PROCESS FOR THE PREPARATION OF 2-CYANOETHYL (4S)-4-(4-CYANO-2-METHOXY-PHENYL)-5-ETHOXY-2,8-DIMETHYL-1,4-DIHYDRO-1,6-NAPHTHYRIDINE-3-CARBOXYLATE BY RESOLUTION OF RACEMATES BY MEANS OF DIASTEREOMERIC TARTARIC ACID ESTERS
20240199599 ยท 2024-06-20
Inventors
Cpc classification
C07C68/00
CHEMISTRY; METALLURGY
International classification
Abstract
The present invention relates to the diastereomeric salts (Va), (Vb), (Vc) and/or (Vd), to a process for preparing the diastereomeric salts (Va), (Vb), (Vc) and/or (Vd) using a chiral substituted tartaric ester of the formula (IIIa) or (IIIb), to a process for preparing the compound of formula (IVa) using the diastereomeric salts (Va), (Vb), (Vc) and/or (Vd), to a process for preparing the compound of the formula (VIIa) using the diastereomeric salts (Va), (Vb), (Vc) and/or (Vd), to a process for preparing the compound of the formula (Ia) using the diastereomeric salts (Va), (Vb), (Vc) and/or (Vd), to the use of the diastereomeric salts (Va), (Vb), (Vc) and/or (Vd) for preparation of one of the compounds of formula (IVa), (VIIa) and/or (Ia), to the use of a chiral substituted tartaric esters of the formula (IIIa) or (IIIb) for preparation of the diastereomeric salts (Va), (Vb), (Vc) and/or (Vd), and to the use of a chiral substituted tartaric ester of the formula (IIIa) or (IIIb) for preparation of one of the compounds of formula (IVa), (VIIa) and/or (Ia).
Claims
1. Diastereomeric salt of the formula ##STR00128## in which Ar is unsubstituted or substituted aryl or heteroaryl.
2. Diastereomeric salt according to claim 1, wherein Ar is one of the formulae ##STR00129## in which * represents the site of attachment.
3. Diastereomeric salt according to claim 1, wherein Ar is one of the formulae ##STR00130## in which * represents the site of attachment.
4. Diastereomeric salt according to claim 1, wherein Ar is one of the formulae ##STR00131## in which * represents the site of attachment.
5. Diastereomeric salt according to claim 1, wherein Ar is one of the formulae ##STR00132## in which * represents the site of attachment.
6. Diastereomeric salt according to claim 1, wherein Ar is ##STR00133## in which * represents the site of attachment.
7. Process for preparing the diastereomeric salt (Va), (Vb), (Vc) and/or (Vd) according to claim 1, comprising the step (i) of (i) optical resolution of racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IV) ##STR00134## with a chiral substituted tartaric ester of the formula (IIIa) or (IIIb) ##STR00135## where Ar is unsubstituted or substituted aryl or heteroaryl.
8. Process according to claim 7, wherein the optical resolution in step (i) is effected at a temperature in the range of 20? C. to 50? C.
9. Process for preparing 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IVa) ##STR00136## comprising steps (i) and (iii): (i) optical resolution of racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IV) ##STR00137## with a chiral substituted tartaric ester of the formula (IIIa) or (IIIb) ##STR00138## to obtain one or more of the diastereomeric salts (Va), (Vb), (Vc) and/or (Vd) where Ar is unsubstituted or substituted aryl or heteroaryl, and (iii) converting the diastereomeric salt obtained in step (i) to the compound of formula (IVa).
10. Process according to claim 9, comprising step (iii): (iii) treating the diastereomeric salt (Va), (Vb), (Vc) and/or (Vd) obtained in step (i) with a base.
11. Process according to claim 9, wherein, in step (iii), the base is an inorganic base and is selected from ammonia, sodium hydroxide solution, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium phosphate, potassium phosphate, ammonium phosphate, sodium hydroxide, sodium phosphate, potassium phosphate.
