Photochemical method for preparing (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

Abstract

The present invention relates to a process for preparing 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); a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia); a process for preparing 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 pyridine of formula (II). The objects of the present invention have in common that compounds of formula (Ia), (Ib), and / or (II) are irradiated with light in a suitable solvent or solvent mixture in the presence of a base. Compounds of formula (Ia), (Ib), and / or (II) are intermediates, by-products, or target compounds in the synthesis of finerenone (a compound according to formula (Ia)).

Description

[Technical Field]

[0001] The present invention relates to a compound of formula (I) [ka] from enantiomer Ia or Ib, comprising the steps of: Step (i): (i) reacting a compound of formula (Ia) and / or (Ib) in a suitable solvent or solvent mixture and in the presence of a base [ka] irradiating the enantiomer of The present invention relates to a method, comprising:

[0002] The present invention further provides a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), comprising the steps of: Steps (ii), (iii), and (iv): (ii) in a suitable solvent or solvent mixture, in the presence of a base, [ka] wherein said compound of formula (Ib) is irradiated with light to form a compound of formula (I): [ka] step of converting the compound into a racemic compound of (iii) Formula (III) [ka] a step of optical resolution of this racemic compound (I) from step (ii) in a spirit / water mixture using the chiral tartaric acid ester of the formula: [ka] is formed, and (iv) treating the diastereomeric salt (IVa) from step (iii) with a base to form the compound of formula (Ia). The present invention relates to a method, comprising:

[0003] The present invention also relates to a compound of formula (I) [ka] racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, Formula (II) [ka] from pyridine of the formula: Step (vi): (vi) irradiating said compound of formula (II) with light in a suitable solvent or solvent mixture in the presence of a base, to form said compound according to formula (I). The present invention relates to a method, comprising:

[0004] Thus, the objects of the present invention have in common that a compound of formula (Ia), (Ib), and / or (II) is irradiated with light in a suitable solvent or solvent mixture in the presence of a base (see steps (i), (ii), or (vi)). The compounds of formula (Ia), (Ib), and / or (II) are intermediates, by-products, or target compounds in the synthesis of finerenone (a compound according to formula (Ia)). When referring to a compound according to formula (I), this refers to racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, or the compound of formula (I) shown below: [ka] This refers to the racemic compound

[0005] Reference herein to "finerenone," "a compound according to formula (Ia)," "enantiomer (Ia)," or "enantiomer (Ia)" refers to (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, or the compound according to formula (Ia) [ka] means a compound according to

[0006] Reference to "enantiomeric compound (Ib)", "enantiomer (Ib)", "enantiomer (Ib)", "wrong enantiomer" or "wrong enantiomer (Ib)" refers to rac-(4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, or the compound of formula (Ib) shown below: [ka] means a compound according to

[0007] When reference is made to "enantiomers of compounds according to formula (I)", this means compounds of formula (Ia) and (Ib) as defined above.

[0008] When referring to "spirits," this means denatured ethanol.

[0009] The abbreviation "h" stands for "hours." Finerenone (Ia) acts as a nonsteroidal antagonist of the mineralocorticoid receptor and can be used as a drug for preventing and / or treating cardiovascular and renal disorders, such as heart failure and diabetic nephropathy. [Background technology]

[0010] Compounds of formula (Ia) and methods for their preparation are described in WO 2008 / 104306 and ChemMedChem 2012, 7, 1385, and also in WO 2016 / 016287. To access compounds of formula (Ia) and (Ib), a racemic mixture of amides (I) [ka] must be separated into the enantiomers of formula (Ia) and (Ib), since only the enantiomer of formula (Ia) is pharmacologically active. [ka]

[0011] In published research-scale syntheses, N-(dicyclopropylmethyl)-N 2A specially synthesized chiral phase containing -methacryloyl-D-leucine amide was used for this purpose (prepared in-house). It was found that separations could also be carried out with readily available commercially available phases: Chiralpak® AS-V phase, 20 μm. The eluent used was a 60:40 mixture of methanol / acetonitrile. In this case, chromatography can be carried out on conventional chromatography columns, but preferably techniques known to those skilled in the art, such as SMB or Varicol® (Computers and Chemical Engineering 27 (2003) 1883-1901), are used.

[0012] The compound of formula (Ia) and methods for its preparation are described in WO 2008 / 104306 and ChemMedChem 2012, 7, 1385, and also in WO 2016 / 016287, both of which disclose detailed discussions of research synthesis.

[0013] In the publication ChemMedChem 2012, 7, 1385, which discloses a research-scale synthesis of the compound of formula (Ia), the compound of formula (Ia) is prepared in 10 steps starting from vanillin with an overall yield of 3.76% of theoretical.

[0014] To access compounds of formula (Ia), the racemic mixture of amides rac-(I) must be separated into the enantiomers of formulas (Ia) and (Ib). In published research-scale syntheses, N-(dicyclopropylmethyl)-N 2A specially synthesized chiral phase containing methacryloyl-D-leucine amide was used for this purpose (prepared in-house). This selector was prepared in a multi-step process and then polymerized on a special silica gel. Methanol / ethyl acetate served as the eluent. A major drawback of this method was the very low loading of 30 mg per separation on a 500 x 63 mm chromatography column. Therefore, there was a strong need to find a separation method as efficient as possible that would enable the separation of enantiomers in the multiton range. International Publication WO 2008 / 104306 demonstrates that separation can also be performed using readily available commercially available phases. This is a 20 μm Chiralpak AS-V phase. The eluent used was a 60:40 mixture of methanol / acetonitrile. This mixture has the great advantage that it can be recovered as an eluent with the same composition (60:40, corresponding to an azeotrope) after distillation workup. In this way, a highly efficient process is achieved, with a separation yield of more than 47% of the theoretical value (50% is theoretically possible). The optical purity here is greater than 93% ee, preferably greater than 98.5% ee. Chromatography can be performed using conventional chromatography columns, 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 racemic amide rac-(I) was isolated using an SMB system, achieving a 48% yield. The product is obtained as a 3-8%, preferably 5-7%, solution in a 30:70 mixture of methanol and acetonitrile and can be used directly for "final processing."

[0015] Here, for example, when referring to a 3% solution, this means that 3 g of compound is dissolved in 100 mL of solvent.

[0016] In solvent ratio diagrams, the ratios are volume to volume (v / v). For example, a solvent mixture consisting of 30:70 methanol / acetonitrile contains 30 ml of methanol and 70 ml of acetonitrile. Therefore, the volumes are based on the total volume of the solvent.

[0017] Other solvent mixtures of acetonitrile and methanol are also contemplated (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 separations. The specific solvent ratio will depend in part on the technical characteristics of the SMB system and must be adjusted accordingly (e.g., changing flow rates, recycling solvent in thin-film evaporators). [ka]

[0018] As well as the target compound finerenone (Ia), the enantiomeric compound (Ib) is obtained in virtually the same yield. [Prior art documents] [Patent documents]

[0019] [Patent Document 1] International Publication No. 2008 / 104306 Brochure [Patent Document 2] International Publication No. 2016 / 016287 Brochure [Non-patent literature]

[0020] [Non-Patent Document 1] ChemMedChem 2012, 7, 1385 [Non-patent document 2] Computers and Chemical Engineering 27(2003)1883~1901 Summary of the Invention [Means for solving the problem]

[0021] In summary, the present invention relates to: (1) Formula (I) [ka] from enantiomer Ia or Ib, comprising the steps of: Step (i): (i) irradiating said enantiomers of formula (Ia) and / or (Ib) in the presence of a base in a suitable solvent or solvent mixture a method comprising: (2) A method for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), comprising the steps of: Steps (ii), (iii), and (iv): (ii) irradiating a compound of formula (Ib) with light in a suitable solvent or solvent mixture in the presence of a base, wherein said compound of formula (Ib) is converted into the racemic compound of formula (I), (iii) optical resolution of the racemic compound (I) from step (ii) in a spirit / water mixture using a chiral tartaric acid ester of formula (III), in which the diastereomeric salt (IVa) is formed; and (iv) treating the diastereomeric salt (IVa) from step (iii) with a base to form the compound of formula (Ia). a method comprising: (3) A process for preparing 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 pyridine of formula (II), comprising the steps of: Step (vi): (vi) irradiating said compound of formula (II) with light in a suitable solvent or solvent mixture in the presence of a base, to form said compound according to formula (I). A method comprising:

[0022] Thus, the objects of the present invention have in common that compounds of formula (Ia), (Ib), and / or (II) are irradiated with light in a suitable solvent or solvent mixture in the presence of a base (see steps (i), (ii), or (vi)). Compounds of formula (Ia), (Ib), and / or (II) are intermediates, by-products, or target compounds in the synthesis of finerenone (a compound according to formula (Ia)). In summary, the method according to the invention provides, inter alia, the following advantages and technical effects:

[0023] The wrong enantiomer (Ib) can be converted into the target compound finerenone (Ia) in a simple manner, which is cost-effective, since it is not necessary to destroy the wrong enantiomer (Ib) in order to resubmit the racemic mixture to enantiomer separation by SMB as described above or optical resolution using, for example, (+)-dibenzoyltartaric acid, but rather by converting the compound of formula (Ib) into the racemic mixture of formula (I), this undesired by-product can be used in the synthesis of finerenone.

