RU2805573C2 - Method of preparation of (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphyridine-3-carboxamide by separation of the racemate using a diastereomeric composite tartaric acid ester - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a method of separating racemate (II) into (Ia) and/or (I) using chiral substituted tartaric acid esters of general formulas (IIIa) or (IIIb), where Ar is

where * denotes the connection point, at the temperatures ranging from 60 to 80°C, with the formation of diastereomeric salts (IVa), (IVb), (IVc) and/or (IVd), which is carried out in mixtures of solvents consisting of water and miscible organic solvents with water.

EFFECT: technical result is a new method of separating racemate (II) which can be used to obtain (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) with high yield and purity, which has the effect of a non-steroidal mineralocorticoid receptor antagonist and can be used in medicine as a means for the prevention and/or treatment of cardiovascular and renal diseases.

16 cl, 1 dwg, 8 tbl, 9 ex

Description

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

as well as to obtain enantiomer (Ia) by resolution of the racemate with chiral substituted tartaric acid esters of general formulas (IIIa) and (IIIb)

where Ar means substituted or unsubstituted aromatic compounds or heteroaromatic compounds.

Finerenone (I) has a non-steroidal mineralocorticoid receptor antagonist effect and may be used as an agent for the prevention and/or treatment of cardiovascular and renal diseases, such as heart failure and diabetic nephropathy.

The compound of formula (I) and the method for its preparation are described in the international patent application WO 2008/104306 and the article ChemMedChem 2012, 7, 1385, as well as in the international patent application WO 2016/016287 A1. To obtain a compound of formula (I) a racemic mixture of amides (II)

must be divided into appropriate antipodes, since only the antipode of formula (I) is active.

In the research synthesis described above (WO 2008/104306), a specially synthesized chiral phase (in-house production) was used for this purpose, which contained poly-N-methacryloyl-D-leucine-dicyclopropylmethylamide as a chiral selector. It has been found that the separation can also be carried out on a commercially readily available phase. In this case we are talking about the Chiralpak AS-V phase, 20 µm. A mixture of methanol/acetonitrile 60:40 was used as an eluent. In this case, chromatography can be carried out on a commercial chromatography column, but preference is given to methods known to one 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).

Although SMB separation provides very good yield and optical purity, the cost of purchasing and operating such a system under GMP conditions is a major challenge and is associated with high costs. Also, the chiral phase used in each case is very expensive and has a limited lifespan, and must be replaced time after time during the production process. For operational reasons, this is not optimal unless there is a second system to guarantee continuous operation, which incurs additional costs. In addition, especially for products that are produced on a scale measured in tons, solvent recovery is a time-consuming step, requires the purchase of huge falling film evaporators, and involves the consumption of enormous amounts of energy.

Therefore, the objective of the present invention was to find alternatives for separating a mixture of enantiomers that were significantly more cost-effective and that could be carried out using conventional pilot plant equipment (stirred tank/isolator). This type of installation is traditionally included in the standard equipment of pharmaceutical production and does not require additional investment. Certification and validation of batch processes is also much easier than with chromatographic processes, which is an added advantage.

Many attempts have been made to perform separations using conventional classical methods to separate the racemate (a variation of a chiral organic acid and solvent), as shown in Table 1:

Among other things, experiments were carried out with the classical separation reagent (+)-tartaric acid.

However, in all cases no salt formation was observed; instead, only the racemate in non-salt form always precipitated out of solution. This is basically in accordance with the expectation of one skilled in the art, which could be deduced from the pKa value of molecule (II), that the classical resolution of the racemate by diastereomeric salt formation with organic acids should not be possible, since the measured pKa value (for the base) is about 4 3 and thus almost eliminates salt formation, so that preferably the possibility of salt formation should only be realized using very strong inorganic or organic mineral acids such as chiral sulfonic acids or phosphonic acids. 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 difference in pK values must be at least 3 pK units to ensure stable salt formation. In fact, this is observed if, for example, the cyclic phosphoric acid ester chlocyphos is used, given below:

When interacting 3 eq. of the said cyclic phosphoric acid ester with the racemate (II), a diastereomeric salt is obtained in which (I) is present in an enantiomeric excess of only 44% ee.

All efforts to achieve enantiomer excess close to >99% ee have been ineffective; In addition, chlocyphos was not commercially available in large quantities, so the search for additional alternatives continued.

No salt formation was observed upon interaction with alkyl-substituted tartaric acid derivatives, such as, for example, (-)-O,O'-dipivaloyl-L-tartaric acid or (-)-O,O-diacetyl-L-tartaric acid.

Upon further development of the topic, it was unexpectedly discovered that aromatically or heteroaromatically substituted tartaric acid derivatives are excellently suited for the formation of “diastereomeric salts” from the racemate (II).

Therefore, the object of the present invention is the separation of the racemate (II)

on (Ia) and/or (I)

using chiral substituted tartaric acid esters of the general formulas (IIIa) or (IIIb)

where Ar means unsubstituted or substituted aromatic compounds or heteroaromatic compounds.

Another subject relates to a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I )

by separation of racemates (II)

with a chiral substituted tartaric acid ester of formula (IIIa)

where Ar means unsubstituted or substituted aromatic compounds or heteroaromatic compounds.

The term "substituted" means that one or more hydrogen atoms of the corresponding atom or group are replaced by one representative from the given group, provided that in the circumstances the normal valence of the corresponding atom is not exceeded. Combinations of substituents and/or variables are allowed.

The term "unsubstituted" means that not a single hydrogen atom has been replaced.

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

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

In the context of the present application, an aryl group is in particular a phenyl group.

Suitable substituents in the context of the present invention are halogen, C1-C6 alkyl, C1-6C alkoxy, nitrile, nitro group, cyano group, CF ₃ group or amide group, such as, for example, NHCOR, in which R may be methyl, ethyl or phenyl, or a group -NRCOR, in which R is as defined above, or CONHR, in which R is as defined above, or CONRR', in which R' is identical to R as defined above, or cyclic amides such as -CO-morpholine residue, -CO-piperidine residue.

The term "halogen" means a fluorine, chlorine, bromine or iodine atom, in particular a fluorine, chlorine or bromine atom.

The term "alkyl with 1-6 carbon atoms" means a linear or branched saturated monovalent hydrocarbon group with 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 isomer thereof . In particular, the group has 1, 2, 3 or 4 carbon atoms ("alkyl with 1-4 carbon atoms"), for example a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl group, in particular with 1, 2 or 3 carbon atoms (“alkyl with 1-3 carbon atoms”), for example a methyl, ethyl, n-propyl or isopropyl group.

The term "C1-6C alkoxy" means a linear or branched saturated monovalent group of the formula (C1-6C alkyl)0-, in which the term "C1-6C alkyl" has the meanings given above, for example methoxy, an ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group or an isomer thereof.

Preferably Ar means:

where R1, R2, R3, R4, R5 respectively represent a hydrogen atom or an alkyl radical, such as, for example, methyl, ethyl, propyl, or a halogen atom, such as, for example, fluorine, chlorine, bromine or iodine, or an ether group such as, for example, O-methyl, O-ethyl, O-phenyl, or a nitro group, a cyano group, a CF ₃ group or an amide group, such as, for example, NHCOR, in which R may be methyl, ethyl or phenyl, or a -NRCOR group in which R is as defined above, or CONHR in which R is as defined above, or CONRR' in which R' is identical to R as defined above, or cyclic amides such as -CO-morpholine residue, -CO-piperidine residue. Substitution patterns can be very different, so theoretically there can be up to 5 different substituents, but as a rule, monosubstituted Ar residues are preferred. However, Ar may also be a substituted heteroaromatic compound, such as preferably pyridine or pyrazine, pyridine or pyrazine. It may also be a polycyclic aromatic hydrocarbon, such as, for example, substituted naphthalene, anthracene or quinoline.

Particularly preferably Ar are:

where * denotes the location of attachment.

Particularly preferably Ar means:

where * denotes the location of attachment.

The most preferred Ar residues are:

where * denotes the location of attachment.

