Photochemical process for producing (4r,4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide

Abstract

The invention relates to processes for producing racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide of formula (I) from the enantiomers (Ia) or (Ib); a process for producing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide of formula (Ia); a process for producing racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide of formula (I) from the pyridine of formula (II). The subjects of the invention have in common the irradiation of the compound of formulas (Ia), (Ib) and / or (II) with light in a suitable solvent, or solvent mixture, in the presence of a base. The compounds of formulas (Ia), (Ib) and / or (II) are intermediate products, by-products or target compounds in the synthesis of finerenone (compound according to formula (Ia)).

Description

[0001] Photochemical process for the preparation of 4SI- 4-(4-Cvano-2-methoxynhenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbox-amide

[0002] The invention relates to a process for the preparation of racemic (4 R,4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I)

[0003] (I), from the enantiomers Ia or Ib, comprising step (i)

[0004] (i) Irradiation of the enantiomers of formula (Ia) and / or (Ib) (Ib), in a suitable solvent or solvent mixture, and in the presence of a base.

[0005] The invention further relates to a process for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), comprising steps (ii), (iii) and (iv):

[0006] (ii) Irradiation of the compound of formula (Ib) in a suitable solvent or solvent mixture in the presence of a base with light, wherein the compound of formula (Ib) is converted into a racemic compound of formula (I)

[0007] (I), is transferred,

[0008] (111) Resolution of this racemic compound (I) from step (ii) with a chiral tartaric acid ester of formula (III) in a brandy-water mixture, wherein the diastereomeric salt (IVa) is formed, and

[0009] (iv) Treating the diastereomeric salt (IVa) from step (iii) with a base, forming the compound of formula (Ia).

[0010] The invention also relates to a process for the preparation of racemic (4 R,4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I)

[0011] (I), from the pyridine of formula (II) comprising step (vi): (vi) Irradiating the compound of formula (II) with light in a suitable solvent, or solvent mixture, in the presence of a base, whereby the compound according to formula (I) is formed.

[0012] The inventions thus have in common the irradiation of the compound of formulas (Ia), (Ib) and / or (II) with light in a suitable solvent or solvent mixture, in the presence of a base (see steps (i), (ii) or (vi)). The compounds of formulas (Ia), (Ib) and / or (II) are intermediates, by-products or target compounds in the synthesis of finerenones (compound of formula (Ia)). When the compound of formula (I) is mentioned here, then the racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide or the racemic compound of formula (I) shown below is meant:

[0013] When we refer to “finerenone”, the “compound of formula (Ia)”, “antipode (Ia)”, or the “enantiomer (Ia)”, we are referring to (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide or the compound of formula (Ia). This is meant. When referring to “enantiomeric compound (Ib)”, “enantiomer (Ib)”, “antipode (Ib)”, “absence antiomer” or “absence antiomer (Ib)”, then rac-(4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl- l,4-dihydro- l,6-naphthyridine-3-carboxamide or the compound shown below according to formula (Ib) is meant. meant.

[0014] When referring to “antipodes of compound according to formula (I)”, then the compounds of formulas (Ia) and (Ib) as defined above are meant.

[0015] When "brandy" is mentioned, it refers to denatured ethanol.

[0016] The abbreviation "h" stands for "hour". Finerenone (Ia) acts as a non-steroidal antagonist of the mineralocorticoid receptor and can be used as a means of prophylaxis and / or treatment of cardiovascular and renal diseases such as heart failure and diabetic nephropathy.

[0017] The compound of formula (Ia) and its preparation process are described in WO 2008 / 104306 Al and ChemMedChem 2012, 7, 1385 as well as in WO 2016 / 016287 Al. To obtain the compound of formula (Ia) and (Ib), the racemic mixture of the amides (I)

[0018] (D (I) into the antipodes of formula (Ia) and (Ib) are separated, since only the antipode of formula (Ia) is pharmacologically active.

[0019] In the published research synthesis, a specially synthesized chiral phase (in-house preparation) was used, which employed N-(dicyclopropylmethyl)-N as a chiral selector. 2-methacryloyl-D-leucinamide. It was found that the separation can also be carried out on a commercially available phase. This is the Chiralpak AS-V phase, 20 pm. A 60:40 mixture of methanol and acetonitrile was used as the mobile phase. Chromatography can be performed on a commercially available chromatography column, but techniques known to those skilled in the art, such as SMB or Varicol (Computers and Chemical Engineering 27 (2003) 1883-1901), are preferably used.

[0020] The compound of formula (Ia) and its preparation process are described in WO 2008 / 104306 Al and ChemMedChem 2012, 7, 1385, as well as in WO 2016 / 016287 Al, both publications revealing a detailed discussion of the research synthesis.

[0021] In the publication ChemMedChem 2012, 7, 1385, in which the research synthesis of the compound of formula (Ia) is disclosed, the compound of formula (Ia) is produced from vanillin in 10 steps with an overall yield of 3.76% of the theory.

[0022] To obtain the compound of formula (Ia), the racemic mixture of the amides rac-(I) must be separated into the antipodes of formulas (Ia) and (Ib). In the published research synthesis, a specially synthesized chiral phase (prepared in-house) was used for this purpose, employing N-(dicyclopropylmethyl)-N as the chiral selector. 2The selector contained methacryloyl-D-leucinamide. This selector was prepared in a multi-step process and then polymerized onto a special silica gel. Methanol / ethyl acetate served as the mobile phase. A major disadvantage of this method was the very low loading rate of 30 mg per separation on a 500 x 63 mm chromatography column, thus creating a significant need to find the most efficient separation method possible, one that would allow antipodal separations on a multi-ton scale. In WO 2008 / 104306 Al, it was described that the separation could also be performed on a commercially readily available phase. This phase is Chiralpak AS-V, 20 pm. A 60:40 mixture of methanol and acetonitrile was used as the mobile phase. This mixture has the significant advantage that it can be recovered as the mobile phase after distillation, with the identical composition (60:40 corresponds to the azeotrope).In this way, a very efficient process is achieved, with a separation yield > 47% of the theoretical yield (50% is theoretically possible). The optical purity is > 93% ee, preferably > 98.5% ee. Chromatography can be carried out on a commercially available chromatography column, but techniques known to those skilled in the art, such as SMB or Varicol (Computers and Chemical Engineering 27 (2003) 1883-1901), are preferably used. For example, approximately 500 kg of the racemic amide rac-(I) was separated using an SMB system, achieving a yield of 48%. The product is prepared as a 3-8%, preferably 5-7%, solution in a 30:70 methanol / acetonitrile mixture and can be directly used in the final processing.

[0023] When, for example, a 3% solution is mentioned, this means that 3 g of the compound is dissolved in 100 mL of the solvent.

[0024] When specifying solvent ratios, the ratio is given as volume to volume (Vol / Vol). A solvent mixture consisting, for example, of methanol / acetonitrile 30:70 contains 30 mL of methanol and 70 mL of acetonitrile. The volume therefore refers to the total volume of the solvent.

[0025] Other solvent mixture ratios between acetonitrile and methanol are also conceivable (90:10 to 10:90). Alternatively, other solvent mixtures, such as acetonitrile / ethanol in ratios of 10:90 to 90:10, can be used for SMB separation. The specific solvent ratio depends in part on the technical characteristics of the SMB system and may need to be adjusted (e.g., different flow rates, solvent recycling at the thin-film evaporator). In addition to the target compound finerenone (Ia), the enantiomeric compound (Ib) is also obtained in almost the same yield.

[0026] In summary, the invention relates to:

[0027] A method for the preparation of racemic (4 R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy- 2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I)

[0028] (I), from the enantiomers Ia or Ib, comprising step (i)

[0029] (i) Irradiation of the enantiomers of formula (Ia) and / or (Ib) in a suitable solvent or solvent mixture, in the presence of a base;

[0030] (2) A process for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), comprising steps (ii), (iii) and (iv):

[0031] (ii) Irradiation of the compound of formula (Ib) in a suitable solvent or solvent mixture in the presence of a base with light, whereby the compound of formula (Ib) is converted into a racemic compound of formula (I),

[0032] (iii) Resolution of this racemic compound (I) from step (ii) with a chiral tartaric acid ester of formula (III) in a spirit-water mixture, forming the diastereomeric salt (IVa), and

[0033] (iv) Treating the diastereomeric salt (IVa) from step (iii) with a base, forming the compound of formula (Ia);

[0034] (3) Process for the preparation of racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) from the pyridine of formula (II) comprising step (vi): (vi) Irradiating the compound of formula (II) with light in a suitable solvent, or solvent mixture, in the presence of a base, wherein the compound of formula (I) is formed.

[0035] The inventions thus have in common the irradiation of the compound of formulas (Ia), (Ib) and / or (II) with light in a suitable solvent or solvent mixture, in the presence of a base (see steps (i), (ii) or (vi)). The compounds of formulas Ia), (Ib) and / or (II) are intermediates, by-products or target compounds in the synthesis of finerenones (compound of formula (Ia)).

[0036] In summary, the inventive method offers, among other things, the following advantages or technical effects:

[0037] The missing enantiomer (Ib) can be easily converted into the target compound finerenone (Ia); this is cost-efficient because the missing enantiomer (Ib) does not have to be destroyed, but allows this unwanted byproduct to be used in the finerenone synthesis by converting the compound of formula (Ib) into a racemic mixture of formula (I) in order to subject it again to enantiomeric separation by means of SMB or racemic resolution, e.g. as described above with (+)-dibenzoyl tartaric acid.

[0038] It is no longer necessary to carry out several complex steps as described in the prior art: instead of 3 process steps (as described in electrochemistry, for example in WO 2017032678 Al), a simplified process has been developed which, under mild conditions (light), leads directly to racemization of the missing enantiomer (Ib) and thus to the racemate (I).

[0039] Depending on the batch size, the reaction (see steps (i), (ii) or (vi)) can be carried out in batch mode or as a flow process: this makes it easy to adapt the reaction to the respective industrial conditions.

[0040] Starting from the missing enantiomer (Ib) to the racemate (I), yields of 50%–75% of the theoretical yield are achieved, and the chemical purities are very high, reaching up to 99.1% (HPLC, area). The enantiomeric excess is < 1–2%. A racemate (I) obtained in this way can be successfully used in a subsequent racemate separation process, either SMB or racemate cleavage with dibenzoyltartaric acid, and meets the required specifications regarding purity and enantiomeric excess. Starting from the pyridine derivative (II), yields of 60%–90% of the theoretical yield of racemate (I) are achieved. The chemical purities are very high, reaching up to > 95% (HPLC, area). The enantiomeric excess is < 1–2%.A material obtained in this way can be successfully used in a subsequent racemate separation process, be it an SMB or a racemate cleavage with dibenzoyl tartaric acid, and meets the requirements for the necessary specifications regarding purity and enantiomeric excess.

[0041] The new inventive process is characterized by high efficiency in terms of yield and chemical purity. The process is environmentally friendly, as light is used as the actual "reagent." The process is scalable to industrial scale, since flow photoreactors have long been used in industry; that is, unlike the electrochemistry described above, no special equipment is required. Therefore, this new inventive process offers enormous economic advantages over the prior art.

[0042] The present invention relates to a new process for the preparation of racemic (4 R,4S)-4-(4-cyano- 2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I)

[0043] (I), from the enantiomers Ia or Ib (Ia) by irradiation with light at a temperature of 0°C to 100°C in a suitable solvent or solvent mixture, and in the presence of a base.