[0024] It is no longer necessary to carry out several complex steps, as described in the prior art: instead of three process steps (as in the case of the electrochemical method described for example in WO 2017032678), a simplified procedure is arrived at, which under mild conditions (light) leads directly to the racemization of the wrong enantiomer (Ib), thus giving the racemate (I).

[0025] Depending on the batch size, the reaction (see steps (i), (ii), or (vi)) may be carried out in batch mode or as a flow process. Thus, the reaction can be easily adjusted to suitable industrial conditions in a simple manner.

[0026] Starting from the wrong enantiomer (Ib), yields of the racemate (I) of 50% to 75% of the theoretical value are achieved, with very high chemical purity, up to 99.1% (HPLC, area), possible. The enantiomeric excess is less than 1% to 2%. The racemate (I) thus obtained can be successfully used in subsequent racemate resolution methods, whether SMB or optical resolution with dibenzoyltartaric acid, meeting the required specifications in terms of purity and enantiomeric excess.

[0027] Starting from the pyridine derivative (II), yields of the racemate (I) of 60% to 90% of theoretical are achieved. Chemical purity is very high, with purities of up to >95% (HPLC, area) being possible. Enantiomeric excesses are less than 1% to 2%. The material thus obtained can be successfully used in subsequent racemate resolution methods, whether SMB or optical resolution using dibenzoyltartaric acid, meeting the required specifications in terms of purity and enantiomeric excess.

[0028] The novel process according to the invention is characterized by high efficiency in terms of yield and chemical purity. Since light is used as the actual "reagent", the process is environmentally friendly. Since photoreactors in flow processes have long been used in industry, the process is scalable to industrial scale, i.e., no special equipment is required, in contrast to the electrochemical methods mentioned above. Therefore, this novel process according to the invention offers enormous economic advantages over the prior art. DETAILED DESCRIPTION OF THE INVENTION

[0029] The present invention relates to a compound of formula (I) [ka] racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide was reacted with enantiomers Ia or Ib [ka] by irradiation with light at temperatures between 0°C and 100°C in the presence of a base in a suitable solvent or solvent mixture.

[0030] In the context of the present invention, compounds of formula (I) [ka] racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide was reacted with enantiomers Ia or Ib [ka] and 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, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, methyl methyl ketone ...

[0033] The preferred method is to prepare the compound by irradiation with light at a temperature of 0°C to 100°C in the presence of a base selected from the group consisting of methyl methyl guanidine, 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-naphthalenediamine, lutidine, pyridine, imidazole, N-methylimidazole, and phosphazene, wherein 1 to 20 equivalents of an organic base are used.

[0031] In the context of the present invention, racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) is prepared by dissolving enantiomers Ia or Ib in a suitable solvent or solvent mixture selected from the group comprising acetone, acetonitrile, dimethylformamide, and dimethylsulfoxide, or mixtures thereof, in a concentration range of 0.05% to 10%. and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, 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, in which 2 to 15 equivalents of an organic base are used.

[0032] In the context of the present invention, compounds of formula (I) [ka] racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide was reacted with enantiomers Ia or Ib [ka] in acetone, acetonitrile, or a mixture thereof, in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo(4.3.0)non-5-ene at a concentration ranging from 0.05% to 10%, by irradiation with light at a temperature of 40°C to 60°C, wherein 5 to 12 equivalents of an organic base are used.

[0033] The present invention also relates to a compound of formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ib) [ka] is converted into a compound of formula (I) by irradiation with light in the presence of a base in a suitable solvent or solvent mixture. [ka] and the racemic compound is converted to a racemic compound of formula (III) [ka] The diastereomeric salt (IVa) was first obtained by optical resolution in a spirit / water mixture using the chiral tartrate of [ka] and then treating this diastereomeric salt (IVa) with a base and removing the solvent.

[0034] Optical resolution may also give the wrong enantiomer (Ib), which may be carried out as described below. In a previously unpublished method, instead of irradiation as used in accordance with the present invention, tartaric acid esters are used, which are now described as follows: for industrial-scale operation, (+)-dibenzoyltartaric acid (III) is used for the optical resolution of (I); both the anhydrous form and the hydrate can be used. [ka]

[0035] The compound of formula (IV) in the previously unpublished method described herein is identical to compound (IVa) of the present invention. The optical resolution is preferably carried out in a spirit / water mixture. In this case, the wrong enantiomer (Ib) remains in the mother liquor and can be isolated for reuse.

[0036] Subsequent release of finerenone (Ia, crude) [ka] is preferably carried out in a spirit / water mixture using sodium phosphate as the base. If reprocessing is required, if the proportion of (+)-dibenzoyltartaric acid (III) is greater than 0.1%, [ka] The reworking is preferably carried out in a spirit / water mixture using sodium phosphate as the base. The final crystallization to obtain pure finerenone (Ia) is preferably carried out using spirit as the solvent.

[0037] The wrong enantiomer (Ib) is isolated from the mother liquor by adjusting the combined mother liquor and washings to pH 7.5 with aqueous sodium phosphate at room temperature. The spirits are then substantially distilled off under reduced pressure (85-65 mbar, internal temperature 38-20°C) and the mixture is reduced to the specified final volume. The mixture is cooled to room temperature, and the precipitated suspension is stirred at 20-22°C. The suspension is filtered off and washed twice with water. The wet product is dried overnight (approximately 16 hours) at 50°C under reduced pressure (<100 mbar). The yield of (Ib) is generally greater than 80% of the theoretical value, based on the racemate (I) used.

[0038] For economic reasons, it was not necessary to destroy this enantiomer of formula (Ib), but it was necessary to devise a method that would allow the conversion of compounds of formula (Ib) into the racemic mixture of formula (I) in order to subject the compounds of formula (Ib) to another enantiomeric separation by SMB, as described above, or to optical resolution using, for example, (+)-dibenzoyltartaric acid.

[0039] In contrast to this racemization using tartaric acid esters, the method according to the invention involves irradiation, which has now surprisingly been found to be achieved by irradiating the wrong enantiomer (Ib) with light in a solvent or solvent mixture in the presence of a base and in the presence of oxygen. [ka]

[0040] This is also achieved by converting finerenone (Ia). [ka]

[0041] For example, attempts to directly racemize compounds of formula (Ib) by treating compound (Ib) with a strong base or strong acid have been unsuccessful, and reaction with transition metal complexes, such as palladium or iridium catalysts, has also not produced the desired results.

[0042] The prior art (WO 2017032678) describes a two-step electrochemical method, in which first a chemical or electrochemical oxidation to pyridine (aromatization of the dihydropyridine) is carried out, followed by an electrochemical reduction. The drawback of this electrochemical method is that it must be carried out in three steps. Thus, direct oxidation (chemical or electrochemical) of the wrong enantiomer (Ib) leads to the optically enriched (due to atropisomerism) pyridine derivative (II), [ka] This is equilibrated to the racemate by heat treatment in a second step and then reduced to the racemate (I) in a third step.

[0043] There is extensive literature on the photochemistry of dihydropyridine derivatives, for example, 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; D.G.Whitten, Y.J.Lee, J.Am.Chem.Soc.1971, 93, 961 - 966; T.J.van Bergen, R.M.Kellogg, J.Am.Chem.Soc 1972, 94, 8451 - 8471; R.Leuschner, J.K.Dohrmann, Journal of Photochemistry 1986, 33, 321 - 331; D.G.Whitte, Y.J.Lee, J.Am.Chem.Soc 1971, 93, 961 - 966; T.J.van Bergen, R.M.Kellogg, J.Am.Chem.Soc 1972, 94, 8451 - 8471; T.J.van Bergen, R.M.Kellogg, J.Am.Chem.Soc 1972, 94, 8451 - 8471; R.Leuschner, J.K.Dohrmann, Journal of Photochemistry 1986, 33, 321 - 331; T.J.van Bergen, R.M.Kellogg, J.Am.Chem.Soc 1972, 94, 8451 - 8471; Jacques Joussot-Dubien, Josette Houdard, Tetrahedron Letters, Volume 8, Number 44, 1967, pp. 4389 - 4391; Journal of Magnetic Resonance (1969), Volume 27, Number 3, September 1977, pp. 371 - 384; Tetrahedron, Volume 28, Number 24, 1972, pp. 5911 - 5921; R.Leuschner, K.Dohrmann, Journal of Photochemistry, Vol. 33, No. 3, June 1986, pp. 321-331; Junko Shibuya, Mami Nabeshima, Hajime Nagano, and Koko Maeda, J.Chem.Soc., Perkin Trans.2, 1988, pp. 1607-1612; Zhong-Li Liu, Chem.Commun., 1998, pp. 2451-2452; Al-Jalal, Molecules, June 30, 2016; 21(7); T.J. Van Bergen and Richard M. Kellogg, Journal of the American Chemical Society 1972, pp. 94 (24), 8451-8471; Tetrahedron Letters, Vol. 10, No. 59, 1969, pp. 5211-5214; Molecules 2016, 21, 866; Hindawi Publishing Corporation International Journal of Photochemistry, Vol. 2014, Article ID 176989, p. 4, http: / / dx.doi.org / 10.1155 / 2014 / 176989; Photochemistry and Photobiology, 2007, 83, 722-729; J.Org.Chem., 2006, 71 (5), pp. 2037-2045; Monatshefte fur Chemie 2002, 133, 661; International Journal of Photoenergy 2015, Article ID 454895.

