Process for preparing 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate by resolution of a racemate with a diastereomeric tartrate ester

Abstract

The present invention relates to diastereomeric salts (Va), (Vb), (Vc) and / or (Vd), a process for preparing diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) using chiral substituted tartaric acid esters of formula (IIIa) or (IIIb), a process for preparing compounds of formula (IVa) using diastereomeric salts (Va), (Vb), (Vc) and / or (Vd), a process for preparing compounds of formula (VII ... the use of diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) for preparing one of the compounds of formula (IVa), (VIIa) and / or (Ia); the use of chiral substituted tartaric acid esters of formula (IIIa) or (IIIb) for preparing diastereomeric salts (Va), (Vb), (Vc) and / or (Vd); and the use of chiral substituted tartaric acid esters of formula (IIIa) or (IIIb) for preparing one of the compounds of formula (IVa), (VIIa) and / or (Ia).

Description

Technical Field

[0001] The present invention relates to a method for preparing diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) using chiral substituted tartaric acid esters of formula (IIIa) or (IIIb), a method for preparing a compound of formula (IVa) using diastereomeric salts (Va), (Vb), (Vc) and / or (Vd), a method for preparing a compound of formula (VIIa) using diastereomeric salts (Va), (Vb), (Vc) and / or (Vd), a method for preparing a compound of formula (Ia) using diastereomeric salts (Va), (Vb), (Vc) and / or (Vd), the use of diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) for preparing one of the compounds of formula (IVa), (VIIa) and / or (Ia), the use of chiral substituted tartaric acid esters of formula (IIIa) or (IIIb) for preparing diastereomeric salts (Va), (Vb), (Vc) and / or (Vd), and the use of chiral substituted tartaric acid esters of formula (IIIa) or (IIIb) for preparing one of the compounds of formula (IVa), (VIIa) and / or (Ia).

Background Art

[0002] The above compounds 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 the compound of formula (Ia)

Chem.

[0003] The compound of formula (I)

Chem.

[0004] The expression "enantiomer of finerenone" or "enantiomer of the compound of formula (I)" refers to the compounds of formulas (Ia) and (Ib)

Chemical formula

[0005] Finerenone (Ia) acts as a non-steroidal antagonist of the mineralocorticoid receptor and can be used as a drug for preventing and / or treating cardiovascular and renal disorders such as heart failure and diabetic nephropathy.

[0006] The compounds of formula (I) or (Ia) and their preparation methods are also described in WO 2008 / 104306 pamphlet and ChemMedChem 2012, 7, 1385, as well as WO 2016 / 016287 pamphlet. To obtain the compound of formula (I), only the enantiomer

Chemical formula

Chemical formula

Chemical formula

[0007] In the published research-scale synthesis (WO 2008 / 104306 pamphlet), N-(dicyclopropylmethyl)-N 2A specially synthesized chiral phase containing methacryloyl-D-leucine amide was used for this purpose (prepared in-house). It was found that separation could also be carried out with readily commercially available phases. This is the Chiralpak AS-V phase, 20 μm. The eluent used was a 60:40 mixture of methanol / acetonitrile. In this case, chromatography can be carried out on a conventional chromatography column, but it is preferable to use 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). [Chemical formula]

[0008] SMB separation results in relatively good yields and optical purities, but the procurement costs and the operation of such equipment under GMP conditions pose major challenges and involve high costs. Each chiral phase used is also very expensive, has a limited lifespan, and must be frequently replaced during continuous production. For manufacturing engineering reasons, this is not optimal without a second plant to ensure continuous operation, which involves additional costs. Furthermore, especially in the case of products manufactured on a ton scale, solvent recovery is a time-limiting step, requires the procurement of huge falling-film evaporators, and involves the consumption of enormous amounts of energy.

[0009] Therefore, the problem to be addressed was to find an alternative synthetic route to enantiomerically pure finerenone (I) that is significantly cheaper and can be carried out using conventional pilot plant equipment (stirred tank / separator). Such equipment is traditionally standard equipment in pharmaceutical manufacturing plants and does not require additional investment. Furthermore, the qualification and validation of batch processes are considerably easier than those of chromatographic processes, which is a further advantage.

[0010] In the novel method of the present invention, instead of the complicated SMB separation of the racemic mixture of amide (I)

Chemical formula

Chemical formula

[0011] The synthesis of the racemic cyanoethanol ester of formula (IV) is described in WO 2016 / 016287 pamphlet (see Example 5 of WO 2016 / 016287 pamphlet; this is the compound of formula (XI)).

[0012] Numerous attempts have been made to develop the optical resolution of the racemate (IV) into the enantiomers (IVa) and (IVb) using conventional and customary methods.

Chemical formula

[0013]

Table 1

[0014] Table 1 lists the acids used for optical resolution. These are 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, and THF, acetone, ethyl acetate, dichloromethane, and several other solvents, and analyzed for diastereomeric salt formation.

[0015] Also, among the experiments conducted, there were experiments using the classical resolving agent (+)-tartaric acid.

[0016] However, in neither case was salt formation observed; instead, the racemate precipitates from the solution without forming a salt. The measured pKa (for the base) is 4.3, and thus, it can be inferred from the pKa of the racemic molecule (IV) that conventional optical resolution by diastereomeric salt formation with an organic acid is not possible because it makes salt formation virtually impossible, which essentially corresponds to the expectations of those skilled in the art. According to the literature, for example, "Handbook of Pharmaceutical Salts - Properties, Selection and Use; P. Heinrich Stahl, Camille G. Wermuth (eds.); Wiley - VCH, page 166", the pK difference should be at least 3 pK units to enable stable salt formation.

[0017] All efforts to obtain diastereomeric salts and then increase the enantiomeric excess to over 99% e.e. in subsequent synthetic steps were unproductive; thus, further alternatives were sought.

[0018] No salt formation was observed in the reaction with alkyl - substituted tartaric acid derivatives such as (-)-O,O'-dipivaloyl - L - tartaric acid or (-)-O,O'-diacetyl - L - tartaric acid.

[0019] However, surprisingly, it was found that aromatic or heteroaromatic substituted derivatives of tartaric acid (IIIa + IIIb) are excellently suitable for obtaining diastereomeric salts and achieving the required enantiomeric excess.

Prior Art Documents

Patent Documents

[0020]

Patent Document 1

Patent Document 2

Non-Patent Literature

[0021]

Non-Patent Literature 1

Non-Patent Literature 2

Non-Patent Literature 3

Non-Patent Literature 4

Summary of the Invention

Means for Solving the Problems

[0022] In summary, the present invention relates to the following main topics: (1) Diastereomeric salts (Va), (Vb), (Vc) and / or (Vd)

Chemical Formula

Chemical Formula

Chemical Formula

Chemical formula

Chemical formula

Chemical formula

[0023] The technical effects of the present invention can be summarized as follows: - The novel method of the present invention can be used in many less expensive methods or plants compared with the above prior art; - The novel method of the present invention can be implemented using conventional pilot plant equipment (stirred tank / insulation device), and such plants are traditionally part of the standard equipment of pharmaceutical manufacturing facilities and do not require additional capital costs. - The novel method of the present invention can be carried out on an industrial scale; - By the method of the present invention, it is possible to prepare diastereomeric salts having an enantiomeric excess of diastereomeric salts in the range of 65% to 80% e.e. - The diastereomeric salts obtained by the method of the present invention are notably of high enantiomeric excess, generally exceeding 95% e.e., which is sufficient to prepare finerenone with >>99% e.e. - The diastereomeric salts do not necessarily have to be dried and can also be used in the wet state in the following method steps. This also enables a one-pot process. - In the conversion of the acid (VIIa or VIIb) in tetrahydrofuran (THF), it has been found that the amide of formula (I) or (Ia) can crystallize directly from the solution and be obtained in high yield and high purity; - In the synthesis of the present invention, it is possible to avoid further intermediate steps, and thus the synthesis can be carried out in a time- and cost-efficient manner; - Examples of such intermediate steps are, for example, further purification of the individual components and / or cost- / energy-intensive recovery, solvent recovery or removal.

[0024] Accordingly, the present application relates to a chiral substituted tartaric acid ester of formula (IIIa)

Chemical formula

Chemical formula

Chemical formula

[0025] The term "substituted" means that one or more hydrogen atoms on the atom or group in question have been replaced by selection from the specified groups, provided that the normal valency of the atom in question is not exceeded under the particular circumstances. Combinations of substituents and / or variables are permitted.

[0026] The term "unsubstituted" means that none of the hydrogen atoms have been replaced.

[0027] A heteroaryl group can be a 5-membered heteroaryl group (e.g., thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl); or a 6-membered heteroaryl group (e.g., pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl); or a tricyclic heteroaryl group (e.g., carbazolyl, acridinyl or phenazinyl); or a 9-membered heteroaryl group (e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl or purinyl); or a 10-membered heteroaryl group (e.g., quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl).