12. Process according to claim 9, wherein, in step (ii), the solvent or solvent mixture, at a temperature of 0? C. to 60? C., then adjusts a pH of 6.9 to 8.0, preferably a pH of 7.0 to 7.5, more preferably pH 7.1, by adding the organic or inorganic base.
13. Process according to claim 9, wherein the racemate (IV) ##STR00139## in step (i) is reacted with di-p-tolyl-D-tartaric acid of the formula (IIIa) ##STR00140## in a spirits/water mixture to give the diastereomeric salt (Va) ##STR00141## and then, in step (iii), cyanoethanol ester (IVa) ##STR00142## is released using sodium phosphate, likewise in a spirits/water mixture.
14. Process for preparing p (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (Ia), comprising steps (i), (iii), (v) and (vi): (i) optical resolution of racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IV) ##STR00143## with a chiral substituted tartaric ester of the formula (IIIa) or (IIIb) ##STR00144## to obtain one or more of the diastereomeric salts (Va), (Vb), (Vc) and/or (Vd) where Ar is unsubstituted or substituted aryl or heteroaryl, (iii) converting the diastereomeric salt obtained in step (i) to the compound of formula (IVa) ##STR00145## (v) hydrolysing the compound of formula (IVa) with sodium hydroxide solution in a THF/water mixture (2:1) to give the compound of the formula (VIIa) ##STR00146## (vi) reacting the compound of the formula (VIIa), in THE as solvent, firstly with 1,1-carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine, adding hexamethyldisilazane and then heating the mixture under reflux for 16-24 hours, and then adding a THF/water mixture, so as to obtain the compound of formula (Ia).
15. (canceled)
Description
EXAMPLES
[0338] 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-00004 TABLE 3
[0339] Analytical method for checking the content of impurities and the enantiomeric purity at the stage of crude finerenone (I)
[0340] Content and Organic Impurities
TABLE-US-00005 RT (min) RRT Finerenone (I) 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 [0341] Instrument: ultrahigh-performance liquid chromatograph (having a pressure range of up to 1200 bar with temperature-controlled column oven and UV detector) [0342] Column:
TABLE-US-00006 YMC Triart C8 [0343] length: 100 mm; internal diameter: 3.0 mm; particle size: 1.9 ?m [0344] Max pressure: 1000 bar [0345] 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 [0346] Eluent: A: 0.1% TFA in water; B: acetonitrile [0347] Gradient:
TABLE-US-00007 time (min) A (%) B (%) 0.0 90.0 10.0 15.0 35.0 65.0 16.0 20.0 80.0 20.0 20.0 80.0
[0348] Enantiomeric Purity:
[0349] Method A
TABLE-US-00008 RT (min) RRT Finerenone (I) about 11 1.00 (Ia) about 9 0.82 [0350] Instrument: high-performance liquid chromatograph with temperature-controlled column oven and UV detector [0351] Column: Chiralpak IA [0352] length: 250 mm, internal diameter: 4.6 mm, particle size: 5.0 ?m [0353] Max pressure: 300 bar [0354] Conditions: 40? C.; 0.8 ml/min; 5 ?l (20? C.); 255 nm/6 nm [0355] Eluent: A: acetonitrile; B: methyl tert-butyl ether (MTBE) [0356] Isocratic: A (%) 90: B (%) [0357] 10
[0358] Enantiomeric Purity
[0359] Method B
TABLE-US-00009 RT(min) RRT Finerenone (I) 5.7 1.00 Enantiomer (Ia) 6.8 1.19 [0360] Instrument/detector: high-performance liquid chromatograph with temperature-controlled column oven, UV detector [0361] and data evaluation system [0362] Measurement wavelength: 252 nm [0363] Oven temperature: 40? C. [0364] Column: Chiralpak IC [0365] length: 150 mm, internal diameter: 4.6 mm, particle size: 3 ?m [0366] Mobile phase: [0367] A: 50% buffer 20 mM NH.sub.4OAc pH 9 [0368] B: 50% acetonitrile [0369] Flow rate: 1 ml/min. [0370] Elution time: 8 min. [0371] Equilibration: unnecessary, isocratic [0372] Sample solvent: eluent [0373] Sample solution: about 0.5 mg/ml of the substance racemate, dissolved in sample solvent Comparative solution: A comparative solution analogous to the sample solution is prepared [0374] Injection volume: 10 ?l
[0375] 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.
