Process for the preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate by resolution of racemates by means of diastereomeric tartaric acid esters

Abstract

The present invention relates to the diastereomer salts (Va), (Vb), (Vc) and / or (Vd), a process for preparing the diastereomer salts (Va), (Vb), (Vc) and / or (Vd) using a chiral-substituted tartaric acid ester of the formula (IIIa) or (IIIb), a process for preparing the compound according to formula (IVa) using the diastereomer salts (Va), (Vb), (Vc) and / or (Vd), a process for preparing the compound according to formula (VIIa) using the diastereomer salts (Va), (Vb), (Vc) and / or (Vd), a process for preparing the compound according to formula (Ia) using the diastereomer salts (Va), (Vb), (Vc) and / or (Vd), the use of the diastereomer salts (Va), (Vb), (Vc) and / or (Vd) for preparing a compound according to formulae (IVa), (VIIa) and / or (Ia); the use of a chiral-substituted tartaric acid ester of the formulae (IIIa) or (IIIb) for preparing the diastereomer salts (Va), (Vb), (Vc) and / or (Vd), and the use of a chiral-substituted tartaric acid ester of the formulae (IIIa) or (IIIb) for preparing a compound of formulae (IVa), (VIIa) and / or (Ia).

Description

[0001] Process for the preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate by racemate cleavage using diastereomeric tartaric acid esters. The present invention relates to the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd), a process for the preparation of the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) using a chiral substituted tartaric acid ester of formula (11a) or (13b), a process for the preparation of the compound according to formula (IVa) using the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd), a process for the preparation of the compound according to formula (V7a) using the diastereomeric salts (Va), (Vb), (Vc), (Vc) and / or (Vd), a process for preparing the compound according to formula (Ia) using the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd), the use of the diastereomeric salts (Va), (Vb),(Vc) and / or (Vd) for the preparation of one of the compounds according to formula (IVa), (Vlla) and / or (Ia); the use of a chiral substituted tartaric acid ester of formula (IlIla) or (Illb) for the preparation of the diastereomeme salts (Va), (Vb), (Vc) and / or (Vd), and the use of a chiral substituted tartaric acid ester of formula (IlIla) or (Illb) for the preparation of one of the compounds according to formula (IVa), (Vlla) and / or (Ia).

[0002] The compounds mentioned above are intermediates or precursors in the synthesis of finerenone (formula (Ia)). The term "finerenone" refers to the compound (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide or to the compound according to formula (Ia). .

[0003] When combining formula (I) This is the Racemat from Finerenone.

[0004] The term “antipodes of finerenone” or “antipodes of the compound according to formula (I)” refers to the compounds according to formula (Ia) and (Ib).

[0005] Finerenone (Ia) acts as a non-steroidal antagonist of the mineralocorticoid receptor and can be used as a means of prophylaxis and / or treatment of cardiovascular and renal diseases such as heart failure and diabetic nephropathy.

[0006] The compound of formula (I) or (Ia) and its preparation process are described in WO 2008 / 104306 and ChemMedChem 2012, 7, 1385 as well as in WO 2016 / 016287 Al. To obtain the compound of formula (I), the racemic mixture of the amides (I) into the antipodes (Ia) and (Ib) can be separated, since only the antipode of formula (Ia) , is active.

[0007] In the published research synthesis (WO 2008 / 104306 A1), a specially synthesized chiral phase (in-house preparation) was used for this purpose, which used N-(dicyclopropylmethyl)-N as a chiral selector. 2 The solution contained -methacryloyl-D-leucinamide. It was found that the separation can also be performed on a commercially available phase. This phase is Chiralpak AS-V, 20 μm. A 60:40 mixture of methanol and acetonitrile was used as the mobile phase. Chromatography can be carried out on a commercially available chromatography column, but techniques known to those skilled in the art, such as SMB (simulated moving bed; G. Paredes, M. Mazotti, Journal of Chromatography A, 1142 (2007): 56-68) or Varicol (Computers and Chemical Engineering 27 (2003) 1883-1901), are preferably employed.

[0008] Although SMB separation yields a fairly good output and optical purity, the acquisition and operation of such a system under GMP conditions is a significant challenge and involves considerable expense. The chiral phase used is also very expensive and has a limited lifespan, requiring frequent replacement during ongoing production. This is not ideal from a production standpoint unless a second system is available to ensure continuous operation, which incurs further costs. Furthermore, especially for products manufactured on a ton scale, solvent recovery is the most time-consuming step, requiring the purchase of enormous falling-film evaporators and consuming vast amounts of energy.

[0009] The task was therefore to find an alternative synthetic route to enantiomerically pure finereones (I) that is significantly more cost-effective and can be carried out using conventional pilot plant equipment (stirred tanks / insulated apparatus). Such systems are traditionally standard equipment in pharmaceutical manufacturing facilities and require no additional investment. Furthermore, the qualification and validation of batch processes is much simpler than with chromatographic methods, which is an additional advantage.

[0010] In the new process according to the invention, instead of the discussed complex SMB separation of the racemic mixture of the amides (I) into the antipodes of formulas (Ia) and (Ib), an advantageous racemic resolution on a synthesis precursor, the racemic building block (IV), The synthesis of the racemic cyanoethanol ester according to formula (IV) is described in WO 2016 / 016287 A1 (see example 5, in WO 2016 / 016287 A1 this is the compound according to formula (XI)).

[0011] Numerous attempts were made to perform a racemate split of racemate (IV) into the antipodes (IVa) and (IVb) using the usual classical methods. to elaborate (variation of chiral organic acid and solvent), as shown in Table 1:

[0012] Table 1: Table 1 lists the acids used for racemic resolution. These were reacted with the racemate (IV) in various organic solvents, such as pure alcohols (methanol, ethanol, 1-propanol, 2-propanol, butanol), as well as their mixtures with water, as well as THF, acetone, ethyl acetate, dichloromethane and a number of other solvents, and investigated for diastheomeric salt formation.

[0013] Among other things, experiments were also carried out with the classic cleavage reagent (+)-tartaric acid.

[0014] However, in all cases no salt formation was observed; instead, only the racemate precipitated from the solution without salt. This essentially corresponds to the expectations of a person skilled in the art, since one could have deduced from the pKa value of the racemic molecule (IV) that classical racemate cleavage via diastereomeric salt formation with organic acids should not be possible, as the measured pKa value (for the base) is 4.3, thus virtually ruling out salt formation. According to literature, such as "Handbook of Pharmaceutical Salts - Properties, Selection and Use; by P. Heinrich Stahl, Camille G. Wermuth (Eds.); Wiley-VCH, p. 166," the pKa value difference should be at least 3 pKa units to allow for stable salt formation.

[0015] All efforts to obtain diastereomeric salts and then increase the enantiomeric excess towards > 99% ee through subsequent synthesis steps were unsuccessful, therefore further alternatives were sought.

[0016] No salt formation was observed during the reaction with alkyl-substituted tartaric acid derivatives such as (-)-O,O'-dipivaloyl-L-tartaric acid or (-)-O,O'-diacetyl-L-tartaric acid.

[0017] However, it was surprisingly found that aromatically or heteroaromatically substituted derivatives of tartaric acid (IIla + Illb) are excellently suited to obtain diastereomeric salts and to achieve the required enantiomeric excess.

[0018] In summary, the invention relates to the following subject matter:

[0019] (1) Diastereomeric salts (Va), (Vb), (Vc) and / or (Vd)

[0020] (2) Method for the preparation of the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) using a chiral substituted tartaric acid ester of formula (11a) or (13b) (3) Method for preparing the compound according to formula (IVa) using the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) (4) Method for preparing the compound according to formula (Vlla) using the diastereomeric salts

[0021] (Va), (Vb), (Vc) and / or (Vd) (5) Method for preparing the compound according to formula (Ia) using the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) (6) Use of the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) to prepare one of the compounds according to formula (IVa), (Vlla) and / or (Ia);

[0022] (7) Use of a chiral substituted tartaric acid ester of formula (11a) or (13b) for the preparation of one of the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd); and

[0023] (8) Use of a chiral substituted tartaric acid ester of formula (11a) or (13b) for the preparation of one of the compounds according to formula (IVa), (V7a) and / or (Ia).

[0024] The technical effects of the invention can be summarized as follows:

[0025] The new methods according to the invention are applicable in many, more cost-effective processes or plants, in contrast to the prior art described above;

[0026] The new processes according to the invention can be carried out with conventional pilot plant equipment (stirring vessels / insulated apparatus) - such plants are traditionally part of the standard equipment of pharmaceutical production plants and do not require any additional investment.

[0027] The new methods according to the invention can be carried out on an industrial scale;

[0028] The methods according to the invention make it possible to produce diastereomeric salts with an enantiomeric excess of the diastereomeric salts in the range of 65% to 80% ee.

[0029] The diastereomeric salts obtained by the inventive process are characterized by a high enantiomeric excess, generally > 95% ee, which is sufficient to produce finerenones in > >99% ee.

[0030] The diastereomeric salts do not necessarily need to be dried; they can also be used moist in the next process step. This also makes one-pot processes possible.

[0031] It was found that when the acid (Vlla or Vllb) is reacted in tetrahydrofuran (THF), the amide of formula (I) or (Ia) can be directly crystallized from the solution and obtained in high yield and purity;

[0032] In the synthesis according to the invention, further intermediate steps can be avoided, thus making the synthesis more time-efficient and cost-effective;

[0033] Examples of such intermediate steps include further purification and / or costly / energy-intensive recovery of individual components, recovery or separation of solvents. The present application therefore relates to a process for the preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa). by racemate separation of the racemate (IV) , with a chiral substituted tartaric acid ester of the formula (1Ila) , where Ar stands for unsubstituted or substituted aryl or heteroararyl. The term "substituted" means that one or more hydrogen atoms on the atom or group in question are replaced by a selection from the specified group, provided that the normal valence of the atom in question is not exceeded under the given circumstances. Combinations of substituents and / or variables are permitted.

[0034] The term "unsubstituted" means that no hydrogen atom has been replaced.

[0035] The heteroaryl group can be a 5-membered heteroaryl group such as thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, or tetrazolyl; or a 6-membered heteroaryl group such as pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl; or a tricyclic heteroaryl group such as carbazolyl, acridinyl, or phenazinyl; or a 9-membered heteroaryl group such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl, or purinyl; or a 10-membered heteroaryl group such as quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl.

[0036] In particular, the heteroaryl group is a pyridinyl, pyrazinyl, pyrrolyl, pyrazolyl or pyrimidinyl group.

[0037] The aryl group within the meaning of the present application is in particular a phenyl group.

