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

Abstract

The present invention relates to diastereomeric salts of formula (Va), (Vb), (Vc) and / or (Vd), methods of preparing one or more of the diastereomeric salts of formula (Va), (Vb), (Vc) and / or (Vd), methods of preparing compounds of formula (IVa), methods of preparing compounds of formula (Ia), and the use of tartrate esters of formula (IIIa) or (IIIb) in methods of preparing compounds of formula (Va), (Vb), (Vc), (Vd), (IVa) and / or (Ia).

Description

Technical Field

[0001] The present invention relates to diastereomeric salts of formula (Va), (Vb), (Vc) and / or (Vd)

Chemical Formula

[0002] The present invention also relates to (i) a compound of formula (IV) optically resolved with a tartrate ester of formula (IIIa) or (IIIb)

Chemical Formula

Chemical Formula

[0003] The present invention further relates to steps (i) and (ii): (i) optically resolving the compound of formula (IV) with a tartrate ester of formula (IIIa) or (IIIb) to form a diastereomeric salt of formula (Va) and / or (Vc); (ii) converting the diastereomeric salt of formula (Va) and / or (Vc) obtained in step (i) to a compound of formula (IVa) and relates to a process for preparing a compound of formula (IVa) comprising.

[0004] The present invention further relates to steps (i), (ii), (iii), (iv) and (v): (i) optically resolving the compound of formula (IV) with a tartrate ester of formula (IIIa) or (IIIb) to form a diastereomeric salt of formula (Va) and / or (Vc); (ii) Step of converting the diastereomeric salt of formula (Va) and / or (Vc) obtained in step (i) into the compound of formula (IVa); (iii) Step of reacting the compound of formula (IVa) obtained in step (ii) with an orthoester under acidic catalysis to obtain the compound of formula (VIIa); (iv) Step of hydrolyzing the compound of formula (VIIa) obtained in step (iii) to obtain the compound of formula (VIIIa); (v) Step of converting the compound of formula (VIIIa) obtained in step (iv) into the compound of formula (Ia), wherein the product from step (iv) 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 relates to a method for preparing the compound of formula (Ia) comprising the above steps.

[0005] The present invention further provides the use of the tartrate ester of formula (IIIa) or (IIIb) in a method for preparing a compound of formula (Va), (Vb), (Vc), (Vd), (IVa) and / or (Ia).

[0006] 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.

[0007] The term "finerenone" relates 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) [Chemical formula] relates to the above.

[0008] The compound of formula (I) [Chemical formula] is the racemate of finerenone.

[0009] The expression "enantiomer of finerenone" or "enantiomer of the compound of formula (I)" refers to the compounds of formulas (Ia) and (Ib) [Chemical formula] relates to.

[0010] The compound of formula (Ia) and its preparation method are also described in WO 2008 / 104306 pamphlet and ChemMedChem 2012, 7, 1385, and WO 2016 / 016287 pamphlet. In order to obtain the compound of formula (Ia), since only the enantiomer of formula (Ia) is active, the racemic mixture of amide (I) [Chemical formula] must be separated into enantiomers.

[0011] In the published research-scale synthesis (WO 2008 / 104306 pamphlet), a specially synthesized chiral phase containing N-(dicyclopropylmethyl)-N 2 -methacryloyl-D-leucine amide as a chiral selector was used for this purpose (prepared in-house). It was found that separation can also be carried out with an easily commercially available phase. 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]

[0012] SMB separation provides relatively good yields and optical purities, but the procurement costs and the operation of such equipment under GMP conditions pose major challenges and are associated with high costs. Even the chiral phases used in each case are very expensive, have a limited lifespan and have to be replaced several times during the manufacturing process. For reasons of manufacturing technology, 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 tonne scale, solvent recovery is a time-limiting step, requiring the procurement of huge falling-film evaporators and involving the consumption of enormous amounts of energy.

[0013] Therefore, the problem to be addressed was to find an alternative synthetic route to enantiomerically pure finerenone (Ia) 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 an additional advantage.

[0014] In the novel method of the present invention, instead of the complicated SMB separation of the racemic mixture of amide (I) [Chemical formula] to the enantiomers (Ia) and (Ib), an advantageous optical resolution is carried out on the synthetic precursor, the racemic unit (II) [Chemical formula]

[0015] Numerous attempts have been made to develop an optical resolution of racemate IV into enantiomers IVa and IVb using conventional and customary methods. ​[Chemistry] (Variation of chiral organic acid and solvent), as shown in Table 1:

[0016] [Table 1]

[0017] 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 mixtures with their water, and THF, acetone, ethyl acetate, dichloromethane, and several other solvents, and analyzed for diastereomeric salt formation.

[0018] Also, among the experiments conducted, there were experiments using the conventional resolving reagent (+)-tartaric acid.

[0019] However, in all cases, salt formation was not 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 impossible 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", in order to enable stable salt formation The difference in pK should be at least 3 pK units. .

[0020] All efforts to obtain diastereomeric salts and then, during the subsequent synthetic steps, to achieve an enantiomeric excess greater than 99% e.e. were unproductive; thus, further alternatives were sought.

[0021] In the reaction with alkyl-substituted tartaric acid derivatives such as (-)-O,O'-dipivaloyl-L-tartaric acid or (-)-O,O'-diacetyl-L-tartaric acid, salt formation was not observed.

[0022] However, surprisingly, aromatic or heteroaromatic substituted derivatives of tartaric acid (IIIa + IIIb) were found to be well-suited for obtaining diastereomeric salts and achieving the required enantiomeric excess. [[Prior Art Documents]] [[Patent Documents]]

[0023] [[Patent Document 1]] Pamphlet of International Publication No. 2008 / 104306 [[Patent Document 2]] Pamphlet of International Publication No. 2016 / 016287 [[Non-Patent Documents]]

[0024] [[Non-Patent Document 1]] ChemMedChem 2012, 7, 1385 [[Non-Patent Document 2]] G. Paredes, M. Mazotti, Journal of Chromatography A, 1142 (2007): 56 - 68 [[Non-Patent Document 3]] Computers and Chemical Engineering 27 (2003) 1883 - 1901 [[Non-Patent Document 4]] Handbook of Pharmaceutical Salts - Properties, Selection and Use; P. Heinrich Stahl, Camille G. Wermuth (eds.); Wiley - VCH, page 166 [[Summary of the Invention]] [[Means for Solving the Problems]]

