PROCESS FOR PRODUCING ACYLOXYMETHYL ESTERS OF (4S)-(4-CYANO-2-METHOXYPHENYL)-5-ETHOXY-2,8-DIMETHYL-1,4-DIHYDRO-1,6-NAPHTHYRIDIN-3-CARBOXYLIC ACID

Abstract

The present invention relates to a process for preparing acyloxymethyl esters of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (IIa) by optical resolution of the compound of the formula (II) using a hydrolase. The invention also relates to a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (Ia), wherein the process comprises the optical resolution of the compound of the formula (II) using a hydrolase. The invention additionally also relates to the use of a hydrolase in a process for preparing a compound of formula (IIa). The invention further relates to the use of a hydrolase in a process for preparing a compound of formula (Ia).

Claims

1. Process for preparing acyloxymethyl esters of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (IIa) ##STR00145## where R is a linear or branched C1-C25 chain optionally substituted by an aromatic radical, by optical resolution of (II) ##STR00146## where R is a linear or branched C1-C25 chain optionally substituted by an aromatic radical, using a hydrolase.

2. Process according to claim 1, wherein, in the compound of formula (IIa), R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl or n-hexyl, and wherein, in the compound of formula (II), R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl or n-hexyl.

3. Process according to claim 1, wherein, in the compound of formula (IIa), R is methyl, and wherein, in the compound of formula (II), R is methyl.

4. Process according to claim 1, wherein the hydrolase used is a lipase, esterase, amidases or proteases.

5. Process according to claim 1, wherein the hydrolase is a lipase.

6. Process according to claim 1, wherein the lipase is selected from type VII lipase from Candida rugosa, lipase from Candida rugosa, Amano lipase M from Mucor javanicus, Amano lipase PS from Burkholderia cepacian, Amano lipase PS-IM, lipase from Aspergillus niger lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica B, lipase from Candida antarctica A, lipase from Aspergillus oryzae, lipase from Humicola insolens, lipase from Candida antarctica B, lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica and lipase from porcine liver.

7. Process according to claim 1, wherein the lipase is AK lipase from Pseudomonas fluorescens.

8. Process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (Ia) ##STR00147## characterized in that the racemic acid of the formula (III) ##STR00148## is reacted with halo esters of the general formula (V) ##STR00149## where R is a linear or branched C1-C25 chain optionally substituted by an aromatic radical, X is chlorine or bromine, to give racemic acyloxymethyl esters of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (II) ##STR00150## where R is a linear or branched C1-C25 chain optionally substituted by an aromatic radical, and this is converted by optical resolution using a hydrolase to the enantiomeric acyloxymethyl ester of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (IIa) ##STR00151## where R is a linear or branched C1-C25 chain optionally substituted by an aromatic radical, and this is hydrolysed in a THF/water mixture (2:1) with sodium hydroxide solution to give the compound of the formula (IIIa) ##STR00152## and this compound of the formula (IIIa) is then reacted in THF as solvent firstly with 1,1-carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine, hexamethyldisilazane is added and then the mixture is heated under reflux for 16-24 hours, and then a THF/water mixture is added.

9. Process according to claim 8, wherein, in the compound of formula (V), R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl, n-pentyl or n-hexyl, and X is bromine, and wherein, in the compound of formula (II), R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl or n-pentyl n-hexyl, and wherein, in the compound of formula (IIa), R is methyl, ethyl, n-propyl, isopropyl, tert-butyl, benzyl, n-butyl or n-pentyl.

10. Process according to claim 8 or 9, wherein, in the compound of formula (V), R is methyl, ethyl and isopropyl, n-butyl or n-pentyl, and X is bromine, and wherein, in the compound of formula (II), R is methyl, ethyl and isopropyl, n-butyl or n-pentyl, and wherein, in the compound of formula (IIa), R is methyl, ethyl and isopropyl, n-butyl or n-pentyl.