[0044] Preferably within the scope of the present invention is a process for the preparation of racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of

[0045] Lormel (I)

[0046] (i), from the enantiomers Ia or Ib by irradiation with light at a temperature of 0°C to 100°C in a suitable solvent or solvent mixture selected from the group consisting of dichloromethane, acetone, toluene, tetrahydrofuran, methanol, 4-methyl-2-pentanone, methyl ethyl ketone, cyclohexanone, acetonitrile, dimethylformamide, dimethyl sulfoxide or mixtures thereof in the concentration range of 0.05% to 10%, and in the presence of a base selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, tributylamine, 1,4-diazabicyclo(2.2.2)octane, 4-(dimethylamino)pyridine, TBD, 7-methyl-1,5,7-triazabicyclo [4.4.0]dec-5 -ene, Tetramethylguanidine, N,N,N,N -Tetramethyl- 1 ,8 -naphthalene-diamine, Lutidine, Pyridine, Imidazole, N-Methylimidazole and Phosphazene, wherein 1-20 equivalents of the organic base are used.

[0047] Preferably within the scope of the present invention is a process for the preparation of racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I), from the enantiomers Ia or Ib, by irradiation with light at a temperature of 30°C to 70°C in a suitable solvent or solvent mixture selected from the group consisting of acetone, acetonitrile, dimethylformamide and dimethyl sulfoxide or mixtures thereof, in the concentration range of 0.05% to 10%, and in the presence of a base selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene and 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, wherein 2 to 15 equivalents of the organic base are used.

[0048] Particularly preferred within the scope of the present invention is a process for the preparation of racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I),

[0049] (I), from the enantiomers Ia or Ib by irradiation with light at a temperature of 40°C to 60°C in acetone or acetonitrile or mixtures thereof in the concentration range of 0.05% to 10%, and in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo(4.3.0)non-5-ene, wherein 5-12 equivalents of the organic base are used. The present invention also relates to a process for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia).

[0050] (Ia), characterized by the fact that one can form a compound of formula (Ib)

[0051] (Ib), in a suitable solvent or solvent mixture in the presence of a base, by irradiation with sulfur to give a racemic compound of formula (I) (I), and this racemic compound by resolution with a chiral tartaric acid ester of formula (III)

[0052] (III), in a brandy-water mixture first into the diastereomeric salt (IVa) The enantiomer is transferred and then treated with a base and the solvent removed. The missing enantiomer (Ib) can also be obtained via a racemic resolution, which can be carried out as described below:

[0053] In a previously unpublished process, a tartaric acid ester is used instead of the irradiation employed according to the invention. This process is now described as follows: For large-scale implementation, (I) (+)-dibenzoyltartaric acid (III) is used for the racemate resolution; both the anhydrous form and the hydrate can be used:

[0054] The compound according to formula (IV) in the previously unpublished process described here is identical to compound (Va) of this invention. The racemic resolution is preferably carried out in a spirit-water mixture. The missing enantiomer (Ib) remains in the mother liquor and can be isolated for recycling.

[0055] The subsequent release of finerenone (Ia, crude),

[0056] (IV) (Ia) is preferably carried out in a spirit-water mixture using sodium phosphate as the base. In cases where a modification is necessary, when the proportion of (+)-dibenzoyl-tartaric acid (III) is > 0.1% The conversion is preferably carried out in a spirit-water mixture using sodium phosphate as a base. The final crystallization to finerenone (Ia), pure, preferably takes place in spirit as a solvent.

[0057] The isolation of the missing enantiomer (Ib) from the mother liquor is achieved by adjusting the pH of the combined mother liquors and washing solutions to 7.5 at room temperature by adding an aqueous sodium phosphate solution. The spirit is then largely distilled off under reduced pressure (85 to 65 mbar, 38° to 20°C internal temperature) and reduced to a defined final volume. It is cooled to room temperature, and the precipitated suspension is stirred at 20°–22°C. The suspension is filtered and washed twice with water. The wet product is dried overnight (approx. 16 h) at 50°C under vacuum (< 100 mbar). Yields of (Ib) are generally > 80% of the theoretical yield based on the amount of racemate (I) used.

[0058] Due to cost-economic considerations, there was a need not to destroy this enantiomer of formula (Ib), but to invent a process that makes it possible to convert the compound of formula (Ib) into a racemic mixture of formula (I) in order to subject it again to enantiomeric separation by means of SMB or racemic resolution, e.g. as described above with (+)-dibenzoyl tartaric acid.

[0059] In contrast to this racemization with a tartaric acid ester, the present process according to the invention involves irradiation. It has now been surprisingly found that this is achieved by irradiating the missing enantiomer (Ib) in a solvent or solvent mixture, in the presence of a base and in the presence of oxygen with light: (Ib) (I)

[0060] The same can be achieved by implementing finerenone (Ia):

[0061] The attempt to directly racemize compound (Ib), for example by treating compound (Ib) with strong bases or acids, was unsuccessful. The reaction with transition metal complexes such as palladium and iridium catalysts also did not lead to the desired result.

[0062] The prior art describes a two-step electrochemical process (WO 2017032678 Al) in which a chemical or electrochemical oxidation to pyridine (aromatization of the dihydropyridine) is performed first, followed by an electrochemical reduction. A disadvantage of the electrochemical process is that it must be carried out in three steps. Thus, the direct oxidation (chemical or electrochemical) of the missing enantiomer (Ib) yields an optically enriched pyridine derivative (II) (due to atropisomerism), which is equilibrated to the racemate by thermal treatment in a second step and subsequently reduced to the racemate (I) in a third step.

[0063] There is extensive literature on the photochemistry of dihydropyridine derivatives, for example in H. Freytag, W. Neudert, J. Prakt. Chem. 1932, 135, 15; H. Freytag, F. Hlucka, J. Prakt. Chem. 1932, 135, 288; H. Freytag, J. Prakt. Chem. 1934, 139, 44; J. Joussot-Dubien, J. Houdard, Tetrahedron Let. 1967, 44, 4389-4391; Koizumi, Bull. Chem. SOC. Jap. 1966, 39, 1221; Koizumi, Bull. Chem. SOC. Jap. 1967, 40, 2486; Koizumi, Bull. Chem. SOC. Jap. 1968, 41, 1056; DG Whitten, YJ Lee, J. Am. Chem. Soc. 1971, 93, 961-966; TJ van Bergen, RM Kellogg, J. Am. Chem. Soc 1972, 94, 8451-8471; R. Leuschner, JK Dohrmann, Journal of Photochemistry 1986, 33, 321-331; DG Whitte, YJ Lee, J. Am. Chem. Soc 1971, 93, 961-966; TJ van Bergen, RM Kellogg, J. Am. Chem. Soc 1972, 94, 8451-8471; TJ van Bergen, RM Kellogg, J. Am. Chem. Soc 1972, 94, 8451-8471; R. Leuschner, JK Dohrmann, Journal of Photochemistry 1986, 33, 321-331; TJ van Bergen, RM Kellogg, J. Am. Chem.Soc 1972, 94, 8451-8471; Jacques Joussot-Dubien, Josette Houdard, Tetrahedron Letters, Volume 8, Issue 44, 1967, S. 4389-4391; Journal of Magnetic Resonance (1969), Volume 27, Issue 3, September 1977, S. 371-384; Tetrahedron, Volume 28, Issue 24, 1972, S 5911- 5921; R. Leuschner, K. Dohrmann, 1 Journal of Photochemistry, Volume 33, Issue 3, June 1986, S. 321-331; Junko Shibuya, Mami Nabeshima, Hajime Nagano and Koko Maeda J. Chem. Soc., Perkin Trans. 2, 1988, 1607-1612; Zhong-Li Liu Chem. Commun, 1998, 2451-2452; Al-Jalal, Molecules. 2016 Jun 30; 21(7); T. J. Van Bergen and Richard M. Kellogg, Journal of the American Chemical Society 1972 94 (24), 8451-8471; Tetrahedron Letters, Volume 10, Issue 59, 1969, Pages 5211-5214; Molecules 2016, 21, 866; Hindawi Publishing Corporation International Journal of Photochemistry Volume 2014, Article ID 176989, 4 pages , http: / / dx.doi.org / 10T 155 / 2014 / 176989; Photochemistry and Photobiology, 2007, 83, 722-729; J. Org. Chem., 2006, 71 (5), pp 2037-2045; Monatshefte für Chemie 2002, 133, 661; International Journal of Photoenergy 2015, Article ID 454895.

[0064] Direct racemization by irradiation with light, as in the process according to the invention, is novel and previously unknown for chiral dihydropyridine derivatives. There was therefore a strong need to arrive at a simplified process, instead of three process steps (as in electrochemistry), that leads directly to racemization of the missing enantiomer (Ib) and thus to the racemate (I) under mild conditions (light). This is achieved with the present novel, inventive process.

[0065] It was surprising to the person skilled in the art that the missing enantiomer (Ib), or finerenone (Ia), cannot be isomerized by reaction with a strong base; that is, racemization is not possible. Surprisingly, this only succeeds, as was found in the inventive process, in the combination of a base, irradiation with light, and the selection of a suitable solvent in the presence of oxygen.

[0066] Organic bases have proven particularly suitable, especially 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, tributylamine, 1,4-diazabicyclo(2.2.2)octane, and 4-(dimethylamino)pyridine.

[0067] 1.5.7-Triazabicyclo[4.4.0]dec-5-ene, 7-methyl-l,5,7-triazabicyclo[4.4.0]dec-5-ene, tetramethylguanidine, N,N,N,N-tetramethyl-l,8-naphthalenediamine, lutidine, pyridine, imidazole, N-nethylimidazole, phosphazene. Particularly preferred are 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene and

[0068] 1.5,7-Triazabicyclo[4.4.0]dec-5-ene and 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, most preferably 1,8-Diazabicyclo[5.4.0]undec-7-ene and 1,5-Diazabicyclo(4.3.0)non-5-ene.

[0069] One to twenty equivalents of an organic base are used, preferably two to fifteen equivalents, particularly preferably five to twelve equivalents.

[0070] Suitable solvents for the photochemical reaction are dichloromethane, acetone, toluene, tetrahydrofuran, methanol, 4-methyl-2-pentanone, methyl ethyl ketone, cyclohexanone, acetonitrile, dimethylformamide, dimethyl sulfoxide, or mixtures thereof, such as acetone / methanol, acetone / methanol, or acetone / tetrahydrofuran. Acetone, acetonitrile, dimethylformamide, and dimethyl sulfoxide are particularly preferred. Acetone and acetonitrile are especially preferred. The concentration range is 0.05% to 10%, depending on the solvent. For example, a concentration range of 0.05% refers to 0.05 g dissolved in 100 mL.

[0071] Irradiation is carried out at temperatures between 0°C and 100°C, depending on the solvent. However, a temperature range of 30°C to 70°C is preferred, with 40°C to 60°C being even more desirable.

[0072] The duration of irradiation ranges from 1 hour to 40 hours and also depends heavily on the solvent and base used.

[0073] In some cases, depending on the solvent chosen, the addition of a photosensitizer may be advantageous. Anthracene, rose bengal, eosin Y, DMPA, benzoquinone, benzophenone, acetophenone, fluorene, xanthone, benzene, N-bromosuccinimide, Ru(bpy)3, or Ru-porphine can be used for this purpose.

[0074] Both mercury lamps and LEDs can be used as irradiation sources. The use of UV filters has proven advantageous; Duran filters (with a cutoff <300 nm) and UV filters with a cutoff of 282 nm have been particularly effective.

[0075] The reaction can be carried out in batch mode or as a flow process, depending on the batch size.

[0076] Photochemical racemization proceeds as a one-pot reaction. In the first phase of irradiation, synthetic air is introduced into the mixture within 0.5 to 5 hours. Alternatively, synthetic air can be introduced initially without irradiation; if air is introduced without irradiation, irradiation then takes place for 0.5 to 5 hours. For the second step of the one-pot reaction, irradiation continues under inert conditions (displacement of trace oxygen by introducing nitrogen or argon). The conversion can be monitored by sampling and checking the optical purity of the sample.