[0028] The heteroaryl group is particularly a pyridinyl, pyrazinyl, pyrrolyl, pyrazolyl or pyrimidinyl group.

[0029] For the purposes of this application, the aryl group is particularly a phenyl group.

[0030] Substituents in the context of the present invention are halogen, C 1 ~C 6 -alkyl, C 1 ~C 6 -alkoxy, nitrile, nitro, cyano, CF 3, an amide group, for example, -NHCOR (wherein R is methyl, ethyl or phenyl), -NRCOR group (wherein R has the definition shown above), -CONHR group (wherein R has the definition shown above), CONRR’ (wherein R can be methyl, ethyl or phenyl, and R’ can be methyl, ethyl or phenyl), or a cyclic amide, for example 3-oxomorpholin-4-yl, 2-oxopiperidin-1-yl, and these may also be similarly substituted.

[0031] The term "halogen" refers to a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom.

[0032] “C 1 ~C 6 -alkyl” refers to a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, for example, 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 represents isomers thereof. The said group particularly has 1, 2, 3 or 4 carbon atoms (“C 1 ~C 4 -alkyl”), for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl group, particularly has 1, 2 or 3 carbon atoms (“C 1 ~C 3 -alkyl”), for example, methyl, ethyl, n-propyl or isopropyl group.

[0033] “C 1 ~C 6The term "C-alkoxy" refers to 1 ~C 6 The term "-alkyl" is as defined above, 1 ~C 6 -alkyl)-O-, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy or n-hexyloxy, or isomers thereof.

[0034] Ar is preferably: [ka] (wherein # represents a binding site; R1, R2, R3, R4, R5 are each 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 (wherein R can be methyl, ethyl or phenyl), or -NRCOR (wherein R has the meaning given above), or CONHR- (wherein R has the meaning given above), or CONRR' (wherein R can be methyl, ethyl or phenyl and R' can be methyl, ethyl or phenyl), or a cyclic amide, such as 3-oxomorpholin-4-yl, 2-oxopiperidin-1-yl, which may also be substituted in the same way). The substitution pattern may vary widely; for example, up to five different substituents are theoretically possible, but monosubstituted Ar groups are generally preferred. Alternatively, Ar may be a substituted heteroaromatic group, preferably a pyridine or pyrazine. Alternatively, Ar may be a polycyclic aromatic hydrocarbon, such as a substituted naphthalene, anthracene or quinoline.

[0035] More preferably, Ar is of the formula [ka] (wherein, * represents a binding site) is one of

[0036] Particularly preferably, Ar is a group of the formula

Chem.

[0037] An extremely particularly preferred Ar group is

Chem.

[0038] Among them, the p-tolyl group and the 4-chlorophenyl group are particularly preferred.

[0039] The p-tolyl group is extremely particularly preferred.

[0040] The preparation of the tartrate ester is known from the literature, for example, as described in Organic Synthesis, Coll. Vol. 9, p. 722 (1998); Vol. 72, p. 86 (1995), and Chirality 2011(23), 3, p. 228.

[0041] A further subject of the present invention relates to the diastereomeric salts (Va to Vd) of the formula

Chem.

Chem.

[0042] Diastereomeric salts in which Ar is p-tolyl are particularly preferred.

[0043] Whether (Va) to (Vd) are truly conventional diastereomeric salts or 1:1 molecular complexes stabilized via hydrogen bond formation cannot be reliably predicted. What is clear is that these molecular 1:1 aggregates are extremely stable, behave like conventional diastereomeric salts, and can be isolated. Therefore, the term diastereomeric salt is used hereinafter. To prepare the diastereomeric salts, tartaric acid derivatives of general formulas (IIIa) and (IIIb) are used:

Chemical formula

[0044] The preparation of the diastereomeric salts (Va to Vd) is carried out as follows:

Chemical formula

Chemical formula

Chemical formula

[0045] The reaction of the racemic mixture (IV) with the tartaric acid derivative of the general formula (IIIa) or (IIIb) results in four options (Va - d) for diastereomeric salt formation. Surprisingly, for example, when rac-(IV) is reacted with the tartaric acid derivative of the general formula (IIIa), the resulting diastereomeric salt is of the general formula (Va), and a preference is observed such that the enantiomer with the S configuration preferentially enters into salt formation. The diastereomeric salt (Va) precipitates almost quantitatively from the solution and can then be isolated therefrom, for example by filtration, leaving the enantiomer with the R configuration in solution. Similarly, in a most surprising manner, the racemate (II) is reacted with the tartaric acid derivative of the general formula (IIIb), and by the fact that the enantiomer with the R configuration preferentially enters into salt formation, the mirror image salt of the general formula (Vb) is prepared. The precipitated diastereomeric salt can be separated almost quantitatively, where the S - enantiomer remains in solution.

[0046] (IV) The stoichiometric ratio of (IIIa) / (IIIb) and the choice of solvent can be used to optimize the yield and enantiomeric purity.

[0047] Finerenone (I) has the S configuration. The tartaric acid esters of the S,S configuration or R,R configuration (depending on the substitution type) can form diastereomeric salts with the 4S - configured enantiomer of the racemate IV.

[0048] For optical resolution, 0.5 - 2.0 equivalents of the tartaric acid ester (IIIa) or (IIIb) are used, preferably 0.7 - 1.5 equivalents, more preferably 0.7 - 1.4 equivalents, and most preferably 0.70 - 1.2 equivalents.

[0049] The diastereomeric salt is formed in an organic solvent or a solvent mixture consisting of water and a water - miscible organic solvent.

[0050] Examples of suitable organic solvents in the context of the present application include ethanol, methanol, isopropanol, 1-propanol, ethyl acetate, isobutanol, dichloromethane, 1-pentanol or acetone, with ethanol being preferably used. The solvent may also be used in commercially available denatured forms of ethanol, such as toluene, methyl ethyl ketone, thiophene, hexane, etc., which also offers significant advantages for cost reasons; thus, in the context of the application, spirit consisting of ethanol, optionally denatured with toluene or methyl ethyl ketone, is particularly suitable for use on an industrial scale. Thus, when referring to "spirit", this means denatured ethanol. The term "spirit" is known to those skilled in the art. Further, 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. In the numerical values of the solvent ratios, the ratios mean volume to volume (v / v). For example, a solvent mixture consisting of methanol / water 80:20 contains 80 ml of methanol and 20 ml of water. Thus, the volume is based on the total volume of the solvent.

[0051] It is preferable to perform optical resolution in ethanol / water with a mixing ratio (v / v) in the range of ethanol:water = 1:1 to 6:1. However, it is preferable to use a mixture of ethanol:water = 6:1 to 3:1. A mixture of ethanol:water = 3:1 is particularly preferable. The mixture can be prepared in advance or can be produced in situ after charging all the components into the pot. The solvent mixture can be used in an excess of 10 to 60 times based on the racemate (IV), that is, 10 l to 40 l of the solvent mixture is used per 1 kg of the racemate. An excess of 10 to 50 times is preferable.

[0052] Optical resolution is typically carried out by first charging all the components into the solvent mixture at room temperature, then heating to 10 to 60 °C, preferably 20 to 50 °C, and continuing stirring at 20 to 50 °C for 1 to 10 hours, preferably 1 to 4 hours, and then cooling to room temperature (about 20 to 23 °C) within 3 to 24 hours, preferably 5 to 16 hours. Thereafter, stirring is continued at room temperature for 2 to 24 hours, preferably 5 to 18 hours, and extremely preferably 12 to 16 hours. Optical resolution is preferably carried out at a temperature of 20 °C to 50 °C.

[0053] Subsequently, the precipitated diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) are isolated.

[0054] Isolation is carried out by methods known to those skilled in the art, for example, by using filtration or a centrifuge. The filter cake thus obtained can be washed one or several times with a solvent or a solvent mixture. Subsequently, it is dried under reduced pressure, preferably at less than 100 mbar and at a high temperature (50 to 80 °C, preferably 50 °C). In some cases, it has been found that the use of a carrier gas is advantageous.

[0055] By the procedure outlined above, it is possible to prepare diastereomeric salts having an enantiomeric excess of diastereomeric salts in the range of 65% to 80% e.e.

[0056] For further purification to increase the enantiomeric excess, extraction stirring from the solvent or solvent - water mixture is repeated.

[0057] The diastereomeric salts do not necessarily have to be dried and can also be used in the next process step in a wet state.

[0058] Examples of suitable organic solvents in the context of this application include ethanol, methanol, isopropanol, 1 - propanol, ethyl acetate, isobutanol, dichloromethane, 1 - pentanol or acetone, with ethanol being preferably used. The solvent can also be used in commercially available modified forms of the denaturants used in ethanol, such as toluene, methyl ethyl ketone, thiophene, hexane, etc., which offers significant advantages for cost reasons. Thus, especially for industrial - scale use, in the context of the application, spirits consisting of ethanol that can optionally be denatured with toluene or methyl ethyl ketone are suitable. Additionally, 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. In the numerical values of the solvent ratio or mixing ratio, the ratio means volume - to - volume (v / v). For example, a solvent mixture consisting of methanol / water 80:20 contains 80 ml of ethanol and 20 ml of water.