Of these, the unsubstituted ring (phenyl) is particularly preferred.

The preparation of tartaric acid esters is known from the literature, for example from Organic Synthesis, Coll. vol. 9, pp. 722 (1998); vol. 72, p. 86 (1995), and also described in Chirality 2011 (23), 3, p. 228.

Another object relates to diastereomeric salts in accordance with the formulas

where Ar means unsubstituted or substituted aromatic compounds or heteroaromatic compounds and has the above meanings.

Particularly preferred are diastereomeric salts in which Ar is phenyl.

It is impossible to unambiguously predict whether in this case we are really talking about a classical diastereomeric salt or about a molecular complex stabilized by a 1:1 hydrogen bond. However, what is certain is that these 1:1 molecular aggregates are very stable and behave and separate like classical diastereomeric salts, so henceforth we will use the name diastereomeric salt. To depict diastereomeric salts, tartaric acid derivatives of the general formula (IIIa) and (IIIb) are used:

where Ar means substituted or unsubstituted aromatic compounds or heteroaromatic compounds.

The preparation of diastereomeric salts is carried out as follows:

The interaction of the racemic mixture (II) with a tartaric acid derivative of the general formula (IIIa) or (IIIb) gives 4 possibilities for the formation of a diastereomeric salt (IVa-d). Surprisingly, a certain preference is observed if, for example, the racemate (II) reacts with a tartaric acid derivative of the general formula (IIIa), in most cases a diastereomeric salt of the general formula (IVa) is obtained, the salt being formed preferably in the antipode of the S configuration. The diastereomeric salt (IVa) precipitates almost quantitatively from solution, from which it can then be isolated, for example by filtration, while the antipode with Reconfiguration remains in solution. A mirror-symmetrical salt of general formula (IVb) is obtained in a very similar manner, according to which the racemate (II) is reacted with a tartaric acid derivative of general formula (IIIb), and a salt is formed preferably at the antipode of Reconfiguration. The precipitated diastereomeric salts can be separated almost quantitatively, with the S-antipode remaining in solution.

By means of the stoichiometric ratio of (II) to (IIIa) or respectively (IIIb) and the choice of solvent, the yield and enantiomeric purity can be optimized.

Since finerenones (I) have an S configuration, it is preferable to use tartaric acid derivatives with an S,S configuration for the separation of racemates, since in this case a diastereomeric salt of the S antipode is preferably formed.

To separate racemates, use 0.4 to 1.2 eq. tartaric acid ester (IIIa) or (IIIb), preferably 0.4 to 0.7 eq., particularly preferably 0.45 to 0.6 eq., most preferably 0.50 to 0.55 eq. .

The formation of a diastereomeric salt occurs in solvent mixtures that consist of water and water-miscible organic solvents.

Suitable organic solvents in the context of the present application are, for example, ethanol, methanol, isopropanol, 1-propanol, ethyl acetate, isobutanol, dichloromethane, 1-pentanol or acetone, but ethanol is preferably used. Solvents can also be used in a commercially available denatured form containing the denaturing agents used for ethanol, e.g. toluene, methyl ethyl ketone, thiophene, hexane, which has great advantages in terms of cost, so wine alcohol is particularly suitable for industrial use, which in the context of this application consists of ethanol, denatured if necessary with toluene or methyl ethyl ketone. Therefore, in the context of the present application, if ethanol is mentioned as a solvent in the following, it should be understood that it means not only pure ethanol, but also, in particular for industrial use, alcohol of wine, in the sense of the above definition. In addition, the following solvents were also used: ethyl acetate/methanol 90:10; methanol/water 80:20; ethanol/water 90:10; ethanol/water 85:15; ethanol/water 80:20; ethanol/water 75:25; ethanol/water 70:30; dichloromethane; 1-propanol/water 80:20; 1-pentanol; 1-pentanol/water 90:10; isopropanol; isopropanol/water 80:20; isobutanol/water 90:10; isobutanol/water 80:20; cyclohexanol/water 90:10; benzyl alcohol/water 90:10; ethylene glycol; ethylene glycol / water 80:20.

Preferably, the racemate separation is carried out in an ethanol/water mixture, the mixtures having ratios (v/v) in the range ethanol:water = 1:1 to 6:1. Preferably, however, a mixture of ethanol:water = 4:1 to 3 is used : 1. It is particularly preferable, however, to use a mixture of ethanol: water = 3: 1. The mixture can be prepared in advance, or on site, after all the components are placed in the container. The solvent mixture can be used in a 10-40-fold excess in terms of the racemate (II), for example, from 10 l to 40 l of the solvent mixture are used per 1 kg of racemate. Preferred is a 10-20 fold excess, in particular a 13-16 fold excess, particularly preferably a 14-15 fold excess.

Typically, the separation of racemates is carried out by first loading all components into a mixture of solvents at room temperature, then heating to 60-80°C, preferably up to 75°C, with additional stirring at 75°C for 2 to 10 hours, preferably 3 to 4 hours and then cooling for 3 to 10 hours, preferably 4 to 5 hours, to room temperature (about 20 to 23°C) (by temperature ramp). The mixture is then left to stir for an additional 2 to 24 hours, preferably 5 to 18 hours, most preferably 12 to 16 hours at room temperature. The separation of the racemate is preferably carried out at a temperature of 75°C.

Upon completion, the precipitated diastereomeric salt (IVa), (IVb), (IVc) and/or (IVd) is isolated.

Isolation is carried out by methods known to a person skilled in the art, for example, by filtration or using a centrifuge. The filter cake thus obtained can be washed again one or more times with a solvent or mixture of solvents. Drying is then carried out under vacuum, preferably <100 mbar, at elevated temperature (50 to 80°C, preferably 50°C). The use of a carrier gas has proven beneficial in some cases.

The procedure described above allows one to obtain chemically very pure diastereomeric salts. The enantiomeric excess of diastereomeric salts is typically >97% ee (see examples).

Diastereomeric salts must be dried if necessary, but they can also be used wet in the next step of the process.

The method steps, in addition to the usual order of execution indicated above, can also be combined or their sequence can be changed, as presented in the following Table 2:

Depending on the type of installation in a pilot system or in production, one or the other option may be beneficial.

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 one skilled in the art, for example by distillation. To obtain chiral compounds (I) and (Ia), a diastereomeric salt of the general formula (IVa), (IVb), (IVc) or (IVd) must be treated with a base, and the target molecule (I) or (1a) precipitates after evaporation organic solvent from solution and is isolated - for example by filtration and washing - and the corresponding tartaric acid ester of formula (IIIa) or (IIIb) remains in salt form in solution.

Suitable bases in the context of the present invention are inorganic and organic bases. For inorganic bases, 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 can be used. However, sodium hydroxide, sodium phosphate or potassium phosphate is preferably used. Particular preference is given to using sodium phosphate or potassium phosphate. It is important to note that inorganic bases can be used both in anhydrous form and in the form of their hydrates, so, for example, sodium phosphate (anhydrous) and sodium phosphate hydrate can be used successfully. As the organic base, aliphatic or aromatic bases can be used, such as, for example, triethylamine, imidazole, N-methylimidazole, Hunig's base, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

Release of the target compound (I) or (Ia) occurs in mixtures of water with water-miscible organic solvents such as ethanol, isopropanol, 1,2-ethanediol, methoxyethanol, methanol or acetone, but ethanol is preferably used. The solvents can also be used in a commercially available denatured form containing denaturing agents used for ethanol, for example toluene, methyl ethyl ketone, thiophene, hexane, preferably using wine alcohol, which in the context of the present application consists of ethanol, which can optionally be denatured with toluene or methyl ethyl ketone, which has great advantages in terms of production costs. It has been proven beneficial to use mixtures of water and ethanol, with the mixtures having ratios (v/v) in the range ethanol:water = 1:6 to 1:3. Preferably, however, a mixture of ethanol:water = 1:4 is used. The mixture can be prepared in advance, or on the spot after all the ingredients are placed in a container. The said mixture can be used in 7-20 times the amount based on the diastereomeric salt used (IVa or IVb or IVc or IVd), for example 1 kg in 7-20 l of the said mixture. Preferably, the said mixture is used in 8-12 times the amount, particularly preferably the said mixture is used in the 9-11 times amount, the most preferred is 10 times the amount.