[0038] Substituents within the meaning of the present invention are halogen, C1-C6 alkyl, C1-C6 alkoxy, nitrile, nitro, cyano, CF3, an amide group such as -NHCOR, in which R can stand for methyl, ethyl or phenyl, an -NRCOR group in which R has the meaning mentioned above, an -CONHR group in which R has the meaning mentioned above, a CONRR' in which R can stand for methyl, ethyl or phenyl and R' can stand for methyl, ethyl or phenyl, or cyclic amides such as 3-oxomorpholin-4-yl, 2-oxopiperidin-1-yl, which in turn can be substituted.

[0039] The term halogen refers to a fluorine, chlorine, bromine or iodine atom, in particular a fluorine, chlorine or bromine atom.

[0040] The term "C1-C6 alkyl" " means a straight-chain or branched saturated monovalent hydrocarbon group with 1, 2, 3, 4, 5 or 6 carbon atoms, for example a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-Dimethylbutyl group or an isomer thereof. The group has, in particular, 1, 2, 3 or 4 carbon atoms (“C1-C4 alkyl”), for example a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl group, in particular 1, 2 or 3 carbon atoms (“C1-C3 alkyl”), for example a methyl, ethyl, n-propyl or isopropyl group.

[0041] The term "C1-C6 alkoxy" " means a straight-chain or branched saturated monovalent group of the formula (C1-C6-alkyl)-O-, in which the term "C1-C6-alkyl" is defined as above, for example a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group or an isomer thereof.

[0042] Ar preferably stands for: where # represents the linkage point, where RI, R2, R3, R4, R5 each represent a hydrogen atom or an alkyl group, such as methyl, ethyl, propyl, or a halogen atom, such as fluorine, chlorine, bromine, or iodine, or an ether group, such as O-methyl, O-ethyl, O-phenyl, or a nitro group, or a cyano group, or a CF3 group, or an amide group, such as -NHCOR, in which R can stand for methyl, ethyl, or phenyl, or -NRCOR in which R has the meaning mentioned above, or CONHR- in which R has the meaning mentioned above, or CONRR', in which R can stand for methyl, ethyl, or phenyl and R' can stand for methyl, ethyl, or phenyl, or for cyclic amides such as 3-oxomorpholin-4-yl, 2-oxopiperidin-1-yl, which in turn may be substituted. The substitution patterns can vary greatly; theoretically, up to 5 different substituents are possible, but usually the monosubstituted Ar groups are preferred.Ar can also be a substituted heteroaromatic compound, preferably pyridine or pyrazine. Alternatively, Ar can represent a political aromatic hydrocarbon, such as a substituted naphthalene, anthracene, or quinoline.

[0043] Ar is particularly preferred for one of the formulas

[0044] where * represents the point of connection. In particular, Ar preferably represents one of the formulas. where * represents the linkage site. Particularly favored argon residues are: where * represents the linkage site. Of these, the p-toloyl group and the 4-chlorophenyl group are particularly favored.

[0045] The p-toloyl residue is particularly favored. The preparation of the tartaric acid esters is well-documented in the literature, for example in Organic Synthesis, Coli. Vol. 9, p. 722 (1998); Vol. 72, p. 86 (1995), as well as in Chirality 2011 (23), 3, p. 228.

[0046] Another subject matter of the invention relates to diastereomeric salts (Va to Vd) according to the formulas

[0047] (V d) wherein Ar represents an unsubstituted or substituted aromatic or heteroaromatic compound and has the meaning given above.

[0048] Diastereomeric salts in which Ar stands for p-toloyl are particularly preferred.

[0049] Whether (Va) to (Vd) are truly classical diastereomeric salts or 1:1 molecule complexes stabilized by hydrogen bonding is not definitively predictable. However, it is certain that these 1:1 molecule aggregates are very stable and behave and can be isolated like classical diastereomeric salts, so we will use the term diastereomeric salt in the following discussion. Tartaric acid derivatives of the general formulas (11a) and (13b) are used to synthesize the diastereomeric salts: where Ar represents a substituted or unsubstituted aromatic or heteroaromatic compound and has the meaning given above. The preparation of the diastereomeric salts (Va to Vd) is carried out as follows:

[0050]

[0051] The reaction of the racemic mixture (IV) with a tartaric acid derivative of the general formula (11a) or (13b) yields the four possible diastereomeric salts (Vad). Surprisingly, a preference is observed such that, for example, when rac-(IV) is reacted with a tartaric acid derivative of the general formula (11a), the diastereomeric salt of the general formula (Va) is obtained, with the antipode of the S configuration preferentially undergoing salt formation. The diastereomeric salt (Va) precipitates almost quantitatively from the solution, from which it can subsequently be isolated, for example, by filtration, with the antipode of the R configuration remaining in solution. Similarly, and quite surprisingly, the mirror-image salt of the general form (Vb) is prepared by reacting the racemate (II) with the tartaric acid derivative of the general formula (13b), with the antipode of the R configuration preferentially undergoing salt formation.The precipitated diastereomeric salts can be separated almost quantitatively, with the S-antipode remaining in solution.

[0052] The yield and enantiomeric purity can be optimized by adjusting the stoichiometric ratio of (IV) to (1Ila) and (Illb) respectively, as well as by selecting the solvent.

[0053] Finerenone (I) possesses the S configuration. Both S,S-configured and R,R-configured tartaric acid esters (depending on the substitution type) can form diastereomeric salts with the 4S-configured enantiomer of racemate IV.

[0054] 0.5 to 2.0 equivalents of tartaric acid esters (1Ila) or (Illb) are used for racemate cleavage, preferably 0.7 to 1.5 equivalents, particularly preferably 0.7 to 1.4 equivalents, and most preferably 0.70 to 1.2 equivalents.

[0055] Diastereomeric salt formation occurs in organic solvents or solvent mixtures consisting of water and water-miscible organic solvents.

[0056] Suitable organic solvents within the meaning of the application include, for example, ethanol, methanol, isopropanol, 1-propanol, ethyl acetate, isobutanol, dichloromethane, 1-pentanol, or acetone; however, ethanol is preferred. The solvents can also be used in commercially available denatured form, such as the denaturants used for ethanol, for example, toluene, methyl ethyl ketone, thiophene, or hexane, which offers significant cost advantages. Therefore, spirits, which within the meaning of the application consist of ethanol that may optionally be denatured with toluene or methyl ethyl ketone, are particularly suitable for large-scale industrial applications. Thus, when "spirits" are mentioned, denatured ethanol is meant. The term "spirits" is familiar to those skilled in the art.In addition, the following solvents were also used: Ethyl acetate / methanol 90:10; Methanol / water 80:20; Ethanol / water 90:10; Ethanol / water 85:15; Ethanol / water 80:20; Ethanol / water 75:25; Ethanol / water 70:30; Dichloromethane; 1-Propanol / water 80:20; 1-Pentanol; 1-Pentanol / water 90:10; Isopropanol; Isopropanol / water 80:20; Isobutanol / water 90:10; Isobutanol / water 80:20; Cyclohexanol / water 90:10; Benzyl alcohol / water 90:10; Ethylene glycol; Ethylene glycol / water 80:20. When specifying solvent ratios, the ratio of volume to volume (Vol / Vol) is meant. A solvent mixture consisting, for example, of ethanol / water 80:20 contains 80 mL of ethanol and 20 mL of water. The volume therefore refers to the total volume of the solvent.Preferably, the resolution of the racemate is carried out in an ethanol / water mixture, with a mixing ratio (vol / vol) in the range of ethanol:water = 1:1 to 6:1. A mixture of ethanol:water = 6:1 to 3:1 is preferred. A mixture of ethanol:water = 3:1 is particularly preferred. The mixture can be prepared beforehand or generated in situ by placing all components in a container. The solvent mixture can be used in a 10- to 60-fold excess of the racemate (IV), i.e., 10 L to 40 L of solvent mixture are used for every 1 kg of racemate. A 10- to 50-fold excess is preferred.

[0057] The resolution of the racemic mixture is usually carried out by first placing all components in the solvent mixture at room temperature, then heating to 10°C to 60°C, preferably to 20°C to 50°C, and stirring for 1 to 10 hours, preferably 1 to 4 hours, at 20°C to 50°C. The mixture is then cooled to room temperature (approximately 20°C to 23°C) within 3 to 24 hours, preferably 5 to 16 hours. Stirring is then allowed to continue at room temperature for 2 to 24 hours, preferably 5 to 18 hours, and most preferably 12 to 16 hours. The resolution of the racemic mixture is preferably carried out at a temperature of 20°C to 50°C.

[0058] The precipitated diastereomeric salt (Va), (Vb), (Vc) and / or (Vd) is then isolated.

[0059] Isolation is carried out using methods known to those skilled in the art, such as filtration or centrifugation. The resulting filter cake can be washed once or several times with a solvent or solvent mixture. Drying then takes place under vacuum, preferably < 100 mbar, at elevated temperature (50–80°C, preferably 50°C). The use of a scavenging gas has proven advantageous in some cases.

[0060] Using the procedure described above, it is possible to produce diastereomeric salts with an enantiomeric excess of the diastereomeric salts in the range of 65% to 80% ee.

[0061] For further purification to increase the enantiomeric excess, the mixture is stirred again from a solvent or solvent-water mixture.

[0062] The diastereomeric salts do not necessarily need to be dried; they can also be used in the next process step while still moist. Suitable organic solvents for the purposes of this application include, for example, ethanol, methanol, isopropanol, 1-propanol, ethyl acetate, isobutanol, dichloromethane, 1-pentanol, or acetone, although ethanol is preferred. The solvents can also be used in their commercially available denatured form, such as the denaturants used with ethanol, for example, toluene, methyl ethyl ketone, thiophene, or hexane, which offers significant cost advantages. Therefore, spirits, which, as defined in this application, consist of ethanol that may optionally be denatured with toluene or methyl ethyl ketone, are particularly suitable for large-scale industrial applications.In addition, the following solvents were also used: Ethyl acetate / methanol 90:10; Methanol / water 80:20; Ethanol / water 90:10; Ethanol / water 85:15; Ethanol / water 80:20; Ethanol / water 75:25; Ethanol / water 70:30; Dichloromethane; 1-Propanol / water 80:20; 1-Pentanol; 1-Pentanol / water 90:10; Isopropanol; Isopropanol / water 80:20; Isobutanol / water 90:10; Isobutanol / water 80:20; Cyclohexanol / water 90:10; Benzyl alcohol / water 90:10; Ethylene glycol; Ethylene glycol / water 80:20. When referring to solvent ratios or mixing ratios, the ratio of volume to volume (Vol / Vol) is meant. A solvent mixture consisting, for example, of ethanol / water 80:20 contains 80 mL of ethanol and 20 mL of water.