[0025] Briefly, the present invention relates to the following subject matters: (1) Diastereomeric salts of formula (Va), (Vb), (Vc) and / or (Vd): (2) (i) Optical resolution of a compound of formula (IV) with a tartrate ester of formula (IIIa) or (IIIb) A method for preparing one or more diastereomeric salts of formula (Va), (Vb), (Vc) and / or (Vd), comprising step (i). (3) Steps (i) and (ii): (i) A step of optically resolving a compound of formula (IV) with a tartrate ester of formula (IIIa) or (IIIb) to form a diastereomeric salt of formula (Va) and / or (Vc); (ii) A step of converting the diastereomeric salt of formula (Va) and / or (Vc) obtained in step (i) into a compound of formula (IVa) A method for preparing a compound of formula (IVa), comprising the steps. (4) Steps (i), (ii), (iii), (iv) and (v): (i) A step of optically resolving a compound of formula (IV) with a tartrate ester of formula (IIIa) or (IIIb) to form a diastereomeric salt of formula (Va) and / or (Vc); (ii) A step of converting the diastereomeric salt of formula (Va) and / or (Vc) obtained in step (i) into a compound of formula (IVa); (iii) A step of reacting the compound of formula (IVa) obtained in step (ii) with an orthoester under acidic catalysis to obtain a compound of formula (VIIa); (iv) A step of hydrolyzing the compound of formula (VIIa) obtained in step (iii) to obtain a compound of formula (VIIIa); (v) The product from step (iv) is first reacted with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as the solvent, hexamethyldisilazane is added, then the mixture is heated under reflux for 16 - 24 hours, and then a THF / water mixture is added, a step of converting the compound of formula (VIIIa) obtained in step (iv) to the compound of formula (Ia). A method for preparing a compound of formula (Ia), comprising. (5) Use of a tartaric acid ester of formula (IIIa) or (IIIb) in a method for preparing a compound of formula (Va), (Vb), (Vc), (Vd), (IVa) and / or (Ia).

[0026] 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 as compared with the prior art above; - The novel method of the present invention can be carried out 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 a diastereomeric salt having an enantiomeric excess of the diastereomeric salt in the range of 65% - 80% e.e. - The diastereomeric salts obtained by the method of the present invention are notably of high enantiomeric excess generally above 95% e.e., which is sufficient to prepare finerenone at >>99% e.e. - The diastereomeric salts do not necessarily have to be dried and can also be used in a wet state in the next method step. This also enables a one-pot method. - It has been found that in the conversion of the acid (VIIa or VIIb) in tetrahydrofuran (THF), the amide of formula (I) or (Ia) crystallizes directly from the solution and can 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.

Mode for Carrying Out the Invention

[0027] The following describes further embodiments and subject matters of the present invention and further embodiments: One embodiment also relates to a method for preparing

Chemical formula

Chemical formula

Chemical formula

[0028] 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 groups, provided that the normal valence of the atom in question is not exceeded in the particular circumstances. Combinations of substituents and / or variables are allowed.

[0029] The term "unsubstituted" means that none of the hydrogen atoms are replaced.

[0030] The 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).

[0031] The heteroaryl group is especially a pyridinyl, pyrazinyl, pyrrolyl, pyrazolyl or pyrimidinyl group.

[0032] In the context of the present application, the aryl group is especially a phenyl group.

[0033] The substituents in the context of the present invention are halogen, C1-C6-alkyl, C1-C6-alkoxy, nitrile, nitro, cyano, trifluoromethyl, amide groups such as -NHCOR (wherein R is methyl, ethyl or phenyl), -NRCOR groups (wherein R has the definition shown above), -CONHR groups (wherein R has the definition shown above), -CONRR (wherein R’ has the same meaning as R defined above), or cyclic amides such as 3-oxomorpholin-4-yl, 2-oxopiperidin-1-yl, and these may also be similarly substituted.

[0034] The term "halogen" refers to a fluorine, chlorine, bromine or iodine atom, preferably a fluorine, chlorine or bromine atom.

[0035] The term "C1-C6-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 isomers thereof. The group preferably has 1, 2, 3 or 4 carbon atoms ("C1-C4-alkyl"), for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl group, and particularly preferably has 1, 2 or 3 carbon atoms ("C1-C3-alkyl"), for example, methyl, ethyl, n-propyl or isopropyl group.

[0036] The term "C1-C6-alkoxy" refers to a straight-chain or branched saturated monovalent group of the formula (C1-C6-alkyl)-O- as defined above for the term "C1-C6-alkyl", for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or isomers thereof.

[0037] Ar is preferably: [Chemical formula] (wherein # represents a bonding 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 (wherein R can be methyl, ethyl or phenyl), or -NRCOR (wherein R has the meaning shown above) or CONHR (wherein R has the meaning shown above), or CONRR’ (wherein 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) is. The substitution patterns can 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.

[0038] More preferably, Ar is of the formula

Chemical formula

[0039] Particularly preferably, Ar is of the formula

Chemical formula

[0040] An extremely particularly preferred Ar group is

Chemical formula

[0041] Among them, a 4-nitrophenyl group [Chemical formula] is preferably prominent.

[0042] The preparation of the tartrate ester is known from the literature, for example, as described in Organic Synthesis, Coll. Vol. 9, page 722 (1998); Vol. 72, page 86 (1995), and Chirality 2011(23), 3, page 228.

[0043] A further subject of the present invention relates to the diastereomeric salts (Va - Vd) of the formula [Chemical formula] [Chemical formula] (wherein Ar is an unsubstituted or substituted aromatic or heteroaromatic group and has the meaning shown above) and relates to the diastereomeric salts (Va - Vd).

[0044] The diastereomeric salts in which Ar is 4-nitrophenyl are particularly preferred.

[0045] Whether (Va)-(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] (wherein Ar is a substituted or unsubstituted aromatic or heteroaromatic group and has the meaning shown above).

[0046] The preparation of the diastereomeric salts (Va - Vd) is carried out as follows: [Chemical formula] [Chemical formula]

[0047] 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 the 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 R-configured enantiomer preferentially entering into salt formation, the mirror image salt of the general formula (Vb) is prepared. The precipitated diastereomeric salt can be separated almost quantitatively, in which case the S enantiomer remains in the solution here and can then be isolated therefrom.

[0048] It has been found that the yield and enantiomeric purity can be optimized using the stoichiometric ratio of (IV) to (IIIa) / (IIIb) and the choice of solvent.

[0049] Finerenone (Ia) has the S configuration. Tartaric acid (depending on the substitution type) with the S,S or R,R configuration can form diastereomeric salts with the 4S-configured enantiomer of the racemate IV.

[0050] For optical resolution, 0.5 to 2.0 equivalents of tartrate ester (IIIa) or (IIIb) is used, preferably 0.7 to 1.5 equivalents, more preferably 0.7 to 1.4 equivalents, and most preferably 0.70 to 1.2 equivalents.

[0051] The diastereomeric salt is formed in an organic solvent, or a solvent mixture, or a solvent mixture consisting of water and a water-miscible organic solvent.

[0052] 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, but it is preferred to use ethanol. The solvent may also be used in a commercially available modified form of a denaturant used in the case of ethanol, such as toluene, methyl ethyl ketone, thiophene, hexane, etc., which also offers great advantages for cost reasons; thus, in the context of use, a spirit consisting of ethanol which may optionally be denatured with toluene or methyl ethyl ketone is particularly suitable for use on an industrial scale. Furthermore, 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.

[0053] 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.

[0054] The execution 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, 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, stirring is continued at room temperature for 2 to 24 hours, preferably 5 to 18 hours, and most preferably 12 to 16 hours.

[0055] 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, 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, stirring is continued at room temperature for 2 to 24 hours, preferably 5 to 18 hours, and most preferably 12 to 16 hours. Optical resolution is preferably carried out at a temperature of 20°C to 50°C.