11. Process according to claim 8, wherein, in the compound of formula (V), R is methyl, and X is bromine, and wherein, in the compound of formula (II), R is methyl, and wherein, in the compound of formula (IIa), R is methyl.

12. Process according to claim 8, wherein, in the formula (V), X is chlorine.

13. Process according to claim 8, wherein, for the optical resolution, lipase is used, or the lipase is selected from type VII lipase from Candida rugosa, lipase from Candida rugosa, Amano lipase M from Mucor javanicus, Amano lipase PS from Burkholderia cepacian, Amano lipase PS-IM, lipase from Aspergillus niger lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica B, lipase from Candida antarctica A, lipase from Aspergillus oryzae, lipase from Humicola insolens, lipase from Candida antarctica B, lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica and lipase from porcine liver, or the lipase is AK lipase from Pseudomonas fluorescens.

14. Use of a hydrolase in a process for preparing a compound of formula (IIa) by optical resolution of the compound (II).

15. (canceled)

Description

EXPERIMENTAL

Abbreviations and Acronyms

[0671]

TABLE-US-00001 EtOH ethanol DB tartaric dibenzoyltartaric acid acid DMSO dimethyl sulfoxide of th. of theory (in yield) HPLC high-pressure, high-performance liquid chromatography 1H-NMR 1H nuclear magnetic resonance spectrometry IT internal temperature MS mass spectrometry RT room temperature RRT relative retention time TFA trifluoroacetic acid TI internal temperature TM jacket temperature XRPD X-ray powder diffraction (powder diffractometer) Spirits ethanol denatured with 2% toluene

EXAMPLES

[0672] Table 3 below shows the structures of the compounds recovered in HPLC. The assignment of the retention times in HPLC is shown below.

TABLE-US-00002 TABLE 3 [00134] (Ia) Finerenone [00135] impurity A [00136] impurity B (unknown structure, always impurity C significantly less than 0.1%) [00137] impurity D [00138] impurity E [00139] impurity G [00140] impurity F [00141] impurity I [00142] impurity J [00143] impurity K

Analytical Method for checking the Content of Impurities and the Enantiomeric Purity at the Stage of Crude Finerenone (Ia)

[0673]

TABLE-US-00003 Content and organic impurities RT (min) RRT Finerenone (Ia) 6.2 1.00 impurity A 3.3 0.53 impurity B 3.7 0.60 impurity C 3.9 0.62 impurity D 4.4 0.70 impurity E 5.5 0.89 impurity F 5.6 0.91 impurity G 6.8 1.10 impurity H 7.6 1.23 impurity K 10.4 1.68 [0674] Instrument: ultrahigh-performance liquid chromatograph (having a pressure range of up to 1200 bar with temperature-controlled column oven and UV detector) [0675] Column: YMC Triart C8 [0676] length: 100 mm; internal diameter: 3.0 mm; particle size: 1.9 ?m [0677] Max pressure: 1000 bar [0678] Conditions: 20? C.; 0.50 ml/min; 1.7 ?l (10? C.); 252 nm/6 nm and 230 nm/6 nm for the evaluation of DB tartaric acid [0679] Eluent: A: 0.1% TFA in water; B: acetonitrile

TABLE-US-00004 Enantiomeric purity: Method A RT (min) RRT Finerenone (Ia) about 11 1.00 (Ia) about 9 0.82 [0680] Instrument: high-performance liquid chromatograph with temperature-controlled column oven and UV detector [0681] Column: Chiralpak IA [0682] length: 250 mm, internal diameter: 4.6 mm, particle size: 5.0 ?m [0683] Max pressure: 300 bar [0684] Conditions: 40? C.; 0.8 ml/min; 5?l (20? C.); 255 nm/6 nm [0685] Eluent: A: acetonitrile; B: methyl tert-butyl ether (MTBE) [0686] Isocratic: A(%) 90: B (%) [0687] 10