[0376] The HPLC analysis data given in the examples which follow with respect to purity and content of the end product pure finerenone (I) refer only 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.
[0377] HPLC Conditions/Methods
[0378] Method (C) [0379] YMC Hydrosphere C18 [0380] 150*4.6 mm, 3.0 ?m [0381] 25? C., 1 ml/min, 270 nm, 4 nm [0382] 0 min: 70% TFA 0.1%*; 30% acetonitrile [0383] 17 min: 20% TFA 0.1%; 80% acetonitrile [0384] 18 min: 70% TFA 0.1%; 30% acetonitrile *: TFA in water
[0385] Method (D) [0386] YMC Hydrosphere C18 [0387] 150*4.6 mm, 3.0 ?m [0388] 25? C., 1 ml/min, 255 nm, 6 nm [0389] 0 min: 90% TFA 0.1%; 10% acetonitrile [0390] 20 min: 10% TFA 0.1%; 90% acetonitrile [0391] 18 min: 10% TFA 0.1%; 90% acetonitrile
[0392] Method (E) [0393] Nucleodur Gravity C18 [0394] 150*2 mm, 3.0 ?m [0395] 35? C., 0.22 ml/min, 255 nm, 6 nm [0396] Solution A: 0.58 g of ammonium hydrogenphosphate and 0.66 g of ammonium dihydrogenphosphate in 1 l of water (ammonium phosphate buffer pH 7.2) [0397] Solution B: acetonitrile [0398] 0 min: 30% B; 70% A [0399] 15 min: 80% B; 20% A [0400] 25 min: 80% B; 20% A
[0401] Method (F)
[0402] Implementation Instructions
TABLE-US-00010 Enantiomeric purity RT(min) RRT Enantiomer IVa 3.8 1.00 Enantiomer IVb 4.8 1.26 [0403] Instrument/detector: high-performance liquid chromatograph with temperature-controlled column oven, UV detector [0404] and data evaluation system [0405] Measurement wavelength: 253 nm, range: 6 nm [0406] Oven temperature: 40? C. [0407] Column: Chiralpak AD-H [0408] length: 250 mm, internal diameter: 4.6 mm, particle size: 5 m [0409] Mobile phase: A: heptane [0410] B: isopropanol+0.1% DEA (diethylamine) [0411] Gradient programme: Time [min] [0412] Flow rate:
TABLE-US-00011 Eluent A [%] Eluent B [%] Start 2 [ml/min] 80 20 [0413] Elution time: 8 min.
Example 1a
Preparation of the diastereomeric salt (Va) of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate with (+) Di-p-tolyl-D-tartaric acid
[0414] 4 g (9.249 mmol) of racemic 2-cyanoethyl (4S, 4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IV) and 3.573 g (9.249 mmol) of (+)-di-p-tolyl-D-tartaric acid were suspended in a mixture of 150 ml of ethanol and 50 ml of water and heated to 30? C. (forming a solution). The mixture was stirred at room temperature overnight, and the precipitate crystals were filtered off and washed twice with 5 ml of a mixture of ethanol/water 3:1. The product was dried under reduced pressure at room temperature.
[0415] Yield: 4.0 g (105.6% of theory) of a colourless crystalline powder.
[0416] Analytical Results:
[0417] Enantiomeric purity (e.e %): 65% e.e. (Method F)
[0418] An amount of the diastereomeric salt enriched in this way was purified further as follows:
[0419] 3.80 g of the diastereomeric salt prepared was suspended in 76 ml of a mixture of ethanol/water 3:1, and the mixture was stirred at 50? C. for 2 h and at room temperature overnight. The precipitated crystals were filtered off and washed twice with 5 ml of a mixture of ethanol/water 3:1. The product is dried under reduced pressure at room temperature.