The release of the target compound (I) or (1a) is carried out by introducing a diastereomeric salt (IVa or IVb or IVc or IVd) into a mixture of solvents at a temperature of from 0 to 80°C, preferably from 20 to 50°C, then adjusting by adding an organic or an inorganic base (either in solid form or in solution, preferably in water) pH value from 6.9 to 9.5, preferably from 7.0 to 8.0, particularly preferably pH 7.5. Optionally, the base can be added very quickly (over several minutes) or very slowly (over several hours), for example, from 5 minutes to 3 hours. In any case, faster addition is preferred, preferably dosing over 5 minutes to 1 hour. For this purpose, you can use a pH meter built into the reactor, with which you monitor the pH and slowly add base. However, it is also possible to add a fixed amount of base (solid or dissolved in a solvent) from the outset, which ensures, based on experimentally obtained values, that the desired pH range is preferably achieved. This procedure is especially preferable in production. It has been found to be beneficial if, after successful pH adjustment, the mixture is stirred again at 10-80°C, preferably 20-60°C, preferably 40-60°C. The overnight stirring time is from 1 to 10 hours, preferably from 2 to 5 hours, particularly preferably from 3 to 4 hours. It is then allowed to cool to 15-25°C, for example with a temperature ramp, and can then be stirred again for 1 to 64 hours (64 hours serves to demonstrate the stability of the process, see example 3b), but it is preferable to stir for 3 to 24 hours, but usually 10 to 20 hours is sufficient.

Isolation is carried out by methods known to a person skilled in the art, for example, by filtration or using a centrifuge. The filter cake thus obtained can be washed again one or more times with a solvent or mixture of solvents. Drying is then carried out under vacuum, preferably <100 mbar, at elevated temperature (50 to 80°C, preferably 50°C). The use of a carrier gas has proven beneficial in some cases.

However, it is also possible to dissolve the filter material in ethanol or a mixture of water and ethanol, and then, after adjusting the amount of water/ethanol in the eluate, proceed directly to the next stage of the method (see below). This procedure is particularly advantageous on an industrial scale as it results in the avoidance of a drying step.

The procedure described above allows one to obtain chemically very pure crude products. The enantiomeric excess of the crude products (I) and (Ia) is typically >96.5% ee.

In the scale-up it was shown that the complete separation of tartaric acid esters (IIIa) and (IIIb) from the crude products (I) and (Ia) is not always technically very easy to achieve, and in the case of these components they come very close to the specification limit. Since the specification requirements for the final active substance are very high (<0.1% (IIIa) in the final active substance), in some cases it has proven advantageous to add a further process step which ensures that the tartaric acid ester content IIIa) is reduced to less than 0. 15%, preferably to less than 0.1% and in particular less than 0.05%, and the final active substance is reproducibly obtained in accordance with the specification. The tartaric acid ester (IIIa) is practically, or almost completely, not depleted during final crystallization to a pure product, so that such an additional stage of the process guarantees a stable operation of the entire method and operation with almost no losses. This process step, which ensures that compound (IIIa) is depleted to less than 0.15%, preferably less than 0.1% and in particular less than 0.05% in the active substance, is also an object of the present invention. The method of reducing the content (IIIa) is carried out as follows. For this purpose, dried or preferably still wet crude product (I) or (Ia) is used. For this, a base is again used: To remove tartaric acid esters of formula (IIIa) or (IIIb), inorganic and organic bases can be used. For inorganic bases, 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 can be used. However, sodium hydroxide, sodium phosphate or potassium phosphate is preferably used. Particular preference is given to using sodium phosphate or potassium phosphate. It is important to note that inorganic bases can be used both in anhydrous form and in the form of their hydrates, so, for example, sodium phosphate (anhydrous) and sodium phosphate hydrate can be used successfully. As the organic base, aliphatic or aromatic bases can be used, such as, for example, triethylamine, imidazole, N-methylimidazole, Hunig's base, pyridine, DBU.

Depletion (IIIa) or (IIIb) occurs in mixtures of water with water-miscible organic solvents such as ethanol, isopropanol, 1,2-ethanediol, methoxyethanol, methanol or acetone, but ethanol is preferably used. The solvents can also be used in a commercially available denatured form containing denaturing agents used for ethanol, eg toluene, methyl ethyl ketone, thiophene, hexane, which has great advantages in terms of production costs. It has been proven beneficial to use mixtures of water and ethanol, with the mixtures having ratios (v/v) in the range ethanol:water = 30:10 to 10:10. Preferably, however, a mixture of ethanol: water = 20: 10 is used. The mixture can be prepared in advance, or on site, after all the components are placed in the container. The said solvent mixture can be used in a 10-20-fold excess based on the diastereomeric salt IVa, IVb, IVc or IVd used, for example 1 kg in 10-20 l of the said mixture. Preferably, said mixture is used in a 10-14-fold amount, particularly preferably, said mixture is used in an 11-12-fold amount.

Depletion (IIIa) or (IIIb) is carried out in such a way that it is introduced into the solvent mixture described above at a temperature of from 40 to 80°C, preferably from 50 to 70°C, then adjusted by adding an organic or inorganic base (or solid form or in solution, preferably in water) pH value from 6.9 to 9.5, preferably from 7.5 to 9.0, particularly preferably pH 8.5. Optionally, the base can be added very quickly (over several minutes) or very slowly (over several hours), for example, from 1 minute to 3 hours. In any case, faster addition is preferred, preferably dosing over 1 minute to 1 hour. For this purpose, you can use a pH meter built into the reactor, with which you monitor the pH and slowly add base. However, it is also possible to add a fixed amount of base (solid or dissolved in a solvent) from the outset, which ensures, based on experimentally obtained values, that the desired pH range is preferably achieved. This procedure is most preferable in production. It has been found to be beneficial if, after successful pH adjustment, the mixture is stirred again at 40-80°C, preferably 50-75°C, preferably 60-70°C. The overnight stirring time is from 1 to 24 hours, preferably from 2 to 10 hours, particularly preferably from 2 to 4 hours. The organic solvent is then largely distilled off; this can be done at normal pressure or more carefully at reduced pressure. Once the organic solvent has been largely distilled off, leave to cool to 15-25°C, for example with a temperature ramp, and then stir again for 1 to 64 hours (64 hours serves to demonstrate the stability of the process, see example 3b ), however, it is preferable to stir for 1 to 24 hours, but generally 1 to 5 hours is sufficient.

Isolation is carried out by methods known to a person skilled in the art, for example, by filtration or using a centrifuge. The filter cake thus obtained can be washed again one or more times with a solvent or mixture of solvents. Drying is then carried out under vacuum, preferably <100 mbar, at elevated temperature (50 to 80°C, preferably 50°C). The use of a carrier gas has proven beneficial in some cases.

It is also possible to set the pH value back to 5-7 before distilling the solvent using an organic acid such as formic acid, citric acid, acetic acid, or an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or an acid salt such as as sodium dihydrogen phosphate, potassium hydrogen sulfate or sodium hydrogen sulfate and then continue as above.

The procedure described above allows one to obtain chemically very pure crude products. The enantiomeric excess of the crude products (I) and (Ia) is typically >97% ee and the content of (IIIa) or (IIIb) is reduced to less than 0.15%, preferably less than 0.1% and in particular less 0.05%.