[0059] Optical resolution is preferably carried out in ethanol / water with a mixing ratio (v / v) in the range of ethanol:water = 1:1 to 6:1. However, it is preferred to use a mixture of ethanol:water = 6:1 to 3:1. A mixture of ethanol:water = 3:1 is particularly preferred. The mixture may be prepared in advance or may be produced in situ after charging all the components into the pot. The solvent mixture can be used in an excess of 10 to 60 times based on the racemate (IV), that is, 10 l to 40 l of the solvent mixture is used per 1 kg of the racemate. An excess of 10 to 50 times is preferred.

[0060] The extraction stirring is typically carried out by first charging all the components into the solvent mixture at room temperature, then heating to 10 to 60 °C, preferably 20 to 50 °C, and continuously stirring at 20 to 50 °C for 1 to 10 hours, preferably 1 to 4 hours, and then cooling to room temperature (about 20 to 23 °C) within 3 to 24 hours, preferably 5 to 16 hours. Thereafter, the stirring is continued at room temperature for 2 to 24 hours, preferably 5 to 18 hours, and most preferably 12 to 16 hours.

[0061] Subsequently, the precipitated diastereomeric salt (Va) or (Vb) or (Vc) and / or (Vd) is isolated.

[0062] The isolation is carried out by methods known to those skilled in the art, for example, by using filtration or a centrifuge. The filter cake thus obtained can be washed one or several times with a solvent or a solvent mixture. Subsequently, it is dried under reduced pressure, preferably below 100 mbar, at a high temperature (50 °C to 80 °C, preferably 50 °C). In some cases, it has been found that the use of a carrier gas is advantageous. The diastereomeric salt thus obtained is notably of a high enantiomeric excess of generally over 95% e.e., which is sufficient to prepare finerenone at >>99% e.e.

[0063] The diastereomeric salt does not necessarily have to be dried and can also be used in a wet state in the next process step.

[0064] In addition to the above conventional procedures, the method steps can also be combined or their order can be changed, as shown in Table 2 below.

[0065]

Table 2A

Table 2B

[0066] Depending on the type of plant in the pilot plant or production, one variant or the other may be advantageous.

[0067] In the next step, the diastereomeric salt is treated with a base and the solvent is removed. The solvent is removed by methods known to those skilled in the art, for example by distillation. To prepare the chiral compounds (IVa) and (IVb), the diastereomeric salts of general formula (Va), (Vb), (Vc) or (Vd) must be treated with a base; when the organic solvent is removed by distillation, the target molecule (IVa) or (IVb) precipitates from the solution, and this is isolated, for example, by filtration and washing on the filter, and the respective tartrate esters of formula (IIIa) or (IIIb) remain in the solution in the form of salts.

Chemical formula

Chemical formula

[0068] Suitable bases in the context of the present invention are inorganic and organic bases. In the case of inorganic bases, ammonia, aqueous sodium hydroxide solution, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, ammonium phosphate can be used. However, it is preferred to use sodium hydroxide, sodium phosphate or potassium phosphate. It is particularly preferred to use sodium phosphate or potassium phosphate. It is important to emphasize that the inorganic bases can be used either in the anhydrous form or in the form of their hydrates; for example, sodium phosphate (anhydrous) and sodium phosphate hydrate can be successfully used. The organic bases used can be aliphatic or aromatic bases such as triethylamine, imidazole, N-methylimidazole, Hunig's base, pyridine, DBU.

[0069] The target compound (IVa) or (IVb) is released in a mixture of water and a water-miscible organic solvent such as ethanol, isopropanol, ethane-1,2-diol, methoxyethanol, methanol or acetone, with ethanol being preferred. The solvent may also be used in a commercially available denatured form of a denaturant used in the case of ethanol, such as toluene, methyl ethyl ketone, thiophene, hexane, etc.; in the context of use, it is preferred to use a spirit consisting of ethanol which may optionally be denatured with toluene or methyl ethyl ketone, which offers significant advantages for cost reasons. It has been found advantageous to use a mixture of water and ethanol in which the mixing ratio (v / v) is in the range of ethanol: water = 1:6 to 1:3. However, it is preferred to use a mixture of ethanol: water = 1:3. The mixture may be pre-prepared or may be produced in situ after charging all the components into the pot. This mixture can be used in an amount 7 to 20 times the amount of the diastereomeric salt (IVa or IVb or IVc or IVd) used, i.e., for example, 1 kg in 7 l to 20 l of this mixture. It is preferred to use 8 to 15 times the amount of this mixture, more preferably 9 to 11 times the amount of this mixture, and most preferably 10 times the amount of this mixture. The target compound (IVa) or (IVb) is released by first charging the diastereomeric salt (Va or Vb or Vc or Vd) into the solvent mixture at 0 °C to 60 °C, preferably 0 °C to 50 °C, and subsequently adding an organic or inorganic base (in solid form or preferably as an aqueous solution in water) to establish a pH of 6.9 to 8.0, preferably pH 7.0 to 7.5, more preferably pH 7.1. Suitable bases in the context of the present invention are inorganic and organic bases. In the case of inorganic bases, it is possible to use ammonia, aqueous 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. However, it is preferred to use sodium hydroxide, sodium phosphate or potassium phosphate. It is particularly is preferred. It is important to emphasize that the inorganic bases can be used either in the anhydrous form or in the form of their hydrates; for example, sodium phosphate (anhydrous) and sodium phosphate hydrate can be used successfully. The organic bases used can be aliphatic or aromatic bases such as triethylamine, imidazole, N-methylimidazole, Hunig's base, pyridine, DBU.

[0070] The base can be added either very rapidly (within a few minutes) or very slowly (within a few hours), for example, within any time from 5 minutes to a maximum of 3 hours. In either case, a faster addition is preferred. A metered addition within 5 minutes to 1 hour is preferred. This purpose can be achieved by a pH meter installed in the reactor, and the adjustment is controlled by the pH meter, and the base is gradually metered in. Alternatively, it is possible to add a fixed amount of base (in solid form or dissolved in a solvent) at the start, which, based on experience, ensures that the desired pH range is preferentially achieved. In production, such a procedure is most preferred. After the pH is established, it has been found advantageous to continue stirring at 0 °C to 50 °C, preferably 20 °C to 50 °C, preferably 0 °C to 20 °C. The duration of continuous stirring can be 1 to 10 hours, preferably 2 to 5 hours, more preferably 3 to 4 hours.

[0071] Isolation is carried out by methods known to those skilled in the art, for example, by using filtration or a centrifuge. The filter cake thus obtained can be washed one or more times with a solvent or a solvent mixture. Subsequently, it is dried under reduced pressure, preferably below 100 mbar, at a high temperature (50 to 80 °C, preferably 50 °C). In some cases, it has been found that the use of a carrier gas is advantageous. As a particularly preferred method, especially for industrial-scale implementation, di-p-tolyl-D-tartaric acid (IIIa') is used, which can be used either in the anhydrous form or in the hydrated form:

Chemical formula

[0072] Optical resolution is preferably carried out in a spirit / water mixture. The subsequent release of (IVa)

Chemical formula

[0073] It is also possible to isolate the target enantiomer from the mother liquor. First, the appropriate diastereomeric salts (Va), (Vb), (Vc) or (Vd), here prepared from either (IVa) or (IVb), are isolated by filtration, and then the pH of the mother liquor containing each enantiomer is adjusted to pH > 7, preferably pH 7.1 - 8, most preferably pH 7.1 by the addition of a base such as ammonia, sodium hydroxide solution, 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, more preferably sodium phosphate and potassium phosphate. Then, the organic solvent - preferably ethanol - is distilled off at atmospheric pressure or under a more gentle reduced pressure. Thereby, the corresponding enantiomer precipitates. The product is filtered off, washed with water or a water / solvent mixture and dried. By appropriate final crystallization from spirit as described, for example, in Example 1c, the compounds (IVa) and (IVb) in the corresponding pure form are obtained.

Chemical formula

[0074] The further conversion to finerenone (Ia) or the enantiomer (Ib) is carried out as follows: Proceeding from the cyanoethyl ether (IVa or IVb), the acid (VIIa or VIIb) is obtained by alkaline hydrolysis and subsequent acidic work-up: [Chemistry] [Chemistry]

[0075] It has been found that the reaction can be carried out very easily in a relatively concentrated form in a THF / water mixture. For this purpose, it is preferred to work in a 2:1 mixture of THF / water (9-fold amount), meter in an aqueous sodium hydroxide solution at 0 °C to 5 °C, and then stir the mixture at 0 °C to 5 °C for 1 to 2 hours. It is also possible to use a potassium hydroxide solution, but a sodium hydroxide solution is preferred. The work-up is carried out by extraction only with MTBE (methyl tert-butyl ether) and ethyl acetate or toluene and isolation by adjusting the pH to 7 with a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid. Subsequently, it is possible to add a saturated ammonium salt solution of the corresponding acid, preferably ammonium chloride solution, to quantitatively crystallize the product. After isolation, the product is washed with water and ethyl acetate or acetonitrile or acetone, preferably acetonitrile, and dried under vacuum at 40 °C to 50 °C. The yield is virtually quantitative (99%).

