EP4045500A1

EP4045500A1 - Process for producing acyloxymethyl esters of (4s)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxylic acid

Info

Publication number: EP4045500A1
Application number: EP20789970.9A
Authority: EP
Inventors: Johannes Platzek; Kai Lovis; Alba HERNANDEZ MARTIN; Silja BRADY
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 2019-10-17
Filing date: 2020-10-12
Publication date: 2022-08-24
Also published as: AU2020365314A1; CR20220161A; JP2022553225A; JOP20220148A1; BR112022005605A2; CL2022000941A1; WO2021074077A1; CO2022004464A2; IL292194A; MX2022004480A; CN114555599A; US20240150344A1; CA3157823A1; KR20220084102A; CN114555599B; PE20221414A1

Abstract

The present invention relates to a process for producing acyloxymethyl esters of (4S)-(4-cyano- 2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxylic acid of formula (IIa) by chiral resolution of the compound of formula (II) using a hydrolase. The invention also relates to a process for producing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide of formula (Ia), said process comprising the chiral resolution of the compound of formula (II) using a hydrolase. In addition, the invention also relates to the use of a hydrolase in a process for producing a compound according to formula (IIa). The invention further relates to the use of a hydrolase in a process for producing a compound according to formula (Ia).

Description

Process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

The present invention relates to a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), by resolution of the compound of the formula (II) using a hydrolase: ffl

The invention also relates to a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia), the process comprising the resolution of the compound of formula (II) using a hydrolase. The invention also relates to a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (Ia), the racemic acid of the formula (III) with halogen esters of the general formula (V) to give racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl -l, 4-dihydro-l, 6-naphthyridine-3-carboxylic acid of the formula (II) and converting this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5 by resolution using a hydrolase -ethoxy-2,8-dimethyl-l, 4-dihydro-l, 6-naphthyridine-3-carboxylic acid of the formula (Ha) converted, and this saponified to the compound of the formula (purple) and this compound of the formula (purple) then reacted in such a way that the compound of formula (Ia) is obtained: In particular, the present invention relates to a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carboxylic acid of formula (Ha)

(Ha), where R stands for a linear or branched C1-C25 ketone, which is optionally substituted by an aromatic radical, by resolution of the compound according to formula (II) where R stands for a linear or branched C1-C25 kete, using a hydrolase.

The invention relates in particular to a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of formula (Ia)

(Ia), where the racemic acid of the formula (III)

(V), where R stands for a linear or branched C1-C25 chain which is optionally substituted by an aromatic radical,

X represents chlorine or bromine, to form racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Formula (II)

(P), where R stands for a linear or branched C1-C25 kete, which is optionally substituted by an aromatic radical, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) - by resolution using a hydrolase 5-ethoxy-2,8-dimethyl-l, 4-dihydro- l, 6-naphthyridine-3-carboxylic acid of the formula (Ha)

(Ila), where R stands for a linear or branched C1-C25 ketone, which is optionally substituted by an aromatic radical, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple )

(purple), saponified and this compound of the formula (purple) is then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane heated under reflux for 16-24 hours and then with a THF / Water mixture added. In addition, the invention also relates to the use of a hydrolase in a process for preparing a compound according to formula (Ha).

The invention also relates to the use of a hydrolase in a process for the preparation of a compound according to formula (Ia). The term "Finerenone" refers to the compound (4S) -4- (4-cyano- 2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carbox-amide or the compound according to formula (Ia)

(Ia).

In the compound of the formula (I) it is the racemate of Finerenone.

The term "antipodes of Finerenone" or "antipodes of the compound according to formula (I)" refers to the compounds according to formula (Ia) and (Ib)

Finerenone (Ia) acts as a non-steroidal antagonist of the mineral corticoid receptor and can be used as an agent for the prophylaxis and / or treatment of cardiovascular and renal diseases such as heart failure and diabetic nephropathy.

The compound of the formula (Ia) and its production process are described in WO 2008/104306 A1 and ChemMedChem 2012, 7, 1385 and in WO 2016/016287 A1. In order to get to the compound of the formula (Ia), the racemic mixture of the amides (I) in the antipodes (Ia) and (Ib) be separated, since only the antipode of formula (Ia)

(Ia), is active.