It has been proven that the crude product of formula (I) or (Ia) thus obtained can be advantageously subjected to a further subsequent crystallization to improve both the chemical and, above all, the optical purity, since the enantiomeric excesses of the crude products are generally >97% her. For this purpose, a final crystallization process has been developed: For this purpose, for GMP technical reasons, the crude product (I) or (Ia) is dissolved in ethanol (if necessary by heating) and then subjected to particle filtration; Preferably, wine alcohol or ethanol denatured with toluene is used. In some cases, depending on the technical equipment, crystallization can also be carried out under pressure, at elevated temperature (advantage: less solvent), but can also be recrystallized from aqueous solutions of ethanol (under pressure or at normal pressure). Then, at normal or correspondingly reduced pressure, the volume is reduced by approximately 3-6 times, preferably 4-5 times, and the product crystallizes out. In some cases, if, for example, large volumes need to be distilled over long periods of time, it has been found to be advantageous to distill under reduced pressure while maintaining a low internal temperature to avoid decomposition and formation of by-products. After distillation is completed, it is cooled to 0°C and then the crystals are isolated and dried in vacuum at a temperature of 40 to 50°C. Yields are typically >88% of theoretical. The achieved degree of chemical purity and content correspond to the criteria for a commercial product accepted for evaluation according to the ICH (International Conference on Harmonization of Technical Requirements for Registration of Medicinal Products for Human Use) recommendations. Residual solvent, in this case ethanol, is typically <0.05% for pilot plant loads. The optical purity is >>99% of it.

As a particularly preferred method, in particular for large-scale production, (+)-dibenzoyltartaric acid (III) is used; Both the anhydrous form and the hydrate form can be used:

The separation of the racemate is preferably carried out in a mixture of wine alcohol and water. Subsequent release of crude finerenone

preferably occurs in a mixture of wine alcohol and water using sodium phosphate as a base. In cases in which additional processing is necessary if the proportion of (+)-dibenzoyltartaric acid (III) is >0.15%

preferably further processing takes place in a mixture of wine alcohol and water using sodium phosphate as a base. The final crystallization to pure finerenone occurs preferably in wine alcohol as a solvent. This achieves a purity of 0.15%, preferably 0.1%, especially preferably less than 0.05% impurities.

It is also possible to isolate the target enantiomer from the mother liquor. In this case, the corresponding diastereomeric salt (IVa), (IVb), (IVc) or (IVd) from (I) or (Ia) is first obtained, then isolated by filtration, and then in the mother liquor, which in this case contains the corresponding antipode, by adding a base, for example ammonia, sodium hydroxide solution, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium phosphate, potassium phosphate, ammonium phosphate, preferably sodium hydroxide , sodium phosphate and potassium phosphate, especially preferably sodium phosphate and potassium phosphate, adjust the pH to >7, with pH 7.5 being preferred. The organic solvent, preferably ethanol, is then distilled off either at normal pressure or more carefully under reduced pressure, whereby the corresponding antipode precipitates. The product is filtered, washed with water or water/solvent mixtures and dried. Appropriate final crystallization from wine alcohol, as for example described in example 1c, gives compounds (I) and (Ia) in the corresponding pure form.

Therefore, another object of the present application is also finerenone (I) with a dibenzoyltartaric acid content of ≤0.15%, obtained by the fact that the racemate (II)

reacts with dibenzoyltartaric acid of formula (III)

in a mixture of wine alcohol and water to obtain diastereomeric salt (VI)

and then finerenone (I)

released using sodium phosphate also in a mixture of wine alcohol and water, and then reacts again with sodium phosphate in a mixture of wine alcohol and water, after which pure finerenone crystallizes with a dibenzoyltartaric acid content of ≤0.15%; in a particularly preferred embodiment, finerenone is prepared with a dibenzoyltartaric acid content of ≤0.1%, in particular preferably a dibenzoyltartaric acid content of less than 0.05%.

experimental part

Abbreviations and abbreviations :

Examples

The following Table 3 shows the structures of the compounds detected by HPLC. A comparison of HPLC retention times is given below.

1) Analytical method for checking impurity content and enantiomeric purity at the dibenzoyltartaric acid stage.

Instrument: Ultra-high performance liquid chromatograph (pressure range up to 1200 bar with thermostatic column oven and UV detector)

Column: YMC Triart C8

length: 100 mm, inner diameter: 3.0 mm, grain size: 1.9 µm

Maximum pressure: 1000 bar

Conditions: 20°C; 0.50 ml/min; 1.7 µl (10°C); 240 nm/6 nm

Eluent: A: 0.1% TFA in water; B: Acetonitrile

Instrument: High performance liquid chromatograph with column oven and UV detector

Column: Chiralpak IC

length: 250 mm, inner diameter: 4.6 mm, grain size: 5.0 µm

Maximum pressure: 300 bar

Conditions: 40°C; 2.0 ml/min; 5 µl; 234 nm/6 nm

Eluent: A: Heptane; B: 0.1% TFA in ethanol;

Isocratically: A(%) 80: B(%) 20

2) Analytical method for checking impurity content and enantiomeric purity at the diastereomeric salt stage.

Instrument: Ultra-high performance liquid chromatograph (pressure range up to 1200 bar with thermostatic column oven and UV detector)

Column: YMC Triart C8

length: 100 mm, inner diameter: 3.0 mm, grain size: 1.9 µm

Maximum pressure: 1000 bar

Conditions: 20°C; 0.50 ml/min; 3.5 µl (10°C); 242 nm/6 nm

Eluent: A: 0.1% TFA in water; B: Acetonitrile

Instrument: High performance liquid chromatograph with column oven and UV detector

Column: Lux 3μm i-Cellulose-5

length: 150 mm, inner diameter: 4.6 mm, grain size: 3.0 µm

Maximum pressure: 300 bar

Conditions: 40 "C; 1.0 ml/min; 10 µl (20°C); 252 nm/6 nm

Eluent: A: 20 mmol ammonium acetate buffer pH 9.0 (adjust to pH 9.0 using 1.54 g ammonium acetate in 1 L of Milli-Q water and ammonia)

; B: Acetonitrile

Isocratically: A(%) 50: B(%) 50

3) Analytical method for checking the impurity content and enantiomeric purity at the stage of finerenone, crude (I).

Instrument: Ultra-high performance liquid chromatograph

(pressure range up to 1200 bar with thermostatically controlled column oven and UV detector)

Column: YMC Triart C8

Length: 100 mm, inner diameter: 3.0 mm, grain size: 1.9 µm

Maximum pressure: 1000 bar

Conditions: 20°C; 0.50 ml/min; 1.7 µl (10°C); 252 nm/6 nm and 230 nm/6 nm for evaluation of DB-tartaric acid

Eluent: A: 0.1% TFA in water; B: Acetonitrile

Instrument: High performance liquid chromatograph with column oven and UV detector

Column: Chiralpak IA

length: 250 mm, inner diameter: 4.6 mm, grain size: 5.0 µm

Maximum pressure: 300 bar

Conditions: 40 "C; 0.8 ml/min; 5 µl (20°C); 255 nm/6 nm

Eluent: A: Acetonitrile; B: Methyl tert-butyl ether (MTBE)

Isocratic: A(%) 90: B(%) 10

Instrument/Detector: High performance liquid chromatograph with column oven, UV detector and data evaluation system

Measuring wavelength: 252 nm

Oven temperature: 40°C

Column: Chiralpak 1C

Length: 150 mm, inner diameter: 4.6 mm, grain size: 3 µm

Mobile phase: A: 50% buffer 20 mM Ammonium Acetate pH 9 B: 50% acetonitrile

Flow: 1ml/min

Completion time: 8 min

Balancing: not required, isocratic

Sample solvent: Eluent

Test solution: approximately 0.5 mg/ml racemate of the substance dissolved in the sample solvent

Comparative solution: a comparative solution is prepared by analogy with the test solution

Injection volume: 10 µl

All measured values for the determination of enantiomers given in the following examples were determined in accordance with method B. Some values, especially for batches obtained in the pilot plant, were measured for comparison using method A and gave comparable results.

The HPLC analysis data given in the following examples regarding the purity and content of the final finerenone product, pure (I), refers only to impurities that are present in the product in amounts >0.05%. This is mainly impurity E. All other impurities listed in the table above are generally <0.05%. The structure of such impurities was determined by isolation from enriched mother liquors.