Enantiomeric Purity

[0688]

TABLE-US-00005 Method B RT(min) RRT Finerenone (Ia) 5.7 1.00 Enantiomer (Ib) 6.8 1.19 [0689] Instrument/detector: high-performance liquid chromatograph with temperature-controlled column oven, UV detector [0690] and data evaluation system [0691] Measurement wavelength: 252 nm [0692] Oven temperature: 40? C. [0693] Column: Chiralpak IC [0694] length: 150 mm, internal diameter: 4.6 mm, particle size: 3 ?m

Mobile Phase:

[0695] A: 50% buffer 20 mM NH.sub.4OAc pH 9 [0696] B: 50% acetonitrile [0697] Flow rate: 1 ml/min. [0698] Elution time: 8 min. [0699] Equilibration: unnecessary, isocratic [0700] Sample solvent: eluent [0701] Sample solution: about 0.5 mg/ml of the substance racemate, dissolved in sample solvent [0702] Comparative solution: A comparative solution analogous to the sample solution is prepared [0703] Injection volume: 10 ?l

[0704] The measured values stated in the examples below for enantiomer determination were all determined by Method B. Some values, especially those of the batches prepared in the pilot plant, were reanalysed with Method A for comparison, and gave comparable results.

[0705] The HPLC analysis data given in the examples which follow with respect to purity and content of the end product pure finerenone (Ia) relate solely to impurities present in the product in an amount of >0.05%. This is essentially impurity E. All other impurities shown in the table listed above are generally <0.05%. The structure of such impurities was determined by isolation from enriched mother liquors.

HPLC Conditions/Methods

Method (C)

[0706] YMC Hydrosphere C18 [0707] 150*4.6 mm, 3.0 ?m [0708] 25? C., 1 ml/min, 270 nm, 4 nm [0709] 0: 70% TFA 0.1%*; 30% acetonitrile [0710] 17: 20% TFA 0.1%; 80% acetonitrile [0711] 18: 70% TFA 0.1%; 30% acetonitrile [0712] *: TFA in water

Method (D)

[0713] YMC Hydrosphere C18 [0714] 150*4.6 mm, 3.0 ?m [0715] 25? C., 1 ml/min, 255 nm, 6 nm [0716] 0: 90% TFA 0.1%; 10% acetonitrile [0717] 20: 10% TFA 0.1%; 90% acetonitrile [0718] 18: 10% TFA 0.1%; 90% acetonitrile

Method (E)

[0719] Nucleodur Gravity C18 [0720] 150*2 mm, 3.0 ?m [0721] 35? C., 0.22 ml/min, 255 nm, 6 nm [0722] Solution A: 0.58 g of ammonium hydrogenphosphate and 0.66 g of ammonium dihydrogenphosphate in 1 1 of water (ammonium phosphate buffer pH 7.2) [0723] Solution B: acetonitrile [0724] 0: 30% B; 70% A [0725] 15: 80% B; 20% A [0726] 25: 80% B; 20% A

Method (F)

[0727] Column: Nucleodur C18 Gravity, 50?3 mm, 1.8 ?m, 45? C., 1.2 ml/min, 210 nm, 1.2 nm; [0728] Solvent A: aqueous 0.1% formic acid solution

[0729] Solvent B: acetonitrile 0.1% formic acid solution [0730] 0: 80% A; 20% B [0731] 1.3: 20% A; 80% B [0732] 2: 20% A; 80% B [0733] 2.5: 80% A; 20% B

TABLE-US-00006 Method (G) RT(min) RRT Acyloxymethyl ester (IIAa) about 9.9 1.00 Acyloxymethyl ester (IIAb) about 11.4 1.15 [0734] Column: Chiralpak AD-H, 250?4.6 mm, 5 ?m, 40? C., 2 ml/min, 207 nm, 6 nm; [0735] Solvent A: n-heptane [0736] Solvent B: ethanol+0.1% diethylamine solution [0737] 0: 95% A; 5% B [0738] 16: 95% A; 5% B [0739] 16.1: 10% A; 90% B [0740] 20: 10% A; 90% B [0741] Equilibration: 10 min