[0063] Preferably, the resolution of the racemate is carried out in an ethanol / water mixture, with a mixing ratio (vol / vol) in the range of ethanol:water = 1:1 to 6:1. A mixture of ethanol:water = 6:1 to 3:1 is preferred. A mixture of ethanol:water = 3:1 is particularly preferred. The mixture can be prepared beforehand or generated in situ by placing all components in a container. The solvent mixture can be used in a 10- to 60-fold excess of the racemate (IV), i.e., 10 L to 40 L of solvent mixture are used for every 1 kg of racemate. A 10- to 50-fold excess is preferred.

[0064] Typically, the mixing process involves first placing all components in the solvent mixture at room temperature, then heating to 10°C to 60°C, preferably to 20°C to 50°C, and stirring for 1 to 10 hours, preferably 1 to 4 hours, at 20°C to 50°C. The mixture is then cooled to room temperature (approximately 20°C to 23°C) within 3 to 24 hours, preferably 5 to 16 hours. Finally, stirring is allowed to continue at room temperature for 2 to 24 hours, preferably 5 to 18 hours, and most preferably 12 to 16 hours.

[0065] The precipitated diastereomeric salt (Va) or (Vb) or (Vc) and / or (Vd) is then isolated.

[0066] Isolation is carried out using methods known to those skilled in the art, such as filtration or centrifugation. The resulting filter cake can be washed once or several times with a solvent or solvent mixture. Drying then takes place under vacuum, preferably < 100 mbar, at elevated temperature (50°C - 80°C, preferably 50°C). The use of a slurry gas has proven advantageous in some cases. The diastereomeric salts obtained in this way are characterized by a high enantiomeric excess, generally > 95% ee, which is sufficient to produce finerenones with > 99% ee.

[0067] The diastereomeric salts do not necessarily need to be dried, but can also be used moist in the next process stage.

[0068] The process steps can be combined or their order changed in addition to the usual procedure mentioned above, as shown in Table 2 below:

[0069] Table 2

[0070] Depending on the type of plant in the pilot plant or in production, one or the other variant may be advantageous. In the next step, the diastereomeric salt is treated with a base and the solvent is removed. The solvent is removed using methods known to those skilled in the art, for example, by distillation. To prepare the chiral compounds (IVa) and (IVb), the diastereomeric salt of the general formula (Va), (Vb), (Vc), or (Vd) must be treated with a base. After distillation of the organic solvent, the target molecule (IVa) or (IVb) precipitates from the solution, is isolated—for example, by filtration and washing—and the respective tartaric acid ester according to formula (11a) or (13b) remains in solution in a saline form.

[0071]

[0072]

[0073] Suitable bases for the purposes of the present invention are inorganic and organic bases. In the case of inorganic bases, ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, and ammonium phosphate can be used. However, sodium hydroxide, sodium phosphate, or potassium phosphate are preferred. Sodium phosphate or potassium phosphate are particularly preferred. It is important to emphasize that the inorganic bases can be used in both anhydrous form and in the form of their hydrates; for example, sodium phosphate (anhydrous) and sodium phosphate hydrate can be used successfully. Suitable organic bases include aliphatic or aromatic bases such as triethylamine, imidazole, N-methylimidazole, Hünig base, pyridine, and DBU.

[0074] The release of the target compound (IVa) or (IVb) occurs in mixtures of water or water-miscible organic solvents such as ethanol, isopropanol, 1,2-ethanediol, methoxyethanol, methanol, or acetone, preferably ethanol. The solvents can also be used in commercially available denatured form, such as the denaturants used with ethanol, for example, toluene, methyl ethyl ketone, thiophene, or hexane. Preferably, spirits, which, as defined in the application, consist of ethanol that may optionally be denatured with toluene or methyl ethyl ketone, are used, offering significant cost advantages. It has proven advantageous to use mixtures of water and ethanol, with a mixing ratio (vol / vol) in the range of ethanol:water = 1:6 to 1:3. However, a mixture of ethanol:water = 1:3 is preferred.The mixture can be prepared beforehand or generated in situ by placing all components in a pot. Seven to twenty times the volume of this mixture, based on the diastereomeric salt (IVa, IVb, IVc, or IVd) used, can be employed; for example, 1 kg in 7 to 20 L of this mixture. Preferably, eight to fifteen times the volume of this mixture is used, more preferably nine to eleven times, and most preferably ten times. The release of the target compound (IVa) or (IVb) is achieved by placing the diastereomeric salt (Va or Vb or Vc or Vd) in a solvent mixture at 0°C to 60°C, preferably 0°C to 50°C, and subsequently adjusting the pH to 6.9 to 8.0, preferably 7.0 to 7.5, particularly preferably 7.1, by adding the organic or inorganic base (either in solid form or as a solution, preferably in water).Suitable bases for the purposes of the present invention are inorganic and organic bases. In the case of inorganic bases, ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, and ammonium phosphate can be used. However, sodium hydroxide, sodium phosphate, or potassium phosphate are preferred. Sodium phosphate or potassium phosphate are particularly preferred. It is important to emphasize that the inorganic bases can be used in both anhydrous form and in the form of their hydrates; for example, sodium phosphate (anhydrous) and sodium phosphate hydrate can be used successfully. Suitable organic bases include aliphatic or aromatic bases such as triethylamine, imidazole, N-methylimidazole, Hünig base, pyridine, and DBU.

[0075] The base can be added either very quickly (within a few minutes) or very slowly (over several hours, for example, from 5 minutes to 3 hours). A faster addition is definitely preferred. Preferably, the base is added within 5 minutes to 1 hour. A pH meter integrated into the reactor can be used for this purpose, allowing the adjustment to be monitored and the base to be added slowly. Alternatively, a fixed quantity of base (solid or dissolved in a solvent) can be added from the beginning, which, based on experience, ensures that the desired pH range is preferably achieved. This approach is most preferred in production. It has proven advantageous to stir again at 0°C–50°C, preferably 20°C–50°C, or more preferably 0°C–20°C, after the pH has been adjusted. The stirring time can be 1 to 10 hours, preferably 2–5 hours, and most preferably 3–4 hours.

[0076] Isolation is carried out using methods known to those skilled in the art, such as filtration or centrifugation. The resulting filter cake can be washed once or several times with a solvent or solvent mixture. Drying then takes place under vacuum, preferably < 100 mbar, at elevated temperature (50–80°C, preferably 50°C). The use of a scavenging gas has proven advantageous in some cases.

[0077] As a particularly preferred method, especially for large-scale industrial implementation, di-p-toloyl-D-tartaric acid (IIIa') is used, which can be used both in anhydrous form and as a hydrate:

[0078]

[0079] The resolution of the racemates is preferably carried out in a mixture of brandy and water. The subsequent release of (IVa) The reaction is preferably carried out in a spirit-water mixture using sodium phosphate as the base. It is also possible to isolate the target enantiomer from the mother liquor. Here, the corresponding diastereomeric salt (Va), (Vb), (Vc), or (Vd) of either (IVa) or (IVb) is first prepared, then isolated by filtration, and subsequently the pH of the mother liquor, which then contains the respective antipode, is adjusted to pH > 7 by adding a base such as ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, ammonium phosphate, preferably sodium hydroxide, sodium phosphate, and potassium phosphate, and particularly preferably sodium phosphate and potassium phosphate. pH 7.1–8 is preferred, and pH 7.1 is most particularly preferred.The organic solvent – ​​preferably ethanol – is then distilled off, either at normal pressure or, more gently, under reduced pressure. The corresponding antipode precipitates out. The product is filtered, washed with water or water / solvent mixtures, and dried. A final crystallization from spirit, as described, for example, in Example 1c, yields compounds (IVa) and (IVb) in appropriately pure form.

[0080] The further conversion to finerenone (Ia) or the antipode (Ib) is carried out as follows: Starting from the cyanoethyl ether (IVa or IVb), the acid (Vlla or Vllb) is obtained by alkaline saponification and subsequent acidic work-up:

[0081]

[0082] It was found that the reaction can be carried out very easily in relatively concentrated THF / water mixtures. Preferably, a 2:1 (9-fold) THF / water mixture is used. The sodium hydroxide solution is added at 0°C to 5°C, followed by stirring for 1-2 hours at 0°C to 5°C. Potassium hydroxide solution can also be used, but sodium hydroxide solution is preferred. For work-up, the mixture is extracted with MTBE (methyl tert-butyl ether) and ethyl acetate, or toluene alone. For isolation, the pH is adjusted to 7 with a mineral acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, but preferably hydrochloric acid. Subsequently, saturated ammonium salt solution of the corresponding acid, but preferably ammonium chloride solution, is added, and the product crystallizes quantitatively. After isolation, the mixture is washed with water and ethyl acetate, or with acetonitrile, or with acetone, but preferably with acetonitrile, and dried under vacuum at 40°C to 50°C.The yield is almost quantitative (99%).

[0083] The subsequent reaction from the acid to the amide (I or Ia) is described as follows: It was found that when the acid (Vlla or Vllb) is reacted with tetrahydrofuran (THF), the amide (I or Ia) crystallizes directly from solution and can be obtained in high yield and purity. For this purpose, the carboxylic acid (Vlla or Vllb) is reacted with 1.1 to 1.6 equivalents, preferably 1.3 to 1.4 equivalents. 1,1'-Carbodiimidazole (CDI) under 4-(Dimethylamino)-pyridine (DMAP) catalysis (5-15 mol%, preferably 10 mol%; in some cases, it has been shown that the reaction can also be carried out without the addition of DMAP) in THF at temperatures between 20-50 °C. The preferred procedure has been to start first at 20 °C, then stir for 1 to 2 hours at this temperature, and then stir for 2 to 3 hours at 50 °C to form the imidazolide.After activation is complete, 3 to 8 equivalents, preferably 4.5 equivalents, of hexamethyldisilazane are added, and the mixture is heated to reflux for 16 to 24 hours, preferably 16 hours. The disylamide compound formed can optionally be isolated. However, it has proven more advantageous to proceed in a one-pot reaction. After the reaction is complete, the mixture is cooled to 0–3 °C, and water or a water / THF mixture is added. Using a water quantity of 0.5 to 0.7 times the reactant volume has proven advantageous; a quantity of 0.52 times the reactant volume is particularly advantageous. The water can be added directly or as a mixture with approximately one to two volumes of THF. After squeezing is complete, the mixture is heated to reflux for a total of 1–3 hours, preferably 1 hour. The mixture is then cooled to 0 °C and stirred at this temperature for 1–5 hours, preferably 3 hours.The product is then isolated by filtration or centrifugation. It is washed with THF and water and dried under vacuum at elevated temperatures.