[0044] Direct racemization by irradiation with light is novel in the method according to the present invention and has not been known so far for chiral dihydropyridine derivatives.

[0045] Therefore, there was a strong need to achieve a simplified method which, instead of three processing steps (as in the electrochemical method), would directly result in the racemization of the wrong enantiomer (Ib) and thus to the racemate (I) under mild conditions (light). This is achieved by the novel method of the present invention.

[0046] It was surprising for those skilled in the art that the wrong enantiomer (Ib) and finerenone (Ia) could not be isomerized by reaction with a strong base, i.e. racemization was not possible. Surprisingly, as has been found in the process according to the invention, this is only possible by combining a base in the presence of oxygen, irradiation with light and the selection of a suitable solvent. [ka]

[0047] Organic bases have proven particularly suitable, and particular mention may be made here 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, phosphazenes. Particular preference is given to 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, and 1,5,7-triazabicyclo[4.4.0]dec-5-ene, and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, with 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicyclo(4.3.0)non-5-ene being very particularly preferred.

[0048] 1 to 20 equivalents, preferably 2 to 15 equivalents, particularly preferably 5 to 12 equivalents of the organic base are used.

[0049] 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 or acetone / tetrahydrofuran. Acetone, acetonitrile, dimethylformamide, and dimethyl sulfoxide are particularly preferred. Acetone and acetonitrile are very particularly preferred. The procedure is carried out in a concentration range of 0.05% to 10%, depending on the solvent. Here, for example, when a concentration range of 0.05% is mentioned, this means that 0.05 g is dissolved in 100 mL.

[0050] Irradiation is carried out at temperatures between 0°C and 100°C depending on the solvent. However, the preferred temperature range is between 30°C and 70°C. 40°C to 60°C is preferred.

[0051] The irradiation time is between 1 hour and 40 hours and is highly dependent on the solvent and base used.

[0052] In some cases, depending on the solvent selected, it may be advantageous to optionally add a photosensitizer: for this purpose, anthracene, rose bengal, eosin Y, DMPA, benzoquinone, benzophenone, acetophenone, fluorene, xanthone, benzene, N-bromosuccinimide, Ru(bpy)3, or Ru-porphyrin may be used.

[0053] As radiation sources, Hg lamps or LEDs can also be used. The use of UV filters has proven to be advantageous, in particular the Duran® filter from 282 nm (cut-off below 300 nm) UV filter.

[0054] Depending on the batch size, the reaction can be carried out in batch mode or as a flow process.

[0055] Photochemical racemization proceeds as a one-pot reaction, where synthetic air is passed through the mixture for 0.5 to 5 hours during the first irradiation step. Alternatively, synthetic air can be introduced initially without irradiation. If air is introduced without irradiation, irradiation is then carried out for 0.5 to 5 hours. For the second step of the one-pot reaction, irradiation is then carried out again under inert conditions (replacement of traces of oxygen by introducing nitrogen or argon). The reaction can be monitored by removing samples and examining their respective optical purities.

[0056] At the end of the reaction, the desired racemate (I) is worked up and isolated as follows: First, the solvent is distilled off to a constant volume under normal or reduced pressure, and a certain amount of water is added (see the Examples for the ratio). The ratio varies depending on the solvent or solvent mixture used. In this case, the racemate (I) precipitates and is then isolated by filtration or centrifugation, followed by drying. Drying is preferably carried out under reduced pressure at temperatures between 40 and 80 °C. Depending on the quality, the obtained product can be further processed directly (SMB separation or optical resolution using dibenzoyltartaric acid). However, a final crystallization for the desired purification can also be performed. Suitable solvents for this purpose are ethanol, isopropanol, methanol, acetonitrile, and tetrahydrofuran, each optionally in combination with water.

[0057] Starting from the wrong enantiomer (Ib), the yield of the racemate (I) achieved is 50%-75% of the theoretical value. The chemical purity is very high, with purities of up to 99.1% (HPLC, area) possible. The enantiomeric excess is less than 1%-2%. The racemate (I) thus obtained can be successfully used in subsequent racemate resolution methods, whether SMB or optical resolution with dibenzoyltartaric acid, meeting the required specifications in terms of purity and enantiomeric excess.

[0058] In addition to the above-described method, i.e., the direct conversion of (Ib) to (I) in a one-pot process, it has surprisingly been found that the racemic form of compound (I) can be obtained by photochemical reduction of the corresponding pyridine compound (II), which is obtained by chemical or electrochemical oxidation (see WO2017032678) starting from the racemate or optically enriched compound, by irradiation in a suitable solvent or solvent mixture in the presence of a base. [ka]

[0059] The present invention also relates to a compound of formula (I) [ka] racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (II) [ka] from pyridine of formula (I) in a suitable solvent or solvent mixture in the presence of a base by irradiation with light.

[0060] In the context of the present invention, compounds of formula (I) [ka] racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula II [ka] pyridine to 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, triethylamine, diisopropylethylamine, trimethylamine, tripropylamine, tributylamine in a concentration range of 0.05% to 10% 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 , 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, by irradiation with light at a temperature of 0°C to 100°C, wherein 1 to 20 equivalents of an organic base are used.

[0061] In the context of the present invention, racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) is reacted with pyridine of formula II in a suitable solvent or solvent mixture selected from the group comprising acetone, acetonitrile, dimethylformamide, and dimethylsulfoxide, or mixtures thereof, in a concentration range of 0.05% to 10%. A method for preparing the compound by irradiation with light at a temperature of 30°C to 70°C 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 an organic base are used, is preferred.

[0062] In the context of the present invention, compounds of formula (I) [ka] racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (II) [ka] in acetone, or acetonitrile, or a mixture thereof, in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo(4.3.0)non-5-ene at a concentration ranging from 0.05% to 10% by irradiation with light at a temperature of 40°C to 60°C, wherein 5 to 12 equivalents of an organic base are used.

[0063] Organic bases have proven particularly suitable, and particular mention may be made here 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, phosphazenes. Particular preference is given to 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo(4.3.0)non-5-ene, and 1,5,7-triazabicyclo[4.4.0]dec-5-ene, and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, with 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicyclo(4.3.0)non-5-ene being very particularly preferred.

[0064] 1 to 20 equivalents, preferably 2 to 15 equivalents, particularly preferably 5 to 12 equivalents of the organic base are used.

[0065] 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 or acetone / tetrahydrofuran. Acetone, acetonitrile, dimethylformamide, and dimethyl sulfoxide are particularly preferred. Acetone and acetonitrile are very particularly preferred. The operation is carried out at a concentration range of 0.05% to 10%, depending on the solvent.

[0066] Irradiation is carried out at temperatures between 0°C and 100°C depending on the solvent, however the preferred temperature range is between 30°C and 70°C.

[0067] The irradiation time is 1 to 40 hours, and is preferably 10 to 20 hours, depending largely on the solvent and base used. In one embodiment, irradiation is carried out for 6 to 40 hours. In one embodiment, the irradiation time is 6 to 35 hours. In one embodiment, the irradiation time is 6 to 20 hours. In one embodiment, the irradiation time is 6 to 15 hours. In one embodiment, the irradiation time is 6 to 10 hours. In one embodiment, the irradiation time is 6 to 9 hours. In one embodiment, the irradiation time is 8 to 20 hours. In one embodiment, the irradiation time is 6 to 34 hours.

[0068] In some cases, depending on the solvent selected, it may be advantageous to optionally add a photosensitizer: for this purpose, anthracene, rose bengal, eosin Y, DMPA, benzoquinone, benzophenone, acetophenone, fluorene, xanthone, benzene, N-bromosuccinimide, Ru(bpy)3, or Ru-porphyrin may be used.

[0069] Mercury lamps or LEDs can also be used as radiation sources. The use of UV filters has been used to advantage, and in particular the Duran filter (cutoff below 300 nm) UV filter from 282 nm has proven to be effective.

[0070] Depending on the batch size, the reaction can be carried out in batch mode or as a flow process.

[0071] At the end of the reaction, the desired racemate (I) is worked up and isolated as follows: The solvent is distilled off to a constant volume under normal or reduced pressure, and a certain amount of water is added (see the Examples for the ratio). The ratio varies depending on the solvent or solvent mixture used. In this case, the product precipitates and can be isolated by filtration or centrifugation, followed by drying. Drying is preferably carried out under reduced pressure at temperatures between 30°C and 80°C, preferably between 40°C and 60°C. Depending on the quality, the obtained product can be further processed directly (SMB separation or optical resolution using dibenzoyltartaric acid). However, a final crystallization for the desired purification can also be carried out. Suitable solvents for this purpose are ethanol, isopropanol, methanol, acetonitrile, and tetrahydrofuran, each optionally in combination with water.