Example 1

Laboratory loading using anhydrous (+)-O,O-dibenzoyl-D-tartaric acid(III)

Example 1a

Preparation of tartrate salt (IV)

250 g (660.616 mmol) of finerenone racemate (II) was placed in 3500 ml of a mixture of toluene-denatured ethanol and water = 75:25 (v/v) at room temperature (approximately 23°C). 130.2 g (363.339 mmol) (+)-O,O-dibenzoyl-D-tartaric acid (III) was added through a solids funnel and then washed with 250 ml of a mixture of toluene-denatured ethanol and water = 75 :25 (v/v). The suspension thus obtained was heated to an internal temperature of 75°C for 0.75 hours, and then further stirred at this temperature for 3.0 hours. The mixture was then cooled from 23° C. at a linear cooling rate for 5.0 hours and further stirred at this temperature overnight (approximately 16 hours). The suspension was filtered on a porous glass filter and washed once with 250 ml of a mixture of toluene-denatured ethanol and water = 75:25 (v/v). Wet product yield: 334.7 g. The wet product was then dried overnight (approximately 16 hours) at 50 ^° C under vacuum (<100 mbar). Yield: 250.2 g (100.08% of theory) colorless crystalline powder.

Analytical results:

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

1H-NMR (500 MHz, dimethyl sulfoxide-d6): δ=1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H) , 5.39 (s, 1H), 5.89 (s, 2H), 6.60-6.84 (m (broadened signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H) , 7.55 (s, 1H), 7.61 (t, 4H), 7.69 (s, 1H), 7.75 (t, 2H), 8.04 (d, 4H), 12.50-15.40 ( very broad signal, 2H) and dimethyl sulfoxide solvent signal and increased water signal: δ=2.5-2.6, as well as small peaks around δ=3.40-3.50 (kV) and δ=1.05-1 ,10 (t), superimposed signals from the residual ethanol solvent.

The colorless crystalline powder (finerenone-(+)-O,O-dibenzoyl-D-tartaric acid (VI) complex) which was obtained according to Example 1a was examined by X-ray powder diffraction (XRPD) under the following conditions at 25°C:

Sample preparation: The powder is prepared as a thin layer between two films (eg polyacetate).

Equipment: X-ray powder diffractometer X'Pert Pro

Generator: 40 kV / 40 mA

Detector: PIXcel

Radiation: CuKa radiation

Wavelength:

Technique: transmission

Scan range:

Step width: 0.013° 2Q

Measurement time: 25 sec/step

The results are shown in Figure 1 and Table 1.

Example 1b

Preparation of the crude product (I)

248 g of the compound (IV) obtained in Example 1a was suspended at room temperature in 2480 ml of a mixture consisting of toluene-denatured ethanol and water = 20:80 (v/v) (measured pH value was pH = 4). Then, 819.6 g of sodium phosphate aqueous solution (100 g of sodium phosphate dissolved in 1000 ml of water) was added dropwise over 60 minutes and the pH was adjusted to pH=7.2. The mixture was further stirred at 23°C for 50 minutes (pH 7.1). Then, 98.3 g of sodium phosphate aqueous solution (100 g of sodium phosphate dissolved in 1000 ml of water) was added dropwise over 10 minutes and the pH was adjusted to pH=7.5. Heated for an hour to an internal temperature of 50°C, and stirred at this temperature for an additional 3.0 hours. Cooled for an hour to 22°C and stirred for an additional hour at this temperature. The crystallisate is filtered on a porous glass filter and washed once with 200 ml and once with 100 ml of a mixture consisting of toluene-denatured ethanol and water = 20:80 (v/v) and twice with 200 g of water. Wet product yield: 263.4 g. The wet product was then dried over a weekend (>48 hours) at 50°C under vacuum (<100 mbar). Yield: 116.9 g (93.52% of theory) colorless crystalline powder.

Analytical results:

MC (Elpos): m/z=379 [M+H]+

1H-NMR (500 MHz, dimethyl sulfoxide-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 (broadened signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H) and the solvent signal of dimethyl sulfoxide and a significantly increased signal of water: δ=2.5-2.6, as well as a very small peak around δ=3.38 (not classified)

Example 1c

Obtaining pure product (I)

16.0 g of the crude product (I) obtained in Example 1b was suspended in 2330 ml of toluene-denatured ethanol and then heated to reflux. In this case, the product went into solution. Stir for an hour at this temperature. The solution was filtered through a heated (T=75°C) pressure filter, and then the pressure filter was washed with 30 ml of toluene-denatured ethanol. The solvent was then distilled off (approximately 1920 ml was distilled off) to reach a final volume of approximately 4 times (relative to the substance used: 116 g × 4 ~ 484 ml). Then cooled to an internal temperature of 23°C (duration approximately 1.5 to 2 hours). Then stirred for two hours at an internal temperature of 3°C. The product was filtered and washed once additionally with 100 ml of toluene-denatured ethanol. Wet product yield: 124 g. The wet product was then dried over a weekend (>48 hours) at 50°C under vacuum (<100 mbar). Yield: 112.6 g (97.07% of theory) colorless crystalline powder, fine needle crystals.

Analytical results:

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

1H-NMR (500 MHz, dimethyl sulfoxide-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 (broadened signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H) and small solvent signals of dimethyl sulfoxide and water around δ=2.5-2.6, as well as a very small peak around δ=3.38 (not classified).

Modification: Mod A (as defined in WO 2016/016287 A1, in which the absolute configuration was determined using x-rays)

Example 2

Laboratory loading using (+)-O,O-dibenzoyl-D-tartaric acid(III) hydrate

Example 2a

Preparation of tartrate

First, 350.0 g of racemate (II) was introduced at room temperature, and then 3112 g of wine alcohol was added. Then 1200 g of water was added. 191.4 g of (+)-O,O-dibenzoyl-D-tartaric acid (III) monohydrate was added through a solids funnel and then washed with 113 g of water. The suspension was heated to an internal temperature of 75°C for one hour and then stirred for 3 hours at 75°C for 3 hours. The mixture was then cooled from 23°C at linear cooling rate for 5.0 hours and further stirred at this temperature overnight (approximately 18 hours). The suspension was filtered on a porous glass filter and washed twice with a mixture of 332.3 g of wine alcohol and 140.2 g of water. Wet product yield: 487.6 g. The wet product was then dried over a weekend (>48 hours) at 50°C under vacuum (<100 mbar). Yield: 351.0 g (100.29% of theory) colorless crystalline powder.

Similarly, as described in Examples 1b and 1c, pure finerenone (I) can be obtained from this tartrate salt.

Example 3

Production of 3 batches of pure finerenone (I) in a technical laboratory, starting from 2 kg of racemate (II).

Example 3a

Preparation of tartrate (IV)

2.00 kg (5.285 mol) of racemic finerenone (II) were placed in 28.0 L of a mixture consisting of toluene-denatured ethanol and water = 75:25 (v/v) at room temperature (approximately 23°C) . 1.042 kg (2.907 mol) (+)-O,O-dibenzoyl-D-tartaric acid (III) was added through a solids funnel and then washed with 2 L of a mixture of toluene denatured ethanol and water = 75:25 (v/v). The suspension thus obtained was heated to an internal temperature of 75°C for 45 minutes, and then further stirred at this temperature for 3.0 hours. The mixture was then cooled from 23° C. at a linear cooling rate for 5.0 hours and further stirred at this temperature overnight (approximately 16 hours). The suspension was filtered on a porous glass filter and washed once with 2 L of a mixture of toluene-denatured ethanol and water = 75:25 (v/v) and pumped to dryness for 10 minutes. Wet product yield: 2.69 kg. The wet product was then dried to constant weight at 50° C. under vacuum (<100 mbar) (constant weight after approximately 17 hours). Yield: 2.009 kg (~100% of theory) colorless crystalline powder.