[0084] Temperature (30°C to 100°C, preferably 40°C to 70°C). Yields are very high, exceeding 93% of theoretical yield. Purity is greater than 99% (HPLC, 100% method). The compound (Vlla or Vllb) can also be obtained directly by reaction with ammonia gas in an autoclave (approximately 25 to 30 bar). For this, the pre-activation described above is carried out, followed by heating under pressure with ammonia gas. After the reaction is complete, the mixture is cooled and the product is filtered off. The yields and purities obtained in this way are comparable.

[0085]

[0086] Final crystallization process (adjustment of the final modification Mod A): For this purpose, (I) (or Ia) is first dissolved in ethanol for GMP reasons, subjected to particle filtration, and then the solvent is distilled off, either under reduced pressure or at room temperature; preferably, ethanol denatured with toluene is used. It is concentrated to approximately 3 to 5 times the volume of (I) (or Ia), during which the product crystallizes. It is cooled to 0°C, and the crystals are then isolated and dried under vacuum at 40°C–50°C. The yields are generally > 90% of theory. The chemical purity achieved is > 99.8%, and the content ~ 100% meets the criteria for commercial products according to the ICH guideline. Residual solvent, in this case ethanol, is < 0.02%. The optical purity is ≥ 99% ee

[0087] The present invention therefore also relates to a process for the preparation of (4S)- 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia)

[0088] characterized by the fact that one obtains enantiomeric cyanoethanol ester 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) in a THF / water mixture (2:1) with sodium hydroxide to give the compound of formula (Vlla) The mixture is saponified and then reacted in THF as a solvent, first with 1,1-carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine, heated under reflux for 16-24 hours after the addition of hexamethyldisilazane, and then mixed with a THF / water mixture. Further embodiments of the invention are described as follows:

[0089] The present invention relates to a process for the preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) by racemic resolution of racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy- 2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IV) with a chiral substituted tartaric acid ester of the formula (1Ila)

[0090] where Ar represents unsubstituted or substituted aryl or heteroraryl. A preferred method is for the preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa). by racemic resolution of racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IV) with a chiral substituted tartaric acid ester of the formula (1Ila) where Ar for where # represents the linkage point, where R1, R2, R3, R4, R5 each represent a hydrogen atom or an alkyl group, such as methyl, ethyl, propyl, or a halogen atom, such as fluorine, chlorine, bromine, or iodine, or an ether group, such as O-methyl, O-ethyl, O-phenyl, or a nitro group, or a cyano group, or a CF3 group, or an amide group, such as -NHCOR, in which R can represent methyl, ethyl, or phenyl, or -NRCOR in which R has the meaning given above, or CONHR- in which R has the meaning given above, or CONRR' in which R' is synonymous with R as defined above, or cyclic amides such as 3-oxomorpholin-4-yl, 2-oxopiperidin-l-yl, which themselves may be substituted. The substitution patterns can vary greatly; theoretically, up to 5 different substituents are possible, but usually the monosubstituted Ar groups are preferred.Ar can also be a substituted heteroaromatic compound, preferably pyridine or pyrazine. Alternatively, Ar can represent a political aromatic hydrocarbon, such as a substituted naphthalene, anthracene, or quinoline.

[0091] A preferred method is for the preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) wherein

[0092] Ar for one of the formulas where * represents the linking point.

[0093] Particularly preferred is a process for the preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) wherein

[0094] Ar for one of the formulas The * indicates the linking point.

[0095] A process for the preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)- is particularly preferred.

[0096] 5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) wherein

[0097] Ar for one of the formulas where * represents the linkage point. A process for the preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)- is particularly preferred.

[0098] 5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) wherein

[0099] Ar for one of the formulas The asterisk (*) represents the linking point.

[0100] Particularly preferred is a process for the preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) wherein

[0101] Ar for The present invention also relates to a process for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia) characterized by the fact that one can make racemic cyanoethanol esters of formula (IV) with a chiral substituted tartaric acid ester of the formula (1Ila) where Ar represents unsubstituted or substituted aryl or heteroraryl, in enantiomeric cyanoethanol ester 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) converted, and this in a THF / water mixture (2:1) with sodium hydroxide to the compound of formula (Vlla)

[0102] saponified and then reacted in THF as solvent first with 1,1-carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine, heated under reflux for 16-24 hours after addition of hexamethyldisilazane and then mixed with a THF / water mixture.

[0103] A preferred method is for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia) characterized by the fact that one can make racemic cyanoethanol esters of formula (IV) with a chiral substituted tartaric acid ester of the formula (1Ila) where Ar for where # represents the linkage point, where R1, R2, R3, R4, R5 each represent a hydrogen atom or an alkyl group, such as methyl, ethyl, propyl, or a halogen atom, such as fluorine, chlorine, bromine, or iodine, or an ether group, such as O-methyl, O-ethyl, O-phenyl, or a nitro group, or a cyano group, or a CF3 group, or an amide group, such as -NHCOR, in which R can represent methyl, ethyl, or phenyl, or -NRCOR in which R has the meaning given above, or CONHR- in which R has the meaning given above, or CONRR' in which R' is synonymous with R as defined above, or cyclic amides such as 3-oxomorpholin-4-yl, 2-oxopiperidin-1-yl, which themselves may be substituted. The substitution patterns can vary greatly; theoretically, up to 5 different substituents are possible, but usually the monosubstituted Ar groups are preferred.Ar can also be a substituted heteroaromatic, such as preferably pyridine or pyrazine. Ar can also represent a polycyclic aromatic hydrocarbon, such as, for example, a substituted naphthalene, anthracene, or quinoline, in the enantiomeric cyanoethanol ester 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (1 IVa).

[0104] converted, and this in a THF / water mixture (2:1) with sodium hydroxide to the compound of formula (Vlla) The mixture is saponified and then reacted in THF as a solvent, first with 1,1-carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine, heated under reflux for 16-24 hours after the addition of hexamethyldisilazane, and then treated with a THF / water mixture. A preferred method is for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), wherein formula (III)

[0105] Ar for one of the formulas

[0106] The * indicates the linking point.

[0107] Particularly preferred is a process for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), wherein in formula (III)

[0108] Ar for one of the formulas The asterisk (*) represents the linking point.

[0109] Particularly preferred is a process for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), wherein in formula (III)

[0110] Ar for one of the formulas where * represents the linking point. A process for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia) is particularly preferred, wherein in formula (III) Ar represents one of the formulas The asterisk (*) represents the linking point.

[0111] Particularly preferred is a process for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), characterized by the fact that one can make racemic cyanoethanol esters of formula (IV) with a chiral substituted tartaric acid ester of the formula (1Ila)

[0112] where Ar for stands, where * stands for the linking point, in enantiomeric cyanoethanol ester 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) converted, and this in a THF / water mixture (2:1) with sodium hydroxide to the compound of formula (Vlla)

[0113] saponified and then reacted in THF as solvent first with 1,1-carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine, heated under reflux for 16-24 hours after addition of hexamethyldisilazane and then mixed with a THF / water mixture.

[0114] Paragraphs 1 to 14.

[0115] Paragraphs 1 to 14 below describe further embodiments of the invention: 1. Process for the preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) by racemic resolution of racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy- 2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IV) with a chiral substituted tartaric acid ester of the formula (1Ila) where Ar stands for unsubstituted or substituted aryl or heteroraryl.

[0116] 2. The method according to paragraph 1 is characterized in that the racemate resolution is carried out in an ethanol / water mixture.

[0117] 3. A method according to one of paragraphs 1 or 2, characterized in that the racemic resolution is carried out at a temperature in the range of 20°C to 50°C. 4. A method according to one of paragraphs 1 to 3, characterized in that the racemic resolution is carried out at a

[0118] Temperatures of 30°C to 50°C are used.

[0119] 5. A method according to one of paragraphs 1 to 4, characterized in that (+) Di-p-tolyl-D-tartaric acid (IIIa')

[0120] is used for race mat separation.

[0121] 6. A method according to any one of paragraphs 1 to 5 characterized in that the precipitated diastereomeric salt (Va), (Vb), (Vc) and / or (Vd) is isolated.

[0122] 7. A method according to any one of paragraphs 1 to 6, characterized in that the diastereomeric salt is treated with a base and the solvent is removed.

[0123] 8. A process according to any one of paragraphs 1 to 7, characterized in that potassium hydroxide, potassium phosphate or sodium phosphate is used as the base. 9. A process according to any one of paragraphs 1 to 8, wherein the racemate (IV) with (+) Di-p-tolyl-D-tartaric acid of formula (IIIa') in a brandy / water mixture to the diastereomeric salt (Va) is reacted, and subsequently cyanoethanol ester (IVa)

[0124] is also released in a spirit / water mixture using sodium phosphate.

[0125] Method for the preparation of (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro- 1,6-naphthyridine-3-carboxamide of formula (Ia) characterized by the fact that one obtains from racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IV) with a chiral substituted tartaric acid ester of the formula (1Ila) where Ar represents unsubstituted or substituted aryl or heteroraryl, in enantiomeric cyanoethanol ester 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) converted, and this in a THF / water mixture (2:1) with sodium hydroxide to form the compound of the formula

[0126] (Vlla)

[0127] The compound of formula (Vlla) is saponified and subsequently reacted in THF as solvent, first with 1,1-carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine, heated under reflux for 16-24 hours after the addition of hexamethyldisilazane, and then treated with a THF / water mixture. The process according to paragraph 10 for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia) characterized by the fact that one obtains racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IV)

[0128] with a chiral substituted tartaric acid ester of formula (IIIa') in enantiomeric cyanoethanol ester 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IVa) converted, and this in a THF / water mixture (2:1) with sodium hydroxide to the compound of formula (Vlla) saponified and the compound of formula (Vlla) subsequently reacted in THF as solvent first with 1,1-

[0129] Carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine are reacted, after addition of hexamethyldisilazane, heated under reflux for 16-24 hours and then treated with a THF / water mixture. Diastereomeric salts according to the formula where Ar represents an unsubstituted or substituted aryl or heteroaryl and has the meaning given above.

[0130] 13. Diastereomeric salt according to paragraph 12, characterized in that Ar is used for where * represents the linking point. 14. Diastereomeric salt according to paragraph 12 or 13, characterized in that Ar represents The * indicates the linking point.

[0131] Paragraphs (1) to (68)

[0132] Further embodiments of the invention are described in the following paragraphs (1) to (68): (1) Diastereomeric salt according to the formula where Ar stands for an unsubstituted or substituted aryl or heteroaryl.