[0072] Starting from the pyridine derivative (II), yields of the racemate (I) of 60% to 90% of theoretical are achieved. Chemical purity is very high, with purities of up to >95% (HPLC, area) being possible. Enantiomeric excesses are less than 1% to 2%. The material thus obtained can be successfully used in subsequent racemate resolution methods, whether SMB or optical resolution using dibenzoyltartaric acid, meeting the required specifications in terms of purity and enantiomeric excess.

[0073] However, in addition to this novel method starting from the pyridine derivative (II), the one-pot method starting from (Ib) is particularly preferred.

[0074] The novel method according to the present invention is characterized by high efficiency in terms of yield and chemical purity. Since light is used as the actual "reagent," the method is environmentally friendly. Since photoreactors in flow processes have long been used in industry, the method is scalable to industrial scale, i.e., no special equipment is required, in contrast to electrochemical methods. Therefore, the novel method according to the present invention offers enormous economic advantages over the prior art.

[0075] Paragraphs 1.~9. Further embodiments of the present invention are described in paragraphs 1 to 9 below.

[0076] 1. Formula (I) [ka] racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide was reacted with enantiomers Ia or Ib [ka] by irradiation with light in the presence of a base in a suitable solvent or solvent mixture.

[0077] 2. Formula (I) [ka] racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide was reacted with enantiomers Ia or Ib [ka] from 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-dimethyl-2-pentanone, methyl ethyl ketone, cyclohexanone, acetonitrile, dimethylformamide, dimethyl sulfoxide, or a mixture thereof, in a concentration range of 0.05% to 10%. 10. The method of paragraph 1, wherein the compound is prepared by irradiation with light at a temperature between 0° C. and 100° C. in the presence of a base selected from the group consisting of 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 to 20 equivalents of an organic base are used.

[0078] 3. Racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) is reacted with enantiomers Ia or Ib in a suitable solvent or solvent mixture selected from the group consisting of acetone, acetonitrile, dimethylformamide, and dimethyl sulfoxide, or mixtures thereof, at a concentration ranging from 0.05% to 10% with 1,8-dihydro-1,6-naphthyridine-3-carboxamide. 3. The method of paragraph 1 or 2, wherein the compound is prepared by irradiation with light at a temperature between 30° C. and 70° C. in the presence of a base selected from the group consisting of azabicyclo[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 an organic base are used.

[0079] 4. Formula (I) [ka] racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide was reacted with enantiomers Ia or Ib [ka] in acetone, or acetonitrile, or a mixture thereof, in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo(4.3.0)non-5-ene at a concentration ranging from 0.05% to 10% by irradiation with light at a temperature between 40° C. and 60° C., wherein 5 to 12 equivalents of an organic base are used.

[0080] 5. (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ia) [ka] A method for preparing a compound of formula (Ib) [ka] is converted into a compound of formula (I) by irradiation with light in the presence of a base at a temperature between 0°C and 100°C in a suitable solvent or solvent mixture. [ka] and the racemic compound is converted to a racemic compound of formula (III) [ka] The diastereomeric salt (IVa) was first obtained by optical resolution in a spirit / water mixture using the chiral tartrate of [ka] and then treating the diastereomeric salt (IVa) with a base and removing the solvent.

[0081] 6. Formula (Ia) [ka] 6. The process according to paragraph 5 for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ib): [ka] is obtained by irradiation of a compound of formula (I) in a suitable solvent or solvent mixture selected from the group including acetone, acetonitrile, dimethylformamide, and dimethyl sulfoxide, or a mixture thereof, at a concentration ranging from 0.05% to 10% in the presence of a base selected from the group including 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, at a temperature between 30°C and 70°C. [ka] wherein 2 to 15 equivalents of an organic base are used; This racemic compound is represented by formula (III) [ka] The diastereomeric salt (IVa) was first obtained by optical resolution in a spirit / water mixture using the chiral tartaric acid ester of [ka] and then treating the diastereomeric salt (IVa) with sodium phosphate and removing the solvent.

[0082] 7. (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ia) [ka] 7. The method of paragraph 5 or 6, for preparing a compound of formula (Ib) [ka] is obtained by irradiation of acetone, acetonitrile, or a mixture thereof at a concentration ranging from 0.05% to 10% in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo(4.3.0)non-5-ene with light at a temperature ranging from 40°C to 60°C. [ka] wherein 5 to 12 equivalents of an organic base are used, This racemic compound is represented by formula (III) [ka] The diastereomeric salt (IVa) was first obtained by optical resolution in a spirit / water mixture using the chiral tartaric acid ester of [ka] and then treating the diastereomeric salt (IVa) with sodium phosphate and removing the solvent.

[0083] 8. Formula (I) [ka] racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (II) [ka] from pyridine of formula (I) in a suitable solvent or solvent mixture in the presence of a base by irradiation with light.

[0084] 9. Formula (I) [ka] racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (II) [ka] in acetone, or acetonitrile, or a mixture thereof, in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo(4.3.0)non-5-ene at a concentration ranging from 0.05% to 10% by irradiation with light at a temperature between 40° C. and 60° C., wherein 5 to 12 equivalents of an organic base are used.

[0085] Paragraphs (1)~(42) Further embodiments of the present invention are described in paragraphs (1) to (42) below.

[0086] (1) Formula (I) [ka] racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, Formula (Ia) and / or (Ib) [ka] from the enantiomer of Step (i): (i) irradiating said enantiomers of formula (Ia) and / or (Ib) with light in a suitable solvent or solvent mixture in the presence of a base; wherein said irradiation in step (i) is optionally carried out at a temperature between 0°C and 100°C.

[0087] (2) The method of paragraph (1), wherein the irradiation with light in step (i) is carried out at a temperature between 30°C and 70°C.

[0088] (3) The method of paragraph (1) or (2), wherein the irradiation with light in step (i) is carried out at a temperature of 40°C to 60°C.

[0089] (4) The method of 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.

[0090] (5) The method of 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, dimethylsulfoxide, and mixtures thereof.

[0091] (6) The method of 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.

[0092] (7) The method of any one of paragraphs (1) to (6), wherein the concentration range of the enantiomer used in the solvent or solvent mixture in step (i) is 0.05% to 10% (m / v) based on the volume of the solvent or solvent mixture.

[0093] (8) The method of 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.

[0094] (9) The method of any one of paragraphs (1) to (8), wherein 1 to 20 equivalents of an organic base are used in step (i).

[0095] (10) The method of any one of paragraphs (1) to (9), wherein 2 to 15 equivalents of an organic base are used in step (i).

[0096] (11) The method of any one of paragraphs (1) to (10), wherein 5 to 12 equivalents of an organic base are used in step (i).

[0097] (12) The method of any one of paragraphs (1) to (11), wherein the irradiation in step (i) is carried out for a period of 1 hour to 40 hours.

[0098] (13) The method of any one of paragraphs (1) to (12), wherein the irradiation in step (i) is carried out for a period of 10 hours to 20 hours.

[0099] (14) Formula (Ia) [ka] 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Steps (ii), (iii), and (iv): (ii) in a suitable solvent or solvent mixture, in the presence of a base, [ka] wherein said compound of formula (Ib) is irradiated with light to form a compound of formula (I): [ka] step of converting the compound into a racemic compound of (iii) Formula (III) [ka] a step of optical resolution of this racemic compound (I) from step (ii) in a spirit / water mixture using the chiral tartaric acid ester of the formula: [ka] is formed, and (iv) treating the diastereomeric salt (IVa) from step (iii) with a base to form the compound of formula (Ia). A method comprising:

[0100] (15) Step (v): (v) Removal of the solvent or the solvent mixture The method of paragraph (14), further comprising:

[0101] (16) The method of paragraph (14) or (15), wherein the irradiation in step (ii) is carried out at a temperature ranging from 0°C to 100°C.

[0102] (17) The method of 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.

[0103] (18) The method of any one of paragraphs (14) to (17), wherein the irradiation with light in step (ii) is carried out at a temperature of 40°C to 60°C.

[0104] (19) The method of 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.

[0105] (20) The method of 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.

[0106] (21) The method of 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.

[0107] (22) The method of any one of paragraphs (14) to (21), wherein the concentration range of the enantiomer used in the solvent or solvent mixture in step (ii) is 0.05% to 10% (m / v) based on the volume of the solvent or solvent mixture.

[0108] (23) The method of 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 mixtures thereof.

[0109] (24) The method of any one of paragraphs (14) to (23), wherein 1 to 20 equivalents of an organic base are used in step (ii).

[0110] (25) The method of any one of paragraphs (14) to (24), wherein 2 to 15 equivalents of an organic base are used in step (ii).

[0111] (26) The method of any one of paragraphs (14) to (25), wherein 5 to 12 equivalents of an organic base are used in step (ii).