[0056] Subsequently, the precipitated diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) are isolated.

[0057] 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 an elevated temperature (50 - 80 °C, preferably 50 °C). In some cases, it has been found that the use of a carrier gas is advantageous.

[0058] By the procedure outlined above, it is possible to prepare diastereomeric salts having an enantiomeric excess in the range of 65% - 80% e.e. of the diastereomeric salt.

[0059] For further purification (to increase the enantiomeric excess), extraction stirring from a solvent or a solvent - water mixture is repeated.

[0060] The diastereomeric salt does not necessarily have to be dried and can also be used in the next process step in a wet state.

[0061] 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 dichloromethane being preferably used. The solvent may also be used in commercially available denatured forms of ethanol, such as denaturants used in the case of ethanol, for example toluene, methyl ethyl ketone, thiophene, hexane, etc., which also offers significant advantages for cost reasons; thus, in the context of the application, spirits consisting of ethanol, which may optionally be denatured with toluene or methyl ethyl ketone, are particularly suitable for use on an industrial scale. Furthermore, 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.

[0062] It is preferred to perform the optical resolution in dichloromethane. The solvent or solvent mixture can be used in an excess of 10 to 60 times based on the racemate (IV), for example, 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.

[0063] 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 continuing to stir 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.

[0064] Subsequently, the precipitated diastereomeric salts (Va), (Vb), (Vc) and / or (Vd) are isolated.

[0065] 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 an elevated temperature (50 - 80 °C, preferably 50 °C). In some cases, it has been found that the use of a carrier gas is advantageous. The diastereomeric salts thus obtained are notably of high enantiomeric excess, generally above 95% e.e., which is sufficient to prepare finerenone (Ia) with >>99% e.e.

[0066] The diastereomeric salts do not necessarily have to be dried and can also be used in the next process step in a wet state.

[0067] In the next step, the diastereomeric salts are treated with a base to remove the solvent. 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 the 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 is isolated, for example, by filtration and washing on the filter, and the respective tartrate esters of the formula (IIIa) or (IIIb) remain in the solution in the form of a salt.

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 used successfully. 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 preferably 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 preferred to use sodium phosphate or potassium phosphate It 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 extremely rapidly (within a few minutes) or extremely 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 period 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 - 80°C, preferably 50°C). In some cases, it has been found that the use of a carrier gas is advantageous.

[0072] As a particularly preferred method, especially for implementation on an industrial scale, di(4-nitrobenzoyl)tartaric acid (IIIb’), in the R,R configuration is used, which can be used either in the anhydrous form or in the form of a hydrate:

Chemical formula

[0073] Optical resolution is preferably carried out in a spirit / water mixture. The subsequent release in (IVa)

Chem.

[0074] It is also possible to isolate the target enantiomer from the mother liquor. First, an appropriate diastereomeric salt (Va), (Vb), (Vc) or (Vd), here prepared from either (IVa) or (IVb), is 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. Thereafter, 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 forms are obtained.

Chem.

[0075] The further conversion to finerenone (Ia) or the enantiomer (Ib) is carried out as follows: Proceeding from dihydropyridine (IVa or IVb), ethyl ether (VIIa or VIIb) is obtained by reaction with an orthoester under acidic catalysis.

Chemical formula

[0076] It has been found that the reaction can be carried out in a solvent such as dimethylacetamide, NMP (1-methyl-2-pyrrolidone) or DMF (dimethylformamide) at a relatively high concentration (up to 1.5 g of solvent per 1 g of reactant), with the addition of 4 - 10 wt%, preferably 6 - 8 wt% of concentrated sulfuric acid. The reaction then proceeds with 2.5 to 5 equivalents of orthoester (triethyl orthoacetate or triethyl orthoformate). It has been found that it is much more convenient to use triethyl orthoacetate corresponding to the reaction as it reacts much cleaner, has a very low flammability and is particularly suitable for industrial procedures. This reaction is preferably carried out at a temperature of 100 - 120 °C, preferably 115 °C, in DMA (dimethylacetamide) and NMP (1-methyl-2-pyrrolidone). More preferably, it is in NMP. Before starting the actual reaction, in order to remove the residue of isopropanol present from the precursor as unwanted by-products may occur, it is advantageous to distill off some of the solvent (DMA or NMP) at an elevated temperature (100 - 120 °C under reduced pressure). The reaction is stirred for 1.5 - 3 hours, preferably 2 hours. For work-up, water is added directly to the mixture and the product crystallizes out. In order to obtain a particularly stable and reproducible method, a part of the water (e.g., 1 / 3) is first measured in, followed by seeding, and the remaining amount of water is added. This procedure ensures that the same crystal polymorph showing the best isolation properties is always obtained. The product is washed with water and dried. The yield is over 92% of the theoretical value.

[0077] Proceeding from cyanoethyl ether (IVa or IVb), acid (VIIa or VIIb) is obtained by alkaline hydrolysis and subsequent acidic work-up:

Chemical formula

[0078] 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 mixture of THF / water 2:1 (9-fold amount), weigh 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 an 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%).

[0079] The subsequent conversion from the acid to the amide (Ia or Ib) 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 with 1.1 - 1.6 equivalents, preferably 1.3 - 1.4 equivalents of 1,1'-carbodiimidazole (CDI) in THF at a temperature of 20 °C to 50 °C (the preferred approach was found to be starting at 20 °C first, then stirring at that temperature for 1 - 2 hours, and then continuing to stir at 50 °C for 2 - 3 hours), under the catalysis of 4-(dimethylamino)pyridine (DMAP) (5 - 15 mol%, preferably 10 mol% / it was also found that the reaction could be carried out without adding DMAP in some cases) 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 be isolated optionally. However, it was 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 measured in. The advantageous amount of water was found to be 0.5 - 0.7 times the amount of the reactants, and in particular, the particularly advantageous amount was found to be 0.52 times the amount of water. 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 an additional 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 exceeds 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. Once the reaction is complete, it is cooled and the product is filtered off. The yields and purities obtained in this way are equivalent.

Chemical formula

[0080] Final crystallization method (establishment of the final modification Mod A): For this purpose, for GMP-related reasons, (Ia) (or Ib) 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 (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.

[0081] The present invention also relates to an enantiomerically pure cyanoethanol ester of formula (IVa), 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0082] Hereinafter, further embodiments of the present invention will be described: The present invention relates to a chiral substituted tartaric acid ester of formula (IIIb)

Chemical formula

Chemical formula

Chemical formula

[0083] The chiral substituted tartaric acid ester of formula (IIIb)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0084] 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) (wherein, Ar is the formula

Chem.

[0085] 2-Cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) (wherein Ar is the formula

Chem.

[0086] 2-Cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) (wherein Ar is the formula

Chem.

[0087] 2-Cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa) (wherein Ar is

Chem.

[0088] The present invention also relates to a racemic cyanoethanol ester of formula (IV)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

[0089] the racemic cyanoethanol ester of formula (IV)

Chem.

Chem.

Chem.

[0090] 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] (wherein * represents a binding site) is one of) is preferred.