In the published research synthesis (WO 2008/104306 A1) a specially synthesized chiral phase was used for this (in-house production) which contained N- (dicyclopropylmethyl) -N ² -methacryloyl-D-leucine amide as the chiral selector. It has been found that the separation can also be carried out on a commercially easily accessible phase. This is the phase Chiralpak AS-V, 20 pm. A mixture of methanol / acetonitrile 60:40 was used as the mobile phase. In this case, the chromatography can be carried out on a commercially available chromatography column, but techniques known to the person skilled in the art such as SMB (simulated moving bed; G. Paredes, M. Mazotti, Journal of Chromatography A, 1142 (2007): 56-68) are preferred or Varicol (Computers and Chemical Engineering 27 (2003) 1883-1901) is used. Although the SMB separation delivers a very good yield and optical purity, the acquisition costs and operation of such a system under GMP conditions are a great challenge and are associated with high costs. The chiral phase used in each case is also very expensive and only has a limited lifespan and has to be replaced again and again in ongoing production. For technical production reasons, this is not optimal if a second system is not available so that continuous operation is guaranteed, which is associated with additional costs. Furthermore, especially in the case of products that are manufactured on a tonnage scale, the recovery of the solvent is the time-determining step and requires the purchase of huge Fallfdm evaporators and is associated with the consumption of enormous amounts of energy.

The object was therefore to provide an alternative synthetic access to enantiomerically pure finereone (Ia), which is significantly more cost-effective and can be carried out with conventional pilot plant equipment (stirred tank / isolation apparatus). Such systems traditionally belong to the standard equipment of pharmaceutical production plants and do not require any additional investments. The qualification and validation of batch processes is also much easier than with chromatographic processes

Procedure, which is an additional advantage.

The present invention relates to a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid the formula (Ha) (Ha), where R stands for a linear or branched C1-C25 kete, by resolution of (II)

(II), where R stands for a linear or branched C1-C25 ketene, using a hydrolase.

The term “CI -C25 kete” means a “Ci-C25 alkyl chain”. The term "Ci-C25-alkyl" means a linear or branched saturated monovalent hydrocarbon group with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 carbon atoms. Examples of alkyl groups that can be used according to the invention are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl,

1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl -, 3,3-dimethylbutyl, 2,3-dimethylbutyl,

1,2-dimethylbutyl or 1,3-dimethylbutyl group or an isomer thereof.

The C1-C25 chain can be linear or branched.

The C1-C25 ketone can be substituted with an aromatic radical. The term “substituted” means that one or more hydrogen atoms on the relevant atom or the relevant group is / are replaced by a selection from the specified group, with the proviso that the normal valence of the relevant atom is not exceeded under the present circumstances . Combinations of substituents and / or variables are allowed.

The term “unsubstituted” means that no hydrogen atom has been replaced.

The term “aromatic radical” includes “aryl” and “heteroaryl”.

The term “aryl” is preferably a monovanlent, aromatic or partially aromatic, mono- or bi- or tricyclic hydrocarbon ring with 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (a “C6-C14 -Aryl "group), in particular a ring with 6 carbon atoms (a" C6-aryl "group), for example a phenyl group; or a ring of 9 carbon atoms (a "C9 aryl" group), e.g. an indanyl or indenyl group or a ring of 10 carbon atoms (a "Clo-aryl" group), e.g. a tetralinyl, dihydronaphthyl or naphthyl group or a biphenyl group (a "C12 aryl" group) or a ring having 13 carbon atoms (a "C13 aryl" group), e.g. a fluorenyl group or a ring of 14 carbon atoms (a "C14-aryl" group) such as an anthracenyl group. Preferably the aryl group is a phenyl group.

The term "heteroaryl" is preferably understood to mean a monovalent, monocyclic, bicyclic or tricyclic aromatic ring system with 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (5- to 14-membered heteroaryl group), in particular with 5 or 6 or 9 or 10 atoms, and the at least one heteroatom, which can be identical or different, the heteroatom being such as oxygen, nitrogen or sulfur and can additionally be benzofused in each case. In particular, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc. and benzoderivatives thereof, such as benzothiazuryl, benzothienyl, benzothienyl, benzothiazolyl, etc. Benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc .; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and benzo derivatives thereof such as quinolinyl, quinazolinyl, isoquinolinyl, etc .; or azocinyl, indolizinyl, purinyl, etc. and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl or oxepinyl, etc.