[0112] (27) The method of any one of paragraphs (14) to (26), wherein the irradiation in step (ii) is carried out for a period of 1 hour to 40 hours.

[0113] (28) The method of any one of paragraphs (14) to (27), wherein the irradiation in step (ii) is carried out for a period of 6 hours to 35 hours.

[0114] (29) Formula (I) [ka] racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, Formula (II) [ka] from pyridine of the formula: Step (vi): (vi) irradiating said compound of formula (II) with light in a suitable solvent or solvent mixture in the presence of a base, to form said compound according to formula (I). A method comprising:

[0115] (30) The method according to paragraph (29), wherein the irradiation in step (vi) is carried out at a temperature of 0°C to 100°C.

[0116] (31) The method according to paragraph (29) or (30), wherein the irradiation with light in step (vi) is carried out at a temperature of 30°C to 70°C.

[0117] (32) The method of any one of paragraphs (29) to (31), wherein the irradiation with light in step (vi) is carried out at a temperature of 40°C to 60°C.

[0118] (33) The method of 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.

[0119] (34) The method of 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.

[0120] (35) The method of 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.

[0121] (36) The method of any one of paragraphs (29) to (35), wherein the concentration range of the enantiomer used in the solvent or solvent mixture in step (vi) is 0.05% to 10% (m / v) based on the volume of the solvent or solvent mixture.

[0122] (37) The method of any one of paragraphs (29) to (36), wherein the base in step (vi) 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.

[0123] (38) The method of any one of paragraphs (29) to (37), wherein 1 to 20 equivalents of an organic base are used in step (vi).

[0124] (39) The method of any one of paragraphs (29) to (38), wherein 2 to 15 equivalents of an organic base are used in step (vi).

[0125] (40) The method of any one of paragraphs (29) to (39), wherein 5 to 12 equivalents of an organic base are used in step (vi).

[0126] (41) The method of any one of paragraphs (29) to (40), wherein the irradiation in step (vi) is carried out for a period of 1 hour to 40 hours.

[0127] (42) The method of any one of paragraphs (29) to (41), wherein the irradiation in step (vi) is carried out for a period of 10 hours to 20 hours. [Example]

[0128] experiment

[0129] [Table 1]

[0130] The following table shows the structures of the compounds recovered by HPLC. The HPLC retention time assignments are shown below. table

[0131] [Table 2A] [Table 2B]

[0132] 1) Analytical methods for confirming the content of impurities and enantiomeric purity at the dibenzoyltartaric acid stage

[0133] [Table 3]

[0134] [Table 4]

[0135] 2) Analytical methods for confirming the content of impurities and enantiomeric purity at the diastereomeric salt stage

[0136] [Table 5]

[0137] [Table 6]

[0138] 3) Analytical method for confirming the content of impurities and enantiomeric purity at the stage of crude finerenone (Ia)

[0139] [Table 7]

[0140] [Table 8]

[0141] Enantiomeric Purity Method B RT(min) RRT Finerenone (Ia) 5.7 1.00 Enantiomer (Ib) 6.8 1.19 Instrument / Detector: High-performance liquid chromatograph with temperature-controlled column oven, UV detector, and data evaluation system Measurement wavelength: 252nm Oven temperature: 40°C Column: Chiralpak IC Length: 150 mm, inner diameter: 4.6 mm, particle size: 3 μm Mobile phase: A: 50% buffer solution 20mM NH4OAc acetate pH 9 B: 50% acetonitrile Flow rate: 1ml / min Elution time: 8 minutes Equilibration: Not required, isocratic Sample solvent: eluent Sample solution: Approximately 0.5 mg / ml of racemic material dissolved in the sample solvent Comparison solution: Prepare a comparison solution similar to the sample solution. Injection volume: 10 μl

[0142] All measurements given in the following examples for enantiomer determination were determined by Method B. Some values, particularly those from batches prepared in a pilot plant, were reanalyzed by Method A for comparison, with comparable results.

[0143] The HPLC analytical data shown in the following examples regarding the purity and content of the final product, pure finerenone (Ia), only relates to the impurity present in the product in an amount greater than 0.05%. This is essentially impurity E. All other impurities shown in the tables listed above are generally less than 0.05%. The structure of such impurities was determined by isolation from concentrated mother liquor. The following equipment was used in the examples:

[0144] Oxygen measuring device An oxygen measurement device from "pyro science sensor technology" was used, the "Firesting O2" model, which uses fiber optics and optional logging to measure and store oxygen content.

[0145] Reactor For screening tests (up to 1000 ml reaction volume), small self-built systems from Peschl Ultraviolett equipped with reactors and accessories were initially used. Similarly, larger initial approaches (1000 ml to 2500 ml reaction volumes) were carried out in self-built systems, also from Peschl Ultraviolett, equipped with components from various manufacturers. Screening and larger batches were then carried out in compact reaction plants from Peschl Ultraviolett.

[0146] To carry out the individual batches, either a batch reactor or a side loop reactor and a falling film reactor were used.

[0147] UV lamp For each batch, low-pressure mercury vapor lamps and LED lamps manufactured by Peschl Ultraviolet were used: TQ 150 (150 W output), TQ 1000 (1000 W), and TQ 2000 (2000 W), as well as LED lamps (40 W output) with wavelengths of 365 nm and 405 nm. The low-pressure mercury vapor lamp (TQ XXX HG) produced light in the spectral range of 260–600 nm.

[0148] "Filters" and glass holders for lamps Each UV lamp was mounted in a glass holder made of clear quartz or Duran glass, which filters out light below 310 nm.

[0149] synthetic air Synthetic air mixtures of 20% oxygen / 80% nitrogen and 30% oxygen / 70% nitrogen were used.

[0150] For even lower oxygen content, synthetic air was diluted with nitrogen.

[0151] The wrong enantiomer (Ib) used in the photochemical recycling process can be obtained, on the one hand, by optical resolution by SMB separation on a chiral stationary phase (using an acetonitrile / methanol eluent mixture, e.g., 70:30, and e.g., a Phase Chiralpak AS-V, 20 μm) (see WO 2016 / 016287), or, on the other hand, by optical resolution using (+)-O,O-dibenzoyl-D-tartaric acid.

[0152] Since the enantiomers (Ia) and (Ib) do not differ in their photochemical properties, both compounds were used in some cases because the results were reversible. Therefore, photochemical recycling was developed using both enantiomers, with the aim of large-scale racemization of the corresponding wrong enantiomer (Ib).

[0153] Example 1 Laboratory batch using anhydrous (+)-O,O-dibenzoyl-D-tartaric acid(III)

[0154] Example 1a Preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ia) tartrate (IVa) 250 g (660.616 mmol) of racemic (I) (rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide) was first added to 3500 mL of ethanol denatured with 75:25 (v / v) toluene / water at room temperature (approximately 23°C). 130.2 g (363.339 mmol) of (+)-O,O-dibenzoyl-D-tartaric acid (III) was added using a solids funnel, followed by a rinse with 250 mL of ethanol (denatured with toluene) / 75:25 (v / v) water. The resulting suspension was heated to an internal temperature of 75°C over 0.75 hours and then stirred at this temperature for 3.0 hours. The mixture was then cooled to 23°C over 5.0 hours using a cooling gradient and then stirred at this temperature overnight (approximately 16 hours). The suspension was filtered off on a frit and rinsed once with 250 ml of a mixture of ethanol (denatured with toluene) / water = 75:25 (v / v). Wet yield: 334.7 g. The wet product was then dried under reduced pressure (less than 100 mbar) at 50°C overnight (approximately 16 hours). Yield: 250.2 g (100.08% of theory) of a colorless crystalline powder. Analysis results:

[0155] [Table 9]

[0156] MS (Method 1C): m / z = 379 [M] + ; 11H-NMR (400 MHz, DMSO-d6): δ = 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 (broad signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (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 DMSO solvent and elevated water signal: δ = 2.5 - 2.6, and small peaks at δ = 3.40 - 3.50 (q) and δ = 1.05 - 1.10 (t), superimposed signal from residual ethanol solvent.

[0157] Example 1b Preparation of crude (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ia) At room temperature, 248 g of compound (IVa) prepared in Example 1a was suspended in 2480 ml of a mixture consisting of ethanol (denatured with toluene) and water at a ratio of 20:80 (v / v) (pH was measured to be pH = 4). Then, 819.6 g of aqueous sodium phosphate solution (100 g of sodium phosphate dissolved in 1000 ml of water) was added dropwise over 60 minutes to adjust the pH to 7.2. The mixture was stirred at 23 °C for an additional 50 minutes (pH = 7.1). Then, 98.3 g of aqueous sodium phosphate solution (100 g of sodium phosphate dissolved in 1000 ml of water) was added dropwise over 10 minutes to adjust the pH to 7.5. The mixture was heated to an internal temperature of 50 °C over 1 hour and stirred at this temperature for 3.0 hours. The mixture was cooled to 22 °C over 1 hour and stirred at this temperature for another hour. The crystals are filtered off on a frit and washed once with 200 ml of a mixture of ethanol (denatured with toluene) / water = 20:80 (v / v), once with 100 ml, and twice with 200 g of water. Wet yield: 263.4 g. The wet product was then dried at 50 ° C over the weekend (more than 48 h) under reduced pressure (less than 100 mbar). Yield: 116.9 g of a colorless crystalline powder (93.52% of theory). Analysis results:

[0158] [Table 10]

[0159] MS (Method 1C): m / z = 379 [M] + ; 1H-NMR (400 MHz, DMSO-d6):δ = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m (broad signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H) and signal from DMSO solvent and significantly enhanced water signal:δ = 2.5-2.6, and a very small peak at δ = 3.38 (not assignable).