[0420] Yield: 3.0 g (79.3% of theory) of a colourless crystalline powder
[0421] Analytical Results:
[0422] Enantiomeric purity (e.e. %): 97% e.e. (Method F)
[0423] MS (EIpos): m/z=433 [M+H].sup.+
[0424] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=1.11 (t, J=7.03 Hz, 1H), 2.03-2.45 (m, 5H), 2.63-2.90 (m, 1H), 3.77 (s, 1H), 3.96-4.24 (m, 1H), 5.18-5.44 (m, 1H), 5.63-6.07 (m, 1H), 7.09-7.52 (m, 2H), 7.53-7.74 (m, 1H), 7.81-8.13 (m, 1H), 8.26-8.57 (m, 1H), 12.82-15.60 (m, 1H).
Example 1b
Preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IVa)
[0425] To 3 g (3.66 mmol) of the title compound from Example 1a was suspended in 30 ml of a mixture of water/ethanol 3:1, and the mixture was cooled to 0? C. Then a 20% aqueous sodium phosphate solution was metered in gradually (over the course of 1 hour) and the pH was adjusted to pH 7.1. The mixture was left to stir at that temperature for a further 4 hours. The precipitated solids were filtered off and washed twice with 10 ml of a mixture (0? C.) of water/ethanol 3:1. The product was dried under reduced pressure at 40? C.
[0426] Yield: 1.51 g (95.4% of theory) of a colourless crystalline powder
[0427] Analytical Results:
[0428] Enantiomeric purity (e.e. %): 97% e.e.
[0429] MS (EIpos): m/z=433 [M+H].sup.+
[0430] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): ?=1.11 (t, 3H), 2.16 (s, 3H), 2.42 (s, 3H), 2.78 (m, 2H), 3.77 (s, 3H), 4.01-4.13 (m, 4H), 5.37 (s, 1H), 7.25 (d, 1H), 7.28-7.33 (m, 2H), 7.60 (s, 1H), 8.35 (s, 1H).
Example 2a
Preparation of the diastereomeric salt (Va) of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate with (+) Di-p-tolyl-D-tartaric acid
[0431] 900.0 g (2.08 mol) of racemic 2-cyanoethyl (4S, 4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IV) and 803.6 g (2.08 mmol) of (+)-di-p-tolyl-D-tartaric acid were suspended in a mixture of 15 l of a mixture of ethanol/water 3:1 and heated to 30? C. (forming a solution). The mixture was stirred at room temperature overnight, and the precipitated crystals were filtered off and washed twice with 1000 ml of a mixture of ethanol/water 3:1. The product was dried under reduced pressure at room temperature.
[0432] Yield: 873.5 g (102.6% of theory) of a colourless crystalline powder.
[0433] Analytical Results:
[0434] Enantiomeric purity (e.e. %): 73% e.e. (Method F)
[0435] An amount of the diastereomeric salt enriched in this way was purified further as follows:
[0436] 870 g of the diastereomeric salt prepared was suspended in 10 l of a mixture of ethanol/water 3:1, and the mixture was stirred at 50? C. for 2 h and at room temperature overnight. The precipitated crystals were filtered off and washed twice with 1000 ml of a mixture of ethanol/water 3:1. The product was dried under reduced pressure at 40? C.
[0437] Yield: 679.4 g (78.6% of theory) of a colourless crystalline powder
[0438] Analytical Results:
[0439] Enantiomeric purity (e.e. %): 98% e.e. (Method F)
Example 2b
Preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IVa)
[0440] To 600 g (732.7 mmol) of the title compound from Example 2a was suspended in 6 l of a mixture of water/ethanol 3:1, and the mixture was cooled to 0? C. Then a 30% aqueous sodium phosphate solution was metered in gradually (over the course of 1 hour) and the pH was adjusted to pH 7.1. The mixture was left to stir at that temperature for a further 4 hours. The precipitated solids were filtered off and washed twice with 1000 ml of a mixture (0? C.) of water/ethanol 3:1. The product was dried under reduced pressure at 40? C.