Example 3b

Preparation of the crude product (I)

2.006 kg of compound (IV) obtained in Example 3a were suspended at room temperature (approx. 23° C.) in 20.0 L of a mixture consisting of toluene-denatured ethanol and water = 1:4 (v/v) (measured the pH value was pH=4). Then, 6.05 kg of 9.09% aqueous sodium phosphate solution was added dropwise and the pH was adjusted to pH=7.2. The mixture was further stirred at 23°C for approximately 50 minutes (pH 7.17). Then, 0.65 kg of 9.09% aqueous sodium phosphate solution was added dropwise and the pH was adjusted to pH=7.5. Heated for an hour to an internal temperature of 50°C, and stirred at this temperature for an additional 3.0 hours. Cool for an hour to 22°C and further stir over the weekend (approximately 64 hours*) at this temperature. The crystallisate is filtered on a K800 Seitz filter plate and washed once with 1.60 L and once with 0.8 L of a mixture consisting of toluene-denatured ethanol and water = 20:80 (v/v) and twice with 1 .6 liters of water. Wet product yield: 1.82 kg. The wet product was then dried to constant weight at 50° C. under vacuum (<100 mbar) (constant weight after approximately 17 hours). Yield: 0.978 kg (97.8% of theory) colorless crystalline powder.

*) For technical reasons, mixing was continued over the weekend, usually 14 hours of additional mixing is sufficient.

Example 3c

Obtaining pure product (I)

250 g of the crude product (I) obtained in Example 3b was suspended in 5000 ml of toluene-denatured ethanol and then heated to reflux. In this case, the product went into solution. Stir for an hour at this temperature. The solution was filtered through a heated (T=85°C) pressure filter, and then the pressure filter was washed with 200 ml of toluene-denatured ethanol. Then the solvent was distilled off (approximately 4200 ml was distilled off) until the final volume was approximately 4 times (relative to the substance used: 250 g × 4 ~ 1000 ml). It was then cooled to an internal temperature of 4-5°C (ramp: duration approximately 4 hours). Then stirred for an additional hour at an internal temperature of 4-5°C. The product was filtered and washed once additionally with 220 ml of toluene-denatured ethanol. Wet product yield: 251.2 g. The wet product was then dried over a weekend (>48 hours) at 50°C under vacuum (<100 mbar). Yield: 223.0 g (89.2% of theory) colorless crystalline powder.

The following Table 4 presents the results of 3 production runs, based on 2 kg of finerenone (II) racemate:

Crude product (I)

In all 3 loads the content of (+)-O,O-dibenzoyl-D-tartaric acid (III) was 0.00%

Pure product (I)

In all 3 loads the content of (+)-O,O-dibenzoyl-D-tartaric acid (III) was 0.00%

Example 4

Industrial execution of the method. The following examples describe the implementation of the method on an industrial scale. The results, such as yield and analytical data, of 2 batches of pure finerenone (I) are finally presented in the table:

Example 4a

Preparation of tartrate salt (IV)

The load size corresponded to 80 kg of racemic finerenone (II).

• 711.0 kg of wine alcohol were placed in a 1600 liter mixing device at an internal temperature (IT) of 20°C, then 300 kg of water were added, then 80.0 kg of racemate (II) and finally 41.7 kg (+ )-dibenzoyltartaric acid (III).

• Heated to IT 75°C and further stirred for 3 hours.

• Cool over 5 hours (ramp) to IT 23°C and further stir for 16 hours.

• The suspension was transferred for centrifugation into an inverted centrifuge, centrifuged and washed with a mixture consisting of 10.7 kg of wine alcohol and 4.5 kg of water, then centrifuged to dryness and unloaded.

• Drying was carried out in a 300 liter ball dryer at a jacket temperature of 50°C and 30 mbar. The drying process was completed at an internal temperature of 45°C (duration approximately 6 hours).

• The mixture was cooled to 15°C and then the product was discharged.

Example 4b

Crude product (I)

The load size corresponded to 89.3 kg of tartrate salt (IV) for use.

• Preparation of sodium phosphate solution

• 360.0 kg of deionized water was placed in a 630 L mixing device at 20°C.

• 36.0 kg sodium phosphate was added and dissolved.

• 141.1 kg of wine alcohol were placed in a 1600 L mixing device at 20°C.

• Then 714.2 kg of water and 89.3 kg of tartrate salt (IV) were added.

• Heated to an internal temperature of 50°C.

• Then 295.1 kg of sodium phosphate solution was dosed

• After 1.5 hours, the pH value was adjusted to pH=7.5 (+/-0.1) by adding 35.4 kg sodium phosphate solution.

• The mixture was left to stir and cooled by ramping (3 hours) to IT=22°C.

• The mixture was then further stirred at IT=22°C (18 hours).

• In a separate container, a mixture of 129.6 kg of water and 25.6 kg of wine alcohol (for additional rinsing) was prepared.

• The suspension was dispensed into an inverted centrifuge (approximately 4 batches + remaining batch) and washed in batches once with a mixture of 129.6 kg of water and 25.6 kg of alcohol of wine and once with 288.0 kg of deionized water.

• The product was discharged and dried in a ball dryer (TM=50°C, 30 mbar, ending at IT=45°C, approximately 6 hours).

• Cool and then unload the product at <30°C.

Example 4c

Additional processing of the crude product (I)

In some cases, where the specification limit for (+)-dibenzoyltartaric acid (III) in the crude product is >0.1%, it has proven advisable to carry out additional processing (see Example 6) which ensures that the limit value <0 is reproducibly achieved. 1%. The additional processing method also takes place almost without losses and, as a rule, gives a crude product with a yield of >95%.

Additional processed crude product (I)

The load size corresponded to 80 kg of crude product (I).

• Preparation of sodium phosphate solution: 2.3 kg of sodium phosphate at room temperature was dissolved in 147.8 kg of water in a 250-liter separate container with a stirrer.

• 198.8 kg of wine alcohol was placed in a 630 L stirrer at 20°C and 120 kg of water was added, then 30 kg of crude product (containing (+)-dibenzoyltartaric acid (III) as indicated in Table 5) was added.

• Heated to an internal temperature of 75°C and stirred for an additional 30 minutes.

• At 70°C, 14.1 kg of the previously prepared sodium phosphate solution was added, the pH was adjusted to pH=8.9 (+/-0.1) and then stirred at 70°C for 20 hours.

• The mixture was cooled to 44°C over 60 minutes by ramping and 300 g of finerenone pure (I) seed crystals were added.

• Then, at 200 mbar and a maximum internal temperature of 60°C, the solvent was distilled off and 369 kg of water was simultaneously added to the stirring device.

• Finally, it was cooled to 22°C for 1.5 hours and the product was isolated on a pressure suction filter and washed in 3 portions with a total of 180 liters of water.

• Then dried at a jacket temperature of 50°C under vacuum (30 mbar) to constant weight.

• Allowed to cool to 15°C and then unloaded the product.

Example 4d

Pure product (I)

The load size corresponded to 26 kg (2 times 13 kg) of crude product (I).

• In a 250 L mixing device, 13 kg of further processed crude product (I) was placed in 184.9 kg of wine alcohol at 20°C, and the mixing device was previously inerted.

• The solution was heated to a jacket temperature of 80°C and stirred for 30 minutes at 78°C (at which time the product went into solution).

• The solution was filtered through a 0.65 µm filter candle (Sartorius PP candle) (GMP filtration) and the filtrate was transferred to a 630 L stirrer.

• Additionally washed with 18.5 kg of wine alcohol.

• Repeat for 2 portions (2 times 13 kg each) and the solutions were combined.

• The solvent was distilled to a final volume of approximately 130 L at normal pressure (in two batches, jacket temperature: 104°C, duration approximately 6 hours).

• The solution was cooled to 0°C with a temperature ramp over 4 hours and then further stirred for one hour.

• The product suspension was isolated on a suction filter operating under pressure and washed with 45.9 kg of wine alcohol.

• The wet product was then dried under vacuum (30 mbar) at 50°C until constant weight (approximately 12 hours). Cooled to 15°C and isolated the product.

Table 5 provides an overview of the yield and analytical results of 3 industrial batches for the preparation of pure finerenone (I).