[0160] Example 1c Preparation of pure product (Ia) of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 116.0 g of crude product (Ia) prepared in Example 1b was suspended in 2330 ml of ethanol (modified with toluene) and then heated to reflux. Upon heating, the product dissolved. Stirring was continued at this temperature for 1 hour. The solution was filtered through a heated pressure filter (T=75°C), and the pressure filter was then rinsed with 30 ml of ethanol (modified with toluene). The solvent was then distilled off (approximately 1920 ml was distilled off) until the final volume was approximately four times larger (based on the material used: 116 g x 4 = approximately 484 ml). The mixture was then cooled to an internal temperature of 23°C (over approximately 1.5-2 hours). The mixture was then stirred at an internal temperature of 3°C for 2 hours. The product was filtered off and rinsed once with 100 ml of ethanol (modified with toluene). Wet yield: 124 g. The wet product was dried at 50°C over the weekend (more than 48 hours) under reduced pressure (less than 100 mbar). Yield: 112.6 g (97.07% of theory) of a colorless crystalline powder (fine needles). Analysis results:

[0161] [Table 11]

[0162] MS (Method 1C): m / z = 379 [M] + ; 1 H-NMR (400 MHz, DMSO-d6):δ = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m (broad signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H) and small signals from DMSO solvent and water at δ = 2.5-2.6 and a very small peak at δ = 3.38 (not assignable) Variant: Mod A (as defined in WO 2016 / 016287)

[0163] Example 1d Isolation of the wrong enantiomer (Ib) from the mother liquor of (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide At room temperature, the combined mother liquor and wash solution from Example 1a (approximately 3750 ml of a yellowish solution, pH=4.5) was adjusted to pH=7.5 by adding 101.1 g of aqueous sodium phosphate (100 g dissolved in 1 L of water). Under reduced pressure (85-65 mbar, internal temperature 38-20°C), the spirits were then substantially distilled off, and the mixture was reduced to a final volume of approximately 0.85 L. The mixture was cooled to room temperature, and the precipitated suspension was stirred over the weekend (more than 48 h) and then at 22°C for a further 2 h. The suspension was filtered off with suction and washed twice with 200 ml of water each time. Wet yield: 139.1 g. The wet product was dried overnight (approximately 16 h) at 50°C under reduced pressure (less than 100 mbar). Yield: 103.1 g (82.48% of theory, based on the racemate (I) used in Example 1a).

[0164] [Table 12]

[0165] Example 2 Photochemistry start-up experiment Influence of solvent (screening experiment to select 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 with an LED at 365 nm for 10 minutes in a solvent or solvent mixture (see table). Two equivalents of DBU were used. The concentration was approximately 1.5%. The results are shown in the table below. At the start, a surprisingly large amount of pyridine compound (II) was found.

[0166] [Table 13]

[0167] [Table 14]

[0168] Example 3 Photochemistry start-up experiment Effect of bases (screening experiments to select optimal bases) 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 with an LED at 365 nm in acetone for 10 minutes. Two equivalents of base were used. The concentration was approximately 1.5%. The results are shown in the table below.

[0169] [Table 15]

[0170] Example 4 Solvent: Acetonitrile

[0171] Example 4a Irradiation of finerenone (Ia) (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide for the preparation of rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Equipment: Optical loop reactor FT03, UV lamp Q1023, Watson-Marlow 620s peristaltic pump at 70 rpm (with integrated GORE® STA-PURE® pump tubing), two 50°C thermostats for reactor and receiver, N2 passed through receiver and lamp. 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) was dissolved in 2.5 L of acetonitrile (1949.99 g) and 51.30 g (6 equivalents) of DBU was added. The reaction was initiated by switching on the lamp and gassing first with synthetic air (30% oxygen) for 30 minutes, then under a constant nitrogen flow. After 5 hours, synthetic air (30% O2) was introduced for another hour, then the constant nitrogen flow was adjusted again. Total irradiation time: 16 hours. After the reaction was complete, a sample of the reaction solution was measured: 12% ee, purity: 87%, content: 81%.

[0172] The reaction solution was then worked up.

[0173] The reaction solution was concentrated to 150 mL. Then, 500 mL of water was added dropwise with stirring over 3 hours. After 200 mL had been added, a milky precipitate was observed. After 300 mL, the solution became cloudy. The mixture was stirred at room temperature (approximately 20°C) for 24 hours. The suspension was filtered, and the product was washed with 100 mL of water. The product was dried at 45°C and 60 mbar for 72 hours. Yield: 16.02 g (76% of theory) of colorless crystalline powder (Irac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide) analysis: Solids: 97.3% Enantiomeric excess: 0.9% Purity: 98.30 area% (HPLC)

[0174] Example 4b Irradiation of the wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide for the preparation of rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Similarly, the wrong enantiomer was irradiated and evaluated after the reaction was complete, as described in Example 4a. Equipment: optical loop reactor, UV lamp TQ 150 (stage 1), Duran glass tube, circulation pump, thermostat (50°C), layer thickness of 5 mm. The wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (2.13 g) was dissolved in 250 mL of acetonitrile (196.69 g) and 4.95 g of DBU (6 equivalents) was added. The lamp was switched on to start the reaction, and the solution was flooded with synthetic air for 30 minutes. The reaction was then placed under a constant nitrogen flow. Total irradiation time: 8.5 hours. After the reaction was complete, a sample of the reaction solution was measured: 9% ee, purity: 91%, content: 91%.

[0175] Example 4c Irradiation of the wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide for the preparation of rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Similarly, the wrong enantiomer was irradiated and evaluated after the reaction was complete, as described in Example 4a. Equipment: optical loop reactor, UV lamp TQ 150 (stage 1), Duran glass tube, circulation pump, thermostat (50°C), layer thickness of 5 mm. The wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (2.11 g) was dissolved in 250 mL of acetonitrile (195 g) and 2.55 g of DBU (3 equivalents) was added. The reaction was initiated by switching on the lamp, and the solution was flooded with synthetic air for 30 minutes. The reaction was then placed under a constant nitrogen flow. Total irradiation time: 13 hours. After the reaction was completed, the sample measurement of the reaction solution was measured: 10.7% ee, purity: 95.93%, content: 97%.

[0176] Example 4d Irradiation of the wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide for the preparation of rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Similarly, the wrong enantiomer was irradiated and evaluated after the reaction was complete, as described in Example 4a. Equipment: optical loop reactor, UV lamp TQ 150 (stage 1), Duran glass tube, circulation pump, thermostat (50°C), layer thickness of 5 mm. The wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (2.15 g) was dissolved in 250 mL of acetonitrile (195 g) and 5.13 g of DBU (6 equivalents) was added. The reaction was started by switching on the lamp and filling the solution with synthetic air for 30 minutes. The reaction was then placed under a constant nitrogen flow. Total irradiation time: 7 hours 45 minutes. After the reaction was completed, the sample measurement of the reaction solution was measured: 15% ee, purity: 95.4%, content: 97%.

[0177] Example 4e Irradiation of the wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide for the preparation of rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Similarly, the wrong enantiomer was irradiated and evaluated after the reaction was complete, as described in Example 4a. Equipment: optical loop reactor, UV lamp TQ 150 (stage 1), Duran glass tube, circulation pump, thermostat (50°C), layer thickness of 5 mm. The wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (2.12 g) was dissolved in 250 mL of acetonitrile (195 g) and 5.12 g of DBU (6 equivalents) was added. The reaction was initiated by switching on the lamp and filling the solution with synthetic air for 15 minutes. The reaction was then placed under a constant nitrogen flow. Total irradiation time: 8 hours 7 minutes. After the reaction was completed, the sample measurement of the reaction solution was measured: 12.6% ee, purity: 95.4%, content: 97.4%.