"Hydrolases" are enzymes that hydrolytically split esters, ethers, peptides, glycosides, acid anhydrides or CC bonds in a reversible reaction. The term is used in the meaning customary for the person skilled in the art. Examples of hydrolases are given below. The term “hydrolase” includes “lipases”, “esterases”, “amidases” and “proteases”. "Lipases", "esterases", "amidases" and "proteases" are a subgroup belonging to the hydrolases. The term is used in the meaning customary for the person skilled in the art. Examples of lipases are given below.

In the new process according to the invention, instead of the complex SMB separation discussed, the racemic mixture of the amides (I) into the antipodes of the formula (Ia) and (Ib), an advantageous enzymatic racemate resolution on a synthesis precursor, the racemic building block (II), performed .

The reaction of racemic dihydropyridine esters with hydrolases, preferably lipases, for racemate resolution is described in the literature. Examples include: Torres et al., Org. Biomol. Chem., 2017, 15, 5171-5181; Xin et al., CN 2016-106279000; Verdecia et al., US 2014/0275042; Torres et al., Tetrahedron 71 (2015) 3976-3984; Sobolev et al., Biocatalysis and Biotransformations, 2004, 231-252 (review); Schnell et al. J. Chem. Soc., Perkin Trans. 1, 2000, 4382-4389; The cleavage of other substrates has also been described: Tetrahedron Letters, Volume 29, Issue 36, 1988, Pages 4623-4624; Biotechnology Letters, September 1994, Volume 16, Issue 9, pp 919-922.

Numerous attempts have been made with the aid of enzymatic methods to synthesize suitable chiral derivatives which can be used for the synthesis of finerenones (Ia). The derivatives described here are characterized by an extremely poor solubility in water («100 mg / L) or in organic solvents which are more miscible with water, so that it was very surprising for the person skilled in the art that conditions could be found which allow chiral acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (Ha) in good yield and high enantiomeric To establish purity. A distinction must be made between two cases for enzymatic saponification. On the one hand, that the target enantiomer with the 4 S configuration (Ha) is saponified and is converted into the acid (purple), which is then separated off or, on the other hand, by saponifying the enantiomer with the 4R configuration (IIb) and the 4 S -configured ester (Ha) remains in the solution and is then converted later to the acid (purple) after separation. Both products, ester and acid, can be separated from one another very easily via extraction. The reaction can be carried out using the following commercially available enzymes:

• Lipase AK from Pseudomonas fluorescens [CAS number 9001-62-1; preferred UniProtKB entry - Q7WZT7 (Sigma- Aldrich, Amano Enzyme)]

• Lipase type VII from Candida rugosa (Sigma-Aldrich, L1754) · Lipase from Candida rugosa (Sigma-Aldrich 62316)

• Amano lipase M, from Mucor javanicus (Sigma-Aldrich 534803)

• Amano lipase PS, from Burkholderia cepacia (Sigma-Aldrich 534641)

• Amano lipase PS-IM (Sigma-Aldrich 709603)

• Lipase from Aspergillus niger (Sigma-Aldrich 62301) · Lipase from Thermomyces lanuginosus (Sigma-Aldrich L0777)

• Lipase from Rhizomucor miehei (Sigma-Aldrich L4277)

• Lipase from Candida antarctica B (Lipozyme, Novozymes)

• Lipase from Candida antarctica A (Novocor AD L, Novozymes)

• Lipase from Aspergillus oryzae (Resinase HT, Novozymes) · Lipase from Humicola insolens (Novozym 51032, Novozymes)

• Lipase from Candida antarctica B, immobilized (Novozym 435, Novozymes)

• Lipase from Thermomyces lanuginosus, immobilized (Lipozyme TL IM, Novozymes)

• Lipase from Rhizomucor miehei, immobilized (Novozym 40086, Novozymes)

• Lipase from Candida antarctica in acrylic resin (Sigma-Aldrich L4777) · Lipase from pig liver (Sigma-Aldrich E3019)