[0133] (2) Diastereomeric salt according to paragraph (1), wherein Ar is selected for a heteroaryl group from the group consisting of thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or by means of a 6-membered heteroaryl group such as pyridinyl, pyridazinyl,

[0134] Pyrimidinyl, pyrazinyl, or triazinyl; or a tricyclic heteroaryl group such as carbazolyl, acridinyl, or phenazinyl; or a 9-membered heteroaryl group such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl, or purinyl; or a 10-membered heteroaryl group such as quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,

[0135] Quinoxalinyl and pteridinyl; or Ar for where # represents the linkage point, where R1, R2, R3, R4, R5 each represent a hydrogen atom or an alkyl group, such as methyl, ethyl, propyl, or a halogen atom, such as fluorine, chlorine, bromine, or iodine, or an ether group, such as O-methyl, O-ethyl, O-phenyl, or a nitro group, or a cyano group, or a CF3 group, or an amide group, such as -NHCOR, in which R can represent methyl, ethyl, or phenyl, or -NRCOR in which R has the meaning given above, or CONHR- in which R has the meaning given above, or CONRR' in which R' is synonymous with R as defined above, or cyclic amides such as 3-oxomorpholin-4-yl, 2-oxopiperidin-1-yl, which themselves may be substituted; or

[0136] Ar stands for a substituted heteroaromatic compound, such as preferably pyridine or pyrazine; or

[0137] Ar stands for a polycyclic aromatic hydrocarbon, such as a substituted naphthalene, anthracene, or quinoline.

[0138] (3) diastereomeric salt according to paragraph (1) or (2), wherein

[0139] Ar for one of the formulas

[0140] (4) diastereomeric salt according to any one of paragraphs (1) to (3), wherein

[0141] Ar for one of the formulas The asterisk (*) represents the linking point.

[0142] (5) diastereomeric salt according to any one of paragraphs (1) to (4), wherein Ar represents one of the formulas where * represents the linking point.

[0143] (6) diastereomeric salt according to any one of paragraphs (1) to (5), wherein

[0144] Ar for one of the formulas (7) diastereomeric salt according to any one of paragraphs (1) to (6), wherein

[0145] Ar for (8) Method for the preparation of the diastereomeric salt (Va), (Vb), (Vc) and / or (Vd) according to one of the

[0146] Paragraphs (1) to (7), comprising the step

[0147] (i) Resolution of racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IV) with a chiral substituted tartaric acid ester of the formula (11a) or (13b) where Ar stands for unsubstituted or substituted aryl or heteroraryl.

[0148] (9) Procedure according to paragraph (8), wherein Ar is defined as in any one of paragraphs (2), (3), (4), (5), (6) or (7).

[0149] (10) Method according to paragraph (8) or (9) wherein the racemic resolution in step (i) is carried out in an organic solvent or in solvent mixtures consisting of water and water-miscible organic solvents.

[0150] (11) Method according to one of paragraph (10), wherein the organic solvent is selected from ethanol, methanol, isopropanol, 1-propanol, ethyl acetate, isobutanol, dichloromethane, 1-pentanol, acetone and spirit.

[0151] (12) The method according to paragraph (10), wherein the solvent mixture is selected from ethyl acetate / methanol 90:10; methanol / water 80:20; ethanol / water 90:10; ethanol / water 85:15; ethanol / water 80:20; ethanol / water 75:25; ethanol / water 70:30; dichloromethane; 1-propanol / water 80:20; 1-pentanol; 1-pentanol / water 90:10; isopropanol; isopropanol / water 80:20; isobutanol / water 90:10; isobutanol / water 80:20; cyclohexanol / water 90:10; benzyl alcohol / water 90:10; ethylene glycol; and ethylene glycol / water 80:20, where the mixing ratios are given in volume per volume (Vol / Vol).

[0152] (13) A process according to paragraph (10) or (12), wherein the solvent mixture is selected from ethanol / water, the mixing ratio (vol / vol) being in the range of ethanol:water from 1:1 to 6:1. (14) A process according to any one of paragraphs (10), (12) or (13), wherein the solvent mixture is selected from ethanol / water, the mixing ratio (vol / vol) being in the range of ethanol:water from 6:1 to 3:1. (15) A process according to any one of paragraphs (10), (12), (13) or (14), wherein the solvent mixture is selected from ethanol / water, the mixing ratio (vol / vol) being in the range of ethanol:water from 3:1.

[0153] 1 is located.

[0154] (16) A method according to any one of paragraphs (8) to (15), wherein the solvent is used in a solvent mixture in a 10- to 60-fold excess, preferably a 10- to 50-fold excess, wherein the

[0155] Excess (in liters) is related to the racemate (IV) (in kilograms).

[0156] (17) Method according to any one of paragraphs (8) to (16) wherein the racemic resolution in step (i) is carried out in an ethanol / water mixture.

[0157] (18) Method according to any one of paragraphs (8) to (17) wherein the racemic resolution in step (i) is carried out at a temperature in the range of 20°C to 50°C.

[0158] (19) Method according to any one of paragraphs (8) to (18) wherein the racemic resolution in step (i) is carried out at a temperature of 30°C to 50°C.

[0159] (20) Method according to any one of paragraphs (8) to (19), wherein (+) di-p-tolyl-D-tartaric acid (IIIa') is used for racemate separation in step (i).

[0160] (21) Procedure according to any of paragraphs (8) to (20), further comprising step (ii):

[0161] (ii) Isolating the precipitated diastereomeric salt (Va), (Vb), (Vc) and / or (Vd), wherein step (ii) is carried out after step (i). (22) A process according to any one of paragraphs (8) to (21) for the preparation of the diastereomeric salt (Va) and / or

[0162] (Vd), wherein in step (i) the chiral substituted tartaric acid ester of formula (lIla) is used and where Ar is defined as in any one of paragraphs (1), (2), (3), (4), (5), (6) or (7).

[0163] (23) A process according to any one of paragraphs (8) to (21) for the preparation of the diastereomeric salt (Vb) and / or (Vc), wherein in step (i) the chiral substituted tartaric acid ester of formula (IIIb) is used and where Ar is defined as in any one of paragraphs (1), (2), (3), (4), (5), (6) or (7).

[0164] (24) Method according to any one of paragraphs (8) to (23) wherein in step (i) 0.5 to 2.0 equivalents of the tartaric acid ester (11a) or (13b) are used for racemate cleavage.

[0165] (25) Method according to any one of paragraphs (8) to (24) wherein in step (i) 0.7 to 1.5 equivalents of the tartaric acid ester (1Ila) or (1IIIb) are used for racemate cleavage.

[0166] (26) Method according to any one of paragraphs (8) to (25) wherein in step (i) 0.7 to 1.4 equivalents of the tartaric acid ester (1Ila) or (1IIIb) are used for racemate cleavage.

[0167] (27) A process according to any one of paragraphs (8) to (26), wherein in step (i) 0.70 to 1.2 equivalents of the tartaric acid ester (11a) or (13b) are used for the racemate cleavage. (28) A process for the preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) encompassing steps (i) and (iii):

[0168] (i) Resolution of racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IV)

[0169] with a chiral substituted tartaric acid ester of the formula (11a) or (13b) wherein one or more of the diasteromeric salts (Va), (Vb), (Vc) and / or (Vd) is obtained, where Ar represents unsubstituted or substituted aryl or heteroraryl, and

[0170] (iii) Reacting the diastereomeric salt obtained in step (i) to give the compound according to formula (IVa). (29) The procedure according to paragraph (28), wherein Ar is defined according to any one of paragraphs (2) to (7). (30) The procedure according to paragraph (28) or (29), wherein step (i) is defined according to any one of paragraphs (8) to (27).

[0171] (31) Procedure according to any of paragraphs (28) to (30), further comprising step (ii):

[0172] (ii) Isolating the precipitated diastereomeric salt (Va), (Vb), (Vc) and / or (Vd), wherein step (ii) is optionally performed after step (i) and before step (iii).

[0173] (32) Procedure according to any one of paragraphs (28) to (30), wherein step (ii) is defined according to any one of paragraphs (21) to (27).

[0174] (33) Procedure according to any of paragraphs (28) to (32), comprising step (iii):

[0175] (iii) Treating the diastereomeric salt (Va), (Vb), (Vc) and / or (Vd) obtained in step (i) with a base.

[0176] (34) Method according to any one of paragraphs (28) to (33) wherein in step (iii) the base is an organic or inorganic base.

[0177] (35) A method according to any of paragraphs (28) to (34) wherein in step (iii) the base is an inorganic base and is selected from ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, ammonium phosphate, sodium hydroxide and mixtures thereof.

[0178] (36) Method according to any one of paragraphs (28) to (34), wherein in step (iii) the base is an organic base and is selected from aliphatic and aromatic bases.

[0179] (37) Method according to any one of paragraphs (28) to (34) or (36), wherein in step (iii) the base is an organic base and is selected from triethylamine, imidazole, N-methylimidazole, Hünigbase, pyridine, DBU and mixtures thereof.

[0180] (38) Method according to any one of paragraphs (28) to (35), wherein in step (iii) the base is selected from potassium hydroxide, potassium phosphate, sodium phosphate and mixtures thereof.

[0181] (39) A method according to any of paragraphs (28) to (38), wherein a solvent is used in step (iii). (40) A method according to any of paragraphs (28) to (39), wherein the

[0182] The solvent is selected from water, water-miscible organic solvents, ethanol, isopropanol, 1,2-ethanediol, methoxyethanol, methanol, acetone, spirits and mixtures thereof. (41) A process according to any of paragraphs (28) to (40), wherein the

[0183] The solvent is selected from mixtures of water and ethanol, with the mixing ratio (Vol / Vol) being in the range of ethanol:water from 1:6 to 1:3.

[0184] (42) Method according to any of paragraphs (28) to (41), wherein the solvent is selected from mixtures of water and ethanol, wherein the mixing ratio

[0185] (Vol / Vol) in the range of ethanol: water at 1:3, where the volume refers to the total volume of the solvent.

[0186] (43) Method according to any one of paragraphs (28) to (42) wherein 7 to 20 times the solvent mixture used in step (iii) is used, based on the diastereomeric salt (IVa) or (IVb) or (IVc) or (IVd) used.

[0187] (44) Method according to any one of paragraphs (28) to (43) wherein 9 to 11 times the solvent mixture is used in step (iii) based on the diastereomeric salt (IVa) or (IVb) or (IVc) or (IVd) used.

[0188] (45) Method according to any one of paragraphs (28) to (44) wherein 10 times the solvent mixture used in step (iii) is used, based on the diastereomeric salt (IVa) or (IVb) or (IVc) or (IVd) used.

[0189] (46) A method according to any one of paragraphs (28) to (45), wherein in step (ii) the solvent or solvent mixture is supplied at a temperature of 0°C to 60°C, preferably 0°C to 50°C, and subsequently a pH of 6.9 to 8.0, preferably a pH of 7.0 to 7.5, particularly preferably pH 7.1 is adjusted by adding the organic or inorganic base.