[0178] Example 4f Irradiation of the wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide for the preparation of rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Similarly, the wrong enantiomer was irradiated and evaluated after the reaction was complete, as described in Example 4a. Equipment: Optical loop reactor FT03, slit width 1.0 mm, UV lamp Q1023, Ismatec MCP-Z gear pump, flow rate 2.4 L / m, two 50 °C thermostats for the reactor and receiver, nitrogen flow through the receiver and lamp. Nitrogen flow receiver: approximately 360 mL / min, adjusted to a specified oxygen content of 0.5% by controlling synthetic air. 10.62 g of the wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide was dissolved in 2.5 L of acetonitrile (1946.32 g) and 25.23 g of DBU (6 equivalents) was added. The reaction mixture was continuously gassed with a nitrogen / oxygen stream, where the oxygen content was controlled at 0.5%. The lamp was switched on to start the reaction. After 6 hours, the irradiation was stopped and the solution was stored overnight under nitrogen / oxygen at RT. Continued: After 8 hours, the irradiation was stopped and the solution was stored overnight under nitrogen / oxygen at RT. Continued: After 2 hours, the oxygen control was switched off. After 5 hours, the batch was stopped and completed. Total irradiation time: 19.5 hours. After the reaction was completed, a sample of the reaction solution was measured: 8.22% ee, purity: 91.47%.

[0179] Example 4g Irradiation of the wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide for the preparation of rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Similarly, the wrong enantiomer was irradiated and evaluated after the reaction was complete, as described in Example 4a. Equipment: Optical loop reactor FT03, slit width 1.0 mm, UV lamp Q1023, Watson-Marlow peristaltic pump, flow rate 4 L / min, two 45°C thermostats for the reactor and receiver, nitrogen flow through the receiver and lamp. Nitrogen flow receiver: approximately 500 mL / min, adjusted to a specified oxygen content of 18.0% by controlling the synthetic air. The wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (7.52 g) was dissolved in 2.5 L of acetonitrile (1952.7 g) and 18.1 g of DBU (6 equivalents) was added. The reaction mixture was first gassed continuously with synthetic air for 30 minutes, where the oxygen content was controlled at 18.6%. After 30 minutes, this was switched to pure nitrogen, and the oxygen content dropped to 0% within approximately 75 minutes. The lamp was switched on to start the reaction. After 8.5 hours, the irradiation was stopped. Total irradiation time: 8.5 hours. After the reaction was completed, a sample of the reaction solution was measured: 8.41% ee, purity: 89.66%.

[0180] Example 4h Irradiation of the wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide for the preparation of rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Similarly, the wrong enantiomer was irradiated and evaluated after the reaction was complete, as described in Example 4a. Equipment: Optical loop reactor FT03, slit width 1.0 mm, UV lamp Q1023, Watson-Marlow peristaltic pump, flow rate 4 L / min, two 45°C thermostats for the reactor and receiver, nitrogen flow through the receiver and lamp. Nitrogen flow receiver: approximately 500 mL / min, adjusted to a nominal oxygen content of 17.0% by synthetic air control. From start to 30 minutes: oxygen content 16.7%. From 30 minutes to 8 hours: oxygen content 0%. 7.50 g of the wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide was dissolved in 2.5 L of acetonitrile (1951 g) and 17.4 g of DBU (6 equivalents) was added. The reaction mixture was first gassed continuously with a synthetic air stream for 30 minutes, controlling the oxygen content at 16.7%. After 30 minutes, this was switched to pure nitrogen, and the oxygen content dropped to 0% within approximately 40 minutes. The lamp was switched on to start the reaction. After 8 hours, the irradiation was stopped. Total irradiation time: 8 hours. After the reaction was completed, a sample of the reaction solution was measured: 4.08% ee, purity: 87.55%.

[0181] Example 4i Irradiation of the wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide for the preparation of rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Similarly, the wrong enantiomer was irradiated and evaluated after the reaction was complete, as described in Example 4a. Equipment: Falling-film photoreactor FORA 01, UV lamp TLED 100 / 365 nm, 45°C thermostat for reactor and receiver, nitrogen and oxygen flow through receiver and reactor. Nitrogen flow through receiver: approx. 300 mL / min, adjusted to a specified oxygen content of 18.0% or 0% by controlling the synthetic air. The wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (3.41 g) was dissolved in 450 mL of ACN (350 g) and 8.2 g of DBU (6 equivalents) was added. The reaction mixture was first gassed continuously with a synthetic air stream for 30 minutes, controlling the oxygen content at 18.4%. After 30 minutes, this 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 in a receiver vessel under nitrogen at 20°C overnight. Total irradiation time: 8 hours. After the reaction was completed, a sample of the reaction solution was measured: 9.45% ee, purity: 83.02%.

[0182] Example 5 Solvent: DMF dimethylformamide

[0183] Example 5a Irradiation of the wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide for the preparation of rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Similarly, the wrong enantiomer (Ib) was irradiated as described in Example 4a and evaluated after the reaction was complete. Equipment: EVO photoreactor FoRA 02 with falling film reactor and 8 hours with TLED 365 lamp and 2 hours with TQ 2000 lamp (in both cases quartz shell tube) 35.0 g of (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ib) and (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide were dissolved in 2500 mL of DMF (2350 g), and 84.5 g of DBU (6 equivalents) was added. The reaction mixture was transferred to a reactor, and the thermostat was set to 45 °C. Synthetic air was supplied, and the oxygen content in the reactor was 18.2%. The circulation pump was turned on and the flow rate was controlled at approximately 90 g / min. The receiver temperature was adjusted to 45 °C, and the reactor temperature was set to 44 °C. Sampling was started to determine the oxygen content. At t=0 min with the lamp turned on at 100% power, the oxygen content was 18%. At t=30 min, switch to nitrogen injection. At t=120 minutes, measure oxygen sample. Result: Oxygen=0.0% At t=240 minutes, measure oxygen sample. Result: Oxygen=0.0% At t=420 minutes, measure oxygen sample. Result: Oxygen=0.0%

[0184] The lamp and thermostat were then switched off, as well as the pump. The nitrogen supply was left on overnight. The TQ 2000 lamp was then reset for further irradiation. After restarting, the oxygen sample was measured again and the oxygen result was = 0.0%. The lamp and pump were then switched off, ending the experiment. After the reaction was completed, a sample of the reaction solution was measured: 3.45% ee, purity: 94.54%.

[0185] Example 5b Irradiation of the wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide for the preparation of rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Similarly, the wrong enantiomer was irradiated and evaluated after the reaction was complete, as described in Example 4a.

[0186] The reaction rate was investigated. Equipment: Large optical loop reactor, UV lamp Q1023, 100% power (U=150V, I=6.8), quartz shell tube, Duran immersion fingers, two 50°C thermostats, Watson-Marlow 620s peristaltic pump at 70 rpm (with integrated GORE STA-PURE pump tubing). Reactor walls are checked and cleaned before each batch. Nitrogen is flushed through the lamp and receiver. 40.54 g of (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide was added to 2.0 L (1881.52 g) of DMF, followed by the addition of 95.84 mL (6 equivalents, 95.91 g) of DBU. The mixture was then degassed in an ultrasonic bath for 10 minutes. The reaction mixture was then transferred (under nitrogen) to a storage container and rinsed with 0.7 L of DMF (696.95 g). The reaction mixture was then equilibrated under nitrogen at a flow rate of 120 L / h for 15 minutes. The UV lamp was turned on to initiate the reaction. The reaction solution was discharged over the weekend and rinsed with 400 mL of DMF (372.19 g). The reaction was then continued. Total irradiation time: 34 hours. The following table shows the results of the racemization over 34 hours.

[0187] [Table 16]

[0188] Example 6 Solvent mixture: acetonitrile / acetone = 19:1 Irradiation of the wrong enantiomer (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ib) for the preparation of rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Similarly, the wrong enantiomer was irradiated and evaluated after the reaction was complete, as described in Example 4a. Equipment: optical loop reactor, UV lamp TQ 150 (stage 1), Duran, circulation pump, thermostat (50°C), layer thickness of 5 mm. 2.12 g of (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ib) was dissolved in 237.5 mL (190.08 g) of acetonitrile and 12.5 mL (9.48 g) of acetone, and 4.89 g of DBU (6 equivalents) was added. The reaction was initiated by turning on the lamp and placed under a constant nitrogen flow at the beginning. After a reaction time of 6 hours 40 minutes, the collection vessel was vented for 10 minutes. The nitrogen flow was interrupted from 7 hours 15 minutes to 8 hours and from 9 hours 30 minutes to 13 hours 10 minutes. Between and after these phases, the reaction was run under a constant nitrogen flow. The total irradiation time was 16 hours 10 minutes. After the reaction was completed, the sample measurements of the reaction solution were measured: 9% ee, purity: 90%, content: 90%.

[0189] Example 7 Solvent: Acetone Irradiation of the wrong enantiomer (Ib) (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide for the preparation of rac (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) Similarly, the wrong enantiomer was irradiated and evaluated after the reaction was complete, as described in Example 4a. Device: Large optical loop reactor, UV lamp Q1023, 100% power (U=150V, I=6.8), quartz shell tube, Duran immersion fingers, two 50°C thermostats, Watson-Marlow 620s peristaltic pump at 70 rpm (with integrated GORE STA-PURE pump tubing). Reactor walls are checked and cleaned before each batch. Nitrogen is flushed through the reactor and receiver. 20.50 g of the wrong enantiomer (4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ib) was added to 2.0 L (1564.06 g) of acetone, followed by 48.28 mL (6 equivalents, 47.75 g) of DBU. The mixture was degassed in an ultrasonic bath for 10 minutes. The reaction mixture was then transferred (under nitrogen) to a storage container and rinsed with 0.6 L of acetone (591.01 g). The reaction mixture was then equilibrated under nitrogen at a flow rate of 120 L / h for 15 minutes. The UV lamp was turned on to initiate the reaction. The total irradiation time was 12 hours.