[0441] Yield: 301.0 g (95.1% of theory) of a colourless crystalline powder
[0442] Analytical Results:
[0443] Enantiomeric purity (e.e. %): 98% e.e.
[0444] MS (EIpos): m/z=433 [M+H].sup.+
[0445] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): ?=1.11 (t, 3H), 2.16 (s, 3H), 2.42 (s, 3H), 2.78 (m, 2H), 3.77 (s, 3H), 4.01-4.13 (m, 4H), 5.37 (s, 1H), 7.25 (d, 1H), 7.28-7.33 (m, 2H), 7.60 (s, 1H), 8.35 (s, 1H).
Example 2c
(4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (VIIa)
[0446] 200 g (4.624 mol) of 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IVa) was dissolved in a mixture of 1.2 l of THF and 600 ml of water and cooled to 0? C. To this solution was added dropwise, at 0? C. over the course of 15 minutes, a sodium hydroxide solution (prepared from 82 g of 45% aqueous sodium hydroxide (924.8 mmol) and 423 ml of water), and the mixture was stirred at 0? C. for a further 1.5 hours. The mixture was extracted twice with 480 ml each time of methyl tert-butyl ether and once with 480 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 205 g of ammonium chloride in 554 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 150 ml each time of water and once with 400 ml of acetonitrile. The product was dried at 40? C. under vacuum under entraining gas.
[0447] Yield: 165.51 g (94.3% of theory) of an almost colourless powder (very slight yellow tint).
[0448] HPLC Method E: RT: about 6.8 min.
[0449] MS (EIpos): m/z=380 [M+H].sup.+
[0450] .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 2d
(4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I)
[0451] To an initial charge of 160 g (422 mmol) of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (VIIa) and 95.8 g (591 mol) of 1,1-carbodiimidazole in 800 ml of THF was added 5.1 g (0.0417 mol) 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. 297.3 g (1.842 mmol) of hexamethyldisilazane was added to this solution, which was boiled under reflux for 22 hours. A further 180 ml of THF was added and the mixture was cooled to 5? C. A mixture of 117 ml of THF and 83.5 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 this temperature for one hour. The product was filtered off and washed twice with 200 ml each time of THE and twice with 320 ml each time of water. The product was dried at 70? C. under vacuum under entraining gas.
[0452] Yield: 150 g (94% of theory) of an almost colourless powder (very slight yellow tint).
[0453] HPLC method D: RT about 6.7 min.
[0454] MS (EIpos): m/z=379 [M+H]+ 1H-NMR (300 MHz, DMSO-d6): ?=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 2e
[0455] Preparation of Pure Product (I=Finerenone)
[0456] 139.20 g of the crude product (I) prepared in Example 2d was suspended in 2796 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 36 ml of ethanol (denatured with toluene). The solvent was then distilled off until about four times the final volume (with respect to substance used: 139.2 g?4?561 ml) had been attained (about 2304 ml was distilled off). 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: 145.60 g. The wet product was dried at 50? C. over the weekend (>48 h) under reduced pressure (<100 mbar). Yield: 133.7 g (96.0% of theory) of a colourless crystalline powder, fine needle-like crystals.