Example 1

[0742] In parallel synthesis equipment, the following racemic acyloxy esters of the general formula (II) were synthesized in 10-15 mg* and characterized via mass spectrometry:

TABLE-US-00007 (II) [00144] II Amount (A-F) RCOOCH.sub.2Br (V A-F) R [M + H].sup.+ (mg) A methyl methyl 452 13 B ethyl ethyl 466 12 C n-propyl n-propyl 480 15 D i-propyl i-propyl 480 10 E n-butyl n-butyl 494 11 F n-pentyl n-pentyl 508 13 *Acid (III) was stirred together with a bromo ester (V A-F)) in DMF and potassium carbonate at 40? C. The solids were filtered off, and the filtrate was chromatographed directly for purification and then isolated by freeze-drying.

Example 2

Screening Results

[0743] For the kinetic separation of the racemic acyloxy esters (II A-F), the potential of multiple hydrolases was tested. The racemic starting material was dissolved in an organic solvent such as DMSO, tert-butyl methyl ether, cyclopentyl methyl ether, 1,4-dioxane, DMF or 2-methyl-THF, and added above a buffered aqueous solution (pH 7) of an enzyme. The following lipases were used: AK lipase from Pseudomonas fluorescens, type VII lipase from Candida rugosa, lipase from Candida rugosa, Amano Lipase M, from Mucor javanicus, Amano Lipase PS, from Burkholderia cepacia, Amano Lipase PS-IM, lipase from Aspergillus niger, lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica B, lipase from Candida antarctica A, lipase from Aspergillus oryzae, lipase from Humicola insolens, lipase from Candida antarctica B, immobilized, lipase from Thermomyces lanuginosus (immobilized), lipase from Rhizomucor miehei (immobilized), lipase from Candida antarctica in acrylic resin or lipase from porcine liver. The resulting biphasic system was stirred at 22 to 36? C. until a conversion level of nearly 50% had been attained. The separation of the product and of the enantiomerically purified substrate was conducted by means of base-acid extraction. The treatment of the organic layer with 5% aqueous potassium phosphate solution separates the desired enantiomerically purified residual ester from the acid, and conducts a chromatographic determination of enantiomeric excess (Method G).

[0744] The enantiomeric excesses (ee) achieved are generally between 70% e.e. and 91% e.e.; the 4R enantiomer is preferentially hydrolysed.

[0745] For further upscaling of the reaction, (?)-acetoxymethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IIA) was selected, since it showed the best results in the screening. In principle, the other esters (II B-F) would also be suitable for suitable upscaling.

Example 3a

[0746] Acetoxymethyl (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IIA)

[0747] An initial charge of 57.68 g (152.024 mmol) of racemic (4S,4R)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (III), 46.51 g (304.049 mmol) of bromomethyl acetate (VA) and 42.02 g (304.05 mmol) of potassium carbonate in 288 ml of dimethylacetamide was stirred at 20? C. for 20 h (full conversion by TLC, ethyl acetate/heptane 1:1, R.sub.f (ester=0.18)). The reaction mixture is filtered (removal of the salts), and the filter residue is washed with 400 ml of ethyl acetate. The filtrate is washed twice with 400 ml of water and then with 200 ml of saturated aqueous sodium chloride solution. The organic phase is concentrated to dryness under reduced pressure, and the residue is recrystallized from 200 ml of tert-butyl methyl ether/50 ml of ethanol.

[0748] Yield: 27.04 g (39% of theory), it was possible to isolate a further 20 g of material from the mother liquor.