[0076] The subsequent conversion from the acid to the amide (I or Ia) is described as follows: In the conversion of the acid (VIIa or VIIb) in tetrahydrofuran (THF), it was found that the amide (I or Ia) crystallized directly from the solution and could be obtained in high yield and high purity. For this purpose, the carboxylic acid (VIIa or VIIb) is reacted at a temperature of 20 - 50 °C (the preferred approach has been found to be to start at 20 °C first, then stir at that temperature for 1 - 2 hours, and then continue stirring at 50 °C for 2 - 3 hours) in THF under 4-(dimethylamino)pyridine (DMAP) catalysis (5 - 15 mol%, preferably 10 mol% / it has also been found that the reaction can be carried out without adding DMAP in some cases) with 1.1 - 1.6 equivalents, preferably 1.3 - 1.4 equivalents of 1,1'-carbodiimidazole (CDI) to obtain an imidazolide. After the activation is complete, 3 - 8 equivalents, preferably 4.5 equivalents of hexamethyldisilazane are added and the mixture is heated under reflux for 16 - 24 hours, preferably 16 hours. The disilylamide compound formed here can optionally be isolated. However, it has been found to be more advantageous to continue with a one-pot reaction. Therefore, after the reaction is complete, the mixture is cooled to 0 °C - 3 °C and water or a water / THF mixture is metered in. The advantageous amount of water has been found to be 0.5 - 0.7 times the amount of the reactants, and the particularly advantageous amount has been found to be 0.52 times the amount of water. The water can be added directly or as a mixture with about 1 - 2 volume equivalents of THF. After the quenching is complete, the mixture is heated under reflux for a total of 1 - 3 hours, preferably 1 hour. The mixture is cooled to 0 °C and stirred at that temperature for a further 1 - 5 hours, preferably 3 hours. Then, the product is isolated by filtration or centrifugation. The product is washed with THF and water and dried under vacuum at a high temperature (30 °C - 100 °C, preferably 40 °C - 70 °C). The yield is very high, exceeding 93% of the theoretical value. The purity is generally over 99% (HPLC, 100% method). The compound (VIIa or VIIb) can also be obtained directly by reacting it with ammonia gas in an autoclave (about 25 - 30 bar).For this purpose, the above pre-activation is carried out, and then the reaction mixture is heated under a pressure of gaseous ammonia. When the reaction is complete, it is cooled and the product is filtered off. The yields and purities thus obtained are equivalent.

Chemical formula

[0077] Final crystallization method (establishment of the final modification Mod A): For this purpose, for GMP-related reasons, (I) (or Ia) is first dissolved in ethanol, subjected to particle filtration, and then the solvent is distilled off under reduced pressure or at standard temperature, but it is preferable to use toluene-modified ethanol. The mixture is concentrated to about 3 to 5 times the volume of (I) (or Ia); the product crystallizes. The mixture is cooled to 0 °C, and then the crystals are isolated and dried at 40 °C to 50 °C under reduced pressure. The yield is generally over 90% of the theoretical value. The achieved chemical purity is over 99.8%, and a content of about 100% corresponds to the standards of commercial products according to the ICH guidelines. The residual solvent is less than 0.02% in the case of ethanol. The optical purity is over 99% e.e.

[0078] Therefore, the present invention also provides an enantiomerically pure cyanoethanol ester of formula (IVa), 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

Chemical formula

Chemical formula

Embodiments for Carrying out the Invention

[0079] Hereinafter, further embodiments of the present invention will be described: The present invention relates to a chiral substituted tartaric acid ester of formula (IIIa) [Chemical formula] (wherein Ar is unsubstituted or substituted aryl or heteroaryl) used in the racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IV) [Chemical formula] optical resolution 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) [Chemical formula] relates to a method for preparing the same.

[0080] The chiral substituted tartaric acid ester of formula (IIIa) [Chemical formula] (wherein Ar is [Chemical formula] (where # represents a binding site, R1, R2, R3, R4, and R5 are each 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 (where R can be methyl, ethyl, or phenyl), or -NRCOR (where R has the meaning shown above) or CONHR- (where R has the meaning shown above), or a CONRR' group (where R' has the same meaning as R defined above), or a cyclic amide such as 3-oxomorpholin-4-yl, 2-oxopiperidin-1-yl, and these may also be similarly substituted. The substitution patterns may vary widely; for example, theoretically up to 5 different substituents are possible, but generally a mono-substituted Ar group is preferred. Alternatively, Ar may preferably be a substituted heteroaromatic group such as pyridine or pyrazine. Alternatively, Ar may be a polycyclic aromatic hydrocarbon such as substituted naphthalene, anthracene, or quinoline.) is) used in the racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IV)

Chemical formula

Chemical formula

[0081] 2-Cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) (wherein, Ar is a formula

Chemical formula

[0082] 2-Cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) (wherein, Ar is a formula

Chemical formula

Chemical formula

[0083] 2-Cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) (wherein, Ar is a formula [Chemical formula] (wherein * represents a binding site) is one of) A method for preparing [compound] is particularly preferred.

[0084] 2-Cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) (wherein Ar is [Chemical formula] (wherein * represents a binding site) is) A method for preparing [compound] is extremely particularly preferred.

[0085] The present invention also relates to a racemic cyanoethanol ester of formula (IV) [Chemical formula] using a chiral substituted tartaric acid ester of formula (IIIa) [Chemical formula] (wherein Ar is unsubstituted or substituted aryl or heteroaryl) to convert to 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 (IVa) [Chemical formula] and hydrolyzing this with a sodium hydroxide solution in a THF / water mixture (2:1) to obtain a compound of formula (VIIa) [Chemical formula] to obtain this, which is then reacted first with 1,1 - carbodiimidazole and a catalytic amount of 4 - (dimethylamino)pyridine in THF as a solvent, hexamethyldisilazane is added, and then the mixture is heated under reflux for 16 - 24 hours, and then a THF / water mixture is added, characterized in that (4S)-4-(4 - cyano - 2 - methoxyphenyl)-5 - ethoxy - 2,8 - dimethyl - 1,4 - dihydro - 1,6 - naphthyridine - 3 - carboxamide of formula (Ia)

Chemical formula

[0086] a chiral substituted tartaric acid ester of formula (IIIa)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0087] A method for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia) (In formula (III), Ar is a formula

Chemical formula

[0088] A method for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia) (In formula (III), Ar is a formula

Chemical formula

[0089] Method for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia) (In formula (III), Ar is a formula

Chemical formula

[0090] Racemic cyanoethanol ester of formula (IV)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0091] Paragraphs 1.~14. The following paragraphs 1.~14 constitute further embodiments of the present invention.

[0092] 1. A chiral substituted tartaric acid ester of formula (IIIa) [Chemical formula] (wherein Ar is unsubstituted or substituted aryl or heteroaryl) used in The optical resolution of the racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IV) [Chemical formula] to obtain 2-Cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) [Chemical formula] A method for preparing

[0093] 2. The method according to paragraph 1, characterized in that the optical resolution is carried out in an ethanol / water mixture.

[0094] 3. The method according to any one of paragraphs 1 and 2, characterized in that the optical resolution is carried out at a temperature in the range of 20 °C to 50 °C.

[0095] 4. The method according to any one of paragraphs 1 to 3, characterized in that the optical resolution is carried out at a temperature of 30 °C to 50 °C.

[0096] 5. (+)-Di-p-tolyl-D-tartaric acid (IIIa') [Chemical formula] The method according to any one of paragraphs 1 to 4, characterized in that it is used for optical resolution.

[0097] 6. The method according to any one of paragraphs 1 to 5, characterized in that the precipitated diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) are isolated.

[0098] 7. The method according to any one of paragraphs 1 to 6, characterized in that the diastereomeric salt is treated with a base to remove the solvent.

[0099] 8. The method according to any one of paragraphs 1 to 7, characterized in that the base used is potassium hydroxide, potassium phosphate or sodium phosphate.

