is an organic base selected from methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, isopropylamine, 1,3-propylenediamine, 1,2-propylenediamine, tripropylamine, cyclohexylamine, dicyclohexylamine, N,N-diisopropylethylamine, aniline, diphenylamine, triphenylamine, monoethanolamine, diethanolamine, triethanolamine, N-methylmorpholine, pyridine, sodium t-butoxide, potassium t-butoxide, sodium ethoxide, and sodium methoxide.

11. By reacting the racemic compound of formula (V) with D-di-o-methylbenzenebenzoyltartaric acid of formula (VI-1) in a binary solvent system of ethanol / water, obtaining a diastereomeric salt of formula (VII-1), Subsequently, finerenone (Va) is decomposed using aqueous sodium phosphate or sodium hydroxide in a binary solvent system of ethanol / water.

9. The method according to claim 8.

12. A diastereomeric salt represented by formula (VIIa), (VIIb), (VIIc) or (VIId): Here, Ar is is selected from Here, * represents a binding site.

13. A diastereomeric salt represented by formula (VII-1):

14. The diastereomeric salt of formula (VII-1) according to claim 13, wherein the diastereomeric salt is in a crystalline form and has diffraction peaks in its XRPD spectrum at 2θ of 8.2°±0.2°, 11.1°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 16.6°±0.2°, 16.9°±0.2°, 18.8°±0.2°, 19.2°±0.2°, 21.9°±0.2°, and 25.7°±0.2°.

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