[0190] (47) Procedure according to any of paragraphs (28) to (46), further comprising step (iv):

[0191] (iv) Removal of the solvent, wherein step (iv) is optionally carried out after step (iii). (48) Method according to any one of paragraphs (28) to (47), wherein the racemate (IV) in step (i) with (+) di-p-tolyl-D-tartaric acid of formula (IIIa') in a brandy / water mixture to the diastereomeric salt (Va) is converted, and then in step (iii) cyanoethanol ester (IVa) (49) Method for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-

[0192] 2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carbox-amide of formula (Ia), include steps (i), (iii), (v), and (vi)

[0193] (i) Resolution of racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IV) with a chiral substituted tartaric acid ester of the formula (11a) or (13b)

[0194] wherein one or more of the diasteromeric salts (Va), (Vb), (Vc) and / or (Vd) is obtained, where Ar represents unsubstituted or substituted aryl or heteroraryl,

[0195] (iii) Reacting the diastereomeric salt obtained in step (i) to the compound according to formula (IVa).

[0196] (v) Saponification of the compound according to formula (IVa) in a THF / water mixture (2:1) with sodium hydroxide to give the compound of formula (Vlla) (vi) The compound of formula (Vlla) is reacted in THF as solvent, first with 1,1-carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine, after addition of hexamethyldisilazane, heated under reflux for 16-24 hours and then treated with a THF / water mixture to obtain the compound of formula (Ia).

[0197] (50) Procedure according to paragraph (49), wherein Ar is defined according to any of paragraphs (2) to (7).

[0198] (51) Procedure according to paragraph (49) or (50), wherein step (i) is defined according to one of paragraphs (8) to (48). (52) Procedure according to one of paragraphs (49) to (51), wherein step (iii) is defined according to one of paragraphs (28) to (48).

[0199] (53) Procedure according to any one of paragraphs (49) to (52), the procedure further comprising step (ii) according to any one of the preceding paragraphs (8) to (48).

[0200] (54) Procedure according to any one of paragraphs (49) to (53), the procedure further comprising step (iv) according to any one of the preceding paragraphs (8) to (48).

[0201] (55) Use of one or more diasteromeric salts (Va), (Vb), (Vc) and / or (Vd) in a process for the preparation of the compound according to formula (IVa) or (IVb).

[0202] (56) Use of one or more diasteromeric salts (Va), (Vb), (Vc) and / or (Vd) in a process for the preparation of the compound according to formula (IVa) or (IVb) according to any of the preceding paragraphs (8) to (54).

[0203] (57) Use of one or more diasteromeric salts (Va), (Vb), (Vc) and / or (Vd) in a process for the preparation of the compound according to formula (Vlla).

[0204] (58) Use of one or more diasteromeric salts (Va), (Vb), (Vc) and / or (Vd) in a process for the preparation of the compound according to formula (Vlla) according to any of the preceding paragraphs (8) to (54).

[0205] (59) Use of one or more diasteromeric salts (Va), (Vb), (Vc) and / or (Vd) in a process for the preparation of the compound according to formula (Ia). (60) Use of one or more diasteromeric salts (Va), (Vb), (Vc) and / or (Vd) in a process for the preparation of the compound according to formula (Ia) according to any one of the preceding paragraphs (8) to (54).

[0206] (61) Use of a chiral substituted tartaric acid ester of formula (11a) or (13b) for the preparation of the diastereomeme salts (Va), (Vb), (Vc) and / or (Vd) according to any one of paragraphs (1) to (7).

[0207] (62) Use of a chiral substituted tartaric acid ester of formula (IIIa') for the preparation of the diastereomeme salts (Va), (Vb), (Vc) and / or (Vd) according to any one of paragraphs (1) to (7). (63) Use of a chiral substituted tartaric acid ester of formula (IIIa) or (IIIb) for the preparation of any one of the compounds according to formula (IVa).

[0208] (64) Use of a chiral substituted tartaric acid ester of formula (IIIa') for the preparation of one of the compounds according to formula (IVa).

[0209] (65) Use of a chiral substituted tartaric acid ester of formula (11a) or (13b) for the preparation of one of the compounds according to formula (Vlla).

[0210] (66) Use of a chiral substituted tartaric acid ester of formula (IIIa') for the preparation of one of the compounds according to formula (Vlla).

[0211] (67) Use of a chiral substituted tartaric acid ester of formula (11a) or (13b) for the preparation of one of the compounds according to formula (1a). (68) Use of a chiral substituted tartaric acid ester of formula (3a') for the preparation of one of the

[0212] Compounds according to formula (Ia).

[0213] Experimental section

[0214] Abbreviations and acronyms

[0215]

[0216] Examples

[0217] Table 3 below shows the structures of the compounds recovered by HPLC. The corresponding retention times in HPLC are given below.

[0218]

[0219] Analytical method for testing the impurity content and enantiomeric purity on the

[0220] Finerenone, crude (I) grade. Content and organic RT(min) RRT

[0221] Contaminants

[0222] Finerenone (I) 5.2 1.00

[0223] Contamination A 3.3 0.53 Contamination B 3.7 0.60 Contamination C 3.9 0.62 Contamination D 1.4 0.70 Contamination E 5.5 0.89 Contamination F 5.6 0.91 Contamination G 5.8 1.10 Contamination H 7.6 1.23 Contamination K 10.4 1.68

[0224] Instrument: Ultra-high-performance liquid chromatograph (with a pressure range up to 1200 bar, thermostatically controlled column oven, and UV detector)

[0225] Column: YMC Triart C8

[0226] Length: 100 mm, Inner diameter: 3.0 mm, Micrometer size: 1.9 μm, Max. pressure: 1000 bar

[0227] Conditions: 20°C; 0.50 mU / min; 1.7 μL (10°C); 252 nm / 6 nm and 230 nm / 6 nm for the evaluation of DB tartaric acid

[0228] Eluent: A: 0.1% TFA in water; B: Acetonitrile

[0229] Gradient: Time (min) A (%) B (%)

[0230] 0.0 90.0 10.0 15.0 35.0 65.0

[0231] 16.0 20.0 80.0

[0232] 20.0 20.0 80.0

[0233] Enantiomeric purity RRT

[0234] RT(min)

[0235] Method A Finerenone (I) Approx. 11 1.00 (Ia) Approx. 9 0.82

[0236] Instrument: High-performance liquid chromatograph with thermostatically controlled column oven and UV detector

[0237] Column: Chiralpak IA

[0238] Length: 250 mm, Inner diameter: 4.6 mm, Micrometer size: 5.0 μm, Max. pressure: 300 bar

[0239] Conditions: 40 °C; 0.8 mL / min; 5 μL (20 °C); 255 nm / 6 nm

[0240] Eluent: A: acetonitrile; B: Methyl tert-butyl ether (MTBE)

[0241] Isocratic: A (%) 90: B (%)

[0242] 10

[0243] Enantiomeric purity Method B RT(min) RRT

[0244] Finerenone (I) 5.7 1.00

[0245] Enantiomer (Ia) 6.8 1.19

[0246] Instrument / Detector: High-performance liquid chromatograph with thermostatically controlled column oven, UV detector and data evaluation system. Measurement wavelength: 252 nm. Oven temperature: 40°C. Column: Chiralpak IC

[0247] Length: 150 mm, Inner diameter: 4.6 mm, Grain size: 3 μm Mobile phase: A: 50% Buffer 20mM NH40Ac pH 9 B: 50% Acetonitrile Flow rate: 1 mL / min.

[0248] Running time: 8 min.

[0249] Equilibration: not necessary, isocratic. Sample solvent: mobile phase.

[0250] Test solution: Dissolve approximately 0.5 mg / mL of the racemate substance with sample solvent. Reference solution: Prepare a reference solution analogous to the test solution.

[0251] Injection volume: 10 μL

[0252] The enantiomer measurements given in the following examples were all determined using Method B. Some values, especially those of the batches produced in the pilot plant, were remeasured using Method A for comparison and yielded comparable results.

[0253] The HPLC analysis data regarding purity and content for the final product finerenone, pure (I), given in the following examples, refer only to impurities present in the product at > 0.05%. This is essentially impurity E. All other impurities shown in the table above are generally < 0.05%. The structure of such impurities was determined by isolation from enriched mother liquors.

[0254] HPLC conditions / methods

[0255] Method (C)

[0256] YMC Hydrosphere C 18

[0257] 150*4.6 mm, 3.0 μm

[0258] 25 °C, 1 ml / min, 270 nm, 4 nm

[0259] 0 min: 70% TFA 0.1%*; 30% acetonitrile

[0260] 17 min: 20% TFA 0.1% ; 80% acetonitrile

[0261] 18 min: 70% TFA 0.1%; 30% Acetonitrile *: TFA in water

[0262] Method (D)

[0263] YMC Hydrosphere C 18

[0264] 150*4.6 mm, 3.0 μm

[0265] 25 °C, 1 ml / min, 255 nm, 6 nm

[0266] 0 min: 90% TFA 0.1%; 10% acetonitrile

[0267] 20 min: 10% TFA 0.1% ; 90% acetonitrile

[0268] 18 min: 10% TFA 0.1%; 90% Acetonitrile Method (E)

[0269] Nucleodur Gravity C 18

[0270] 150*2 mm, 3.0 μm

[0271] 35°C, 0.22 ml / min, 255 nm, 6 nm

[0272] Solution A: 0.58 g ammonium hydrogen phosphate and 0.66 g ammonium dihydrogen phosphate in 1 L water (ammonium phosphate buffer pH 7.2)

[0273] Solution B: Acetonitrile 0 min: 30% B; 70% A 15 min: 80% B; 20% A 25 min: 80% B; 20% A

[0274] Method (F)

[0275] Handling instructions Enantiomeric purity RT(min) RRT Enantiomer IVa 3.8 1.00

[0276] Enantiomer IVb 4.8 1.26

[0277] Instrument / Detector: High-performance liquid chromatograph with thermostatically controlled column oven, UV detector and data evaluation system

[0278] Measurement wavelength: 253 nm, bandwidth: 6 nm

[0279] Oven temperature: 40 °C

[0280] Column: Chiralpak AD-H

[0281] Length: 250 mm, inner diameter: 4.6 mm, grain size: 5 μm

[0282] Mobile Phase: A: Heptane

[0283] B: Isopropanol +0.1% DEA (diethylamine)

[0284] Gradient program: Time [min]

[0285] Flow:

[0286] Eluent A [%] Eluent B [%]

[0287] Start 2 [mL / min] 80 20

[0288] Running time: 8 min.