[0457] Analytical Results:
TABLE-US-00012 Finerenone (I) Purity: 99.86 area (HPLC); Content: 99.5% by weight Enantiomeric excess 100% e.e. Largest secondary component impurity E 0.07% Residual solvents: EtOH 0.05% toluene 0.00% water (Karl Fischer) 0.00%
[0458] MS (EIpos): m/z=379 [M+H].sup.+
[0459] .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 6=2.5-2.6 and a very small peak at 6=3.38 (not assignable)
[0460] Modification: Mod A (as defined in WO2016/016287 A1)
Example 3a
Preparation of the diastereomeric salt (Va) of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate with (+) Di-p-tolyl-D-tartaric acid
[0461] 1000 g (2.31 mol) of racemic 2-cyanoethyl (4S, 4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IV) and 695.5 g (1.80 mol) of (+)-di-p-tolyl-D-tartaric acid were suspended in a mixture of 15 l of a mixture of ethanol/water 3:1 and heated to 30? C. (forming a solution). The mixture was stirred at room temperature overnight, and the precipitate crystals were filtered off and washed twice with 1000 ml of a mixture of ethanol/water 3:1. The product was dried under reduced pressure at room temperature.
[0462] Yield: 950.5 g (100.5% of theory) of a colourless crystalline powder.
[0463] Analytical Results:
[0464] Enantiomeric purity (e.e. %): 78% e.e. (Method F)
[0465] An amount of the diastereomeric salt enriched in this way was purified further as follows:
[0466] 950 g of the diastereomeric salt prepared was suspended in 10 l of a mixture of ethanol/water 3:1, and the mixture was stirred at 50? C. for 2 h and at room temperature overnight. The precipitated crystals were filtered off and washed twice with 1000 ml of a mixture of ethanol/water 3:1. The product was dried under reduced pressure at 40? C.
[0467] Yield: 781.3 g (82.6% of theory) of a colourless crystalline powder
[0468] Analytical Results:
[0469] Enantiomeric purity (e.e. %): 99% e.e. (Method F)
Example 3b
Preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IVa)
[0470] To 600 g (732.7 mmol) of the title compound from Example 3a was suspended in 6 l of a mixture of water/ethanol 3:1, and the mixture was cooled to 0? C. Then a 20% aqueous sodium carbonate solution was metered in gradually (over the course of 1 hour) and the pH was adjusted to pH 7.1. The mixture was left to stir at that temperature for a further 4 hours. The precipitated solids were filtered off and washed twice with 1000 ml of a mixture (0? C.) of water/ethanol 3:1. The product was dried under reduced pressure at 40? C.
[0471] Yield: 308.0 g (97.2% of theory) of a colourless crystalline powder
[0472] Analytical Results:
[0473] Enantiomeric purity (e.e. %): 99% e.e.
[0474] In an analogous manner (as described in Examples 2c-2e), this prepared intermediate (IVa) was converted to the final stage (finerenone (Ia), pure):
[0475] Analytical Results:
TABLE-US-00013 Finerenone (Ia) Purity: 99.83 area (HPLC); Content: 99.3% by weight Enantiomeric excess 100% e.e. Largest secondary component impurity E 0.08% Residual solvents: EtOH 0.05% toluene 0.00% water (Karl Fischer) 0.00%
[0476] Modification: Mod A (as defined in WO2016/016287 A1)
Example 4
[0477] Examples of Various Tartaric Acid Derivatives and Further Solvents
Example 4a
Preparation of the diastereomeric salt (Va) of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate with (?)-di-O,O-p-tolyl-L-tartaric acid
[0478] 1.00 g of racemate (IV) was suspended together with 1.3 g (1.5 eq.) of (?)-di-O,O-p-tolyl-L-tartaric acid in 50 ml of a mixture of ethanol/water 3:1, stirred and left to stand. After some time, the diastereomeric salt precipitated out. This was filtered off and dried (980 mg, 100% of theory), and the enantiomeric excess was measured. The measurement gave an enantiomeric excess of 73.28% e.e. in favour of (IVb).