The reaction takes place in a one- or two-phase system with an aqueous buffer, such as, for example, sodium phosphate, potassium phosphate, preferably potassium phosphate, and one which is or is not miscible with water miscible organic solvents, such as. B. ethanol, methanol, n-butanol, isopropanol, acetone, THF, DMF, DMSO, tert-butyl methyl ether, cyclopentyl methyl ether, 1,4-dioxanes, 2-methyl-THF, toluene or mixtures thereof. The reaction takes place at a pH of 7.0 to pH 10, preferably between pH 7-8, particularly preferably pH 7. The pH can be kept constant by sufficient buffer capacity or by slowly adding an inorganic base dropwise such as KOH or NaOH, both as an aqueous solution. In some cases it has proven to be advantageous to add additives such as sugar, glycerine, Mg salts, Ca salts.

The reaction takes place at temperatures of 22-45 ° C., preferably 25-38 ° C., and the mixture is stirred for 10 hours to 10 days (depending on the enzyme used).

The following combinations of solvents have proven to be particularly effective:

• 2-Methl-THF / potassium phosphate buffer pH 7

• 10% DMSO / 90% 50 mM potassium phosphate buffer pH 7

• 20% tert-butyl methyl ether / 80% 50 mM potassium phosphate buffer pH 7

• Water, saturated tert-butyl methyl ether / various buffers pH 7 - pH 7.5

• 50% cyclopentyl methyl ether / 50% 50 mM K-phosphate buffer pH 7

• 1: 1 w / w Triton X-100, 1.5% DMF / 98.5% 50 mM potassium phosphate buffer pH 7 - pH 8

• Water saturated 1,4-dioxane / various buffers pH 7 - pH 7.5

To work up the reaction solution, the reaction can be stopped by adding saturated sodium chloride solution (or another salt solution such as CaC12) and then the product can be extracted by extraction with a suitable solvent. The product can be further purified by chromatography. In many cases the crude product can also be recrystallized directly. It has generally proven to be an advantage to recrystallize the products (which generally show ee% values of> 70%) again in order to obtain ee% values of> 99%. Mixtures of tert-butyl methyl ether with alcohols such as ethanol, methanol, isopropanol or ethyl acetate or isopropyl acetate have proven to be useful as solvents for the final recrystallization.

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

(III), with halogen esters of the general formula (V) in which

R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical,

X stands for chlorine or bromine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (II) where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) - by resolution using a hydrolase 5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha) where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, converted, and this in a THF / water mixture (2: 1) with sodium hydroxide to give the compound of the formula (purple)

(purple), saponified and this compound of the formula (purple) is then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane, heated under reflux for 16-24 hours and then mixed with a THF / water mixture.

The further conversion of the chiral acyloxymethyl ester (Ha) to finerenones (Ia) is described below.

Starting from the chiral acyloxymethyl esters (Ha or Ilb), the acid (lavender or Illb) is obtained by alkaline saponification and subsequent acidic work-up:

The saponification can be carried out in a manner known per se by the methods known to the person skilled in the art in organic solvents or water-miscible solvents with the aid of an inorganic base. It has been found that the reaction can very easily be carried out in a relatively concentrated manner in mixtures of THF / water. For this purpose, a mixture of THF / water 2: 1 (9 times) is preferred, the sodium hydroxide solution is metered in at 0 ° -5 ° C., then stirred at 0 ° -5 ° C. for 1-2 hours. Potassium hydroxide can also be used, but sodium hydroxide or potassium hydroxide is preferred. For work-up, extraction is carried out with MTBE (methyl tert-butyl ether) and ethyl acetate or just toluene and, for isolation, the pH is adjusted to 7 with a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid, but preferably hydrochloric acid. A saturated ammonium salt solution of the corresponding acid, but preferably ammonium chloride solution, can then be added, the product crystallizing out quantitatively. After isolation, it is washed with water and with ethyl acetate or acetonitrile or acetone, but preferably acetonitrile, and dried in vacuo at 40.degree.-50.degree. The yield is almost quantitative (99%). The consequence conversion of the acid (lilac or IIIb) to the amide (Ia or Ib) is described as follows: It was found that when the acid (lilac or IIIb) is converted into THF, the amide (Ia or Ib) is derived directly the solution crystallized out and can be obtained in high yield and purity. For this purpose, the carboxylic acid (purple or IIIb) is added with 1.1 to 1.6 equivalents, preferably 1.3-1.4 equivalents of l, l'-carbodiimidazole under DMAP catalysis (5-15 mol%, preferably 10 mol% / in some cases it has been shown that you can get the reaction without