Tartrate salt (IV)

Crude product (I)

Crude product (I) after further processing

Pure product, finerenone, pure (I)

Example 5

Several options similar to the procedure in Example 1b are suitable for the release of crude finerenone (I). The goal was to keep as small a proportion of (+)-O,O-dibenzoyl-D-tartaric acid (III) in the crude product as possible (0.15% or less). In particular, the final pH value after dosing the sodium phosphate solution, the temperature, the dosing time of the sodium phosphate solution and the subsequent stirring time were changed, and the effect on the content of (+)-O,O-dibenzoyl-D-tartaric acid in the crude product was studied.

Load size: 100 g tartaric acid (IV) in 158.0 g ethanol and 799.8 g water

Analytical data of the original tartrate salt (IV):

The following Table 6 summarizes the results:

Example 6

Additional processing method

Example 6a

Additional processed crude product: Reducing the proportion of (+)-O.O-dibenzoyl-D-tartaric acid to <0.1%.

This experiment served to demonstrate the reliability of the post-treatment process, which intentionally used a batch with a higher content of (+)-0,0-dibenzoyl-P-tartaric acid (III).

For further processing, the crude product was used, which was still analyzed to contain 0.77% (+)-O,O-dibenzoyl-D-tartaric acid (III).

Additional processing of the crude product: Reducing the proportion of (+)-O.O-dibenzoyl-D-tartaric acid (III) to <0.1%.

For further processing, the crude product was used, which was still analyzed to contain 0.77% (+)-O,O-dibenzoyl-D-tartaric acid (III). The procedure for this was as follows:

150 g of crude product (I) (containing 0.77% (+)-O,O-dibenzoyl-D-tartaric acid (III)) was added to 600 g of water and 953.9 g of alcohol of wine and heated to 70°C. Within one hour everything went into solution. Then further stirred at 70°C for 30 minutes. The pH value was pH=5.0. The pH value was adjusted to pH=8.5 by adding 44.6 g of sodium phosphate aqueous solution (15 g of sodium phosphate per 985 g of water), and then stirred at 70°C for 2 hours. Cooled to 53°C for 30 minutes and seeded with clean material (seed crystals). Then the mixture was further stirred for 30 minutes at 50-52°C. At a pressure of 200 to 155 mbar and internal temperature, the ethanol was distilled off almost completely, and at the same time 1845 ml of water was dosed (the level was kept constant: amount distilled off = amount of water added). The heating was turned off and the suspension was further stirred at 23°C overnight. The crystallisate was filtered on a porous glass filter and washed three times with 300 ml of water each time. Wet product yield: 218.9 g. The wet product was then dried over a weekend (>48 hours) at 50°C under vacuum (<100 mbar). Yield: 146.7 g (97.8% of theory)

Example 6b

Demonstration of stability, stirring 20 hours at 70°C

Additional processing of the crude product: Reducing the proportion of (+)-O,O-dibenzoyl-D-tartaric acid (III) to <0.1%.

For further processing, the crude product was used, which was still analyzed to contain 0.77% (+)-O,O-dibenzoyl-D-tartaric acid (III). The procedure for this was as follows:

150 g of crude product (I) (containing 0.77% (+)-O,O-dibenzoyl-D-tartaric acid (III)) was added to 600 g of water and 953.9 g of alcohol of wine and heated to 70°C. Within one hour everything went into solution. Then further stirred at 70°C for 30 minutes. The pH value was pH=5.0. The pH value was adjusted to pH=8.5 by adding 45.2 g of sodium phosphate aqueous solution (15 g of sodium phosphate per 985 g of water), and then stirred at 70° C. for 20 hours. Cooled to 53°C for 30 minutes and seeded with clean material (seed crystals). Then the mixture was further stirred for 30 minutes at 50-52°C. At a pressure of 200 to 155 mbar and internal temperature, the ethanol was distilled off almost completely, and at the same time 1845 ml of water was dosed (the level was kept constant: amount distilled off = amount of water added). The heating was turned off and the suspension was further stirred at 23°C overnight. The crystallisate was filtered on a porous glass filter and washed three times with 300 ml of water each time. Yield of wet product: 194.3 g. The wet product was then dried overnight (approx. 16 hours) at 50° C. under vacuum (<100 mbar). Yield: 143.1 g (95.4% of theory)

Example 6c

Additional processing of the crude product: Reducing the proportion of (+)-O,O-dibenzoyl-D-tartaric acid (III) to <0.1%. Back titrate the pH value with sodium dihydrogen phosphate to pH 7.0.

For further processing, the crude product was used, which was still analyzed to contain 0.77% (+)-O,O-dibenzoyl-D-tartaric acid (III). The procedure for this was as follows:

375.0 g of crude product (I) (containing 0.77% (+)-O,O-dibenzoyl-D-tartaric acid (III)) was added to 1500 g of water and 2384.8 g of alcohol of wine and heated to 70° WITH. Within one hour everything went into solution. Then further stirred at 70°C for 30 minutes. The pH value was pH=4.9. The pH value was adjusted to pH=8.5 by adding 101.4 g of sodium phosphate aqueous solution (15 g of sodium phosphate per 985 g of water), and then stirred at 70° C. for 20 hours. Then the pH value was adjusted to pH=7 using a sodium dihydrogen phosphate solution (50 g sodium dihydrogen phosphate in 200 ml water). Cooled to 53°C for 30 minutes and seeded with clean material (seed crystals). Then the mixture was further stirred for 30 minutes at 50-52°C. At a pressure of 200 to 155 mbar and internal temperature, ethanol was distilled off almost completely, and at the same time 4610 ml of water were dosed (the level was kept constant: amount distilled off = amount of water added). After this, it was cooled to 23°C over 90 minutes. The mixture was then further stirred at 22°C over the weekend (approximately 70 hours). The crystallisate was filtered on a porous glass filter and washed three times with 750 ml of water each time. Yield of wet product: 402.3 g. The wet product was then dried overnight (approx. 16 hours) at 50° C. under vacuum (<100 mbar). Yield: 336.6 g (89.76% of theory)

Example 6d

Final crystallization of portions from Example 6c

80.0 g of the crude product (I) obtained in Example 6c was suspended in 1600 ml of toluene-denatured ethanol and then heated to reflux. In this case, the product went into solution. Stir for an hour at this temperature. The solution was filtered through a heated (T=75°C) filter operating under pressure and then washed with 100 ml of ethanol denatured with toluene. Then the solvent was distilled off under vacuum (jacket temperature 45-47°C) until the final volume was reached, approximately 5 times (relative to the substance used: 80 g × 5 ~ 400 ml). It was then cooled over an hour to an internal temperature of 2°C and stirred for about an hour at this temperature. The product was filtered and washed once additionally with 80 ml of toluene-denatured ethanol. Yield of wet product: 83.3 g. The wet product was then dried overnight (approx. 16 hours) at 50° C. under vacuum (<100 mbar). Yield: 71.4 g (89.3% of theory) colorless crystalline powder, fine needle crystals.

Analytical results:

Example 7

Isolation of finerenone enantiomer (Ia)

Example 7a

Preparation of (-)-O,O-dibenzoyl-L-tartaric acid salt

First, 187.2 g of racemate (II) was introduced at room temperature, and then 1662.5 g of wine alcohol was added. Then 485.5 g of water was added. 97.5 g % (-)-O,O-dibenzoyl-L-tartaric acid (IIIa) was added through a solids funnel and then washed with 156.0 g water. The suspension was heated to an internal temperature of 75°C for one hour and then stirred for 3 hours at 75°C for 3 hours. The mixture was then cooled to 23°C at linear cooling rate over 5.0 hours and further stirred at this temperature overnight (approximately 18 hours). The suspension was filtered on a porous glass filter and washed twice with a mixture of 178 g of wine alcohol and 75 g of water. Yield of wet product: 255.4 g. The wet product was then dried overnight (approximately 16 hours) at 50° C. under vacuum (<100 mbar). Yield: 188.6 g (100.73% of theory) colorless crystalline powder. The mother liquor and the wash solution were combined (approximately 3200 ml of a yellowish solution, pH=4.6), and crude finerenone (I) was isolated from it (Example 7b).