[0077] After the reaction is complete, the desired racemate (I) is processed and isolated as follows: First, the solvent is distilled off at atmospheric or reduced pressure to a specific volume, and a specific amount of water is added (see examples for the proportions. The proportions vary depending on the solvent or solvent mixture used). Racemate (I) precipitates and is then isolated by filtration through a filter or by centrifugation and subsequently dried. It is preferably dried at reduced pressure at temperatures of 40°–80°C. Depending on the quality of the products obtained, further processing can be carried out directly (SMB separation or racemate cleavage with dibenzoyl tartaric acid). Alternatively, a final crystallization can be performed for purification.Suitable solvents include ethanol, isopropanol, methanol, acetonitrile, and tetrahydrofuran, each also in combination with water. Starting from the missing enantiomer (Ib) to the racemate (I), yields of 50%–75% of the theoretical yield are achieved. The chemical purities are very high, with purities up to 99.1% (HPLC, surface area) attainable. The enantiomeric excess is < 1–2%. A racemate (I) obtained in this way can be successfully used in a subsequent racemate separation process, be it SMB or racemate cleavage with dibenzoyltartaric acid, and meets the required specifications regarding purity and enantiomeric excess.

[0078] In addition to the above-described method of direct conversion of (Ib) to (I) in a one-pot process, it was surprisingly found that photochemical reduction by irradiation with light in a suitable solvent or solvent mixture, as well as the presence of a base, the corresponding pyridine compound (II), which can be obtained, for example, by chemical or electrochemical oxidation starting from racemic or optically enriched compounds (see WO 2017032678 Al), yields compound (I) in racemic form.

[0079] (P) (I)

[0080] The present invention also relates to a new process for the preparation of racemic (4 R,4S)-4-(4- cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I)

[0081] (I) from the pyridine of formula (II) (II) by irradiation with light in a suitable solvent or solvent mixture, as well as the presence of a base.

[0082] Preferably within the scope of the present invention is a process for the preparation of racemic (4 R, 4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I)

[0083] (I), from the pyridine of formula II

[0084] (P), by irradiation with light at a temperature of 0°C to 100°C in a suitable solvent or solvent mixture selected from the group consisting of dichloromethane, acetone, toluene, tetrahydrofuran, methanol, 4-methyl-2-pentanone, methyl ethyl ketone, cyclohexanone, acetonitrile, dimethylformamide, dimethyl sulfoxide or mixtures thereof in the concentration range of 0.05% to 10%, and the presence of a base selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, tributylamine, 1,4-diazabicyclo(2.2.2)octane, 4-(dimethylamino)pyridine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 7-Methyl-1,5,7-triazabicyclo [4.4.0] dec-5-ene , Tetramethylguanidine, N,N,N,N-Tetramethyl-1,8-naphthalenediamine, Lutidine, Pyridine, Imidazole, N-Methylimidazole and Phosphazene, wherein 1-20 equivalents of the organic base are used.

[0085] Preferably within the scope of the present invention is a process for the preparation of racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) from the pyridine of formula II by irradiation with fluorine at a temperature of 30°C to 70°C in a suitable solvent or solvent mixture selected from the group consisting of acetone, acetonitrile, dimethylformamide and dimethyl sulfoxide or mixtures thereof, in the concentration range of 0.05% to 10%, and in the presence of a base selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene and 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, wherein 2 to 15 equivalents of the organic base are used.Particularly preferred within the scope of the present invention is a process for the preparation of racemic (4 R, 4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine- 3 -carboxamide of formula (I).

[0086] (I) from the pyridine of formula (II) (II) by irradiation with light at a temperature of 40°C to 60°C in acetone or acetonitrile or mixtures thereof in the concentration range of 0.05% to 10%, and in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo(4.3.0)non-5-ene, wherein 5-12 equivalents of the organic base are used.

[0087] Organic bases have proven particularly suitable, especially 1,8-diazabicyclo[5 4.0]undec-7-ene, 1,5-diazabicyclo(4.3 0)non-5-ene, triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, tributylamine, 1,4-diazabicyclo(2.2.2)octane, 4-(dimethylamino)pyridine,

[0088] 1.5.7-Triazabicyclo[4.4.0]dec-5-ene, 7-methyl-l,5,7-triazabicyclo[4.4.0]dec-5-ene, tetramethylguanidine, N,N,N,N-tetramethyl-l,8-naphthalenediamine, lutidine, pyridine, imidazole, N-nethylimidazole, phosphazene. Particularly preferred are 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene and

[0089] 1.5,7-Triazabicyclo[4.4.0]dec-5-ene and 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, most preferably 1,8-Diazabicyclo[5.4.0]undec-7-ene and 1,5-Diazabicyclo(4.3.0)non-5-ene.

[0090] One to twenty equivalents of an organic base are used, preferably two to fifteen equivalents, particularly preferably five to twelve equivalents.

[0091] Suitable solvents for the photochemical reaction are dichloromethane, acetone, toluene, tetrahydrofuran, methanol, 4-methyl-2-pentanone, methyl ethyl ketone, cyclohexanone, acetonitrile, dimethylformamide, dimethyl sulfoxide, or mixtures thereof, such as acetone / methanol, acetone / methanol, or acetone / tetrahydrofuran. Acetone, acetonitrile, dimethylformamide, and dimethyl sulfoxide are particularly preferred. Acetone and acetonitrile are especially preferred. Concentrations of 0.05% to 10% are used, depending on the solvent.

[0092] Irradiation is carried out at temperatures between 0°C and 100°C, depending on the solvent. However, a temperature range of 30°C to 70°C is preferred.

[0093] The duration of irradiation ranges from 1 hour to 40 hours and also depends strongly on the solvent and base used, preferably 10 to 20 hours. In one embodiment, the irradiation lasts from 6 to 40 hours. In another embodiment, the duration of irradiation is 6 to 35 hours. In another embodiment, the duration of irradiation is 6 to 20 hours. In another embodiment, the duration of irradiation is 6 to 15 hours. In another embodiment, the duration of irradiation is 6 to 10 hours. In another embodiment, the duration of irradiation is 6 to 9 hours. In another embodiment, the duration of irradiation is 8 to 20 hours. In another embodiment, the duration of irradiation is 6 to 34 hours.

[0094] In some cases, depending on the solvent chosen, the addition of a photosensitizer may be advantageous. Anthracene, rose bengal, eosin Y, DMPA, benzoquinone, benzophenone, acetophenone, fluorene, xanthone, benzene, N-bromosuccinimide, Ru(bpy)3, or Ru-porphine can be used for this purpose.

[0095] Mercury lamps and LEDs can be used as irradiation sources. The use of UV filters has proven advantageous; Duran filters (with a cutoff < 300 nm) and UV filters with a cutoff of 282 nm have been particularly effective.

[0096] The reaction can be carried out in batch mode or as a flow process, depending on the batch size.

[0097] After the reaction is complete, the desired racemate (I) is processed and isolated as follows: The solvent is distilled off at atmospheric or reduced pressure to a specific volume, and a specific amount of water is added (see examples for the ratios. The ratios vary depending on the solvent or solvent mixture used). The product precipitates and can then be isolated by filtration through a filter or by centrifugation and subsequently dried. It is preferably dried at reduced pressure at temperatures of 30°–80°C, preferably at 40°–60°C. Depending on the quality of the products obtained, further processing can be carried out directly (e.g., SMB separation or racemate hydrolysis with dibenzoyltartaric acid). Alternatively, a final crystallization can be performed for purification.Suitable solvents for this purpose include ethanol, isopropanol, methanol, acetonitrile and tetrahydrofuran, each also in combination with water.

[0098] Starting from the pyridine derivative (II), yields of 60%–90% of the theoretical yield of racemate (I) are achieved. Chemical purities are very high, with purities up to >95% (HPLC, surface area) attainable. The enantiomeric excess is <1–2%. Material obtained in this way can be successfully used in subsequent racemate separation processes, such as SMB or racemate cleavage with dibenzoyltartaric acid, and meets the required specifications regarding purity and enantiomeric excess.

[0099] Besides this new process starting from the pyridine derivative (II), the one-pot process starting from (Ib) is particularly preferred. The new inventive process is characterized by high efficiency in terms of yield and chemical purity. The process is environmentally friendly, as light is used as the actual "reagent." The process is scalable to industrial scale, since flow photoreactors have long been used in industry; that is, unlike electrochemistry, no special equipment is required. Therefore, this new inventive process offers enormous economic advantages over the prior art.

[0100] Paragraphs 1 to 9.

[0101] Further embodiments of the invention are described in the following paragraphs 1 to 9:

[0102] 1. Method for the preparation of racemic (4 R, 4S)- 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8- dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I)

[0103] (I), from the enantiomers Ia or Ib by irradiation with light in a suitable solvent or solvent mixture, and in the presence of a base. Method according to paragraph 1 for the preparation of racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I)

[0104] (I), from the enantiomers Ia or Ib by irradiation with light at a temperature of 0°C to 100°C in a suitable solvent or solvent mixture selected from the group consisting of dichloromethane, acetone, toluene, tetrahydrofuran, methanol, 4-methyl-2-pentanone, methyl ethyl ketone, and cyclohexanone.

[0105] Acetonitrile, dimethylformamide, dimethyl sulfoxide or mixtures thereof in the concentration range of 0.05% to 10%, as well as the presence of a base selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, triethylamine,

[0106] Diisopropylethylamine, trimethylamine, tripropylamine, tributylamine, 1,4-diazabicyclo(2.2.2)octane, 4-(dimethylamino)pyridine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, tetramethylguanidine, N,N,N,N-tetramethyl-1,8-naphthalenediamine, lutidine, pyridine, imidazole, N-methylimidazole and phosphazene, wherein 1-20 equivalents of the organic base are used. Method according to paragraph 1 or 2 for the preparation of racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I), from enantiomers Ia or Ib, by irradiation with light at a temperature of 30°C to 70°C in a suitable solvent, or solvent mixture, selected from the group consisting of acetone, acetonitrile, dimethylformamide and dimethyl sulfoxide or mixtures thereof, in the concentration range of 0.05% to 10%, and in the presence of a base selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-Diazabicyclo(4.3.0)non-5-ene, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene and 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, wherein 2 to 15 equivalents of the organic base are used.

[0107] Method according to paragraph 1, 2 or 3 for the preparation of racemic (4 R, 4S)-4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I),

[0108] (I), from the enantiomers Ia or Ib by irradiation with light at a temperature of 40°C to 60°C in acetone or acetonitrile or mixtures thereof in the concentration range of 0.05% to 10%, and in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo(4.3.0)non-5-ene, wherein 5-12 equivalents of the organic base are used.

[0109] Method for the preparation of (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ia)

[0110] (Ia), characterized by the fact that one can form a compound of formula (Ib)

[0111] (Ib), in a suitable solvent or solvent mixture at a temperature of 0°C to 100°C in the presence of a base by irradiation with light to give a racemic compound of formula (I)

[0112] (I), converted, and this racemic compound by racemic resolution with a chiral tartaric acid ester of formula (III) in a brandy-water mixture first into the diastereomeric salt (IVa)

[0113] (IVa), transferred, and then treated with a base and the solvent removed.

[0114] Method according to paragraph 5 for the preparation of (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia)

[0115] (Ia), characterized by the fact that one can form a compound of formula (Ib)

[0116] (Ib), by irradiation with light at a temperature of 30°C to 70°C in a suitable solvent, or solvent mixture selected from the group consisting of acetone, acetonitrile, dimethylformamide and dimethyl sulfoxide or mixtures thereof, in the concentration range of 0.05% to 10%, and in the presence of a base selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, 1,5,7-triazabicyclo[4.4.0]dec-5-ene and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, wherein 2 to 15 equivalents of the organic base are used, into a racemic compound of formula (I)

[0117] (I), converted, and this racemic compound by racemic resolution with a chiral tartaric acid ester of formula (III) (III), in a spirit-water mixture first into the diastereomeric salt (IVa) transferred, and then treated with sodium phosphate and the solvent removed. 7. Process according to paragraph 5 or 6 for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-

[0118] 2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ia)

[0119] (Ia), characterized in that a compound of formula (Ib) (Ib) is prepared at a temperature of 40°C to 60°C in acetone or acetonitrile or mixtures thereof in the concentration range of 0.05% to 10%, and in the presence of 1.8-

[0120] Diazabicyclo[5.4.0]undec-7-ene or 1,5-Diazabicyclo(4.3.0)non-5-ene, wherein 5-12 equivalents of the organic base are used, are converted by irradiation with light into a racemic compound of the

[0121] Formula (I) converted, and this racemic compound by racemic resolution with a chiral tartaric acid ester of formula (III)

[0122] (III), in a brandy-water mixture first into the diastereomeric salt (IVa)

[0123] (IVa), transferred, and then treated with sodium phosphate and the solvent removed.