DMAP addition) reacted in THF to the imidazolide, this takes place at temperatures between 20 ° - 50 ° C, the preferred procedure has been found to first start at 20 ° C, then stir for 1 to 2 hours at this temperature and then stir for 2 to 3 hours at 50 ° C. After activation has ended, 3-8 equivalents, preferably 4.5 equivalents, of hexamethyldisilazane are added and the mixture is refluxed for 16-24 hours, but preferably 16 hours. The resulting disilylamide compound can optionally be isolated, but it has been found to be more advantageous to continue in a one-pot reaction. When the reaction has ended, the mixture is therefore cooled to 0 ° -3 ° C. and a mixture of water / or a mixture with THF is metered in; It has proven to be advantageous to use an amount of water of 0.5 to 0.7 times (based on the starting material), and an amount of 0.52 times of water is particularly advantageous. The water can be metered in directly or in a mixture with approximately one to twice the volume of THF. After quenching has ended, the mixture is refluxed for a total of 1-3 hours, preferably 1 hour. The mixture is cooled to 0 ° C. and stirred for 1-5 hours, preferably 3 hours, at this temperature, then the product is isolated by filtration or centrifugation. It is rewashed with THF and water and dried in vacuo at an elevated temperature (30 ° to 100 ° C., preferably at 40 ° C. to 70 ° C.). The yields are very high and are generally> 93% of theory. Theory. The purity is usually> 99% (HPLC, 100% method). The compound (Ia) can also be obtained directly by reaction with ammonia gas in an autoclave (approx. 25 to 30 bar). To do this, the preactivation described above is carried out and then heated under pressure under ammonia gas. When the reaction has ended, the mixture is cooled and the product is filtered off. The yields and purities achieved in this way are comparable.

Final crystallization process (setting of the final modification Mod A): For GMP technical reasons, (Ia) is first dissolved in ethanol, subjected to particle filtration and then the solvent is distilled off either under reduced pressure or at normal temperature, preferably with Toluene denatured ethanol used. It is concentrated to a volume of approx. 3 to 5 times, and the product crystallizes out. It is cooled to 0.degree. C. and then the crystals are isolated and dried at 40-50.degree. C. in vacuo. The yields are generally> 90% of theory. Theory. The achieved chemical purity is> 99.8% and the content ~ 100% corresponds to the criteria for commercial products according to the ICH guideline. Residual solvent, in this case ethanol, is <0.02%. The optical purity is »99% ee. The new inventive method described here is distinguished by several advantages over the prior art. No special equipment (such as SMB, chiral chromatographic methods) is required to separate the enanatiomers on the precursors of the finerenone synthesis (Ia). The enzymatic cleavage can be carried out in completely normal stirred reactors. The use of water as the reaction medium saves costs in terms of expensive solvents. The disposal of waste is also more environmentally friendly than previous methods. With the enzymatic Resolution of the racemate gives intermediate product (Ha) as a rule with 70-91% enantiomeric excess (ee%). The enantiomeric excesses can be increased to> 99% ee by a relatively simple crystallization, whereby it is known that one can already obtain highly pure finerenones (Ia) with 93% ee material, since in the subsequent synthesis sequence the Missing enantiomer loses. Therefore, ester (Ha) can be recrystallized in a relatively more concentrated manner in order to keep the losses as low as possible.

Further embodiments of the invention are described as follows:

The present invention relates to a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid the formula (Ha)

(Da), where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, by resolution of (II)

(II), where R stands for a linear or branched C1-C25 ketene, which is optionally substituted by an aromatic radical, using a hydrolase.

Preferred within the scope of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine -3-carboxylic acid of the formula (Ha)

(Ha), where R stands for a linear or branched C1-C25 ketone, which is optionally substituted by an aromatic radical, by resolution of (II)

(II), where R stands for a linear or branched C1-C25 kete, which is optionally substituted by an aromatic radical, using a lipase.

(Ha), where R stands for a linear or branched C1-C25 ketone, which is optionally substituted by an aromatic radical, by resolution of (II) where R stands for a linear or branched C1-C25 kete, which is optionally substituted by an aromatic radical, using lipase AK from Pseudomonas fluorescens.