[0091] 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] (wherein * represents a binding site) is one of) is particularly preferred.

[0092] 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] (wherein * represents a binding site) is one of) is especially preferred.

[0093] Racemic cyanoethanol ester of formula (IV) [Chemical formula] with a chiral substituted tartaric acid ester of formula (IIIb) [Chemical formula] (wherein Ar is [Chemical formula] (wherein * represents a binding site) is) react with the enantiomeric cyanethanol ester 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate of formula (IVa)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0094] The synthesis of racemic cyanoethanol ester (IV) is described in WO 2016 / 016287 pamphlet (Example 4). The cyanoethanol ester stage (IVa + IVb) is converted by a method known as described in WO 2016 / 016287 pamphlet for the racemic compound to obtain the final finerenone product (Ia) or the enantiomer (Ib). The present invention essentially relates to a novel method for preparing the chiral form of cyanoethanol ester by optical resolution with chiral substituted tartaric acid esters of general formulas (IIIa) and (IIIb).

[0095] Paragraphs 1 to 14. The following describes further embodiments in paragraphs 1 to 14:

[0096] 1. Chiral substituted tartaric acid ester of formula (IIIb)

Chemical formula

Chemical formula

Chemical formula

[0097] 2. The method according to paragraph 1, characterized in that the optical resolution is carried out in an ethanol / water mixture.

[0098] 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.

[0099] 4. The method according to any one of paragraphs 1, 2, and 3, characterized in that the optical resolution is carried out at a temperature of 30°C to 50°C.

[0100] 5. (2R,3R)-2,3-bis(4-nitrobenzoyl)tartaric acid (IIIb’)

Chemical formula

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 9. Racemate (IV)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0105] 10. Racemic cyanoethanol ester of formula (IV)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0106] 11. Racemic cyanoethanol ester of formula (IV) [Chemical formula] With a chiral substituted tartaric acid ester of formula (IIIb) [Chemical formula] (wherein Ar is [Chemical formula] (wherein * represents a bonding site) is) React with Enantiomeric cyanoethanol ester of formula (IVa) 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate [Chemical formula] To obtain This is reacted with triethyl orthoformate or triethyl orthoacetate and concentrated sulfuric acid as an acidic catalyst under acidic catalysis to react with the orthoester to give a compound of formula (VIIa) [Chemical formula] Convert to This is hydrolyzed with sodium hydroxide in a THF / water mixture (2:1) to give a compound of formula (VIIIa) [Chemical formula] to obtain Next, the compound of formula (VIIIa) 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

[0107] 12. A diastereomeric salt of the formula

Chemical formula

[0108] 13. The diastereomeric salt according to paragraph 12, characterized in that Ar is one of the formulas

Chemical formula

[0109] 14. The diastereomeric salt according to paragraph 12 or 13, characterized in that Ar is

Chemical formula

[0110] Paragraphs (1) - (72) Hereinafter, further embodiments in paragraphs (1) - (72) will be described: ​​​

[0111] 1. The diastereomeric salts of formula (Va), (Vb), (Vc) and / or (Vd) [Chemical formula] [Chemical formula] (wherein Ar is unsubstituted or substituted aromatic or heteroaromatic) and the diastereomeric salts thereof.

[0112] 2. When Ar is [Chemical formula] (wherein # represents the bonding 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 (wherein R can be methyl, ethyl, or phenyl), or -NRCOR (wherein R has the meaning shown above) or CONHR (wherein R has the meaning shown above), or CONRR’ (wherein 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 diastereomeric salts according to paragraph (1). The substitution patterns can widely vary; 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.

[0113] (3) When Ar is of the formula [Chemical formula] (wherein * represents a binding site) One of the diastereomeric salts according to claim 1 or 2.

[0114] (4) Ar is of the formula

Chem.

[0115] (5) Ar is of the formula

Chem.

[0116] (6) Ar is of the formula

Chem.

[0117] (7) Ar is

Chem.

[0118] (8) (i) By the tartrate ester of formula (IIIa) or (IIIb)

Chem.

[0119] (9) The method according to paragraph (8), wherein in step (i), 0.5 to 2.0 equivalents of tartaric acid ester (IIIa) or (IIIb) are used for optical resolution.

[0120] (10) The method according to paragraph (8) or (9), wherein in step (i), 0.7 to 1.5 equivalents of tartaric acid ester (IIIa) or (IIIb) are used for optical resolution.

[0121] (11) The method according to any of paragraphs (8) to (10), wherein in step (i), 0.7 to 1.4 equivalents of tartaric acid ester (IIIa) or (IIIb) are used for optical resolution.

[0122] (12) The method according to any of paragraphs (8) to (11), wherein in step (i), 0.7 to 1.2 equivalents of tartaric acid ester (IIIa) or (IIIb) are used for optical resolution.

[0123] (13) The method according to any of paragraphs (8) to (12), wherein the optical resolution in step (i) is carried out in an organic solvent or a solvent mixture consisting of water and a water-miscible organic solvent.

[0124] (14) The method according to any of paragraphs (8) to (12), wherein in step (i), the organic solvent or solvent mixture is selected from the group consisting of ethanol, methanol, isopropanol, 1-propanol, ethyl acetate, isobutanol, dichloromethane, 1-pentanol, acetone and mixtures thereof.

[0125] (15) In step (i), the organic solvent or solvent mixture is selected from the group consisting of 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 mixtures thereof, and the mixing ratio is volume / volume (v / v), and the method according to any one of paragraphs (8) to (14).

[0126] (16) In step (i), the organic solvent or solvent mixture is selected from the group consisting of ethanol / water, and the mixing ratio (v / v) is in the range of ethanol:water of 1:1 to 6:1, and the method according to any one of paragraphs (8) to (15).

[0127] (17) In step (i), the organic solvent or solvent mixture is selected from the group consisting of ethanol:water, and the mixing ratio (v / v) is in the range of ethanol:water of 6:1 to 3:1, and the method according to any one of paragraphs (8) to (16).

[0128] (18) In step (i), the organic solvent or solvent mixture is selected from the group consisting of ethanol:water, and the mixing ratio (v / v) is in the range of ethanol:water of 3:1, and the method according to any one of paragraphs (8) to (17).

[0129] (19) The optical resolution in step (i) is carried out at a temperature in the range of 10 to 60 °C, and the method according to any one of paragraphs (8) to (18).

[0130] (20) The optical resolution in step (i) is carried out at a temperature in the range of 20 to 50 °C, and the method according to any one of paragraphs (8) to (19).

[0131] (21) The method according to any one of paragraphs (8) to (20), wherein the optical resolution in step (i) is carried out at a temperature in the range of 30 to 40 °C.

[0132] (22) The optical resolution in step (i) is - a step of initially charging components into the solvent mixture according to any one of the above paragraphs at room temperature, - a step of heating to 10 to 60 °C or 20 to 50 °C, - a step of continuously stirring at 20 to 50 °C for 1 to 10 hours or 1 to 4 hours, and - a step of cooling to room temperature within 3 to 24 hours or 5 to 16 hours The method according to any one of paragraphs (8) to (21), comprising:

[0133] (23) The method according to any one of paragraphs (8) to (22), wherein in step (i), the tartaric acid ester of formula (IIIa) is used.