[0124] Method for the preparation of racemic (4 R,4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I)

[0125] (I), from the pyridine of formula (II)

[0126] (P), by irradiation with light in a suitable solvent or solvent mixture, and the presence of a base.

[0127] 9. Process according to paragraph 8 for the preparation of racemic (4 R,4S)-4-(4-cyano-2-methoxyphenyl)- 5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I)

[0128] (I), from the pyridine of formula (II)

[0129] (II) by irradiation with light at a temperature of 40°C to 60°C in acetone or acetonitrile or mixtures thereof in the concentration range of 0.05% to 10%, and in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo(4.3.0)non-5-ene, wherein 5-12 equivalents of the organic base are used.

[0130] Paragraphs (1) to (42)

[0131] Further embodiments of the invention are described in the following paragraphs (1) to (28): (1) Process for the preparation of racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) (I), from the enantiomers of formulas (Ia) and / or (Ib) comprehensive the step (i):

[0132] (i) Irradiation of the enantiomers of formulas (Ia) and / or (Ib) with light in a suitable solvent or solvent mixture in the presence of a base, wherein the irradiation in step (i) optionally takes place at a temperature of 0°C to 100°C. (2) The method according to paragraph (1), wherein the irradiation with light in step

[0133] (i) at a temperature of 30°C to 70°C.

[0134] (3) A process according to paragraph (1) or (2), wherein the irradiation with light in step (i) is carried out at a temperature of 40°C to 60°C. (4) A process according to any one of paragraphs (1) to (3), wherein the solvent or solvent mixture in step (i) is selected from the group consisting of dichloromethane, acetone, toluene, tetrahydrofuran, methanol, 4-methyl-2-pentanone, methyl ethyl ketone, cyclohexanone, acetonitrile, dimethylformamide, dimethyl sulfoxide and mixtures thereof.

[0135] (5) A method according to any one of paragraphs (1) to (4), wherein the solvent or solvent mixture in step (i) is selected from the group consisting of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide and mixtures thereof.

[0136] (6) A method according to any one of paragraphs (1) to (5), wherein the solvent or solvent mixture in step (i) is selected from the group consisting of acetone, acetonitrile and mixtures thereof.

[0137] (7) Method according to any one of paragraphs (1) to (6), wherein the concentration range of the enantiomer used in step (i) in the solvent or solvent mixture is 0.05% to 10% (w / V) based on the volume of the solvent or solvent mixture.

[0138] (8) A method according to any one of paragraphs (1) to (7), wherein the base in step (i) is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, tributylamine, 1,4-diazabicyclo(2.2.2)octane, 4-(dimethylamino)pyridine, TBD, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, tetramethylguanidine, N,N,N,N-tetramethyl-1,8-naphthalenediamine, lutidine, pyridine, imidazole, N-methylimidazole, phosphazene and mixtures thereof.

[0139] (9) Method according to any one of paragraphs (1) to (8) wherein 1 to 20 equivalents of the organic base are used in step (i).

[0140] (10) Method according to any one of paragraphs (1) to (9) wherein 2 to 15 equivalents of the organic base are used in step (i).

[0141] (11) Method according to any one of paragraphs (1) to (10) wherein 5 to 12 equivalents of the organic base are used in step (i).

[0142] (12) Method according to any one of paragraphs (1) to (11) wherein the irradiation in step (i) is carried out for a duration of 1 hour to 40 hours.

[0143] (13) A process according to any one of paragraphs (1) to (12), wherein the irradiation in step (i) is carried out for a duration of 10 to 20 hours. (14) A process for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia)

[0144] (Ia), comprising steps (ii), (iii) and (iv):

[0145] (ii) Irradiation of the compound of formula (Ib)

[0146] (Ib), in a suitable solvent or solvent mixture in the presence of a base with light, wherein the compound of formula (Ib) is converted into a racemic compound of formula (I)

[0147] (I), is transferred,

[0148] (111) Resolution of this racemic compound (I) from step (ii) with a chiral tartaric acid ester of formula (III)

[0149] (III), in a brandy-water mixture, wherein the diastereomeric salt (IVa) is formed, and

[0150] (iv) Treating the diastereomeric salt (IVa) from step (iii) with a base, forming the compound of formula (Ia).

[0151] (15) The method according to paragraph (14), wherein the method further comprises step (v): (v) removal of the solvent or solvent mixture.

[0152] (16) A method according to any one of paragraphs (14) or (15), wherein the irradiation in step (ii) is carried out at a temperature of 0°C to 100°C. (17) A method according to any one of paragraphs (14) to (16), wherein the irradiation with light in step (ii) is carried out at a temperature of 30°C to 70°C.

[0153] (18) Method according to any one of paragraphs (14) to (17) wherein the irradiation with light in step (ii) takes place at a temperature of 40°C to 60°C.

[0154] (19) A method according to any one of paragraphs (14) to (18), wherein the solvent or solvent mixture in step (ii) is selected from the group consisting of dichloromethane, acetone, toluene, tetrahydrofuran, methanol, 4-methyl-2-pentanone, methyl ethyl ketone, cyclohexanone, acetonitrile, dimethylformamide, dimethyl sulfoxide and mixtures thereof.

[0155] (20) A method according to any one of paragraphs (14) to (19), wherein the solvent or solvent mixture in step (ii) is selected from the group consisting of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide and mixtures thereof.

[0156] (21) A method according to any one of paragraphs (14) to (20), wherein the solvent or solvent mixture in step (ii) is selected from the group consisting of acetone, acetonitrile and mixtures thereof.

[0157] (22) Method according to any one of paragraphs (14) to (21) wherein the concentration range of the enantiomer used in step (ii) in the solvent or solvent mixture is 0.05% to 10% (w / V) based on the volume of the solvent or solvent mixture.

[0158] (23) A method according to any one of paragraphs (14) to (22), wherein the base in step (ii) is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, tributylamine, 1,4-diazabicyclo(2.2.2)octane, 4-(dimethylamino)pyridine, TBD, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, tetramethylguanidine, N,N,N,N-tetramethyl-1,8-naphthalenediamine, lutidine, pyridine, imidazole, N-methylimidazole, phosphazene and their derivatives Mixtures.

[0159] (24) Method according to any one of paragraphs (14) to (23) wherein 1 to 20 equivalents of the organic base are used in step (ii).

[0160] (25) Method according to any one of paragraphs (14) to (24) wherein 2 to 15 equivalents of the organic base are used in step (ii).

[0161] (26) A method according to any one of paragraphs (14) to (25), wherein 5 to 12 equivalents of the organic base are used in step (ii). (27) A method according to any one of paragraphs (14) to (26), wherein the irradiation in step (ii) is carried out for a duration of 1 hour to 40 hours. (28) A method according to any one of paragraphs (14) to (27), wherein the irradiation in step (ii) is carried out for a duration of

[0162] This takes place between 6 and 35 hours.

[0163] (29) Method for the preparation of racemic (4 R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I)

[0164] (I), from the pyridine of formula (II)

[0165] (P), encompassing the step (vi):

[0166] (vi) Irradiating the compound of formula (II) with light in a suitable solvent, or

[0167] Solvent mixture, in the presence of a base, wherein the compound is formed according to formula (I). (30) Method according to paragraph (29), wherein the irradiation in step (vi) is carried out at a temperature of 0°C to 100°C.

[0168] (31) Method according to any one of paragraphs (29) to (30), wherein the irradiation with light in step (vi) takes place at a temperature of 30°C to 70°C.

[0169] (32) Method according to any one of paragraphs (29) to (31), wherein the irradiation with light in step (vi) takes place at a temperature of 40°C to 60°C.

[0170] (33) A method according to any one of paragraphs (29) to (32), wherein the solvent or solvent mixture in step (vi) is selected from the group consisting of dichloromethane, acetone, toluene, tetrahydrofuran, methanol, 4-methyl-2-pentanone, methyl ethyl ketone, cyclohexanone, acetonitrile, dimethylformamide, dimethyl sulfoxide and mixtures thereof.

[0171] (34) A method according to any one of paragraphs (29) to (33), wherein the solvent or solvent mixture in step (vi) is selected from the group consisting of acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide and mixtures thereof.

[0172] (35) A method according to any one of paragraphs (29) to (34), wherein the solvent or solvent mixture in step (vi) is selected from the group consisting of acetone, acetonitrile and mixtures thereof.

[0173] (36) Method according to any one of paragraphs (29) to (35) wherein the concentration range of the enantiomer used in step (vi) in the solvent or solvent mixture is 0.05% to 10% (w / V) based on the volume of the solvent or solvent mixture.

[0174] (37) A process according to any one of paragraphs (29) to (36), wherein the base in step (iv) is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, tributylamine, 1,4-diazabicyclo(2.2.2)octane, 4-(dimethylamino)pyridine, TBD, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, tetramethylguanidine, N,N,N,N-tetramethyl-1,8-naphthalenediamine, lutidine, pyridine, imidazole, N-methylimidazole, phosphazene and their derivatives Mixtures.

[0175] (38) A method according to any one of paragraphs (29) to (37), wherein 1 to 20 equivalents of the organic base are used in step (vi). (39) A method according to any one of paragraphs (29) to (38), wherein 2 to 15 equivalents of the organic base are used in step (vi).

[0176] (40) Method according to any one of paragraphs (29) to (39), wherein 5 to 12 equivalents of the organic base are used in step (vi).

[0177] (41) A method according to any one of paragraphs (29) to (40), wherein the irradiation in step (vi) is carried out for a duration of 1 hour to 40 hours. (42) A method according to any one of paragraphs (29) to (41), wherein the irradiation in step (vi) is carried out for a duration of 10 hours to 20 hours.