[0100] 9. Racemate (IV) [Chemical formula] in a spirit / water mixture with di-p-tolyl-D-tartaric acid of formula (IIIa') [Chemical formula] React with to obtain the diastereomeric salt (Va) [Chemical formula] to obtain, and then, similarly, in a spirit / water mixture, using sodium phosphate, the cyanoethanol ester (IVa) [Chemical formula] The method according to any one of paragraphs 1 to 8, which releases

[0101] 10. Racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IV) [Chemical formula] with a chiral substituted tartaric acid ester of formula (IIIa) [Chemical formula] (wherein Ar is unsubstituted or substituted aryl or heteroaryl) to convert to 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 (IVa) [Chemical formula] and hydrolyze this with a sodium hydroxide solution in a THF / water mixture (2:1) to obtain the compound of formula (VIIa) [Chemical formula] Obtained, then the compound of formula (VIIa) is first reacted with 1,1 - carbodiimidazole and a catalytic amount of 4 - (dimethylamino)pyridine in THF as a solvent, hexamethyldisilazane is added, then the mixture is heated under reflux for 16 - 24 hours, and then a THF / water mixture is added, characterized in that (4S)-4-(4 - Cyano - 2 - methoxyphenyl)-5 - ethoxy - 2,8 - dimethyl - 1,4 - dihydro - 1,6 - naphthyridine - 3 - carboxamide of formula (Ia)

Chemical formula

[0102] 11. Racemic 2 - cyanoethyl (4S)-4-(4 - cyano - 2 - methoxyphenyl)-5 - ethoxy - 2,8 - dimethyl - 1,4 - dihydro - 1,6 - naphthyridine - 3 - carboxylate of formula (IV)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0103] 12. Formula

Chemical formula

Chemical formula

[0104] 13. Ar is

Chemical formula

[0105] 14. Ar is

Chemical formula

[0106] Paragraphs (1) to (68) Further embodiments of the present invention are also described in the following paragraphs (1) to (68):

[0107] (1) The diastereomeric salt of the formula

Chemical formula

Chemical formula

[0108] (2) Ar is thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl or purinyl; or a 10-membered heteroaryl group, for example, quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl and pteridinyl, a heteroaryl group selected from the group consisting of is or Ar is

Chemical formula

[0109] (3) Ar is of the formula [Chemical formula] (wherein * represents the binding site) is one of the diastereomeric salt described in paragraph (1) or (2).

[0110] (4) Ar is of the formula [Chemical formula] (wherein * represents the binding site) is one of the diastereomeric salt described in any one of paragraphs 1 to 3.

[0111] (5) Ar is of the formula [Chemical formula] (wherein * represents a binding site) is one of the diastereomeric salts described in any one of paragraphs 1 to 4.

[0112] (6) Ar is of the formula

Chemical formula

[0113] (7) Ar is

Chemical formula

[0114] (8) (i) Using a chiral substituted tartaric acid ester of formula (IIIa) or (IIIb)

Chemical formula

Chemical formula

[0115] (9) The method according to paragraph (8), wherein Ar is as defined in any one of paragraphs (2), (3), (4), (5), (6) and (7).

[0116] (10) The method according to paragraph (8) or (9), wherein the optical splitting in step (i) is carried out in an organic solvent or a solvent mixture consisting of water and a water-miscible organic solvent.

[0117] (11) The method according to one of paragraphs (10), wherein the organic solvent is selected from ethanol, methanol, isopropanol, 1-propanol, ethyl acetate, isobutanol, dichloromethane, 1-pentanol, acetone and spirit.

[0118] (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, and the mixing ratio is reported as volume per volume (v / v).

[0119] (13) The method according to paragraph (10) or (12), wherein the solvent mixture is selected from ethanol / water and the mixing ratio (v / v) is in the range of ethanol:water of 1:1 to 6:1.

[0120] (14) The method according to any one of paragraphs (10), (12) and (13), wherein the solvent mixture is selected from ethanol / water and the mixing ratio (v / v) is in the range of ethanol:water of 6:1 to 3:1.

[0121] (15) The method according to any one of paragraphs (10), (12), (13) and (14), wherein the solvent mixture is selected from ethanol / water and the mixing ratio (v / v) is within the range of ethanol:water of 3:1.

[0122] (16) The method according to any one of claims (8) to (15), wherein the solvent is used in a 10- to 60-fold excess, preferably a 10- to 50-fold excess, of the solvent mixture, and the excess (liters) is based on the racemate (IV) (kilograms).

[0123] (17) The method according to any one of paragraphs (8) to (16), wherein the optical resolution in step (i) is carried out in an ethanol / water mixture.

[0124] (18) The method according to any one of paragraphs (8) to (17), wherein the optical resolution in step (i) is carried out at a temperature in the range of 20°C to 50°C.

[0125] (19) The method according to any one of paragraphs (8) to (18), wherein the optical resolution in step (i) is carried out at a temperature in the range of 30°C to 50°C.

[0126] (20) (+)-Di-p-tolyl-D-tartaric acid (IIIa’)

Chemical formula

[0127] (21) Step (ii): (ii) Isolating the precipitated diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) (step (ii) follows step (i)) The method according to any one of paragraphs (8) to (20), further comprising this step.

[0128] (22) In step (i), the chiral substituted tartaric acid ester of formula (IIIa)

Chemical formula

[0129] (23) In step (i), a chiral substituted tartaric acid ester of formula (IIIb) [Chemical formula] The method according to any one of paragraphs (8) to (21), wherein in step (i), a chiral substituted tartaric acid ester of formula (IIIb) is used and Ar is as defined in any one of paragraphs (1), (2), (3), (4), (5), (6) and (7) to prepare a diastereomeric salt (Vb) and / or (Vc).

[0130] (24) The method according to any one of paragraphs (8) to (23), wherein in step (i), 0.5 to 2.0 equivalents of tartaric acid ester (IIIa) or (IIIb) are used for optical resolution.

[0131] (25) The method according to any one of paragraphs (8) to (24), wherein in step (i), 0.7 to 1.5 equivalents of tartaric acid ester (IIIa) or (IIIb) are used for optical resolution.

[0132] (26) The method according to any one of paragraphs (8) to (25), wherein in step (i), 0.7 to 1.4 equivalents of tartaric acid ester (IIIa) or (IIIb) are used for optical resolution.

[0133] (27) The method according to any one of paragraphs (8) to (26), wherein in step (i), 0.70 to 1.2 equivalents of tartaric acid ester (IIIa) or (IIIb) are used for optical resolution.

[0134] (28) Steps (i) and (iii): (i) A chiral substituted tartaric acid ester of formula (IIIa) or (IIIb) [Chemical formula] using the racemic 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IV) [Chemical formula] obtaining one or more of the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) by optical resolution of (wherein Ar is unsubstituted or substituted aryl or heteroaryl), and (iii) converting the diastereomeric salt obtained in step (i) into a compound of formula (IVa) comprising 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) [Chemical formula] A method for preparing

[0135] (29) The method according to paragraph (28), wherein Ar is as defined according to any one of paragraphs (2) to (7).

[0136] (30) The method according to paragraph (28) or (29), wherein step (i) is as defined according to any one of paragraphs (8) to (27).

[0137] (31) Step (ii): (ii) isolating the precipitated diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) (step (ii) optionally follows step (i) and precedes step (iii)) The method according to any one of paragraphs (28) to (30), further comprising

[0138] (32) The method according to any one of paragraphs (28) to (30), wherein step (ii) is as defined according to any one of paragraphs (21) to (27).

[0139] (33) Step (iii): (iii) Treating the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) obtained in step (i) with a base The method according to any one of paragraphs (28) to (32), comprising

[0140] (34) The method according to any one of paragraphs (28) to (33), wherein in step (iii), the base is an organic or inorganic base.

[0141] (35) The method according to any one of paragraphs (28) to (34), wherein in step (iii), the base is an inorganic base and is selected from ammonia, sodium hydroxide solution, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, ammonium phosphate, sodium hydroxide and mixtures thereof.

[0142] (36) The 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.

[0143] (37) The method according to any one of paragraphs (28) to (34) and (36), wherein in step (iii), the base is an organic base and is selected from triethylamine, imidazole, N-methylimidazole, Hunig's base, pyridine, DBU and mixtures thereof.

[0144] (38) The 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.

[0145] (39) The method according to any one of paragraphs (28) to (38), wherein a solvent is used in step (iii).

[0146] (40) The method according to any one of paragraphs (28) to (39), wherein the solvent is selected from water, a water-miscible organic solvent, ethanol, isopropanol, ethane-1,2-diol, methoxyethanol, methanol, acetone, spirit, and mixtures thereof.

[0147] (41) The method according to any one of paragraphs (28) to (40), wherein the solvent is selected from a mixture of water and ethanol, and the mixing ratio (v / v) is in the range of ethanol:water of 1:6 to 1:3.

[0148] (42) The method according to any one of paragraphs (28) to (41), wherein the solvent is selected from a mixture of water and ethanol, the mixing ratio (v / v) is in the range of ethanol:water of 1:3, and the volume is based on the total volume of the solvent.

[0149] (43) The method according to any one of paragraphs (28) to (42), wherein the amount of the solvent mixture used in step (iii) is 7 to 20 times the amount of the diastereomeric salt (IVa) or (IVb) or (IVc) or (IVd) used.

[0150] (44) The method according to any one of paragraphs (28) to (43), wherein the amount of the solvent mixture used in step (iii) is 9 to 11 times the amount of the diastereomeric salt (IVa) or (IVb) or (IVc) or (IVd) used.