[0134] (24) In step (i), the tartaric acid ester of formula (IIIb) or (IIIb’) (2R,3R)-2,3-bis(4-nitrobenzoyl)tartaric acid (IIIb’)

Chemical formula

[0135] (25) The method according to any one of paragraphs (8) to (24), wherein the method in step (i) further comprises isolating the diastereomeric salt.

[0136] (26) Steps (i) and (ii): (i) A step of optically resolving the compound of formula (IV) with the tartaric acid ester of formula (IIIa) or (IIIb) to form a diastereomeric salt of formula (Va) and / or (Vc); (ii) A step of converting the diastereomeric salt of formula (Va) and / or (Vc) obtained in step (i) into the compound of formula (IVa). A method for preparing a compound of formula (IVa) comprising

[0137] (27) The method according to paragraph (26), wherein step (i) is as defined in any of paragraphs (8) to (25).

[0138] (28) The method according to paragraph (26) or (27), wherein step (ii) is defined as follows: (ii) Treating the diastereomeric salt (Va) and / or (Vc) obtained in step (i) with a base to obtain a compound of formula (IVa).

[0139] (29) The method according to any of paragraphs (26) to (28), wherein the base is selected from the group consisting of inorganic bases, organic bases, and mixtures thereof.

[0140] (30) The method according to any of paragraphs (26) to (29), wherein the base is selected from the group consisting of 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, and mixtures thereof.

[0141] (31) The method according to any of paragraphs (26) to (30), wherein the base is selected from the group consisting of sodium hydroxide, sodium phosphate, potassium phosphate, and mixtures thereof.

[0142] (32) The method according to any of paragraphs (26) to (31), wherein the base is selected from the group consisting of aliphatic organic bases, aromatic organic bases, and mixtures thereof.

[0143] (33) The method according to paragraph (32), wherein the base is selected from the group consisting of triethylamine, imidazole, N-methylimidazole, Hunig's base, pyridine, DBU, and mixtures thereof.

[0144] (34) A method according to any of paragraphs (26) to (33), wherein a solvent or solvent mixture selected from the group consisting of water, water-miscible organic solvents or mixtures thereof is used in step (ii).

[0145] (35) A method according to any of paragraphs (26) to (34), wherein in step (ii), the solvent or solvent mixture is selected from the group consisting of ethanol, isopropanol, ethane-1,2-diol, methoxyethanol, methanol, acetone and mixtures thereof.

[0146] (36) A method according to any of paragraphs (26) to (35), wherein in step (ii), the organic solvent or solvent mixture is selected from the group consisting of water / ethanol, and the mixing ratio (v / v) is in the range of ethanol:water of 1:6 to 1:3.

[0147] (37) A method according to any of paragraphs (26) to (36), wherein in step (ii), the organic solvent or solvent mixture is selected from the group consisting of water / ethanol, and the mixing ratio (v / v) is in the range of ethanol:water of 1:3.

[0148] (38) A method according to any of paragraphs (26) to (37), wherein step (ii) is carried out at a temperature of 0°C to 60°C.

[0149] (39) A method according to any of paragraphs (26) to (38), wherein step (ii) is carried out at a temperature of 0°C to 50°C.

[0150] (40) A method according to any of paragraphs (26) to (39), wherein step (ii) is carried out at pH 6.9 to 8.0.

[0151] (41) A method according to any of paragraphs (26) to (40), wherein step (ii) is carried out at pH 7.0 to 7.5.

[0152] (42) A method according to any of paragraphs (26) to (41), wherein step (ii) is carried out at pH 7.1.

[0153] (43) In step (i), the method according to any one of paragraphs (26) to (41), wherein (2R,3R)-2,3-bis(4-nitrobenzoyl)tartaric acid (IIIb’)

Chem.

[0154] (44) Racemate (IV)

Chem.

Chem.

Chem.

Chem.

[0155] (45) Steps (i), (ii), (iii), (iv) and (v): (i) A step of optically resolving a compound of formula (IV) with a tartaric acid ester of formula (IIIa) or (IIIb) to form a diastereomeric salt of formula (Va) and / or (Vc); (ii) A step of converting the diastereomeric salt of formula (Va) and / or (Vc) obtained in step (i) into a compound of formula (IVa) (preferably: treating the diastereomeric salt (Va) and / or (Vc) obtained in step (i) with a base to obtain a compound of formula (IVa)); (iii) Reacting the compound of formula (IVa) obtained in step (ii) with an orthoester under acidic catalysis to obtain a compound of formula (VIIa); (iv) Hydrolyzing the compound of formula (VIIa) obtained in step (iii) to obtain a compound of formula (VIIIa); (v) Reacting the compound of formula (VIIIa) obtained in step (iv) with 1,1 - carbodiimidazole and a catalytic amount of 4 - (dimethylamino)pyridine in THF as a solvent, then adding hexamethyldisilazane, then heating the mixture under reflux for 16 - 24 hours, and then adding a THF / water mixture to convert it to a compound of formula (Ia) A process for preparing a compound of formula (Ia), comprising:

[0156] (46) The process according to paragraph (45), wherein step (i) is as defined in any of paragraphs (8) to (44).

[0157] (47) The process according to paragraph (45) or (46), comprising one or more steps defined according to any of paragraphs (8) to (44).

[0158] (48) The process according to any of paragraphs (45) to (47), wherein the orthoester in step (iii) is an ethyl orthoester of an alkyl -, aryl - or arylalkyl - carboxylic acid.

[0159] (49) The process according to any of paragraphs (45) to (48), wherein the orthoester in step (iii) is selected from the group consisting of triethyl orthoacetate, triethyl orthoformate, triethyl orthobenzoate, triethyl orthopropionate, triethyl orthobutyrate and mixtures thereof.

[0160] (50) The process according to any of paragraphs (45) to (49), wherein 2.5 - 5 equivalents of the orthoester are used.

[0161] (51) The method according to any one of paragraphs (45) to (50), wherein the acidic catalyst used in step (iii) is sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid, or a mixture thereof.

[0162] (52) The method according to any one of paragraphs (45) to (51), wherein in step (iii), 4 to 10 or 6 to 8 weight percent (wt%) of the acidic catalyst is used, and the weight percentage is based on g per compound (IVa) used.

[0163] (53) The method according to any one of paragraphs (45) to (52), wherein a solvent or solvent mixture selected from the group consisting of dimethylacetamide, NMP (1-methyl-2-pyrrolidone), DMF (dimethylformamide), and mixtures thereof is used in step (iii).

[0164] (54) The method according to any one of paragraphs (45) to (53), wherein step (iii) is carried out at a temperature of 100°C to 120°C.

[0165] (55) The method according to any one of paragraphs (45) to (54), wherein step (iii) is carried out at a temperature of 115°C.

[0166] (56) The method according to any one of paragraphs (45) to (55), wherein alkaline hydrolysis is carried out in step (iv).

[0167] (57) The method according to any one of paragraphs (45) to (56), wherein step (iv) is carried out in a THF / water mixture.