[0178] Examples

[0179] Experimental section Abbreviations and acronyms:

[0180] The following table lists the structures of the compounds recovered by HPLC. The corresponding retention times in HPLC are given below. Table ) Analytical method for testing the impurity content and enantiomeric purity at the di-benzoyl tartaric acid level

[0181] Content and RT(min) RRT organic

[0182] Di-benzoyl tartaric acid Approx. 11.1 1.00

[0183] Contaminants

[0184] Mono-benzoyl acetic acid Approx. 5.1 0.46 Benzoic acid Approx. 7.6 0.69

[0185] Instrument: Ultra-high-performance liquid chromatograph (with a pressure range up to 1200 bar, thermostatically controlled column oven, and UV detector)

[0186] Column: YMC Triart C8

[0187] Length: 100 mm, Inner diameter: 3.0 mm, Measurement size: 1.9 pm

[0188] Maximum pressure: 1000 bar

[0189] Conditions: 20°C; 0.50 mU / min; 1.7pU(10°C); 240nm / 6nm

[0190] Eluent: A: 0.1% TFA in water; B: Acetonitrile

[0191] Gradient: Time (min) A (%) B (%)

[0192] 0.0 90.0 10.0

[0193] 15.0 35.0 65.0

[0194] 16.0 20.0 80.0

[0195] 20.0 20.0 80.0

[0196] RT(min) RRT

[0197] (+)-Di-Benzoyl-Voic acid 2.1 1.00

[0198] (-)-Di-Benzoyl-tartaric acid 3.9 1.86 High-performance liquid chromatograph with thermostatically controlled column oven and UV detector

[0199] Column: Conditions: 40 °C; 2.0 mL / min; 5 pL: 234nm / 6nm

[0200] Eluent: A: heptane; B: 0.1% TFA in ethanol

[0201] Isocratic: A (%) 80: B (%) 20 ) Analytical method for testing impurity content and enantiomeric purity at the diastereomeric salt level

[0202] Content and organic RT (min) RRT

[0203] Finerenone (Ia) 6.2 1.00

[0204] Impurities 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 G 6.8 1.10 Impurity F 7.2 1.17 Impurity H 7.7 1.25 Impurity I 7.8 1.27 Impurity J 8.4 1.36 Impurity K 10.4 1.69 Impurity N 11.1 1.80

[0205] Instrument: Ultra-high-performance liquid chromatograph (with a pressure range up to 1200 bar, thermostatically controlled column oven, and UV detector)

[0206] Column: YMC Triart C8

[0207] Catches: 100 mm, inner diameter^, 0 mm, size: 1.9 pm

[0208] Maximum pressure: 1000 bar

[0209] Conditions: 20°C; 0.50 mF / min; 3.5 pF (10°C); 242 nm / 6 nm

[0210] Eluent: A: 0.1% TFA in water; B: Acetonitrile

[0211] Gradient: Time A (%) B (%)

[0212] 0.0 90.0 10.0

[0213] 15.0 35.0 65.0

[0214] 16.0 20.0 80.0

[0215] 20.0 20.0 80.0 Enantiomeric purity: RT(min) RRT

[0216] Finerenone (Ia) 5.34 1.00

[0217] (Ib) 6.14 1.15

[0218] Instrument: High-performance liquid chromatograph with thermostatically controlled column oven and UV detector

[0219] Column: Lux 3mhi i-Cellulose-5

[0220] Length: 150 mm, Inner diameter: 4.6 mm, Size: 3.0 mih

[0221] Maximum pressure: 300 bar

[0222] Conditions: 40 °C; 1.0 mL / min; 10 pL (20 °C); 252 nm / 6 nm

[0223] Eluent: A: 20 mmol ammonium acetate buffer pH 9.0 (1.54 g ammonium acetate in 1 L Milli-Q water and adjusted to pH 9.0 with ammonia)

[0224] ; B: Acetonitril

[0225] Isocratic: A(%) 50: B (%) 50 ) Analytical method for testing the impurity content and enantiomeric purity at the finerenone, crude (Ia) level.

[0226] Content and organic RT(min) RRT

[0227] Impurities Finerenone (Ia) 6.2 1.00

[0228] Contamination A 3.3 0.53 Contamination B 3.7 0.60 Contamination C 3.9 0.62 Contamination D 4.4 0.70 Contamination E 5.5 0.89 Contamination F 5.6 0.91 Contamination G 6.8 1.10 Contamination H 7.6 1.23 Contamination K 10.4 1.68 Contamination N 11.1 1.79

[0229] Instrument: Ultra-high-performance liquid chromatograph (with a pressure range up to 1200 bar, thermostatically controlled column oven, and UV detector)

[0230] Column: YMC Triart C8

[0231] Catches: 100 mm, inner diameter^, 0 mm, size: 1.9 pm

[0232] Maximum pressure: 1000 bar

[0233] Conditions: 20°C; 0.50 mF / min; 1.7 pF (10°C); 252 nm / 6 nm and 230 nm / 6 nm for the evaluation of DB tartaric acid

[0234] Eluent: A: 0.1% TFA in water; B: Acetonitrile

[0235] Gradient: Time (min) AB (%) 0.0 90.0 10.0 15.0 35.0 65.0 16.0 20.0 80.0 20.0 20.0 80.0

[0236] Enantiomeric purity: RT(min) RRT

[0237] Method A Finerenone (Ia) Approx. 11 1.00 (Ib) Approx. 9 0.82 Instrument: High-performance liquid chromatograph with thermostatically controlled column oven and UV detector

[0238] Column: Chiralpak IA

[0239] Length: 250 mm, Inner diameter: 4.6 mm, Condensation size: 5.0 µm, Max. pressure: 300 bar

[0240] Conditions: 40°C; 0.8 m / min; 5 pL(20°C); 255nm / 6nm

[0241] Eluent: A: acetonitrile; B: Methyl tert-butyl ether (MTBE)

[0242] Isocratic: A (%) 90: B (%) 10

[0243] Enantiomeric purity

[0244] Method B RT(min) RRT

[0245] Finerenone (Ia) 5.7 1.00

[0246] Enantiomer (Ib) 6.8 1.19

[0247] Instrument / Detector: High-performance liquid chromatograph with thermostatically controlled column oven, UV detector and data evaluation system. Measurement wavelength: 252 nm. Oven temperature: 40°C. Column: Chiralpak IC

[0248] Length: 150 mm, inner diameter: 4.6 mm, grain size: 3 pm

[0249] Mobile phase: A: 50% buffer 20mM NH40Ac pH 9 B: 50% acetonitrile

[0250] Flow rate: 1 mL / min.

[0251] Running time: 8 min.

[0252] Equilibration: not necessary, isocratic. Sample solvent: mobile phase.

[0253] Test solution: Dissolve approximately 0.5 mg / mL of the racemate substance with sample solvent. Reference solution: Prepare a reference solution analogous to the test solution.

[0254] Injection volume: 10 pL

[0255] The enantiomeric Be determination values ​​given in the following examples were all determined using Method B. Some values, especially those of the batches produced in the pilot plant, were remeasured using Method A for comparison and yielded comparable results.

[0256] The HPLC analysis data regarding purity and content for the final product finerenone, pure (Ia), given in the following examples, refer only to impurities present in the product at > 0.05%. This is essentially impurity E. All other impurities shown in the table above are generally < 0.05%. The structure of such impurities was determined by isolation from enriched mother liquors.

[0257] The following devices were used in the examples:

[0258] Oxygen meter

[0259] An oxygen measuring device from the company "pyro Science sensor technology" was used. It was the "Firesting 02" model, which measures and stores oxygen levels using a fiber optic fiber and optional logging.

[0260] reaction apparatus

[0261] For screening experiments (up to 1000 ml reaction volume), a small, in-house built system with reactors and accessories from Peschl Ultraviolett was initially used. Similarly, initial larger-scale experiments (between 1000 and 2500 ml reaction volume) were conducted in an in-house built system using parts from various manufacturers, including Peschl Ultraviolett. Later, screening and larger experiments were carried out in compact reaction systems from Peschl Ultraviolett. Batch reactors, sideloop reactors, and falling film reactors were used for the individual experiments.

[0262] UV lamps

[0263] For the individual experiments, low-pressure mercury vapor lamps and LED lamps from Peschl Ultraviolet were used. Specifically, these were TQ 150 (150 W power), TQ 1000 (1000 W), and TQ 2000 (2000 W), as well as UED lamps (40 W power) with wavelengths of 365 nm and 405 nm. The low-pressure mercury vapor lamps (TQ XXX HG) emitted light in the spectral range of 260 to 600 nm.

[0264] „ Filters or glass holders for the lamps

[0265] The respective UV lamps were mounted in glass holders made of clear quartz or Duran glass. The Duran glass filters below 310 nm.

[0266] Svnthethische Luft

[0267] Synthetic air with 20% oxygen / 80% nitrogen and also 30% oxygen / 70% nitrogen was used.

[0268] At even lower oxygen levels, the synthetic air was diluted with nitrogen.

[0269] The missing enantiomer (Ib), which is used in the photochemical recycling process, can be obtained either by racemic resolution via SMB separation on a chiral stationary phase (using a mobile phase mixture of acetonitrile / methanol, such as e.g. 70:30 and e.g. phase Chiralpak AS-V, 20 pm), see WO 2016 / 016287 Al, or by racemic resolution with (+)-0,0-Dibenzoyl-D-tartaric acid.

[0270] Since the antipodes (Ia) and (Ib) do not differ in their photochemical properties, both compounds were used in some studies because the results are transferable. Therefore, photochemical recycling was developed using both antipodes, with the ultimate goal of racemizing the corresponding missing antiomer (Ib) on an industrial scale.

[0271] Example 1

[0272] Laboratory approach using anhydrous (+)-0,0-dibenzoyl-D-tartaric acid (III) Example aa

[0273] Tartrate salt (IVa) Production of (4SI- 4-(4-Cvano-2- 2,8-dimcthyl-l .4-dihvdro- 1.6-naphthyridine-3 -carboxamide

[0274] 250 g (660.616 mmol) of racemate (I) (rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide) were placed in 3500 ml of a mixture consisting of ethanol, denatured toluene / water = 75:25 (v / v) at room temperature (approx. 23°C). 130.2 g (363.339 mmol) of (+)-0,0-dibenzoyl-D-tartaric acid (III) were added via a solids funnel and then rinsed with 250 ml of a mixture consisting of ethanol, denatured toluene / water = 75:25 (v / v). The resulting suspension was heated to an internal temperature of 75 °C within 0.75 hours and then stirred for 3.0 hours at this temperature. It was then cooled from 23 °C over a cooling ramp within 5.0 hours and stirred overnight (approximately 16 hours) at this temperature. The suspension was filtered through a frit and washed once with 250 ml of a mixture consisting of ethanol, denatured toluene / water = 75:25 (v / v). Wet yield: 334.7 g.The wet product was then dried overnight (approx. 16 hours) at 50°C under vacuum (< 100 mbar). Yield: 250.2 g (100.08% of theory) of a colorless crystalline powder.

[0275] Analytical results:

[0276] MS (EIpos): m / z = 379 [M+H]

[0277] Ή-NMR (400 MHz, DMSO-d6): d = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.39 (s, 1H), 5.89 (s, 2H), 6.60-6.84 (m (wide signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55

[0278] (s, 1H), 7.61 (t, 4H), 7.69 (s, 1H), 7.75 (t, 2H), 8.04 (d, 4H), 12.50-15.40 (very broad signal, 2H) and signal from solvent DMSO and increased water signal: d = 2.5-2.6, as well as small peaks at d = 3.40 - 3.50 (q) and d = 1.05-1.10 (t), superimposed signals from residual solvent ethanol.

[0279] Example lb: Production of crude product of (4SI- 4-(4-Cvano-2-methoxyphenvD-5-ethoxy-2.8-dimethyl-1.4-dihvdro-

[0280] 1.6-naphthyridine-3 -carboxamide

[0281] 248 g of the compound prepared in Example 1a (IVa) was suspended at room temperature in 2480 ml of a mixture consisting of ethanol, denatured toluene / water = 20:80 (v / v) (a pH of 4 was measured). Subsequently, 819.6 g of an aqueous sodium phosphate solution (100 g sodium phosphate dissolved in 1000 ml water) were added dropwise over 60 minutes, and the pH was adjusted to 7.2. The mixture was stirred for 50 minutes at 23°C (pH 7.1). Then, 98.3 g of an aqueous sodium phosphate solution (100 g sodium phosphate dissolved in 1000 ml water) were added dropwise over 10 minutes, and the pH was adjusted to 7.5. The mixture was heated to 50°C over one hour and stirred for 3 hours at this temperature. It was cooled to 22°C within one hour and stirred for another hour at that temperature.The crystallizate was filtered through a frit and washed once with 200 ml and once with 100 ml of a mixture consisting of ethanol, toluene / water = 20:80 (v / v) and twice with 200 g of water. Wet yield: 263.4 g. The wet product was then dried over the weekend (> 48 hours) at 50°C under vacuum (< 100 mbar). Yield: 116.9 g (93.52% of theory) of a colorless crystalline powder. Analytical results: MS (EIpos): m / z = 379 [M+H]

[0282] Tf-NMR (400 MHz, DMSO-d6): d = 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 (wide signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H) and signal from the solvent DMSO and significantly increased water signal: d = 2.5-2.6, as well as a very small peak at d = 3.38 (not assignable).