[0151] (45) The method according to any one of paragraphs (28) to (44), wherein the amount of the solvent mixture used in step (iii) is 10 times the amount of the diastereomeric salt (IVa) or (IVb) or (IVc) or (IVd) used.

[0152] (46) The solvent or solvent mixture of step (ii) is first charged at a temperature of from 0 °C to 60 °C, preferably from 0 °C to 50 °C, and then adjusted to a pH of from 6.9 to 8.0, preferably from pH 7.0 to 7.5, more preferably pH 7.1 by adding an organic or inorganic base, the method according to any one of paragraphs (28) to (45).

[0153] (47) Step (iv): (iv) The step of removing the solvent (Step (iv) optionally follows step (iii)) The method according to any one of paragraphs (28) to (46), further comprising

[0154] (48) In step (i), the racemate (IV)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0155] (49) Steps (i), (iii), (v) and (vi) (i) A chiral substituted tartaric acid ester of formula (IIIa) or (IIIb)

Chemical formula

[0156] (50) The method according to paragraph (49), wherein Ar is as defined according to any one of paragraphs (2) to (7).

[0157] (51) The method according to paragraph (49) or (50), wherein step (i) is as defined according to any one of paragraphs (8) to (48).

[0158] (52) The method according to any one of paragraphs (49) to (51), wherein step (iii) is as defined according to any one of paragraphs (28) to (48).

[0159] (53) The method according to any one of paragraphs (49) to (52), further comprising step (ii) as described in any one of paragraphs (8) to (48).

[0160] (54) The method according to any one of paragraphs (49) to (53), further comprising step (iv) as described in any one of paragraphs (8) to (48).

[0161] (55) Use of one or more diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) in a method for preparing a compound of formula (IVa) or (IVb).

[0162] (56) Use of one or more diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) in a method for preparing a compound of formula (IVa) or (IVb) according to any one of paragraphs (8) to (54).

[0163] (57) Use of one or more diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) in a method for preparing a compound of formula (VIIa).

[0164] (58) Use of one or more diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) in a method for preparing a compound of formula (VIIa) according to any one of paragraphs (8) to (54).

[0165] (59) Use of one or more diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) in a method for preparing a compound of formula (Ia).

[0166] Use of one or more diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) in a process for preparing a compound of formula (Ia) as described in any of paragraphs (8) to (54) above.

[0167] (61) Use of a chiral substituted tartaric acid ester of formula (IIIa) or (IIIb) for preparing one of the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) as described in any of paragraphs (1) to (7).

[0168] (62) Use of a chiral substituted tartaric acid ester of formula (IIIa’) for preparing one of the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) as described in any of paragraphs (1) to (7).

[0169] (63) Use of a chiral substituted tartaric acid ester of formula (IIIa) or (IIIb) for preparing one of the compounds of formula (IVa).

[0170] (64) Use of a chiral substituted tartaric acid ester of formula (IIIa’) for preparing one of the compounds of formula (IVa).

[0171] (65) Use of a chiral substituted tartaric acid ester of formula (IIIa) or (IIIb) for preparing one of the compounds of formula (VIIa).

[0172] (66) Use of a chiral substituted tartaric acid ester of formula (IIIa’) for preparing one of the compounds of formula (VIIa).

[0173] (67) Use of a chiral substituted tartaric acid ester of formula (IIIa) or (IIIb) for preparing one of the compounds of formula (Ia).

[0174] (68) Use of a chiral substituted tartaric acid ester of formula (IIIa’) for preparing one of the compounds of formula (Ia).

[0175] Experiment

[0176]

Table 3

[0177] Example The following Table 3 shows the structures of the compounds recovered by HPLC. The retention time assignments in HPLC are shown below.

[0178]

Table 4

[0179] Analytical method for confirming the impurity content and enantiomeric purity at the stage of crude finerenone (I)

[0180]

Table 5

[0181] Enantiomeric purity Method B RT (min) RRT Finerenone (I) 5.7 1.00 Enantiomer (Ia) 6.8 1.19 Instrument / detector: High performance liquid chromatograph equipped with a temperature-controlled column oven, UV detector and data evaluation system Measurement wavelength: 252 nm Oven temperature: 40 °C Column: Chiralpak IC Length: 150 mm, inner diameter: 4.6 mm, particle size: 3 μm Mobile phase: A: 50% buffer 20 mM NH4OAc pH 9 B: 50% acetonitrile Flow rate: 1 ml / min Elution time: 8 min Equilibration: Not necessary, isocratic Sample solvent: Eluent Sample solution: Approximately 0.5 mg / ml racemate of the substance dissolved in the sample solvent Comparative solution: Prepare a comparative solution similar to the sample solution. Injection volume: 10 μl

[0182] All the measured values described in the following examples for enantiomer determination were determined by Method B. Some values, especially those for batches prepared in the pilot plant, were re-analyzed by Method A for comparison and equivalent results were obtained.

[0183] The HPLC analysis data shown in the following examples regarding the purity and content of pure finerenone (I) in the final product refer only to the impurities present in the product in an amount exceeding 0.05%. This is essentially impurity E. All other impurities shown in the table listed above are generally less than 0.05%. The structure of such impurities was determined by isolation from the concentrated mother liquor.

[0184] HPLC conditions / methods Method (C) YMC Hydrosphere C18 150 * 4.6 mm, 3.0 μm 25 °C, 1 ml / min, 270 nm, 4 nm 0 min: 70% 0.1% TFA * ; 30% acetonitrile 17 min: 20% 0.1% TFA; 80% acetonitrile 18 min: 70% 0.1% TFA; 30% acetonitrile * : TFA in water Method (D) YMC Hydrosphere C18 150 * 4.6 mm, 3.0 μm 25 °C, 1 ml / min, 255 nm, 6 nm 0 min: 90% 0.1% TFA; 10% acetonitrile 20 min: 10% 0.1% TFA; 90% acetonitrile 18 min: 10% 0.1% TFA; 90% acetonitrile Method (E) Nucleodur Gravity C18 150 * 2 mm, 3.0 μm 35 °C, 0.22 ml / min, 255 nm, 6 nm Solution A: 0.58 g ammonium hydrogen phosphate and 0.66 g ammonium dihydrogen phosphate in 1 l of water (ammonium phosphate buffer pH 7.2) Solution B: Acetonitrile 0 min: 30% B; 70% A 15 min: 80% B; 20% A 25 min: 80% B; 20% A Method (F) Implementation instructions Enantiomeric purity RT (min) RRT Enantiomer IVa 3.8 1.00 Enantiomer IVb 4.8 1.26 Equipment / detector: Temperature-controlled column oven, UV detector And data evaluation system High-performance liquid chromatograph equipped with Measurement wavelength: 253 nm, range: 6 nm Oven temperature: 40 °C Column: Chiralpak AD-H Length: 250 mm, inner diameter: 4.6 mm, particle size: 5 μm Mobile phase: A: Heptane B: Isopropanol + 0.1% DEA (diethylamine) Gradient program: Time [min] Flow rate: Eluent A [%] Eluent B [%] Start 2 [ml / min] 80 20 Elution time: 8 min

[0185] Example 1a (+) Di-p-tolyl-D-tartaric acid was used for the 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 Racemic 2-cyanoethyl (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IV) 4 g (9.249 mmol) and (+)-di-p-tolyl-D-tartaric acid 3.573 g (9.249 mmol) were suspended in a mixture of 150 ml of ethanol and 50 ml of water and heated to 30 °C (to form a solution). The mixture was stirred at room temperature overnight, and the precipitated crystals were filtered off and washed twice with 5 ml of a 3:1 mixture of ethanol / water. The product was dried under reduced pressure at room temperature. Yield: 4.0 g of colorless crystalline powder (105.6% of theory). Analysis results: Enantiomeric purity (e.e.%): 65% e.e. (Method F) The amount of the thus-concentrated diastereomeric salt was further purified as follows: 3.80 g of the prepared diastereomeric salt was suspended in 76 ml of a 3:1 mixture of ethanol / water, and the mixture was stirred at 50 °C for 2 hours and at room temperature overnight. The precipitated crystals were filtered off and washed twice with 5 ml of a 3:1 mixture of ethanol / water. The product was dried under reduced pressure at room temperature. Yield: 3.0 g of colorless crystalline powder (79.3% of theory) Analysis results: Enantiomeric purity (e.e.%): 97% e.e. (Method F) MS (EIpos): m / z = 433 [M+H] + 1 H-NMR (400 MHz, DMSO-d 6 ): 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), 7.81 - 8.13 (m, 1 H), 8.26 - 8.57 (m, 1 H), 12.82 - 15.60 (m, 1 H).