[0190] The table below shows the results of the racemization over a 12 hour period.

[0191] [Table 17]

[0192] Example 8 Preparation of rac (I) (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide from pyridine derivatives (II) Equipment: Optical loop reactor, UV lamp TQ 150 (new lamp), M282 shell tube, circulation pump, thermostat (50°C), 5 mm layer thickness. Lamp checked before test. Argon minimized by gas regulator. UV / VIS reaction monitoring: 1 mm flow-through cuvette placed between pump outlet and inlet to reactor. OceanOptics FLAME spectrometer, deuterium / halogen light source. 3.75 g of pyridine derivative (II) was dissolved in 250 mL of acetone and degassed in an ultrasonic bath for 15 minutes. The reaction mixture was a clear yellow solution. It was then placed in a reactor in a storage container and kept under argon (flow rate 500 mL / min).

[0193] The reaction mixture was then heated to 50°C and equilibrated under argon for 30 minutes. 9 mL (9.18 g, 6 eq.) of DBU was then added under argon (DBU was stored under nitrogen). The reaction mixture was a clear, yellowish solution. Irradiation was then initiated. After 5 hours and 34 minutes, a plateau appeared in the UV, after which the lamp was switched off. 2 eq. of DBU (3 mL) was then added, and the reaction was continued. The total irradiation time was 6 hours. result: 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) Pyridine derivatives (II): 1.5%

[0194] Example 9 Irradiation batch reproducibility Similarly, as described in Example 4a, several batches were used with different amounts and different solvents (acetone and acetonitrile), the concentration being approximately 1%, and in each case 6 equivalents of DBU were used.

[0195] The product obtained after aqueous precipitation was dried and then recrystallized from spirits (i.e., ethanol). The crystallization was carried out as follows: 30 g of the racemate (I) obtained after work-up (concentration of the reaction solution, precipitation with water, isolation and drying) was added to 600 ml of spirits, and the suspension was then heated to gentle reflux (T 内部 = 75°C). From an internal temperature of about 57°C a yellow solution formed. The mixture was further stirred at this temperature for 30 minutes. The mixture was then clarified by filtering through a P4 frit covered with diatomaceous earth (soaked in 50 ml of spirits) and washing with 50 ml.

[0196] The spirits were distilled off under reduced pressure, reducing the volume by approximately one-fifth. Crystallization began toward the end of the distillation, resulting in an easily stirrable pale yellow suspension. The mixture was allowed to cool to 23°C. The mixture was further stirred at an internal temperature of 23°C overnight. The mixture was then cooled to an internal temperature of 2°C and stirred at this temperature for an additional 2 hours. The crystals were isolated on a 45mm P3 frit and washed once with 45ml of chilled spirits.

[0197] This was dried in a vacuum drying cabinet under nitrogen supply air at 50° C. and about 100 mbar. The results are summarized in the table below.

[0198] [Table 18]

[0199] Example 10 Preparation of finerenone (Ia) from recycled rac product (I) from Example 4a (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0200] Example 10a Preparation of (+)O,O-Dibenzoyltartaric Acid Salt (IVa) (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ia) 14.3 g of the title compound (I) from Example 4a was first added to 127.1 g of spirits, followed by 53.7 g of water. 7.4 g of (+)-O,O-dibenzoyl-D-tartaric acid was then added. The slightly yellowish suspension was heated to an internal temperature of 75°C over 1 h (bath temperature: 82-85°C) and then stirred at this temperature for 3 h. The oil bath was switched off, the internal temperature was cooled to 22°C over approximately 5 h, and the mixture was further stirred at this temperature overnight (crystals settled quite quickly if the stirrer was switched off). The suspension was isolated on a P4 frit (50 ml) and washed once with a mixture of 15.5 g of spirits and 6.5 g of water; wet yield: 23.2 g. Drying was carried out overnight in a vacuum drying cabinet under nitrogen at 50°C and below 100 mbar. Yield: 14.0 g of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ia) tartrate (IVa) analysis: Purity >98% (HPLC) Enantiomeric excess: 96.42% ee

[0201] Example 10b (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, crude (Ia) 13.00 g of the title compound from Example 10a was suspended in 104.0 g of water, followed by the addition of 20.5 g of toluene-denatured ethanol (spirits). The pH was pH=4.0. The mixture was heated to an internal temperature of 50°C over 1 hour and a bath temperature of 60-62°C. The suspension was adjusted to pH=7.3 with sodium phosphate solution (100 g Na3PO4 / 1 L water) over approximately 30 minutes. The suspension was then stirred at an internal temperature of 50°C for 60 minutes and readjusted to pH=7.5 with sodium phosphate solution (100 g Na3PO4 / 1 L water). The mixture was then stirred at an internal temperature of 50°C for 180 minutes. The oil bath was turned off and allowed to cool. The mixture was further stirred overnight at an internal temperature of 23°C. The crystals were isolated on a 50 mm P3 frit and washed once with a mixture of 4.0 g ethanol and 20.4 g water, then twice with 21 g water each time. Wet yield: 7.6 g. This was dried overnight at 50° C. in a vacuum drying cabinet under nitrogen bleed air. Yield: 6.3 g of the title compound. analysis: Purity >99.21% (HPLC) Enantiomeric excess: 97.21% ee

[0202] Example 10c (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, pure (Ia) 5.0 g of the title compound from Example 10b was added to 100 ml (20x) of toluene-denatured ethanol (=spirits). The suspension was heated to gentle reflux. The internal temperature was 75°C, and the bath temperature was approximately 90-92°C. From an internal temperature of approximately 70°C, the solution was completely dissolved. Stirring was continued at this temperature for 1 hour. The solvent was then distilled off under slight vacuum (bath temperature of 40°C) to concentrate approximately 5x (approximately 25 ml). This was stirred overnight at room temperature, then cooled to an internal temperature of 1-2°C and further stirred at this temperature for approximately 2 hours. The crystals were isolated using a 30 mm P4 frit and then washed twice with 5 ml of cold toluene-denatured ethanol each time. Wet yield: 5.2g Drying was carried out overnight in a vacuum drying cabinet at 80° C. under nitrogen / air supply below 100 mbar. Yield: 4.4 g of the title compound analysis: Purity >99.62% (HPLC) Enantiomeric excess: 99.45% ee

Claims

1. Formula (I) 【Chemical 1】 racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, Formula (Ia) and / or (Ib) 【Chemistry 2】 from the enantiomer of Step (i): (i) irradiating said enantiomers of formula (Ia) and / or (Ib) with light in a suitable solvent or solvent mixture in the presence of a base wherein said irradiation in step (i) is optionally carried out at a temperature between 0°C and 100°C.

2. 10. The method of claim 1, wherein the irradiation with light in step (i) is carried out at a temperature of 30°C to 70°C.

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

5. 5. The method of 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 mixtures thereof.

6. 6. The method of any one of claims 1 to 5, wherein the irradiation in step (i) is carried out for a period of from 1 hour to 40 hours.

7. Formula (Ia) 【Chemistry 3】 1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula Steps (ii), (iii), and (iv): (ii) reacting a compound of formula (Ib) in the presence of a base in a suitable solvent or mixture of solvents 【Chemistry 4】 wherein said compound of formula (Ib) is irradiated with light to form a compound of formula (I): 【Chemistry 5】 step of converting the compound into a racemic compound of (iii) Formula (III) 【Chemistry 6】 optical resolution step of the racemic compound (I) from step (ii) in a denatured ethanol / water mixture using a chiral tartaric acid ester of diastereomeric salt (IVa) 【Chemistry 7】 is formed, and (iv) treating the diastereomeric salt (IVa) from step (iii) with a base to form the compound of formula (Ia). A method comprising:

8. 8. The method of claim 7, wherein the irradiation in step (ii) is carried out at a temperature between 0°C and 100°C.

9. 9. The method of claim 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. 10. The method of any one of claims 7 to 9, wherein the concentration range of enantiomers used in step (ii) in the solvent or solvent mixture is 0.05% to 10% (m / v) based on the volume of the solvent or solvent mixture.

11. 11. The method of 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. 12. The method of any one of claims 7 to 11, wherein the irradiation in step (ii) is carried out for a period of from 1 hour to 40 hours.

13. Formula (I) 【Chemistry 8】 racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, Formula (II) 【Chemistry 9】 from pyridine of the formula: Step (vi): (vi) irradiating said compound of formula (II) with light in a suitable solvent or solvent mixture in the presence of a base, whereby said compound according to formula (I) is formed. A method comprising:

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

15. 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 the base in step (vi) 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, methyl methyl ketone ...

15. The method of claim 13 or 14, wherein the methylaminopyridine is selected from the group consisting of ethylamine, 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.

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