Example 4b
Preparation of the diastereomeric salt (Va) of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate with (?)-di-O,O-p-tolyl-L-tartaric acid
[0479] 100 mg of racemate (IV) was suspended with (?)-di-O,O-p-tolyl-L-tartaric acid in a mixture of ethanol/water 3:1 and stirred at 40? C. for 3 hours and then left to stand at 20? C. for 16 hours. After some time, the diastereomeric salt precipitated out. This was filtered off and dried, and the enantiomeric excess (EE) was measured. The measurements gave enantiomeric excesses in favour of (IVb). The following table summarizes the results:
TABLE-US-00014 (?)-di-O,O-p-tolyl- L-tartaric acid Amount Amount EE Equiv. [mg] Solvent [ml] value 1.1 98 ethanol/water 75:25 4 62.34 1.1 98 ethanol/water 75:25 5 82.8 1.2 107 ethanol/water 75:25 4 74.26 1.2 107 ethanol/water 75:25 5 80.7 1.3 116 ethanol/water 75:25 4 78.22 1.3 116 ethanol/water 75:25 5 81.52 1.4 125 ethanol/water 75:25 4 80.28 1.4 125 ethanol/water 75:25 5 83.84 1.5 134 ethanol/water 75:25 4 75.7 1.5 134 ethanol/water 75:25 5 80.34 2 179 ethanol/water 75:25 4 77.84 2 179 ethanol/water 75:25 5 60.06
Example 4c
Preparation of the diastereomeric salt (Va) of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate with (?)-di-O,O-p-tolyl-L-tartaric acid
[0480] In a series of experiments, 100 mg of racemate (IV) was suspended with (?)-di-O,O-p-tolyl-L-tartaric acid in a mixture of ethanol/water and stirred at 50? C. for 3 hours and then left to stand at 20? C. for 16 hours. After some time, the diastereomeric salt precipitated out. This was filtered off and dried, and the enantiomeric excess was measured. The measurements gave enantiomeric excesses in favour of (IVb). The following table summarizes the results:
TABLE-US-00015 (?)-di-O,O-p-tolyl- L-tartaric acid Amount Amount EE Equiv. [mg] Solvent [ml] value 0.8 71 ethanol/water 70:30 2 69.7 0.8 71 ethanol/water 70:30 4 86.6 1.05 94 ethanol/water 75:25 2 72.6 1.05 94 ethanol/water 75:25 4 88.5 1.05 94 ethanol/water 75:25 6 76.4 1.05 94 ethanol/water 70:30 2 68.4 1.05 94 ethanol/water 70:30 4 84.9 1.05 94 ethanol/water 70:30 6 85.3 1.2 107 ethanol/water 75:25 2 76.4 1.2 107 ethanol/water 75:25 4 87.8 1.2 107 ethanol/water 75:25 6 88.9 1.2 107 ethanol/water 70:30 4 81.6 1.2 107 ethanol/water 70:30 6 86.4
Example 4c
Preparation of the diastereomeric salts (Va) of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate by use of different tartaric acid derivatives
[0481] 100 mg of racemate (IV) was suspended with a tartaric acid derivative in a mixture in 4 ml of solvent and stirred at 50? C. for 3 hours and then left to stand at 20? C. for 16 hours. After some time, the diastereomeric salt precipitated out. This was filtered off and dried, and the enantiomeric excess and also the .sup.1H-NMR and mass by mass spectrometer were measured. The measurements gave enantiomeric excesses in favour of (IVa). The following table summarizes the results:
TABLE-US-00016 Amount EE Reagent (eq) (mg) Solvent value (?)-di-O,O-p- 1.05 103 ethanol/water 77.26 chlorobenzoyl-D- (70:30) tartaric acid MS (EIpos): m/z = 433 [M + H].sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ? = 0.93-1.35 (m, 2 H), 1.88-2.34 (m, 2 H), 3.63-3.87 (m, 2 H), 3.94-4.32 (m, 2 H), 5.12-5.48 (m, 1 H), 5.69-6.06 (m, 1 H), 7.06-7.43 (m, 2 H), 7.53-7.85 (m, 3 H), 7.91-8.81 (m, 3 H), 12.68-15.10 (m, 1 H) (?)-di-O,O-p- 1.05 125 ethanol/water 71.64 bromobenzoyl-D- (70:30) tartaric acid MS (EIpos): m/z = 433 [M + H].sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ? = 0.89-1.33 (m, 1 H), 2.03-2.45 (m, 2 H), 2.60-3.01 (m, 1 H), 3.77 (s, 1 H), 3.86-4.26 (m, 1 H), 5.36 (s, 1 H), 5.86 (s, 1 H), 7.04-7.41 (m, 1 H), 7.60 (s, 1 H), 7.73-8.04 (m, 3 H), 8.26-8.52 (m, 1 H), 12.80-14.97 (m, 1 H) (+)-di-O,O-(2,4- 1.05 120 n-propanol/water 76.85 dichlorobenzoyl)- (70:30) D-tartaric acid MS (EIpos): m/z = 433 [M + H].sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ? = 1.11 (t, J = 7.03 Hz, 1 H), 2.16 (s, 1 H), 2.42 (s, 1 H), 2.67-3.00 (m, 1 H), 3.77 (s, 1 H), 3.95-4.46 (m, 1 H), 5.36 (s, 1 H), 5.90 (s, 1 H), 7.22-7.38 (m, 1 H), 7.58-7.74 (m, 1 H), 7.82-7.93 (m, 1 H), 8.31-8.45 (m, 1 H), 13.37-15.42 (m, 1 H)
Example 5a
Preparation of the diastereomeric salt (Va) of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate with (?)-di-O,O-p-chlorobenzoyl-D-tartaric acid
[0482] 1000 g (2.31 mol) of racemic 2-cyanoethyl (4S, 4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IV) and 854.38 g (2.0 mol) of (+)-di-O,O-p-chlorobenzoyl-D-tartaric acid are suspended in a mixture of 30 l of a mixture of ethanol/water 7:3 and heated to 50? C. (forming a solution). The mixture is stirred at room temperature overnight, and the precipitate crystals are filtered off and washed twice with 1000 ml of a mixture of ethanol/water 7:1. The product was dried under reduced pressure at room temperature.
[0483] Yield: 1105.0 g (111.3% of theory) of a colourless crystalline powder
[0484] Analytical Results:
[0485] Enantiomeric purity (e.e. %): 79% e.e.
[0486] An amount of the diastereomeric salt enriched in this way was purified further as follows:
[0487] 1104 g of the diastereomeric salt prepared was suspended in 10 l of a mixture of ethanol/water 7:1, and the mixture was stirred at 50? C. for 2 h and at room temperature overnight. The precipitated crystals were filtered off and washed twice with 1000 ml of a mixture of ethanol/water 3:1. The product was dried under reduced pressure at 40? C.
[0488] Yield: 812.7 g (81.8% of theory) of a colourless crystalline powder
[0489] Analytical Results:
[0490] Enantiomeric purity (e.e. %): 99% e.e.
Example 5b
Preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IVa)
[0491] To 600 g (697.95 mmol) of the title compound from Example 5a was suspended in 6 l of a mixture of water/ethanol 3:1, and the mixture was cooled to 0? C. Then a 20% aqueous sodium carbonate solution was metered in gradually (over the course of 1 hour) and the pH was adjusted to pH 7.1. The mixture was left to stir at that temperature for a further 4 hours. The precipitated solids were filtered off and washed twice with 1000 ml of a mixture (0? C.) of water/ethanol 3:1. The product was dried under reduced pressure at 40? C.
[0492] Yield: 285.8 g (94.7% of theory) of a colourless crystalline powder
[0493] Analytical Results:
[0494] Enantiomeric purity (e.e. %): 99% e.e.
[0495] In an analogous manner (as described in Examples 2c-2e), this prepared intermediate (IVa) was converted to the final stage (finerenone, pure):
[0496] Analytical results:
TABLE-US-00017 Finerenone (I) Purity: 99.87 area (HPLC); Content: 99.9% by weight Enantiomeric excess 100% e.e. Largest secondary component impurity E 0.04% Residual solvents: EtOH 0.05% toluene 0.00% water (Karl Fischer) 0.00%
[0497] Modification: Mod A (as defined in WO2016/016287 A1).