[0283] Example lc

[0284] Production of pure product of (4SI- 4-(4-Cvano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihvdro- 1.6-naphthyridine-3 -carboxamide

[0285] 116.0 g of the crude product (Ia) prepared in Example 1b were suspended in 2330 ml of denatured toluene ethanol and then heated to reflux. The product dissolved. The solution was stirred for one hour at this temperature. It was filtered through a heated pressure filter (T = 75°C), which was then rinsed with 30 ml of denatured toluene ethanol. The solvent was then distilled off (approximately 1920 ml were distilled off) until a final volume of approximately four times the initial volume (based on the initial substance: 116 g x 4 ~ 484 ml) was reached. The solution was then cooled to an internal temperature of 23°C (approximately 1.5 to 2 hours). It was then stirred for two hours at an internal temperature of 3°C. The product was filtered and washed once with 100 ml of denatured ethanol and toluene. Wet yield: 124 g. The wet product was dried at 50°C over the weekend (> 48 h) under vacuum (< 100 mbar). Yield: 112.6 g (97).0.7% of the theory) of a colorless crystalline powder (fine needle crystals).

[0286] Analytical results:

[0287] MS (EIpos): m / z = 379 [M+H]

[0288] Tf-NMR (400 MHz, DMSO-d6): d = 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 (wide 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 from the solvent DMSO and water at d = 2.5-2.6 as well as a very small peak at d = 3.38 (not assignable)

[0289] Modification: Mod A (according to the definition in WO2016 / 016287 Al)

[0290] Example ld Isolation of the missing enantiomer üb) from the mother liquor of (4R)- 4-(4-Cvano-2-

[0291] 2.8-dimethyl-1.4-dihydro-1.6-naphthyridine-3-carboxamide

[0292] The combined mother liquor and wash solution from Example 1a (approx. 3750 ml yellowish solution, pH = 4.5) was adjusted to pH = 7.5 at room temperature by adding 101.1 g of an aqueous sodium phosphate solution (100 g dissolved in 1 L water). The spirit was then largely distilled off under reduced pressure (85 to 65 mbar, 38° to 20°C ambient temperature) and reduced to a final volume of approximately 0.85 L. It was cooled to room temperature, and the precipitated suspension was stirred over the weekend (> 48 hours), followed by a further 2 hours of stirring at 22°C. The suspension was filtered and washed twice with 200 ml of water each time. Wet yield: 139.1 g. The wet product was dried overnight (approx. 16 h) at 50°C under vacuum (< 100 mbar). Yield: 103.1 g (82.48% of theory based on racemate (I) used in example aa).

[0293] Example 2

[0294] Initial experiments in photochemistry:

[0295] Influence of solvent (screening trials for selecting the optimal solvent): S-Finerenone (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (> 99% ee) was irradiated in a solvent or solvent mixture (see tables) with a 365 nm LED for 10 min. Two equivalents of DBU were used. The concentration was approximately 1.5%. The following tables show the results:

[0296] Initially, surprisingly large quantities of pyridine compound (II) were found:

[0297] Example 3

[0298] Initial experiments in photochemistry:

[0299] Influence of Base (Screening Experiments for Selecting the Optimal Base): S-Finerenone (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (> 99% ee) was irradiated in acetone with a 365 nm LED for 10 min. Two equivalents of base were used. The concentration was approximately 1.5%. The following tables show the results:

[0300] Example 4

[0301] Solvent: Acetonitrile Example 4a

[0302] Irradiation of finerenone (4SI- 4-(4-Cvano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l .4-dihvdro-

[0303] 1,6-naphthyridine-3-carboxamide for the production of rac (4S. 4R1- 4-(4-Cyano-2-methoxyphenyll-5-ethoxy-

[0304] 2.8-dimethyl-1.4-dihvdro-1.6-naphthyridine-3-carboxamide (II

[0305] Equipment: Photo-loop reactor FT03, UV lamp Ql 023, Watson-Marlow 620s peristaltic pump (with GORE STA-PURE Pump Tubing built in) with 70 rpm, 2 thermostats at 50°C for reactor and receiver, N2 through receiver and lamp.

[0306] 21.16 g of S-Finerenone (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (> 99% ee) were dissolved in 2.5 L of acetonitrile (1949.99 g) and 51.30 g of DBU (6 equivalents) were added. The reaction was started by switching on the lamp, initially gassed with synthetic air (30% oxygen) for 30 min, and then kept under a constant nitrogen stream. After 5 h, synthetic air (30% oxygen) was introduced for another hour, and then a constant nitrogen stream was resumed. Total irradiation time: 16 h. A sample measurement of the reaction solution was taken after completion of the reaction: 12% ee, purity: 87%, concentration: 81%.

[0307] The reaction solution was then processed:

[0308] The reaction solution was concentrated to 150 mL. Then, 500 mL of water were added dropwise over 3 hours while stirring. A milky precipitate was observed upon addition of 200 mL. After 300 mL, the solution became cloudy. The mixture was stirred for 24 hours at room temperature (approx. 20°C). The suspension was filtered, and the product was washed with 100 mL of water. The product was dried for 72 hours at 45°C and 60 mbar.

[0309] Yield: 16.02 g (76% of theory) of a colorless crystalline powder (I rac (4S,4R)- 4-(4-Cyano-2- methoxyphenyl)-5 -ethoxy-2,8-dimethyl- 1 ,4-dihydro- 1 ,6-naphthyridin-3 -carbox-amide)

[0310] Analytics:

[0311] Solids content: 97.3%

[0312] Enantiomeric excess: 0.9%

[0313] Purity: 98.30 fl.% (HPLC)

[0314] Example 4b

[0315] Irradiation of the missing antiomer (Ib) (4R)- 4-(4-Cvano-2-methoxyr)henyl)-5-ethoxy-2.8-dimethyl-1.4-dihvdro-1.6-naphthyridine-3-carbox-amide to produce rac (4S. 4R1- 4-(4-Cvano-2-mctho\vphcnyl)-5- ethoxy-2.8-dimethyl-1.4-dihvdro-1.6-naphthyridine-3-carboxamide (II

[0316] In an analogous manner to that described in Example 4a, the missing enantiomer was irradiated and evaluated after the reaction was complete.

[0317] Equipment: Photoloop reactor, UV lamp TQ 150 (stage 1), Duran glass tube, circulation pump, thermostat (50 °C), layer thickness 5mm.

[0318] 2.13 g of the missing enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide were dissolved in 250 mL of acetonitrile (196.69 g) and 4.95 g (6 equivalents) of DBU were added. The reaction was started by switching on the lamp and flooded with synthetic air for 30 minutes. Afterward, the reaction was carried out under a constant nitrogen stream. Total irradiation time: 8.5 h. A sample measurement of the reaction solution was taken after completion of the reaction: 9% ee, purity: 91%, content: 91%. Example 4c

[0319] Irradiation of the missing enantiomer (Ibf - 4-(4-Cvano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l .4- dihvdro-1.6-naphthyridine-3-carbox-amide for the production of rac(4S.4R)-4-(4-Cvano-2-methoxyphenyl)-5-ethoxy-2.8-dimethyl-1.4-dihvdro-1.6-naphthyridine-3-carbox-amide (I)

[0320] In an analogous manner to that described in Example 4a, the missing enantiomer was irradiated and evaluated after the reaction was complete.

[0321] Equipment: Photoloop reactor, UV lamp TQ 150 (stage 1), Duran glass tube, circulation pump, thermostat (50 °C), layer thickness 5mm.

[0322] 2.11 g of the missing enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide were dissolved in 250 mL of acetonitrile (195 g) and 2.55 g (3 equivalents) of DBU were added. The reaction was started by switching on the lamp and flooded with synthetic air for 30 minutes. The reaction was then carried out under a constant nitrogen stream. Total irradiation time: 13 h.

[0323] A sample measurement of the reaction solution was taken after the reaction was completed: 10.7% ee , purity: 95.93%, content: 97%.

[0324] Example 4d

[0325] Irradiation of the missing enantiomer (Ib) (4R)- 4-(4-Cvano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide to prepare rac (4S, 4R)- 4-(4-Cvano-2-methoxyphenyl ' )-5-ethoxy-2.8-dimethyl-1.4-dihvdro-1.6-naphthyridine-3-carboxamide (II

[0326] In an analogous manner to that described in Example 4a, the missing enantiomer was irradiated and evaluated after the reaction was complete.

[0327] Equipment: Photoloop reactor, UV lamp TQ 150 (stage 1), Duran glass tube, circulation pump, thermostat (50 °C), layer thickness 5mm.

[0328] 2.15 g of the missing enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide were dissolved in 250 mL of acetonitrile (195 g) and 5.13 g (6 equivalents) of DBU were added. The reaction was started by switching on the lamp and flooded with synthetic air for 30 minutes. The reaction was then carried out under a constant nitrogen stream. Total irradiation time: 7 h 45 min. A sample measurement of the reaction solution was taken after completion of the reaction: 15% ee, purity: 95.4%, concentration: 97%.

[0329] Example 4e

[0330] Irradiation of the missing enantiomer (Ib) (4R)- 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2.8-dimethyl-1 .4- dihydro-1.6-naphthyridin-3-carbox-amide for the preparation of rac (4S. 4R)- 4-(4-Cyano-2-methoxyphenylB-5-ethoxy-2.8-dimethyl-1.4-dihydro-1.6-naphthyridin-3-carbox-amide (I) bi analogously as described in Example 4a, the missing enantiomer was irradiated and evaluated after completion of the reaction.

[0331] Equipment: Photoloop reactor, UV lamp TQ 150 (stage 1), Duran glass tube, circulation pump, thermostat (50 °C), layer thickness 5mm.

[0332] 2.12 g of the missing enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide were dissolved in 250 mL of acetonitrile (195 g) and 5.12 g (6 equivalents) of DBU were added. The reaction was started by switching on the lamp and flooded with synthetic air for 15 minutes. The reaction was then carried out under a constant nitrogen stream. Total irradiation time: 8 h 7 min.

[0333] A sample measurement of the reaction solution was taken after the reaction was completed: 12.6% ee, purity: 95.4%, content: 97.4%.

[0334] Example 4f

[0335] Irradiation of the missing enantiomer (Ib! (4R)- 4-(4-Cvano-2-metho\vphenyl)-5-ethoxy\v-2,8-dimethyl-1,4-dihydroxy-1,6-naphthyridine-3-carboxamide to prepare rac (4S. 4R1- 4-(4-Cvano-2-metho\vphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydroxy-1,6-naphthyridine-3-carboxamide (II

[0336] In an analogous manner to that described in Example 4a, the missing enantiomer was irradiated and evaluated after the reaction was complete.

[0337] Equipment: Photoloop reactor FT03, gap width 1.0 mm, UV lamp Q1023, Ismatec MCP-Z gear pump, 2.4 L / min flow rate, 2 thermostats at 50°C for reactor and receiving flask, nitrogen supplied through receiving flask and lamp. Nitrogen flow rate receiving flask: approx. 360 mL / min, adjustment of synthetic air to maintain a defined oxygen content of 0.5%. 10.62 g of the missing enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide were dissolved in 2.5 L of acetonitrile (1946.32 g) and 25.23 g (6 equivalents) of DBU were added. The reaction mixture was constantly fumigated with a stream of nitrogen and oxygen, with the oxygen content regulated to 0.5%. The reaction was started by switching on the lamp. After 6 hours, the irradiation was stopped and the mixture was stored overnight under nitrogen / oxygen at room temperature. Continued: After 8 hours, the irradiation was stopped and the mixture was stored overnight at room temperature under nitrogen / oxygen.Continued: Oxygen supply switched off after 2 hours. Stopped after 5 hours and the procedure concluded. Total irradiation time: 19.5 hours.

[0338] A sample measurement of the reaction solution was taken after the reaction was completed: 8.22% ee, purity: 91.47%.