[0289] Example la

[0290] Preparation of the diastereomeric salt (Val) of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate with (+) di-p-toloyl-D-tartaric acid: 4 g (9.249 mmol) of racemic 2-cyanoethyl (4S, 4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IV) and 3.573 g (9.249 mmol) of (+) di-p-toloyl-D-tartaric acid were suspended in a mixture of 150 ml ethanol and 50 ml water and heated to 30°C (a solution was formed). The mixture was stirred overnight at room temperature. The precipitated crystals were filtered off and the product was washed twice with 5 ml of a 3:1 ethanol / water mixture. It was dried under vacuum at room temperature.

[0291] Yield: 4.0 g (105.6% of theory) of a colorless crystalline powder. Analytical results:

[0292] Enantiomeric purity (ee%): 65% ee (Method F)

[0293] A quantity of the diastereomeric salt enriched in this way was further purified as follows:

[0294] 3.80 g of the prepared diastereomeric salt were suspended in 76 ml of a 3:1 ethanol / water mixture, stirred for 2 h at 50°C, and stirred overnight at room temperature. The precipitated crystals were filtered off and washed twice with 5 ml of a 3:1 ethanol / water mixture. The product was dried under vacuum at room temperature.

[0295] Yield: 3.0 g (79.3% of theory) of a colorless crystalline powder. Analytical results:

[0296] Enantiomeric purity (ee%): 97% ee (Method F)

[0297] MS (EIpos): m / z = 433 [M+H] +

[0298] 1H-NMR (400 MHz, DMSO-d6): δ = 1.11 (t, J=7.03 Hz, 1 H), 2.03 - 2.45 (m, 5 H), 2.63 - 2.90 (m, 1 H), 3.77 (s, 1 H), 3.96 - 4.24 (m, 1 H), 5.18 - 5.44 (m, 1 H), 5.63 - 6.07 (m, 1 H), 7.09 - 7.52 (m, 2 H), 7.53 - 7.74 (m, 1 H),

[0299] 7.81 - 8.13 (m, 1 H), 8.26 - 8.57 (m, 1 H), 12.82 - 15.60 (m, 1 H).

[0300] Beispiel 1b

[0301] Herstellung von 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6- naphthyridine-3-carboxylat (IVa)

[0302] Three grams (3.66 mmol) of the title compound from Example 1a were suspended in 30 ml of a 3:1 water / ethanol mixture, and the mixture was cooled to 0°C. A 20% aqueous sodium phosphate solution was then slowly added (over 1 hour), and the pH was adjusted to 7.1. The mixture was stirred for 4 hours at this temperature. The precipitated solid was filtered off and washed twice with 10 ml of a 3:1 water / ethanol mixture (at 0°C). The product was dried under vacuum at 40°C.

[0303] Yield: 1.51 g (95.4% of theory) of a colorless crystalline powder. Analytical results:

[0304] Enantiomeric purity (ee%): 97% ee MS (EIpos): m / z = 433 [M+H] +

[0305] 1 H-NMR (300 MHz, DMSO-d6): δ = 1.11 (t, 3H), 2.16 (s, 3H), 2.42 (s, 3H), 2.78 (m, 2H), 3.77 (s, 3H), 4.01-4.13 (m, 4H), 5.37 (s, 1H), 7.25 (d, 1H), 7.28-7.33 (m, 2H), 7.60 (s, 1H), 8.35 (s, 1H). example 2a

[0306] Preparation of the diastereomeric salt (Va) of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate with (+) di-p-toloyl-D-tartaric acid

[0307] 900.0 g (2.08 mol) of racemic 2-cyanoethyl (4S, 4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IV) and 803.6 g (2.08 mmol) of (+) di-p-toloyl-D-tartaric acid were suspended in 15 L of a 3:1 ethanol / water mixture and heated to 30°C (resulting in a solution). The mixture was stirred overnight at room temperature, the precipitated crystals were filtered off, and the product was washed twice with 1000 mL of a 3:1 ethanol / water mixture. The product was dried under vacuum at room temperature.

[0308] Yield: 873.5 g (102.6% of theory) of a colorless crystalline powder. Analytical results:

[0309] Enantiomeric purity (ee%): 73% ee (Method F)

[0310] A quantity of the diastereomeric salt enriched in this way was further purified as follows:

[0311] 870 g of the prepared diastereomeric salt were suspended in 10 L of a 3:1 ethanol / water mixture, stirred for 2 h at 50°C, and stirred overnight at room temperature. The precipitated crystals were filtered off and washed twice with 1000 mL of a 3:1 ethanol / water mixture. The product was dried under vacuum at 40°C.

[0312] Yield: 679.4 g (78.6% of theory) of a colorless crystalline powder. Analytical results:

[0313] Enantiomeric purity (ee%): 98% ee (Method F)

[0314] Example 2b

[0315] Preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IVa)

[0316] 600 g (732.7 mmol) of the title compound from Example 2a were suspended in 6 L of a 3:1 water / ethanol mixture and the mixture was cooled to 0°C. A 30% aqueous sodium phosphate solution was then slowly added (over 1 hour) and the pH was adjusted to 7.1. The mixture was stirred for 4 hours at this temperature. The precipitated solid was filtered off and washed twice with 1000 mL of a 3:1 water / ethanol mixture (at 0°C). The product was dried under vacuum at 40°C.

[0317] Yield: 301.0 g (95.1% of theory) of a colorless crystalline powder. Analytical results:

[0318] Enantiomeric purity (ee%): 98% ee

[0319] MS (EIpos): m / z = 433 [M+H] +

[0320] 1 H-NMR (300 MHz, DMSO-d6): δ = 1.11 (t, 3H), 2.16 (s, 3H), 2.42 (s, 3H), 2.78 (m, 2H), 3.77 (s, 3H), 4.01-4.13 (m, 4H), 5.37 (s, 1H), 7.25 (d, 1H), 7.28-7.33 (m, 2H), 7.60 (s, 1H), 8.35 (s, 1H).

[0321] Example 2c

[0322] (4S) 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (Vlla) 200 g (4.624 mol) of 2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IVa) were dissolved in a mixture of 1.21 THF and 600 ml water and cooled to 0°C. A sodium hydroxide solution (prepared from 82 g of 45% aqueous sodium hydroxide (924.8 mmol) and 423 ml water) was added dropwise to this solution over 15 minutes at 0°C and stirred for 1.5 hours at 0°C. Extractions were made twice with 480 ml of methyl tert-butyl ether and once with 480 ml of ethyl acetate. The aqueous solution was adjusted to pH 7 at 0°C with dilute hydrochloric acid (prepared from 37.1 g of 37% HCl and 151 ml of water). The solution was then warmed to 20°C and an aqueous solution of 205 g of ammonium chloride in 554 ml of water was added. The mixture was stirred for 1 hour at 20°C, filtered, and washed twice with 150 ml of water and once with 400 ml of acetonitrile.Drying was carried out at 40°C in a vacuum under circulating gas.

[0323] Yield: 165.51 g (94.3 % of theory) of an almost colorless powder (very slight yellow tint).

[0324] HPLC method E: RT: approx. 6.8 min.

[0325] MS (EIpos): m / z = 380 [M+H] +

[0326] 1 H-NMR (300 MHz, DMSO-d6): δ = 1.14 (t, 3H), 2.14 (s, 3H), 2.37 (s, 3H), 3.73 (s, 3H), 4.04 (m, 2H), 5.33 (s, 1H), 7.26 (m, 2H), 7.32 (s, 1H), 7.57 (s, 1H), 8.16 (s, 1H), 11.43 (br. s, 1H).

[0327] Example 2d

[0328] (4S) 4-(4-Cyano-2-methoxyphenyl)-5-ethoxv-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I)

[0329] 160 g (422 mmol) of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (Vlla) and 95.8 g (591 mmol) of 1,1-carbodiimidazole were placed in 800 ml of THF, and 5.1 g (0.0417 mol) of DMAP were added at 20°C. The mixture was stirred for one hour at 20°C (gas evolution!) and then heated to 50°C for 2.5 hours. 297.3 g (1.842 mol) of hexamethyldisilazane were added to this solution, and the mixture was boiled under reflux for 22 hours. A further 180 ml of THF was added, and the mixture was cooled to 5°C. A mixture of 117 ml THF and 83.5 g water was added over 3 hours, maintaining a temperature between 5 and 20°C. The mixture was then boiled under reflux for one hour, cooled to 0°C via a ramp process (3 hours), and stirred for one hour at this temperature. The product was filtered and washed twice with 200 ml THF and twice with 320 ml water. Drying was carried out under vacuum at 70°C with a carrying gas. Yield: 150 g (94% of the total volume).Theory) of an almost colorless powder (very slight yellow tint).

[0330] HPLC method D: RT approx. 6.7 min.

[0331] MS (EIpos): m / z = 379 [M+H]+

[0332] 1H-NMR (300 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, 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H).

[0333] Example 2e

[0334] Production of pure product (I = Finerenone)

[0335] 139.20 g of the crude product (I) prepared in Example 2d were suspended in 2796 ml of denatured toluene ethanol and then heated to reflux. The product dissolved. The solution was stirred for one hour at this temperature. The solution was filtered through a heated pressure filter (T = 75°C), and the pressure filter was then rinsed with 36 ml of denatured toluene ethanol. The solvent was then distilled off (approximately 2304 ml were distilled off) until a final volume of approximately four times the initial volume (based on the initial substance: 139.2 g x 4 ~ 561 ml) was reached. The solution was then cooled to an internal temperature of 23°C (duration approximately 1.5 to 2 hours). Stirring continued for two hours at an internal temperature of 3°C. The product was filtered and washed once with 100 ml of denatured ethanol and toluene. Wet yield: 145.60 g. The wet product was dried at 50°C over the weekend (> 48 h) under vacuum (< 100 mbar). Yield: 133.7 g (96.0% of theory).) of a colorless crystalline powder, fine needle-like crystals.

[0336] Analytical results: MS (EIpos): m / z = 379 [M+H] +

[0337] 1 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, ³H), 5.37 (s, ³H), 6.60–6.84 (m (wide signal), ³H), 7.14 (d, ³H), 7.28 (dd, ³H), 7.37 (d, ³H), 7.55 (s, ³H), 7.69 (s, ³H) and small signals from the solvent DMSO and water at d = 2.5–2.6, as well as a very small peak at d = 3.38 (unassignable)

[0338] Modification: Mod A (according to the definition in WO2016 / 016287 A1)

[0339] Example 3a

[0340] Preparation of the diastereomeric salt (Va) of 2-cvanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate with (+) di-p-toloyl-D-tartaric acid

[0341] 1000 g (2.31 mol) of racemic 2-cyanoethyl (4S, 4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IV) and 695.5 g (1.80 mol) of (+) di-p-toloyl-D-tartaric acid were suspended in 15 L of a 3:1 ethanol / water mixture and heated to 30°C (resulting in a solution). The mixture was stirred overnight at room temperature, the precipitated crystals were filtered off, and the product was washed twice with 1000 mL of a 3:1 ethanol / water mixture. The product was dried under vacuum at room temperature.