[0168] (58) The method according to any one of paragraphs (45) to (57), wherein step (iv) is carried out in a THF / water mixture at a ratio of 2:1 (v / v).

[0169] (59) The method according to any one of paragraphs (45) to (58), wherein alkalization is carried out in step (iv) with a sodium hydroxide solution or a potassium hydroxide solution.

[0170] (60) The method according to any one of paragraphs (45) to (59), wherein the alkalization in step (iv) is carried out at a temperature of 0°C to 5°C.

[0171] (61) The method according to any one of paragraphs (45) to (60), wherein the conversion of the compound of formula (VIIIa) obtained in step (iv) to the compound of formula (Ia) is carried out as follows: The product from step (iv) is first reacted with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, then hexamethyldisilazane is added, and then the mixture is heated under reflux for 16 to 24 hours.

[0172] (62) Racemic cyanoethanol ester of formula (IV)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0173] (63) Racemic cyanoethanol ester of formula (IV) [Chemical formula] is converted using a chiral substituted tartaric acid ester of formula (IIIb) [Chemical formula] (wherein Ar is [Chemical formula] (wherein * represents a bonding site) ) to obtain enantiomeric cyanoethanol ester of formula (IVa) 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate [Chemical formula] to obtain This is reacted with an orthoester under acid catalysis using triethyl orthoformate or triethyl orthoacetate and concentrated sulfuric acid as an acid catalyst to obtain a compound of formula (VIIa) [Chemical formula] to convert to This is hydrolyzed with sodium hydroxide in a THF / water mixture (2:1) to give a compound of formula (VIIIa). [Chemical formula] to obtain Next, the compound of formula (VIIIa) is reacted first 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 to 24 hours, and then a THF / water mixture is added, which is a method according to any one of paragraphs (45) to (62).

[0174] (64) Use of the tartrate ester of formula (IIIa) in a method for preparing a compound of formula (Va), (Vb), (Vc) and / or (Vd).

[0175] (65) Use of the tartrate ester of formula (IIIb) in a method for preparing a compound of formula (Va), (Vb), (Vc) and / or (Vd).

[0176] (66) Use of the tartrate ester of formula (IIIb’) in a method for preparing a compound of formula (Va), (Vb), (Vc) and / or (Vd).

[0177] (67) Use of the tartrate ester of formula (IIIa) in a method for preparing a compound of formula (IVa).

[0178] (68) Use of the tartrate ester of formula (IIIb) in a method for preparing a compound of formula (IVa).

[0179] (69) Use of the tartrate ester of formula (IIIb’) in a method for preparing a compound of formula (IVa).

[0180] (70) Use of the tartrate ester of formula (IIIa) in a method for preparing a compound of formula (Ia).

[0181] (71) Use of the tartrate ester of formula (IIIb) in the process for preparing the compound of formula (Ia).

[0182] (72) Use of the tartrate ester of formula (IIIb’) in the process for preparing the compound of formula (Ia).

[0183] Experiment

[0184] [Table 2]

[0185] Examples The following Table 3 shows the structures of the compounds recovered by HPLC. The retention time assignments in HPLC are shown below.

[0186] [Table 3A] [Table 3B]

[0187] Analytical method for confirming the impurity content and enantiomeric purity at the stage of crude finerenone (I)

[0188] [Table 4]

[0189] Enantiomeric purity Method B RT (min) RRT Finerenone (I) 5.7 1.00 Enantiomer (Ia) 6.8 1.19 Instrument / detector: Temperature-controlled column oven, UV detector and a high-performance liquid chromatograph equipped with a 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: About 0.5 mg / ml racemate of the substance dissolved in the sample solvent Reference solution: Prepare a reference solution similar to the sample solution Injection volume: 10 μl

[0190] All the measured values described in the following examples for enantiomer determination were determined by Method B. Some values, especially those of batches prepared in the pilot plant, were re-analyzed by Method A for comparison and equivalent results were obtained.

[0191] The HPLC analysis data shown in the following examples regarding the purity and content of the pure finerenone (I) in the final product refer only to the impurities present in the product in an amount greater than 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.

[0192] HPLC conditions / method Method (C) YMC Hydrosphere C18 150 * 4.6 mm, 3.0 μm 25 °C, 1 ml / min, 270 nm, 4 nm 0’: 70% TFA 0.1% * ; 30% acetonitrile 17’: 20% TFA 0.1%; 80% acetonitrile 18’: 70% TFA 0.1%; 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’: 90% TFA 0.1%; 10% acetonitrile 20’: 10% TFA 0.1%; 90% acetonitrile 18’: 10% TFA 0.1%; 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 of ammonium hydrogen phosphate and 0.66 g of ammonium dihydrogen phosphate in 1 l of water (ammonium phosphate buffer pH 7.2) Solution B: Acetonitrile 0’: 30% B; 70% A 15’: 80% B; 20% A 25’: 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: High performance liquid chromatograph equipped with a temperature-controlled column oven, UV detector and data evaluation system 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 Dissolution time: 8 minutes

[0193] Example 1a Preparation of diastereomeric salts of 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate using (2S,3S)-2,3-bis(4-nitrobenzoyl)tartaric acid 2.00 g of racemic 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IV) was suspended in 54 ml of dichloromethane together with 2.375 g (1.05 equivalents) of (2S,3S)-2,3-bis(4-nitrobenzoyl)tartaric acid, heated to 39 °C for 45 minutes, and stirred at that temperature for 4 hours. The mixture was cooled to 20 °C over 2 hours and stirred at that temperature for an additional 18 hours. After some time, the diastereomeric salt precipitated. This was filtered off, dried (2.1 g = 49.8% of theory), and the enantiomeric excess was measured. The measurement gave an enantiomeric excess of 84% e.e. (Method F) in favor of 2-cyanoethyl (4R)-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate. MS (EIpos): m / z = 405 [M+H] + 1 H NMR (600 MHz, DMSO-d6) δ ppm 1.90 - 2.18 (m, 2 H) 2.35 (s, 2 H) 2.67 - 2.97 (m, 1 H) 3.75 (s, 2 H) 3.93 - 4.06 (m, 1 H) 4.08 - 4.34 (m, 1 H) 5.08 - 5.36 (m, 1 H) 5.98 (s, 1 H) 6.89 - 7.01 (m, 1 H) 7.07 - 7.42 (m, 2 H) 7.97 - 8.31 (m, 3 H) 8.44 (d, J = 8.80 Hz, 2 H) 10.19 - 11.33 (m, 1 H) 12.58 - 15.01 (m, 1 H)