[0339] Example 4g

[0340] Irradiation of the missing enantiomer - 4-(4-Cvano-2-methoxynhenyl-5-ethoxy-2,8-dimethyl-1,4- dihvdro-1.6-naphthyridine-3-carbox-amide for the production of rac(4S, 4R)-4-(4-Cvano-2-methoxyphenyl)-5-ethoxy-2.8-dimethyl-1.4-dihvdro-1.6-nar)hthyridine-3-carbox-amide (I)

[0341] In an analogous manner to that described in Example 4a, the missing enantiomer was irradiated and evaluated after the reaction was complete.

[0342] Equipment: Photoloop reactor FT03, gap width 1.0 mm, UV lamp Q1023, Watson-Marlow peristaltic pump, flow rate 4 L / min, 2 thermostats at 45°C for reactor and receiving chamber, nitrogen supplied through receiving chamber and lamp. Nitrogen flow rate to receiving chamber: approx. 500 mL / min, controlled addition of synthetic air to maintain a defined oxygen content of 18.0%.

[0343] 7.52 g of the missing enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide were dissolved in 2.5 L of acetonitrile (1952.7 g) and 18.1 g of DBU (6 equivalents) was added. The reaction mixture was initially fumigated for 30 minutes with a constant stream of synthetic air, the oxygen content being regulated to 18.6%.

[0344] After 30 minutes, the mixture was switched to pure nitrogen, and the oxygen content dropped to 0% within approximately 75 minutes. The reaction was started by switching on the lamp. Irradiation was stopped after 8.5 hours. Total irradiation time: 8.5 hours.

[0345] A sample measurement of the reaction solution was taken after the reaction was complete: 8.41% ee, purity: 89.66%. Example 4 h

[0346] Irradiation of the missing enantiomer - 4-(4-Cvano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1 .4- dihvdro-1.6-naphthyridine-3-carbox-amide for the production of rac (4S. 4R1- 4-(4-Cvano-2-methoxyphenyl)-5-ethoxy-2.8-dimethyl-1.4-dihvdro-1.6-naphthyridine-3-carbox-amide (II

[0347] In an analogous manner to that described in Example 4a, the missing enantiomer was irradiated and evaluated after the reaction was complete.

[0348] Equipment: Photoloop reactor FT03, gap width 1.0 mm, UV lamp Q1023, Watson-Marlow peristaltic pump, 4 L / min flow rate, 2 thermostats at 45°C for reactor and reservoir, nitrogen supplied through reservoir and lamp. Nitrogen flow rate in reservoir: approx. 500 mL / min, controlled addition of synthetic air to maintain a defined oxygen content of 17.0%. Start-up up to 30 minutes: oxygen content 16.7%. 30 minutes to 8 hours: oxygen content 0%.

[0349] 7.50 g of the missing enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide were dissolved in 2.5 L of acetonitrile (1951 g) and 17.4 g (6 equivalents) of DBU were added. The reaction mixture was initially fumigated with a constant stream of synthetic air for 30 minutes, with the oxygen content regulated to 16.7%. After 30 minutes, the gas supply was switched to pure nitrogen, and the oxygen content decreased to 0% within approximately 40 minutes. The reaction was initiated by switching on the lamp. Irradiation was stopped after 8 hours. Total irradiation time: 8 h.

[0350] A sample measurement of the reaction solution was taken after the reaction was completed: 4.08% ee purity: 87.55%.

[0351] Example 4i

[0352] Irradiation of the missing enantiomer (Ib) (4R)- 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2.8-dimethyl-1 .4- dihydro-1.6-naphthyridin-3-carbox-amide for the preparation of rac (4S. 4R)- 4-(4-Cyano-2-methoxyphenylB-5-ethoxy-2.8-dimethyl-1.4-dihydro-1.6-naphthyridin-3-carbox-amide (I) bi analogously as described in Example 4a, the missing enantiomer was irradiated and evaluated after completion of the reaction.

[0353] Equipment: FORAOl photoresist reactor, TLED 100 / 365nm UV lamp, thermostat set to 45°C for reactor and receiving flask, nitrogen and oxygen supplied through receiving flask and reactor. Nitrogen flow rate to receiving flask: approx. 300 mL / min, controlled supply of synthetic air to maintain a defined oxygen content of 18.0% or 0%. 3.41 g of the missing enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide were dissolved in 450 mL of ACN (350 g) and 8.2 g (6 equivalents) of DBU were added. The reaction mixture was initially aerated for 30 minutes with a constant flow of synthetic air, the oxygen content being regulated to 18.4%. After 30 minutes, the process was switched to pure nitrogen, and the oxygen content dropped to 0.4% within approximately 30 minutes. After 60 minutes, the oxygen content was 0.0%. Irradiation was stopped after 8 hours, and the reaction mixture was stored overnight at 20°C under nitrogen in the holding vessel.Total irradiation duration: 8 h.

[0354] A sample measurement of the reaction solution was taken after the reaction was completed: 9.45% ee, purity: 83.02%.

[0355] Example 5

[0356] Solvent: DMF (Dimethylformamide)

[0357] Example 5a

[0358] Irradiation of the missing antiomer (Ib) (4R)- 4-(4-Cvano-2-methoxyr)henyl)-5-ethoxy-2.8-dimethyl-1.4-dihvdro-1.6-nanhthyridine-3-carbox-amide to produce rac (4S. 4R1- 4-(4-Cvano-2-methoxyr>henyl!-5- ethoxy-2.8-dimethyl-1.4-dihvdro-1.6-nar)hthyridine-3-carboxamide (I)

[0359] In an analogous manner to that described in Example 4a, the missing enantiomer (Ib) was irradiated and evaluated after the reaction was complete.

[0360] Equipment: EVO photoreactor FoRA02 with falling film reactor and lamp TLED365 for 8 hours and lamp TQ2000 for 2 hours, each with quartz sheathing tube

[0361] 35.0 g of (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide (Ib) (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide were dissolved in 2500 ml of DMF (2350 g) and 84.5 g (6 equivalents) of DBU were added. The reaction mixture was transferred to the reactor and the thermostat was set to 45 °C. Synthetic air was introduced, resulting in an oxygen content of 18.2% in the reactor. The circulation pump was switched on and the flow rate was set to approximately 90 g / min. The temperature of the sample was set to 45°C and the temperature of the reactor to 44°C. Sampling was started to determine the oxygen content.

[0362] At t= 0 min, the lamp was ignited at 100% power; the oxygen content was 18%.

[0363] At t= 30 min, the system switches to nitrogen injection.

[0364] An oxygen sample is measured at t = 120 min, result: oxygen = 0.0%. An oxygen sample is measured at t = 240 min, result: oxygen = 0.0%.

[0365] An oxygen sample is measured at t = 420 min; result: oxygen = 0.0%

[0366] Afterwards, the lamp, thermostat, and pump were switched off. The nitrogen injection continued overnight. Then, the system was converted to the TQ2000 lamp for further irradiation.

[0367] After restarting, another oxygen sample was measured; result: oxygen = 0.0%

[0368] Then the lamp and the pump were switched off and the experiment was ended.

[0369] A sample measurement of the reaction solution was taken after the reaction was completed: 3.45% ee, purity: 94.54%

[0370] Example 5b

[0371] Irradiation of the missing enantiomer - 4-(4-Cvano-2-methoxyr)henylI-5-ethoxy-2,8-dimethyl-L4- dihvdro-1.6-naphthyridine-3-carbox-amide for the production of rac(4S.4R)-4-(4-Cvano-2-metho\vphenyl)-5-ethoxy-2.8-dimethyl-1.4-dihvdro-1.6-nat)hthyridine-3-carbox-amide

[0372] In an analogous manner to that described in Example 4a, the missing enantiomer was irradiated and evaluated after the reaction was complete.

[0373] The kinetics of the reaction were investigated.

[0374] Equipment: Large photoloop reactor, UV lamp Ql 023, 100% power (U=150V, λ=6.8), quartz cladding tube, Duran immersion finger, 2 thermostats @ 50°C, Watson-Marlow 620s peristaltic pump (with integrated GORE STA-PURE pump tubing) at 70 rpm, reactor inner wall checked and cleaned before preparation. Nitrogen passed through the lamp and receiver.

[0375] 40.54 g of (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide (Ib) were added to 2.0 F (1881.52 g) of DMF, followed by the addition of 95.84 mF (6 equivalents, 95.91 g) of DBU. The mixture was then degassed in an ultrasonic bath for 10 minutes. This reaction mixture was then transferred to a storage vessel (under nitrogen) and rinsed with 0.7 F DMF (696.95 g). Equilibration was then carried out for 15 minutes under nitrogen at a flow rate of 120 F / h. The reaction was initiated by switching on the UV lamp. Over the weekend, the reaction solution was drained and rinsed with 400 mF DMF (372.19 g). The reaction was then continued. Total irradiation time: 34 h. The following table shows the result of the racemization over 34 h:

[0376] Example 6

[0377] Solvent mixture: Acetonitrile / Acetone = 19:1 Irradiation of the missing enantiomer - 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4- dihydro-1,6-naphthyridin-3-carbox-amide for the preparation of rac (4S. 4R1- 4-(4-Cvano-2- methoxyphenyll-5-ethoxy-2,8-dimethyl- 1,4-dihydro- 1,6-naphthyridin-3 -carbox-amide (II In an analogous manner as described in Example 4a, the missing enantiomer was irradiated and evaluated after completion of the reaction.

[0378] Equipment: Photoloop reactor, UV lamp TQ 150 (stage 1), Duran, circulation pump, thermostat (50 °C), layer thickness 5 mm. 2.12 g of (4R)-4-(4-Cvano-2-methophenyl)-5-etho-2,8-dimethyl-1,4-dihydroxydro-1,6-naphthyridine-3-carboxamide dissolved in 237.5 mL (190.08 g) acetonitrile and 12.5 mL (9.48 g) acetone and 4.89 g (6 equivalents) DBU were added. The reaction was started by switching on the lamp and initially maintained under a constant nitrogen flow. After 6 hours and 40 minutes of reaction time, the collection vessel was aerated for 10 minutes. The nitrogen flow was shut off after 7 1 / 2 minutes to 8 hours and again from 9 hours and 30 minutes to 13 1 / 0 minutes of reaction time. Between and after these phases, the reaction was carried out under a constant nitrogen flow. The total irradiation time was 16 hours and 10 minutes.

[0379] A sample measurement of the reaction solution was taken after the reaction was complete: 9% ee, purity: 90%, content: 90%. Example 7

[0380] Solvent: Acetone

[0381] Irradiation of the missing enantiomer (Ib) (4R- 4-(4-Cvano-2-methoxyr)henyl)-5-ethoxy-2,8-dimethyl-

[0382] 1,4-dihvdro-1,6-naphthyridine-3-carboxamide for the preparation of rac (4S. 4R1- 4-(4-Cvano-2- methoxyphenyll-5-ethoxy-2,8-dimethyl- 1,4-dihvdro- 1,6-naphthyridine-3 -carboxamide (II In an analogous manner as described in Example 4a, the missing enantiomer was irradiated and evaluated after completion of the reaction.

[0383] Devices:

[0384] Large photoloop reactor, UV lamp Ql 023, 100% power (U=150V, 1=6.8), quartz cladding tube, Duran immersion finger, 2 thermostats @ 50°C, Watson-Marlow 620s peristaltic pump (with integrated GORE STA-PURE pump tubing) at 70 rpm, reactor inner wall checked and cleaned before preparation. Nitrogen passed through the reactor and receiver.

[0385] 20.50 g of the missing enantiomer (4R-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ib)) were added to 2.0 L (1564.06 g) of acetone, followed by the addition of 48.28 mL (6 equivalents, 47.75 g) of DBU. The mixture was degassed in an ultrasonic bath for 10 min. It was then transferred to a storage vessel (under nitrogen) and rinsed with 0.6 L of acetone (591.01 g). Equilibration was then carried out under nitrogen for 15 min at a flow rate of 120 L / h. The reaction was initiated by switching on the UV lamp. The total irradiation time was 12 h.