[0342] Yield: 950.5 g (100.5% of theory) of a colorless crystalline powder. Analytical results:

[0343] Enantiomeric purity (ee%): 78% ee (Method F)

[0344] A quantity of the diastereomeric salt enriched in this way was further purified as follows:

[0345] 950 g of the prepared diastereomeric salt were suspended in 10 L of a 3:1 ethanol / water mixture, stirred for 2 h at 50°C, and stirred overnight at room temperature. The precipitated crystals were filtered off and washed twice with 1000 mL of a 3:1 ethanol / water mixture. The product was dried under vacuum at 40°C.

[0346] Yield: 781.3 g (82.6% of theory) of a colorless crystalline powder. Analytical results:

[0347] Enanthate purity (ee%): 99% ee (Method F)

[0348] Example 3b

[0349] Preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate 600 g (732.7 mmol) of the title compound from Example 3a were suspended in 6 L of a 3:1 water / ethanol mixture and the mixture was cooled to 0°C. A 20% aqueous sodium carbonate solution was then slowly added (over 1 hour) and the pH was adjusted to 7.1. The mixture was stirred for 4 hours at this temperature. The precipitated solid was filtered off and washed twice with 1000 mL of a 3:1 water / ethanol mixture (at 0°C). The product was dried under vacuum at 40°C.

[0350] Yield: 308.0 g (97.2% of theory) of a colorless crystalline powder. Analytical results:

[0351] Enantiomeric purity (ee%): 99% ee. In an analogous manner (as described in Example 2c - 2e), this prepared intermediate (IVa) was converted into the final stage (finerenone (Ia), pure):

[0352] Analytical results:

[0353] Modification: Mod A (according to the definition in WO2016 / 016287 A1) Example 4

[0354] Examples of various tartaric acid derivatives and other solvents

[0355] Example 4a

[0356] Preparation of the diastereomeric salt (Va) of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate with (-)-Di-O,O'-p-toluyl-L-tartaric acid. 1.00 g of racemate (IV) were reacted with 1.3 g (1.5 eq.) of (-)-Di-O,O'-p-toluyl-L-tartaric acid in 50 ml of a mixture of

[0357] Ethanol / water 3:1 was suspended, stirred, and allowed to stand. After some time, the diastereomeric salt precipitated. This was filtered off, dried (980 mg, 100% TH), and the enantiomeric excess was measured. The measurement showed an enantiomeric excess of 73.28% ee in favor of (IVb). Example 4b

[0358] Preparation of the diastereomeric salt (Va) of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate with (-)-Di-O-O'-p-toloyl-L-tartaric acid. 100 mg of racemate (IV) were suspended with (-)-Di-O,O'-p-toluyl-L-tartaric acid in a 3:1 ethanol / water mixture and stirred at 40°C for 3 hours, then allowed to stand at 20°C for 16 hours. After some time, the diastereomeric salt precipitated. This was filtered off, dried, and the enantiomeric excess (EE) was measured. The measurements showed enantiomeric excesses favoring (IVb). The following table summarizes the results:

[0359] Example 4c

[0360] Preparation of the diastereomeric salt (Va) of 2-cyanoethyl (4S)y4-(4-cvano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate with (-)-Di-O,O'-p-toloyl-L-tartaric acid. In a further series of experiments, 100 mg of racemate (IV) was suspended with (-)-Di-O,O'-p-toluyl-L-tartaric acid in a mixture of ethanol / water and stirred for 3 hours at 50°C, then left to stand for 16 hours at 20°C. After some time, the diastereomeric salt precipitated. This was filtered off, dried, and the enantiomeric excess was measured. The measurements showed enantiomeric excesses favoring (IVb). The following table summarizes the results:

[0361] Example 4c

[0362] Preparation of the diastereomeric salts (Va) of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxyv-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate by using different tartaric acid derivatives. 100 mg of racemate (IV) were suspended with a tartaric acid derivative in a mixture in 4 ml of solvent and stirred for 3 hours at 50°C, then left to stand for 16 hours at 20°C. After some time, the diastereomeric salt precipitated. This was filtered off, dried, and the enantiomeric excess, as well as the 1 The mass was measured by ¹H NMR and mass by mass spectrometer. The measurements showed enantiomeric excesses favoring (IVa). The following table summarizes the results:

[0363] Example 5a

[0364] Preparation of the diastereomeric salt (Val) of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate with (+)-Di-O,O'-p-chlorobenzoyl-D-carboxylic acid: 1000 g (2.31 mol) of racemic 2-cyanoethyl (4S, 4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IV) and 854.38 g (2.0 mol) of (+)-Di-O,O'-p-chlorobenzoyl-D-tartaric acid are suspended in a mixture of 30 L of a 7:3 ethanol / water mixture and Heated to 50°C (a solution forms). Stirred overnight at room temperature, the precipitated crystals filtered off, and washed twice with 1000 ml of a 7:1 ethanol / water mixture. The product was dried under vacuum at room temperature. Yield: 1105.0 g (111.3% of theory) of a colorless crystalline powder. Analytical results:

[0365] Enantiomeric purity (ee%): 79% ee

[0366] A quantity of the diastereomeric salt enriched in this manner was further purified as follows: 1104 g of the prepared diastereomeric salt were suspended in 10 L of a 7:1 ethanol / water mixture, stirred for 2 h at 50°C, and stirred overnight at room temperature. The precipitated crystals were filtered off and washed twice with 1000 mL of a 3:1 ethanol / water mixture. The product was dried under vacuum at 40°C.

[0367] Yield: 812.7 g (81.8% of theory) of a colorless crystalline powder. Analytical results:

[0368] Enantiomeric purity (ee%): 99% ee

[0369] Example 5b

[0370] Preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxv-2,8-dimethyl-1x,-dihydro-1,6-naphthyridine-3-carboxylate (IVa)

[0371] 600 g (697.95 mmol) of the title compound from Example 5a were suspended in 6 L of a 3:1 water / ethanol mixture and the mixture was cooled to 0°C. A 20% aqueous sodium carbonate solution was then slowly added (over 1 hour) and the pH was adjusted to 7.1. The mixture was stirred for 4 hours at this temperature. The precipitated solid was filtered off and washed twice with 1000 mL of a 3:1 water / ethanol mixture (at 0°C). The product was dried under vacuum at 40°C.

[0372] Yield: 285.8 g (94.7% of theory) of a colorless crystalline powder. Analytical results:

[0373] Enantiomeric purity (ee %): 99% ee In an analogous manner (as described in Example 2c - 2e), this prepared intermediate (IVa) was converted into the final stage (finerenone, pure):

[0374] Analytical results:

[0375] Modification: Mod A (according to the definition in WO2016 / 016287 A1).

Claims

Patent claims where Ar stands for an unsubstituted or substituted aryl or heteroaryl.

2. Diastereomeric salt according to claim 1, wherein Ar represents one of the formulas The * indicates the linking point.

3. Diastereomeric salt according to claim 1 or 2, wherein Ar represents one of the formulas where * represents the linkage point.

4. Diastereomeric salt according to any one of claims 1 to 3, wherein Ar for one of the formulas The * indicates the linking point.

5. Diastereomeric salt according to any one of claims 1 to 4, wherein Ar represents one of the formulas The * indicates the linking point.

6. Diastereomeric salt according to any one of claims 1 to 5, wherein Ar represents The * indicates the linking point.

7. Method for the preparation of the diastereomeric salt (Va), (Vb), (Vc) and / or (Vd) according to any one of claims 1 to 6, comprising step (i) (i) Resolution of racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IV) with a chiral substituted tartaric acid ester of formula (11a) or (13b) where Ar stands for unsubstituted or substituted aryl or heteroraryl.

8. Method according to claim 7, wherein the racemate resolution in step (i) is carried out at a temperature in the range of 20°C to 50°C.

9. Process for the preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl- 1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) encompassing steps (i) and (iii): (i) Resolution of racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IV) with a chiral substituted tartaric acid ester of formula (11a) or (13b) wherein one or more of the diasteromeric salts (Va), (Vb), (Vc) and / or (Vd) is obtained, where Ar represents unsubstituted or substituted aryl or heteroraryl, and (iii) Reaction of the diasteromeric salt obtained in step (i) to the compound according to formula (IVa).

10. The method of claim 9, comprising step (iii): (iii) Treating the diastereomeric salt (Va), (Vb), (Vc) and / or (Vd) obtained in step (i) with a base.

11. The method of claim 9 or 10, wherein in step (iii) the base is an inorganic base selected from ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, ammonium phosphate, sodium hydroxide, sodium phosphate, potassium phosphate.

12. Method according to any one of claims 9 to 11, wherein in step (ii) the solvent or solvent mixture is subsequently adjusted to a pH of 6.9 to 8.0, preferably a pH of 7.0 to 7.5, particularly preferably pH 7.1 by adding the organic or inorganic base at a temperature of 0°C to 60°C.

13. Method according to any one of claims 9 to 12, wherein the racemate (IV) in step (i) with (+) di-p-tolyl-D-tartaric acid of formula (IIIa') in a brandy / water mixture to the diastereomeric salt (Va) is converted, and then in step (iii) cyanoethanol ester (IVa) is also released in a spirit / water mixture using sodium phosphate.

14. Method for the preparation of (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), comprising steps (i), (iii), (v), and (vi): (i) Resolution of racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of the formula (IV) with a chiral substituted tartaric acid ester of formula (11a) or (13b) wherein one or more of the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) is obtained, where Ar represents unsubstituted or substituted aryl or heteroraryl, (iii) reacting the diastereomeric salt obtained in step (i) to give the compound according to formula (IVa) (v) Saponification of the compound according to formula (IVa) in a THF / water mixture (2:1) with sodium hydroxide to give the compound of formula (Vlla) (vi) The compound of formula (Vlla) is reacted in THF as a solvent, first with 1,1-carbodiimidazole and catalytic amounts of 4-(dimethylamino)pyridine, after addition of hexamethyldisilazane, heated under reflux for 16-24 hours and then treated with a THF / water mixture to obtain the compound of formula (Ia).

15. Use of one or more diasteromeric salts (Va), (Vb), (Vc) and / or (Vd) in a process for the preparation of the compound according to formula (IVa) or (IVb), (Vlla) or (Ia).