[0749] MS (ES+): 452 [M+H].sup.+,

[0750] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): ?=1.10 (t, J=7.09 Hz, 3 H), 1.96 (s, 3 H), 2.16 (s, 3 H), 2.42 (s, 3 H), 3.75 (s, 3 H), 3.99-4.11 (m, 2 H), 5.32 (s, 1 H), 5.56-5.64 (m, 2 H), 7.21-7.27 (m, 2 H), 7.31 (s, 1 H), 7.61 (s, 1 H), 8.50 (s, 1 H) ppm.

Example 3b

[0751] Acetoxymethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IIa: R=Me))

[0752] A 61 jacketed glass reactor was initially charged with AK lipase from Pseudomonas fluorescens (22.5 g, 21 000 U/g), potassium phosphate buffer (2.1 1, 50 mM, pH 7.0) and a solution of racemic (?)-acetoxymethyl (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IIA) (15 g, 33.224 mmol) in 2-methyltetrahydrofuran (2-Me-THF, 0.9 l). The resulting biphasic mixture was stirred at 28.5? C. and 110 rpm (emulsion) for 7 days. Additional amounts of enzyme were added after 2, 3 and 4 days to give a total of 45 g (1:3 wt./wt. substrate/enzyme). After a conversion of 55% (enantiomerically enriched ester (IIa: R=Me; 92% ee)), the reaction was stopped by adding sodium chloride (150 g) and extracted with 2-MeTHF (2?11). The organic phases were combined with 2 l of a 5% aqueous potassium phosphate solution at 0? C. and stirred for 40 min. The organic phase was removed, dried with sodium sulfate, filtered and concentrated to dryness under reduced pressure.

[0753] An orange oil was obtained (8.34 g). The crude reaction product was purified by flash chromatography on silica gel using a solvent gradient (15% EtOAc/heptane-100% EtOAc). This gives 4.78 g (32% of theory) of a white solid.

[0754] Enantiomeric excess: 91% e.e. (Method G)

[0755] t.sub.R (HPLC Method F): 1.1 min;

[0756] MS (ES+): 452 [M+H].sup.+,

[0757] .sup.1H-NMR (500 MHz, DMSO-d.sub.6): ?=1.10 (t, J=7.09 Hz, 3 H), 1.96 (s, 3 H), 2.16 (s, 3 H), 2.42 (s, 3 H), 3.75 (s, 3 H), 3.99-4.10 (m, 2 H), 5.31 (s, 1 H), 5.56-5.64 (m, 2 H), 7.21-7.28 (m, 2 H), 7.31 (s, 1 H), 7.61 (s, 1 H), 8.49 (s, 1 H) ppm.

[0758] 10 batches proceeding from 15 g of racemic (?)-acetoxymethyl (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IIA) were enzymatically hydrolysed, and the crude products were combined. This gave 46 g of material with 91% e.e. This crude product was recrystallized from 120 ml of tert-butyl methyl ether/30 ml of ethanol, and 41 g of the optically pure ester (IIa: R=Me; e.e.% >99%) was obtained.

[0759] This material was converted to finerenone (Ia) in analogy to the processes described in WO 2016/016287 A1. This is described in the examples that follow.

Example 3c

[0760] (4S)-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (IIIa)

[0761] 40.0 g (88.69 mmol) of acetoxymethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IIa: R=Me)) was dissolved in a mixture of 240 ml of THF and 120 ml of water, and cooled down to 0? C. To this solution was added dropwise, at 0? C. within 15 minutes, a sodium hydroxide solution (prepared from 16.4 g (184.96 mmol) of 45% aqueous sodium hydroxide solution and 85 ml of water), and the mixture was stirred at 0? C. for 1.5 hours. The mixture was extracted twice with 100 ml each time of methyl tert-butyl ether and once with 100 ml of ethyl acetate. The aqueous solution at 0? C. was adjusted to pH 7 with dilute hydrochloric acid (prepared from 37.1 g of 37% HCl and 151 ml of water). The solution was allowed to warm up to 20? C., and an aqueous solution of 41 g of ammonium chloride in 110 ml of water was added. The solution was stirred at 20? C. for 1 hour, and the product was filtered off and washed twice with 30 ml each time of water and once with 80 ml of acetonitrile. The product was dried at 40? C. under vacuum under entraining gas.