[0194] Example 1b Preparation of diastereomeric salts of 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate using (2R,3R)-2,3-bis(4-nitrobenzoyl)tartaric acid 2.00 g of the racemate (IV) was suspended in 54 ml of dichloromethane together with 2.375 g (1.05 equivalents) of (2S,3R)-2,3-bis(4-nitrobenzoyl)tartaric acid and heated at 39 °C for 45 minutes and stirred at that temperature for an additional 4 hours. The mixture was cooled to 20 °C over 2 hours and stirred at that temperature for an additional 18 hours. After some time, the diastereomeric salt precipitated. This was filtered off, dried (2.0 g = 47.4% of theory), and the enantiomeric excess was measured. The measurement gave an enantiomeric excess of 85% e.e. (Method F) in favor of (4S)-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate 2-cyanoethyl ester. MS (EIpos): m / z = 405 [M+H] + 1 H NMR (600 MHz, DMSO-d6) δ ppm 1.90 - 2.18 (m, 2 H) 2.35 (s, 2 H) 2.67 - 2.97 (m, 1 H) 3.75 (s, 2 H) 3.93 - 4.06 (m, 1 H) 4.08 - 4.34 (m, 1 H) 5.08 - 5.36 (m, 1 H) 5.98 (s, 1 H) 6.89 - 7.01 (m, 1 H) 7.07 - 7.42 (m, 2 H) 7.97 - 8.31 (m, 3 H) 8.44 (d, J = 8.80 Hz, 2 H) 10.19 - 11.33 (m, 1 H) 12.58 - 15.01 (m, 1 H)

[0195] Example 2a Preparation of diastereomeric salts of 2-cyanoethyl 4(S)-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate using (2R,3R)-2,3-bis(4-nitrobenzoyl)tartaric acid 200 g (494.5 mmol) of the racemate (IV) was suspended in 5400 ml of dichloromethane together with 237.5 g (1.05 equivalents) of (2R,3R)-2,3-bis(4-nitrobenzoyl)tartaric acid and heated at 39 °C for 45 minutes and stirred at that temperature for an additional 4 hours. The mixture was cooled to 20 °C over 2 hours and stirred at that temperature for an additional 18 hours. After some time, the diastereomeric salt precipitated. This was filtered off, dried (209 g), and the enantiomeric excess was measured. The measurement gave an enantiomeric excess of 83% e.e., which is advantageous for 2-cyanoethyl (4S)-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate. The amount of the thus-concentrated diastereomeric salt was further purified as follows: 209 g of the prepared diastereomeric salt was suspended in 2000 ml of dichloromethane and stirred at 50 °C for 2 hours and at room temperature overnight. The precipitated crystals were filtered off and washed twice with 300 ml of dichloromethane. The product was dried under reduced pressure at 40 °C. Yield: 163.6 g (38.8% of theory) of a colorless crystalline powder. Analysis results: Enantiomeric purity (e.e.%): 98% e.e. MS (EIpos): m / z = 405 [M+H] + 1 H NMR (600 MHz, DMSO-d6) δ ppm 1.90 - 2.18 (m, 2 H) 2.35 (s, 2 H) 2.67 - 2.97 (m, 1 H) 3.75 (s, 2 H) 3.93 - 4.06 (m, 1 H) 4.08 - 4.34 (m, 1 H) 5.08 - 5.36 (m, 1 H) 5.98 (s, 1 H) 6.89 - 7.01 (m, 1 H) 7.07 - 7.42 (m, 2 H) 7.97 - 8.31 (m, 3 H) 8.44 (d, J = 8.80 Hz, 2 H) 10.19 - 11.33 (m, 1 H) 12.58 - 15.01 (m, 1 H)

[0196] Example 2b Preparation of 2-cyanoethyl (4S)-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (IVa) 600 g (732.7 mmol) of the labeled 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 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: 269.5 g (94.7% of theory) of a colorless crystalline powder. Analysis results: Enantiomeric purity (e.e.%): 98% e.e. MS (EIpos): m / z = 405 [M+H] + 1 1H-NMR (300 MHz, DMSO-d6): δ = 2.03 (s, 3H), 2.35 (s, 3H), 2.80 (m, 2H), 3.74 (s, 3H), 4.04 (m, 1H), 4.11 (m, 1H), 5.20 (s, 1H), 6.95 (s, 1H), 7.23 (dd, 1H), 7.28 - 7.33 (m, 2H), 8.18 (s, 1H), 10.76 (s, 1H).

[0197] Example 2c 2-Cyanoethyl (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (VIIa) 257.04 g (0.636 mol) of 2-cyanoethyl (4S)-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (IVa) and 282 g (1.74 mol) of triethyl orthoacetate were dissolved in 420 g of NMP (1-methyl-2-pyrrolidone), and 18.9 g of concentrated sulfuric acid was added. The mixture was heated at 115 °C for 1.5 hours and then cooled to 50 °C. At 50 °C, 264 ml of water was added dropwise over 30 minutes. After the addition was complete, 11 g of the labeled compound was added as a seed crystal, and an additional 528 ml of water was added dropwise at 50 °C over 30 minutes. The mixture was cooled to 0 °C (gradient, 2 hours) and then stirred at 0 °C for 2 hours. The product was filtered off, washed twice with 480 ml of water each, and dried at 50 °C under reduced pressure. Yield: 254.3 g of pale yellow solid (92.5% of theoretical value). MS (EIpos): m / z = 433 [M+H] + 1 1H-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).

[0198] Example 2d (4S)-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (VIIIa) (4S)-2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (VII) (250 g, 0.578 mol) was dissolved in a mixture of 1.5 l of THF and 750 ml of water and cooled to 0 °C. To this solution, a sodium hydroxide solution (prepared from 164 g (924.8 mmol) of 45% aqueous sodium hydroxide and 846 ml of water) was added dropwise at 0 °C over 15 minutes, and the mixture was stirred at 0 °C for an additional 1.5 hours. The mixture was extracted twice with 576 ml of methyl tert-butyl ether and once with 600 ml of ethyl acetate. The aqueous solution at 0 °C was adjusted to pH 7 with dilute hydrochloric acid (prepared from 74.2 g of 37% HCl and 302 ml of water). The solution was warmed to 20 °C, and an aqueous solution of 246 g of ammonium chloride in 665 ml of water was added. The solution was stirred at 20 °C for 1 hour, and the product was filtered off and washed twice with 190 ml of water and once with 500 ml of acetonitrile. The product was dried at 40 °C under a stream of swirling gas. Yield: Almost colorless powder (very slight yellow tint) 207.7 g (94.7% of theoretical value). HPLC method E: RT: approximately 6.8 minutes. MS (EIpos): m / z = 380 [M+H] + 1H-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).

[0199] Example 2e (4S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (Ia) To an initial charge of 200 g (527.1 mmol) of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (VIIIa) and 119.8 g (738.8 mol) of 1,1-carbodiimidazole in 1000 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 hour (generation of gas!), then heated to 50 °C for 2.5 hours. 371.6 g (2.30 mol) of hexamethyldisilazane was added to this solution and it was boiled under reflux for 22 hours. A further 225 ml of THF was added and the mixture was cooled to 5 °C. A mixture of 146 ml of THF and 104 g of water was added over 3 hours while keeping the temperature between 5 °C and 20 °C. Then the mixture was boiled under reflux for 1 hour, then cooled to 0 °C via a gradient (3 hours) and stirred at that temperature for 1 hour. The product was filtered off and washed twice with 250 ml of THF each time and twice with 400 ml of water each time. The product was dried under vacuum at 70 °C under a swirling gas. Yield: 186.3 g (93.4% of theory) of a nearly colorless powder (very slight yellow tint). HPLC method D: RT about 6.7 minutes. 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).