[0186] Example 1b (+) Di-p-tolyl-D-tartaric acid was used for the 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 The labeled compound 3g (3.66 mmol) of Example 1a was suspended in 30 ml of a 3:1 mixture of water / ethanol, and the mixture was cooled to 0 °C. Then, an aqueous 20% sodium phosphate solution was gradually added (over 1 hour) to adjust the pH to pH 7.1. The mixture was stirred at that temperature for an additional 4 hours. The precipitated solid was filtered off and washed twice with 10 ml of a 3:1 mixture of water / ethanol (0 °C). The product was dried under reduced pressure at 40 °C. Yield: 1.51 g of colorless crystalline powder (95.4% of theory) Analysis results: Enantiomeric purity (e.e.%): 97% e.e. MS (EIpos): m / z = 433 [M+H] + 1 H-NMR (300 MHz, DMSO-d 6 ): 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).

[0187] Example 2a (+) Di-p-tolyl-D-tartaric acid was used for the 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 Racemic 2-cyanoethyl (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IV) 900.0 g (2.08 mol) and (+)-di-p-tolyl-D-tartaric acid 803.6 g (2.08 mmol) were suspended in 15 l of a 3:1 mixture of ethanol / water and heated to 30 °C (to form a solution). The mixture was stirred at room temperature overnight, and the precipitated crystals were filtered off and washed twice with 1000 ml of a 3:1 mixture of ethanol / water. The product was dried under reduced pressure at room temperature. Yield: 873.5 g of colorless crystalline powder (102.6% of theory). Analysis results: Enantiomeric purity (e.e.%): 73% e.e. (Method F) The amount of the diastereomeric salt thus concentrated was further purified as follows: 870 g of the prepared diastereomeric salt was suspended in 10 l of a 3:1 mixture of ethanol / water, and the mixture was stirred at 50 °C for 2 hours and at room temperature overnight. The precipitated crystals were filtered off and washed twice with 1000 ml of a 3:1 mixture of ethanol / water. The product was dried at 40 °C under reduced pressure. Yield: 679.4 g of colorless crystalline powder (78.6% of theory) Analysis results: Enantiomeric purity (e.e.%): 98% e.e. (Method F)

[0188] Example 2b (+) Di-p-tolyl-D-tartaric acid was used for the 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 600 g (732.7 mmol) of the title compound of Example 2a was suspended in 6 l of a 3:1 mixture of water / ethanol, and the mixture was cooled to 0 °C. Then, an aqueous 30% sodium phosphate solution was gradually added (over 1 hour) to adjust the pH to pH 7.1. The mixture was kept stirred at that temperature for an additional 4 hours. The precipitated solid was filtered off and washed twice with 1000 ml of a 3:1 mixture of water / ethanol (0 °C). The product was dried at 40 °C under reduced pressure. Yield: 301.0 g of colorless crystalline powder (95.1% of theory) Analysis results: Enantiomeric purity (e.e.%): 98% e.e. MS (EIpos): m / z = 433 [M+H] + 1 H-NMR (300 MHz, DMSO-d 6 ): 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).

[0189] Example 2c (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (VIIa) Dissolve 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) in a mixture of 1.2 l of THF and 600 ml of water, and cool to 0 °C. To this solution, add dropwise a sodium hydroxide solution (prepared from 82 g (924.8 mmol) of 45% aqueous sodium hydroxide and 423 ml of water) at 0 °C over 15 minutes, and stir the mixture at 0 °C for an additional 1.5 hours. Extract the mixture twice with 480 ml of methyl tert-butyl ether and once with 480 ml of ethyl acetate. Adjust the aqueous solution at 0 °C to pH 7 with dilute hydrochloric acid (prepared from 37.1 g of 37% HCl and 151 ml of water). Warm the solution to 20 °C, and add an aqueous solution of 205 g of ammonium chloride in 554 ml of water. Stir the solution at 20 °C for 1 hour, filter off the product, and wash it twice with 150 ml of water and once with 400 ml of acetonitrile. Dry the product under vacuum at 40 °C under a swirling gas. Yield: Approximately colorless powder (very slight yellow tint) 165.51 g (94.3% of theory). HPLC method E: RT: Approximately 6.8 minutes. MS (EIpos): m / z = 380 [M+H] + 1 H-NMR (300 MHz, DMSO-d 6 ): 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).

[0190] Example 2d (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (I) To an initial charge of 160 g (422 mmol) of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (VIIa) and 95.8 g (591 mmol) of 1,1-carbodiimidazole in 800 ml of THF, 5.1 g (0.0417 mol) of DMAP was added at 20 °C. The mixture was stirred at 20 °C for 1 h (evolution of gas!), then heated to 50 °C for 2.5 h. 297.3 g (1.842 mmol) of hexamethyldisilazane was added to this solution and it was boiled under reflux for 22 h. A further 180 ml of THF was added and the mixture was cooled to 5 °C. A mixture of 117 ml of THF and 83.5 g of water was added over 3 h such that the temperature remained between 5 and 20 °C. The mixture was then boiled under reflux for 1 h, then cooled to 0 °C via a gradient (3 h) and stirred at this temperature for 1 h. The product was filtered off and washed twice with 200 ml of THF each time and twice with 320 ml of water each time. The product was dried under vacuum at 70 °C under a swirling gas. Yield: 150 g (94% of theory) of a nearly colorless powder (very slight yellow tint). HPLC method D: RT ca. 6.7 min. MS (EIpos): m / z = 379 [M+H]+ 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).

[0191] Example 2e (+) Di-p-tolyl-D-tartaric acid was used for the 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 139.20 g of the crude product (I) prepared in Example 2d was suspended in 2796 ml of ethanol (denatured with toluene) and then heated to reflux. Upon heating, the product dissolved. Stirring was continued at this temperature for 1 hour. The solution was filtered through a heated pressure filter (T = 75 °C) and then the pressure filter was rinsed with 36 ml of ethanol (denatured with toluene). Then, the solvent was distilled off until a final volume of approximately 4 times (with respect to the starting material: 139.2 g × 4 ~ 561 ml) was reached (about 2304 ml was distilled off). The mixture was then cooled to an internal temperature of 23 °C (over about 1.5 - 2 hours). The mixture was then stirred at an internal temperature of 3 °C for 2 hours. The product was filtered off and rinsed once with 100 ml of ethanol (denatured with toluene). Wet yield: 145.60 g. The wet product was dried under reduced pressure (less than 100 mbar) at 50 °C over the weekend (more than 48 hours). Yield: 133.7 g of a colorless crystalline powder, fine needle-like crystals (96.0% of theory).

[0192]

Table 6

[0193] MS (EIpos): m / z = 379 [M+H] + 1 H-NMR (400 MHz, DMSO-d 6 ): δ = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99 - 4.07 (m, 2H), 5.37 (s, 1H), 6.60 - 6.84 (m (broad signal)), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H) and small signals of the DMSO solvent and water at δ = 2.5 - 2.6 and a very small peak at δ = 3.38 (not assignable) Modification: Mod A (as defined in WO 2016 / 016287 pamphlet)

[0194] Example 3a (+) Di-p-tolyl-D-tartaric acid was used for the 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 1000 g (2.31 mol) of racemic 2-cyanoethyl (4S,4R)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IV) and 695.5 g (1.80 mol) of (+)-di-p-tolyl-D-tartaric acid were suspended in 15 l of a 3:1 mixture of ethanol / water and heated to 30 °C (to form a solution). The mixture was stirred at room temperature overnight, the precipitated crystals were filtered off and washed twice with 1000 ml of a 3:1 mixture of ethanol / water. The product was dried under reduced pressure at room temperature. Yield: 950.5 g (100.5% of theory) of a colorless crystalline powder. Analysis results: Enantiomeric purity (e.e.%): 78% e.e. (Method F) The amount of the diastereomeric salt thus concentrated was further purified as follows: 950 g of the prepared diastereomeric salt were suspended in 10 l of a 3:1 mixture of ethanol / water and the mixture was stirred at 50 °C for 2 hours and at room temperature overnight. The precipitated crystals were filtered off and washed twice with 1000 ml of a 3:1 mixture of ethanol / water. The product was dried under reduced pressure at 40 °C. Yield: 781.3 g (82.6% of theory) of a colorless crystalline powder Analysis results: Enantiomeric purity (e.e.%): 99% e.e. (Method F)

[0195] Example 3b (+) Di-p-tolyl-D-tartaric acid was used for the 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 600 g (732.7 mmol) of the title compound of Example 3a were suspended in 6 l of a 3:1 mixture of water / ethanol and the mixture was cooled to 0 °C. Then, 20% aqueous sodium carbonate solution was gradually added (over 1 hour) to adjust the pH to pH 7.1. The mixture was kept stirred at that temperature for a further 4 hours. The precipitated solid was filtered off and washed twice with 1000 ml (0 °C) of a 3:1 mixture of water / ethanol. The product was dried under reduced pressure at 40 °C. Yield: 308.0 g of colorless crystalline powder (97.2% of theoretical value) Analysis results: Enantiomeric purity (e.e.%): 99% e.e. In a similar manner (as described in Examples 2c - 2e), this prepared intermediate (IVa) was converted to the final stage (finerenone (Ia), pure):

[0196] [Table 7]

[0197] Example 4 Examples of various tartaric acid derivatives and further solvents

[0198] Example 4a (-) Di-O,O'-p-tolyl-L-tartaric acid was used for the 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 1.00 g of racemate (IV) was suspended in 50 ml of a 3:1 mixture of ethanol / water together with 1.3 g (1.5 equivalents) of (-)-di - O,O’ - p - tolyl - L - tartaric acid, stirred and allowed to stand. After a while, the diastereomeric salt precipitated. This was filtered off, dried (980 mg, 100% of theoretical value), and the enantiomeric excess was measured. By measurement, an enantiomeric excess of 73.28% e.e. in favor of (IVb) was obtained.