Likewise, as described in Examples 1b and 1c, the finerenone enantiomer (Ia) can be prepared from this tartrate salt.

Example 7b

Isolation of crude finerenone (I) from the mother liquor

The combined mother liquor and wash solution from Example 7a (approximately 3200 ml of a yellowish solution, pH = 4.6) at room temperature were adjusted to pH = 7 by adding 43.3 g of aqueous sodium phosphate solution (100 g dissolved in 1 L of water), 6. The wine alcohol was then largely distilled off under reduced pressure (85 to 65 mbar, internal temperature 38 to 20°C) and reduced to a final volume of approximately 0.8 L. Cooled to room temperature and stirred the resulting suspension for 2 hours at 22°C. The suspension was filtered and washed twice with 150 ml of water, respectively. Yield of wet product: 159.1 g. The wet product was then dried overnight (approx. 16 hours) at 50° C. under vacuum (<100 mbar). Yield: 86.3 g (92.2% of theory based on the racemate (II) used in example 7a).

Similarly, as described in example 1c, finerenone (I) can be obtained in pure form from this crude product.

Example 8

Example 8a

Isolation of the unwanted enantiomer (1a) from the mother liquor

The combined mother liquor and wash solution from Example 1a (approximately 3750 ml of a yellowish solution, pH = 4.5) at room temperature were adjusted to pH = 7 by adding 101.1 g of aqueous sodium phosphate solution (100 g dissolved in 1 L of water), 5. The wine alcohol was then largely distilled off under reduced pressure (85 to 65 mbar, internal temperature 38 to 20°C) and reduced to a final volume of approximately 0.85 L. Cool to room temperature and the resulting suspension was stirred over the weekend (>48 hours) and then stirred at 22°C for an additional 2 hours. The suspension was filtered and washed twice with 200 ml of water each. Yield of wet product: 139.1 g. The wet product was then dried overnight (approx. 16 hours) at 50° C. under vacuum (<100 mbar). Yield: 103.1 g (82.48% of theory, based on the racemate (II) used in example 1a).

Example 8b

Industrial batch for isolation of finerenone enantiomer (Ia)

The combined mother liquor and wash solution from Example 4 (commercial production of tartrate) were processed as follows: A quantity of approximately 1165 kg of solution

• Preparation of sodium phosphate solution: 7.3 kg of sodium phosphate was dissolved in 73.1 kg of water at 20°C.

• 1165 kg of mother liquor (including wash solution) was placed in a 1600 L mixing device at 20°C and the pH was adjusted to 7.5 (+/-0.1) using 28 kg of previously prepared sodium phosphate solution.

• Stir for an additional 0.25 hours and then distill the wine alcohol under reduced pressure (65 mbar, IT approx. 22°C) to a level of approx. 310 l.

• Then stirred further at 20°C for 2 hours and the suspension was isolated using an inverted centrifuge, each case washed with 20 kg of water.

• The wet product was dried in a ball dryer at 50°C under vacuum (30 mbar; approximately 6 hours).

• Cooled to 15°C and isolated the product.

Analytical data of the used mother liquor (including wash solution) for loading 1

Analytical data of the used mother liquor (including wash solution) for load 2

Load Analytics 1

Load Analytics 2

Example 9

Examples of other tartaric acid derivatives and other solvents

Example 9a

(+)-O,O-di-p-anisoyl-D-tartaric acid

100 mg of the racemate was dissolved with 111 mg of (+)-O,O-di-p-anisoyl-D-tartaric acid in 5 ml of dichloromethane and left alone. After some time, the diastereomeric salt precipitated. It was filtered and the enantiomeric excess was measured. The measurement showed an enantiomeric excess of 68% ee with a predominance of Ia).

Example 9b

(-)-O,O-di-p-toluyl-L-tartaric acid

100 mg of racemate was dissolved with 0.55 eq. (-)-O,O-di-p-toluyl-L-tartaric acid in 4 ml of solvent and left alone. After some time, the diastereomeric salt precipitated. It was filtered and the enantiomeric excess was measured. The measurement showed an enantiomeric excess of % ee with a predominance of (Ia) The following table 7 summarizes the results

Example 9c

(+)-O,O'-dibenzoyl-D-tartaric acid

100 mg of racemate was dissolved with 0.55 eq. (+)-O,O-dibenzoyl-D-tartaric acid in 4 ml of solvent and left alone. After some time, the diastereomeric salt precipitated. It was filtered and the enantiomeric excess was measured. The measurement showed an enantiomeric excess of % ee with a predominance of (I). The following table 8 summarizes the results

Description of the drawing

Fig. 1: X-ray powder diffraction (XRPD) of compound (VI) obtained as a colorless crystalline powder according to Example 1a.

Claims (82)

1. Separation of the racemate (II) on (Ia) and/or (I) using chiral substituted tartaric acid esters of the general formulas (IIIa) or (IIIb) where Ar means where * denotes the point of attachment, characterized in that the separation of the racemate is carried out at a temperature in the range from 60 to 80°C, the formation of a diastereomeric salt is carried out in mixtures of solvents consisting of water and miscible organic solvents with water, and organic solvents miscible with water are selected from ethanol, isopropanol, 1,2-ethanediol, methoxyethanol, methanol, acetone, wine alcohol and mixtures thereof. 2. Method according to claim 1, characterized in that the separation of the racemate (II) on (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I) carry out using a chiral substituted tartaric ester of formula (IIIa) 3. The method according to claim 1, characterized in that the separation of the racemate is carried out in a mixture of ethanol and water. 4. Method according to claim 1, characterized in that Ar is phenyl. 5. Method according to claim 1, characterized in that dibenzoyl-tartaric acid (III) used to separate the racemate. 6. The method according to claim 1, characterized in that the racemate reacts with one of the chiral substituted tartaric acid esters of general formulas (IIIa) or (IIIb) such that at least one of the diastereomeric salts (IVa), (IVb), (IVc) and/or (IVd) is obtained with Ar meaning where * denotes the location of attachment. 7. Method according to claim 1, characterized in that at least one of the diastereomeric salts (IVa), (IVb), (IVc) and/or (IVd) precipitate, with Ar meaning where * denotes the location of attachment. 8. Method according to claim 6, characterized in that the diastereomeric salt (IVa), (IVb), (IVc) and/or (IVd) is precipitated and isolating the precipitated diastereomeric salt (IVa), (IVb), (IVc) and/or (IVd), wherein Ar is where * denotes the location of attachment. 9. The method according to claim 8, characterized in that the diastereomeric salt is treated with a base and the solvent is removed. 10. The method according to claim 9, characterized in that potassium hydroxide, potassium phosphate or sodium phosphate is used as a base. 11. Method according to one of paragraphs. 1-10, and racemic reacts with dibenzoyltartaric acid of formula (III) in a mixture of wine alcohol and water to obtain diastereomeric salt (VI) and then finerenone (I) released using sodium phosphate, also in a mixture of wine alcohol and water. 12. Application of racemate separation according to one of claims. 2-11 in a process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (I ) by resolution of the racemate (II) using a chiral substituted tartaric ester of formula (IIIa) with Ar meaning where * denotes the location of attachment. 13. Use according to claim 12, where finerenone (I) with a dibenzoyl-tartaric acid content of ≤0.15% is obtained in such a way that the racemate (II) reacts with dibenzoyltartaric acid of formula (III) in a mixture of wine alcohol and water to obtain diastereomeric salt (VI) and then finerenone (I) released using sodium phosphate also in a mixture of wine alcohol and water, and then reacts again with sodium phosphate in a mixture of wine alcohol and water, after which pure finerenone crystallizes with a dibenzoyltartaric acid content of ≤0.15%. 14. Use according to claim 13, where finerenone (I) is obtained with a dibenzoyltartaric acid content of ≤0.1%. 15. Diastereomeric salt according to the formula where Ar means where * denotes the location of attachment. 16. Diastereomeric salt according to claim 15, characterized in that Ar is phenyl.