[0386] The following table shows the result of the racemization over 12 hours:

[0387] 5

[0388] Example 8

[0389] Preparation of rac(I)(4S.4R)-4-(4-Cvano-2-methoxyDhenyl)-5-ethoxy-2.8-dimethyl-1.4-dihvdro-1.6-naphthyridine-3-carbox-amide from pyridine derivative Equipment: Photoloop reactor, UV lamp TQ 150 (new lamp), M282 sheathing tube, circulation pump, thermostat (50 °C), layer thickness 5 mm. Lamp checked before experiment. Argon set to minimum via gas regulator. UV / VIS reaction monitoring: 1 mm flow cuvette installed between pump outlet and reactor inlet. Ocean Optics FLAME spectrometer, deuterium / halogen light source.

[0390] 3.75 g of pyridine derivative (II) were dissolved in 250 mL of acetone and degassed in an ultrasonic bath for 15 minutes. The reaction mixture is a clear, yellow solution. It was then placed in the reactor in the storage vessel and kept under argon (flow rate 500 mL / min). The reaction mixture was then heated to 50 °C and equilibrated under argon for 30 minutes. 9 mL (9.18 g, 6 equivalents) of DBU were then added under argon (DBU was stored under nitrogen). The reaction mixture is a clear, yellowish solution. Irradiation was then started. After 5 h 34 min, the lamp was switched off after a plateau was observed in the UV. 2 equivalents of DBU (3 mL) were then added while the reaction continued. The total irradiation time was 6 h.

[0391] Result:

[0392] Rac-(I)rac-(4S,4R)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide: Purity: 91.4% (HPLC)

[0393] Pyridine derivative (II): 1.5%

[0394] Example 9

[0395] Reproducibility of the irradiation approaches

[0396] Similarly to Example 4a, several trials with different quantities and different solvents (acetone and acetonitrile) were conducted. The concentration was approximately 1%, and 6 equivalents of DBU were used in each trial.

[0397] The products obtained after water precipitation were dried and then recrystallized from brandy (or ethanol). The crystallization was carried out as follows: For example:

[0398] 30 g of racemate (I), obtained after work-up (concentration of the reaction solution, water precipitation, isolation and drying), was added to 600 ml of brandy, the suspension then subjected to weak reflux (Ti nnenThe solution was heated to approximately 75°C; a yellow solution formed at an internal temperature of approximately 57°C. It was stirred for 30 minutes at this temperature. The solution was then filtered through a P4 frit coated with diatomaceous earth (soaked with 50 ml of brandy) and washed with 50 ml.

[0399] The brandy was distilled under reduced pressure, reducing the volume to approximately five times. Crystallization began towards the end of the distillation, yielding a readily stirrable, pale yellow suspension. The mixture was allowed to cool to 23°C. It was stirred overnight at an internal temperature of 23°C. Subsequently, it was cooled to an internal temperature of 2°C and stirred for two hours at this temperature. The crystallizate was isolated using a 45 mm P3 frit and washed once with 45 ml of brandy at cold temperatures.

[0400] Drying was carried out in a vacuum drying oven at 50°C with nitrogen-filled air at approximately 100 mbar. The following table summarizes the results.

[0401] Example 10

[0402] Production of finerenone from recycled rac product (I) from Example 4a (4SI-4-(4-Cvano-2-methoxythenyl)-5-ethoxy-2.8-dimethyl-1.4-dihvdro-l.6-naDhthyridin-3-carboxamide

[0403] Example 10a

[0404] (+)OQ-Dibenzoyl tartrate salt Production of (4SI- 4-(4-Cvano-2- 2.8- 14.3 g of the title compound from Example 4a (I) were placed in 127.1 g of spirit and 53.7 g of water were added. Then 7.4 g of (+)-0,0-dibenzoyl-D-tartaric acid were added. The slightly yellowish suspension was heated to an internal temperature of 75 °C within one hour (bath temperature was 82–85 °C) and stirred at this temperature for three hours. The oil bath was turned off and cooled to an internal temperature of 22 °C within approximately five hours, and stirred overnight at this temperature (if the stirrer was stopped, the crystallizate settled quite rapidly). The suspension was isolated via a P4 frit (50 ml) and washed once with a mixture of 15.5 g brandy and 6.5 g water: wet yield: 23.2 g. It was dried overnight in a vacuum drying oven at 50°C and < 100 mbar under nitrogen.

[0405] Yield: 14.0 g tartrate salt (IVa) of (4S)- 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4- dihydro-l,6-naphthyridin-3-carboxamide (Ia)

[0406] Analytics:

[0407] Purity > 98% (HPLC)

[0408] Enantiomeric excess: 96.42% ee

[0409] Example 10b

[0410] (4SI-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2.8-dimethyl-1.4-dihydro-1.6-naphthyridine-3-carboxamide. raw

[0411] 13.00 g of the compound from Example 10a were suspended in 104.0 g of water, and then 20.5 g of ethanol, dehydrated (brandy), were added. The pH was adjusted to 4.0. Within one hour, the mixture was heated to an internal temperature of 50°C and a bath temperature of 60–62°C. Within approximately 30 minutes, the pH was adjusted to 7.3 using a sodium phosphate solution (100 g Na₃PO₄ / 1 L water). The mixture was then stirred for 60 minutes at an internal temperature of 50°C and adjusted to 7.5 using a sodium phosphate solution (100 g Na₃PO₄ / 1 L water). Stirring continued for 180 minutes at an internal temperature of 50°C. The oil bath was then turned off and allowed to cool. Stirring continued overnight at an internal temperature of 23°C. The crystallizate was isolated via a 50mm P3 frit and washed once with a mixture of 4.0 g ethanol and 20.4 g water and then twice with 21 g water each time.

[0412] Moisture yield: 7.6 g. Drying was carried out in a vacuum drying oven at 50°C with nitrogen-enriched air overnight.

[0413] Yield: 6.3 g of the title compound. Analysis:

[0414] Purity > 99.21% (HPLC)

[0415] Enantiomeric excess: 97.21% ee Example 10c

[0416] (4SI- 4-(4-Cvano-2- 2.8-dimcthyl-l .4-dihvdro- 1.6-naphthyridine-3-carbo\-amide. pure (Ial

[0417] 5.0 g of the compound from Example 10b was added to 100 ml of denatured toluene ethanol (20-fold). The suspension was heated to slight reflux, with an internal temperature of 75°C and a bath temperature of approximately 90–92°C. The solution was fully dissolved at an internal temperature of approximately 70°C. It was stirred for one hour at this temperature. The solvent was then distilled off under slight vacuum (bath temperature 40°C) and concentrated to approximately 5-fold (approximately 25 ml). It was stirred overnight at room temperature, then cooled to an internal temperature of 1–2°C and stirred for approximately two hours at this temperature. The crystallizate was isolated using a 30 mm P4 frit and washed twice with 5 ml of cold denatured toluene ethanol each time.

[0418] Moisture yield: 5.2 g

[0419] Drying took place overnight in a vacuum drying oven at 80°C under nitrogen with ambient air <100mbar

[0420] Yield: 4.4 g of the title compound

[0421] Analysis: Purity > 99.62% (HPLC)

[0422] Enantiomeric excess: 99.45% ee

Claims

Patent claims 1. Method for the preparation of racemic (4 R,4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) (I), from the enantiomers of formulas (Ia) and / or (Ib) comprehensive the step (i): (i) Irradiation of the enantiomers of formulas (Ia) and / or (Ib) with light in a suitable solvent or solvent mixture in the presence of a base, wherein the irradiation in step (i) optionally takes place at a temperature of 0°C to 100°C.

2. Method according to claim 1, wherein the irradiation with light in step (i) takes place at a temperature of 30°C to 70°C.

3. A method according to claim 1 or 2, wherein the solvent or solvent mixture in step (i) is selected from the group consisting of dichloromethane, acetone, toluene, Tetrahydrofuran, methanol, 4-methyl-2-pentanone, methyl ethyl ketone, cyclohexanone, acetonitrile, dimethylformamide, dimethyl sulfoxide and mixtures thereof.

4. Method according to any one of claims 1 to 3, wherein the concentration range of the enantiomer used in step (i) in the solvent or solvent mixture is 0.05% to 10% (w / V) based on the volume of the solvent or solvent mixture.

5. A method according to any one of claims 1 to 4, wherein the base in step (i) is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, tributylamine, 1,4-diazabicyclo(2.2.2)octane, 4-(dimethylamino)pyridine, TBD, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, tetramethylguanidine, N,N,N,N-tetramethyl-1,8-naphthalenediamine, lutidine, pyridine, imidazole, N-methylimidazole, phosphazene and their derivatives Mixtures.

6. Method according to any one of claims 1 to 5, wherein the irradiation in step (i) is carried out for a duration of 1 hour to 40 hours.

7. Method for the preparation of (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of Lormel (Ia) (Ia), comprising steps (ii), (iii) and (iv): (ii) Irradiation of the Lormel joint (Ib) in a suitable solvent or solvent mixture in the presence of a base with light, the compound of formula (Ib) is converted into a racemic compound of formula (I) (I), is transferred, (iii) Resolution of this racemic compound (I) from step (ii) with a chiral tartaric acid ester of formula (III) (III), in a brandy-water mixture, wherein the diastereomeric salt (IVa) is formed, and (iv) Treating the diastereomeric salt (IVa) from step (iii) with a base, forming the compound of formula (Ia).

8. Method according to claim 7, wherein the irradiation in step (ii) takes place at a temperature of 0°C to 100°C.

9. A method according to one of claims 7 or 8, wherein the solvent or solvent mixture in step (ii) is selected from the group consisting of dichloromethane, acetone, toluene, tetrahydrofuran, methanol, 4-methyl-2-pentanone, methyl ethyl ketone, cyclohexanone, acetonitrile, dimethylformamide, dimethyl sulfoxide and mixtures thereof.

10. Method according to any one of claims 7 to 9, wherein the concentration range of the enantiomer used in step (ii) in the solvent or solvent mixture is 0.05% to 10% (w / V) based on the volume of the solvent or solvent mixture.

11. A method according to any one of claims 7 to 10, wherein the base in step (ii) is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, tributylamine, 1,4-diazabicyclo(2.2.2)octane, 4-(dimethylamino)pyridine, TBD, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, tetramethylguanidine, N,N,N,N-tetramethyl-1,8-naphthalenediamine, lutidine, pyridine, imidazole, N-methylimidazole, phosphazene and mixtures thereof.

12. Method according to any one of claims 7 to 11, wherein the irradiation in step (ii) is carried out for a duration of 1 hour to 40 hours.

13. Method for the preparation of racemic (4 R,4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) (I), from the pyridine of formula (II) (II), encompassing the step (vi): (vi) Irradiation of the compound of formula (II) with light in a suitable solvent, or solvent mixture, in the presence of a base, wherein the compound of formula (I) is formed.

14. The method of claim 13, wherein the irradiation in step (vi) is carried out at a temperature of 0°C to 100°C and / or wherein the irradiation in step (vi) is carried out for a duration of 1 hour to 40 hours.

15. The method of claim 13 or 14, wherein the solvent or solvent mixture in step (vi) is selected from the group consisting of dichloromethane, acetone, toluene, tetrahydrofuran, methanol, 4-methyl-2-pentanone, methyl ethyl ketone, cyclohexanone, acetonitrile, dimethylformamide, dimethyl sulfoxide and mixtures thereof, and / or wherein the base in step (iv) is selected from the group consisting of l,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, tributylamine, l,4-diazabicyclo(2.2.2)octane, 4-(dimethylamino)pyridine, TBD, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 7-methyl-l,5,7-triazabicyclo[4.4.0]dec-5-ene, tetramethylguanidine, N,N,N,N-tetramethyl-l,8-naphthalenediamine, lutidine, pyridine, imidazole, N-methylimidazole, Phosphazene and its mixtures.