[0200] Example 2f Preparation of pure product (Ia = finerenone) 140.0 g of the crude product (I) prepared in Example 2e was suspended in 2796 ml of ethanol (denatured with toluene), and then heated to reflux. When heated, 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 the final volume reached about 4 times the volume of the substance used (139.2 g × 4 ~ 561 ml) (about 2304 ml was distilled off). Then, the mixture was cooled to an internal temperature of 23 °C (over about 1.5 - 2 hours). Then, the mixture was 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: 143.70 g. The wet product was dried under reduced pressure (less than 100 mbar) at 50 °C over the weekend (for more than 48 hours). Yield: 131.3 g of colorless crystalline powder, fine needle crystals (93.8% of the theoretical value).

[0201]

Table 5

[0202] MS (EIpos): m / z = 379 [M + H] + 11H-NMR (400 MHz, DMSO-d6): δ = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99 - 4.07 (m, 2H), 5.37 (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 = 3.37 (not assignable) Modifier: Mod A (as defined in WO 2016 / 016287 pamphlet)

[0203] Example 3 Preparation of diastereomeric salts of 2-cyanoethyl 4(S)-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate using (2S,3S)-2,3-bis(4-nitrobenzoyl)tartaric acid 2.00 g of the racemate (IV) was suspended in 54 ml of propylene carbonate together with 2.375 g (1.05 equivalents) of (2S,3S)-2,3-bis(4-nitrobenzoyl)tartaric acid and heated at 39 °C for 45 minutes and stirred at that temperature for an additional 4 hours. The mixture was cooled to 20 °C over 2 hours and stirred at that temperature for an additional 18 hours. After some time, the diastereomeric salt precipitated. This was filtered off, dried (2.05 g = 48.6% of theory), and the enantiomeric excess was measured. The measurement gave an enantiomeric excess of 76.2% e.e. in favor of (4R)-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate 2-cyanoethyl ester. MS (EIpos): m / z = 405 [M+H] + 11H NMR (600 MHz, DMSO-d6) δ ppm 1.90 - 2.18 (m, 2 H) 2.35 (s, 2 H) 2.67 - 2.97 (m, 1 H) 3.75 (s, 2 H) 3.93 - 4.06 (m, 1 H) 4.08 - 4.34 (m, 1 H) 5.08 - 5.36 (m, 1 H) 5.98 (s, 1 H) 6.89 - 7.01 (m, 1 H) 7.07 - 7.42 (m, 2 H) 7.97 - 8.31 (m, 3 H) 8.44 (d, J = 8.80 Hz, 2 H) 10.19 - 11.33 (m, 1 H) 12.58 - 15.01 (m, 1 H).

Claims

1. The diastereomeric salts of formula (Va), (Vb), (Vc) and / or (Vd) 【Chemical 1】 wherein Ar is a formula 【Chemical Formula 2】 (wherein * represents the bonding site) one of or Ar is a formula [Chemical Formula 3] (wherein * represents the bonding site) one of or Ar is a formula 【Chemical 4】 (wherein * represents the bonding site) one of or Ar is a formula ​ (wherein * represents the bonding site) one of or Ar is 【Chemical Formula 6】 (wherein * represents the bonding site) ).

2. (i) The optical resolution of the compound of formula (IV) with a tartrate ester of formula (IIIa) or (IIIb) wherein Ar is as defined in claim 1 【Chemical Formula 7】 to prepare one or more diastereomeric salts of formula (Va), (Vb), (Vc) and / or (Vd) according to claim 1, comprising step (i).

3. 【Chemical 8】 The method according to claim 2, wherein the optical resolution in step (i) is carried out at a temperature of 10 to 60 °C.

4. The method according to claim 2 or 3, wherein in step (i), the organic solvent or solvent mixture is selected from the group consisting of ethanol, methanol, isopropanol, 1-propanol, ethyl acetate, isobutanol, dichloromethane, 1-pentanol, acetone and mixtures thereof.

5. Steps (i) and (ii): (i) The compound of formula (IV) is optically resolved with a tartrate ester of formula (IIIa) or (IIIb) wherein Ar is as defined in claim 1 to form a diastereomeric salt of formula (Va) and / or (Vc) wherein Ar is as defined in claim 1; 【Chemical Formula 9】 (ii) Converting the diastereomeric salt of formula (Va) and / or (Vc) obtained in step (i) into a compound of formula (IVa). A method for preparing a compound of formula (IVa). 【Chemical Formula 10】

6. 【Chemical 11】 The method according to claim 5, wherein step (i) is as defined in any one of claims 2 to 4.

7. Step (ii) is as follows: 【Chemical Formula 12】 (ii) Treating the diastereomeric salt (Va) and / or (Vc) obtained in step (i) with a base to obtain a compound of formula (IVa). The method according to claim 5 or 6, as defined.

8. The method according to any one of claims 5 to 7, wherein step (ii) is carried out at a temperature of 0 °C to 60 °C.

9. ​ ​ ​ ​ ​ The method according to any one of claims 5 to 8, wherein step (ii) is carried out at pH 6.9 to 8.

0.

10. Steps (i), (ii), (iii), (iv) and (v): (i) A tartrate ester of formula (IIIa) or (IIIb) 【Chemical 13】 (wherein Ar is as defined in claim 1) is used to resolve a compound of formula (IV) 【Chemical 14】 to form a diastereomeric salt of formula (Va) and / or (Vc) 【Chemical Formula 15】 (wherein Ar is as defined in claim 1); (ii) converting the diastereomeric salt of formula (Va) and / or (Vc) obtained in step (i) into a compound of formula (IVa) 【Chemical 16】 ; (iii) reacting the compound of formula (IVa) obtained in step (ii) with an orthoester under acidic catalysis to obtain a compound of formula (VIIa) 【Chemical 17】 ; (iv) hydrolyzing the compound of formula (VIIa) obtained in step (iii) to obtain a compound of formula (VIIIa) 【Chemical 18】 ; (v) reacting the compound of formula (VIIIa) obtained in step (iv) with 1,1-carbodiimidazole and a catalytic amount of 4-(dimethylamino)pyridine in THF as a solvent, then adding hexamethyldisilazane, then heating the mixture under reflux for 16 to 24 hours, and then adding a THF / water mixture to convert it into a compound of formula (Ia) A method for preparing a compound of formula (Ia) 【Chemical Formula 19】 comprising the above steps.

11. The method according to claim 10, wherein step (III) is carried out at a temperature of 100°C to 120°C.

12. The method according to claim 10 or 11, wherein the alkaline hydrolysis is carried out in step (iv).

13. A compound of formula (Va), (Vb), (Vc) and / or (Vd) 【Chemical 20】 (wherein Ar is as defined in claim 1), a compound of formula (IVa) 【Chemical 21】 and / or a compound of formula (Ia) 【Chemical 22】 The use of a tartrate ester of formula (IIIa), (IIIb) and / or (IIIb') 【Chemical 23】 (wherein Ar is as defined in claim 1) in a method for preparing the same.

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