[0199] Example 4b (-)-Di-O,O'-p-tolyl-L-tartaric acid was used for the 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 100 mg of racemate (IV) was suspended in a mixture of ethanol / water 3:1 together with (-)-di - O,O’ - p - tolyl - L - tartaric acid, stirred at 40 °C for 3 hours, and then allowed to stand at 20 °C for 16 hours. After a while, the diastereomeric salt precipitated. This was filtered off, dried, and the enantiomeric excess (EE) was measured. By measurement, an enantiomeric excess in favor of (IVb) was obtained. The following table summarizes the results:

[0200] [Table 8]

[0201] Example 4c (-)-Di-O,O'-p-tolyl-L-tartaric acid was used for the 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 In a series of experiments, 100 mg of racemate (IV) was suspended in a mixture of ethanol / water together with (-)-di-O,O'-p-tolyl-L-tartaric acid, stirred at 50 °C for 3 hours, and then allowed to stand at 20 °C for 16 hours. After a while, the diastereomeric salt precipitated. This was filtered off, dried, and the enantiomeric excess was measured. By measurement, an enantiomeric excess favorable to (IVb) was obtained. The following table summarizes the results:

[0202] [Table 9]

[0203] Example 4c (-)-Di-O,O'-p-chlorobenzoyl-D-tartaric acid was used for the 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 100 mg of racemate (IV) was suspended in 4 ml of solvent together with a tartaric acid derivative, stirred at 50 °C for 3 hours, and then allowed to stand at 20 °C for 16 hours. After a while, the diastereomeric salt precipitated. This was filtered off, dried, and the enantiomeric excess as well as 1 the mass by 1H-NMR and mass spectrometer were also measured. By measurement, an enantiomeric excess favorable to (IVa) was obtained. The following table summarizes the results:

[0204] [Table 10A] [Table 10B]

[0205] Example 5a (-)-Di-O,O'-p-chlorobenzoyl-D-tartaric acid was used for the 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 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 were suspended in 30 l of a 7:3 mixture of ethanol / water and heated to 50 °C (to form a solution). The mixture was stirred overnight at room temperature, the precipitated crystals were filtered off and washed twice with 1000 ml of a 7:1 mixture of ethanol / water. The product was dried under reduced pressure at room temperature. Yield: 1105.0 g (111.3% of theory) of a colorless crystalline powder. Analysis results: Enantiomeric purity (e.e.%): 79% e.e. The amount of the diastereomeric salt thus concentrated was further purified as follows: 1104 g of the prepared diastereomeric salt were suspended in 10 l of a 7:1 mixture of ethanol / water and the mixture was stirred at 50 °C for 2 hours and overnight at room temperature. The precipitated crystals were filtered off and washed twice with 1000 ml of a 3:1 mixture of ethanol / water. The product was dried under reduced pressure at 40 °C. Yield: 812.7 g (81.8% of theory) of a colorless crystalline powder. Analysis results: Enantiomeric purity (e.e.%): 99% e.e.

[0206] Example 5b (-)-Di-O,O'-p-chlorobenzoyl-D-tartaric acid was used for the 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 600 g (697.95 mmol) of the title compound of Example 5a were suspended in 6 l of a 3:1 mixture of water / ethanol and the mixture was cooled to 0 °C. Then, 20% aqueous sodium carbonate solution was gradually added (over 1 hour) to adjust the pH to pH 7.1. The mixture was kept stirred at that temperature for an additional 4 hours. The precipitated solid was filtered off and washed twice with 1000 ml (0 °C) of a 3:1 mixture of water / ethanol. The product was dried under reduced pressure at 40 °C. Yield: 285.8 g (94.7% of theory) of a colorless crystalline powder. Analysis results: Enantiomeric purity (e.e.%): 99% e.e. In a similar manner (as described in Examples 2c - 2e), this prepared intermediate (IVa) was converted to the final stage (Finerenone, pure):

[0207] [Table 11]

Claims

1. The formula 【Chemical 1】 (wherein Ar is the formula [Chemical 2] (wherein, * represents the bonding site)) One of Diastereomeric salts.

2. Ar is the formula 【Chemical 3】 (wherein ＊ represents a binding site) One of The diastereomeric salt according to Claim 1.

3. Ar is the formula [Chemical Formula 4] (wherein, ＊ represents a binding site) One of The diastereomeric salt according to Claim 1 or 2.

4. Ar is the formula 【Chemical Formula 5】 (wherein ＊ represents a binding site) One of The diastereomeric salt according to any one of Claims 1 to 3.

5. Ar is [Chemical Formula 6] (wherein ＊ represents a binding site) That is The diastereomeric salt according to any one of Claims 1 to 4.

6. (i) A chiral substituted tartaric acid ester of formula (IIIa) or (IIIb) [Chemical Formula 7] (wherein Ar is as defined in Claim 1) Used Racemic 2-cyanoethyl-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IV) 【Chemical 8】 Optical resolution A method for preparing the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) according to any one of Claims 1 to 5, comprising step (i).

7. The method according to Claim 6, wherein the optical resolution in step (i) is carried out at a temperature in the range of 20 °C to 50 °C.

8. Steps (i) and (iii): (i) A chiral substituted tartaric acid ester of formula (IIIa) or (IIIb) 【Chemical Formula 9】 (wherein Ar is as defined in Claim 1) Used Racemic 2-cyanoethyl-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IV) 【Chemical 10】 By optical resolution of Obtaining one or more of the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) 【Chemical 11】 (wherein Ar is as defined in Claim 1), and (iii) Converting the diastereomeric salt obtained in step (i) into a compound of formula (IVa) Including 2-Cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) 【Chemical Formula 12】 A method for preparing.

9. Step (iii): (iii) Treating the diastereomeric salt (Va), (Vb), (Vc) and / or (Vd) obtained in step (i) with a base Including The method according to Claim 8. In step (iii), the base is an inorganic base and is selected from ammonia, sodium hydroxide solution, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, ammonium phosphate, sodium hydroxide, sodium phosphate, potassium phosphate, the method according to claim 8 or 9.

11. Step (iii) comprises initially charging the diastereomeric salt obtained in step (i) into a solvent or solvent mixture at a temperature of 0 ° C to 60 ° C, and then adjusting the pH to 6.9 to 8.0 by adding an organic or inorganic base. The method according to any one of claims 8 to 10.

12. In step (i), the racemate (IV) 【Chemical 13】 is reacted with di-p-toluoyl-D-tartaric acid of formula (IIIa') 【Chemical 14】 in a spirit / water mixture to obtain a diastereomeric salt (Va) 【Chemical Formula 15】 , and then in step (iii), sodium phosphate is used in the same spirit / water mixture to release the cyanoethanol ester (IVa) 【Chemical Formula 16】 . The method according to any one of claims 8 to 11.

13. Steps (i), (iii), (v) and (vi) (i) A chiral substituted tartaric acid ester of formula (IIIa) or (IIIb) 【Chemical 17】 (wherein Ar is as defined in claim 1) is used to optically resolve the racemic 2-cyanoethyl-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IV) 【Chemical 18】 to obtain one or more of the diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) 【Chemical Formula 19】 (wherein Ar is as defined in claim 1), (iii) converting the diastereomeric salt obtained in step (i) into a compound of formula (IVa) 【Chemical 20】 , (v) hydrolyzing the compound of formula (IVa) with a sodium hydroxide solution in a THF / water mixture (2:1) to obtain a compound of formula (VIIa) 【Chemical 21】 . (vi) Reacting the compound of formula (VIIa) first with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, adding hexamethyldisilazane, then heating the mixture under reflux for 16 to 24 hours, and then adding a THF / water mixture to obtain the compound of formula (Ia) (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia) 【Chemical 22】 A process for its preparation. [

14. ] Compounds of formula (IVa) or (IVb), (VIIa) or (Ia) 【Chemical 23】 One or more diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) 【Chemical Formula 24】 (wherein Ar is as defined in claim 1) Use thereof. [

15. ] The method according to claim 11, wherein the pH is adjusted to 7.0 to 7.

5. [

16. ] The method according to claim 15, wherein the pH is adjusted to 7.1.

Images