[0762] Yield: 30.6 g (91.0% of theory) of an almost colourless powder (very slight yellow tint).

[0763] HPLC Method E: RT: about 6.8 min.

[0764] MS (EIpos): m/z=380 [M+H].sup.+

[0765] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): ?=1.14 (t, 3H), 2.14 (s, 3H), 2.37 (s, 3H), 3.73 (s, 3H), 4.04 (m, 2H), 5.33 (s, 1H), 7.26 (m, 2H), 7.32 (s, 1H), 7.57 (s, 1H), 8.16 (s, 1H), 11.43 (br. s, 1H).

Example 3d

[0766] (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ia)

[0767] To an initial charge of 30 g (79.13 mmol) of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (IIIa) and 17.96 g (110.8 mmol) of 1,1-carbodiimidazole in 150 ml of THF was added 956 mg (7.82 mmol) of DMAP at 20? C. The mixture was stirred at 20? C. for one hour (evolution of gas!) and then heated to 50? C. for 2.5 hours. 55.7 g (0.345 mol) of hexamethyldisilazane was added to this solution, which was boiled under reflux for 22 hours. A further 34 ml of THF was added and the mixture was cooled to 5? C. A mixture of 22 ml of THF and 15.7 g of water was added over 3 hours such that the temperature remained between 5 and 20? C. The mixture was subsequently boiled under reflux for one hour, then cooled via a gradient (3 hours) to 0? C. and stirred at that temperature for one hour. The product was filtered off and washed twice with 38 ml each time of THF and twice with 60 ml each time of water. The product was dried at 70? C. under vacuum under entraining gas.

[0768] Yield: 27.67 g (92.5% of theory) of an almost colourless powder (very slight yellow tint).

[0769] HPLC method D: RT about 6.7 min.

[0770] MS (EIpos): m/z=379 [M+H].sup.+

[0771] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): ?=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H).

Example 3e

Preparation of Pure Product (Ia=Finerenone)

[0772] 27.0 g of the crude product (Ia) prepared in Example 3d was suspended in 540 ml of ethanol (denatured with toluene) and then heated to reflux. On heating, the product went into solution. Stirring was continued at this temperature for one hour. The solution was filtered off through a heated pressure filter (T=75? C.) and the pressure filter was then rinsed with 7 ml of ethanol (denatured with toluene). The solvent was then distilled off (about 444 ml was distilled off) until a final volume of about 4 times the substance used (27.0 g?4?110 ml) had been attained. The mixture was then cooled to internal temperature 23? C. (over about 1.5 to 2 hours). The mixture was then stirred at internal temperature 3? C. for 2 hours. The product was filtered off and rinsed once with 100 ml of ethanol (denatured with toluene). Wet yield: 28 g. The wet product was dried at 50? C. over the weekend (>48 h) under reduced pressure (<100 mbar). Yield: 25.67 g (95.1% of theory) of a colourless crystalline powder, fine needle-like crystals.

Analytical Results:

[0773]

TABLE-US-00008 Finerenone (Ia) Purity: 99.85 area (HPLC); Content: 99.7% by weight Enantiomeric excess 100% e.e. Largest secondary component impurity E 0.05% Residual solvents: EtOH 0.05% toluene 0.00% water (Karl Fischer) 0.00%

[0774] MS (Elpos): m/z=379 [M+H].sup.+

[0775] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m (broad signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H) and small signals of the DMSO solvent and water at ?=2.5-2.6 and a very small peak at ?=3.38 (not assignable)

[0776] Modification: Mod A (as defined in WO2016/016287 A1)