Preferred in the context of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxylic acid of the formula (Ha) where R is methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, by resolution of (II), where R is methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, using a hydrolase.

Preferred in the context of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxylic acid of the formula (Ha) where R is methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, represents ^ by resolution of (II), where R is methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, using a lipase.

Preferred in the context of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxylic acid of the formula (Ha) where R is methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, by resolution of (II), where R is methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, using Lipase AK from Pseudomonas fluorescens. Preferred in the context of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxylic acid of the formula (Ha), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl, by resolution of (II), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl using a hydrolase.

Preferred in the context of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxylic acid of the formula (Ha), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl, by resolution of (II), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl stands using a lipase. Preferred in the context of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxylic acid of the formula (Ha), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl, by resolution of (II), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl using Lipase AK from Pseudomonas fluorescens.

Particularly preferred in the context of the present invention is a process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine -3 -carboxylic acid of the formula (Ha)

(Ha), where R stands for methyl _j by resolution of (II)

(P), where R is methyl, using a hydrolase.

(Ha), where R stands for methyl, by resolution of (II)

(P), where R is methyl, using a lipase.

(Ila), where R stands for methyl, by resolution of (II) (II), where R stands for methyl, using lipase AK from Pseudomonas fluorescens.

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

(Ia), characterized in that the racemic acid of the formula (III)

(III), with halogen esters of the general formula (V)

(V), where

R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, X represents chlorine or bromine, to form racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Formula (II)

(P), where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2 -methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha) where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, transferred, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple)

Preferred in the context of the present invention is a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine- 3-carboxamide of the formula (Ia)

(Ia), characterized in that the racemic acid of the formula (III)

(HI), with halogen esters of the general formula (V) in which

(P), where R stands for a linear or branched C1-C25 kete, which is optionally substituted by an aromatic radical, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) by resolution using a lipase -5-ethoxy-2,8-dimethyl-l, 4-dihydro- l, 6-naphthyridine-3-carboxylic acid of the formula (Ha) where R stands for a linear or branched C1-C25 kete, which is optionally substituted by an aromatic radical, and this in a THF / water mixture (2: 1) with sodium hydroxide to give the compound of the formula (purple)

(Illa), saponified and this compound of the formula (purple) is then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane heated under reflux for 16-24 hours and then with a THF / Water mixture added. Preferred in the context of the present invention is a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine- 3-carboxamide of the formula (Ia)

(Ia), characterized in that the racemic acid of the formula (III)

(III), with halogen esters of the general formula (V)

(V), in which

(P), where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, and converts this into the enantiomeric acyloxymethyl ester (4S) - ( 4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha)

(There), where R stands for a linear or branched C1-C25 kete, which is optionally substituted by an aromatic radical, and this in a THF / water mixture (2: 1) with sodium hydroxide to give the compound of the formula (purple)

(purple), saponified and this compound of the formula (purple) then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane, heated under reflux for 16-24 hours and then mixed with a THF / water mixture.

Preferred in the context of the present invention is a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine- 3-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) is mixed with halogen esters of the general formula (V), where

R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, X is chlorine or bromine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8- dimethyl-1,4-dihydro-1,4-naphthyridin-3-carboxylic acid of the formula (II), where R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl is converted, and this is converted into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy- 2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where

R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, is converted, and this is saponified in a THF / water mixture (2: 1) with sodium hydroxide solution to give the compound of the formula (purple) and this compound of the formula (purple) then first reacted in THF as a solvent with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane, heated under reflux for 16-24 hours and then mixed with a THF / water mixture.

R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl,

X represents chlorine or bromine, to form racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Formula (II), where

R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, converts, and this by resolution using a lipase, in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine -3-carboxylic acid of the formula (Ha), where

R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, is converted, and this is saponified in a THF / water mixture (2: 1) with sodium hydroxide solution to give the compound of the formula (purple) and this compound of the formula (purple) then first reacted in THF as solvent with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane heated under reflux for 16-24 hours and then mixed with a THF / water mixture.

R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, converts, and this by resolution using lipase AK from Pseudomonas fluorescens, in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where

R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, is converted, and this is saponified in a THF / water mixture (2: 1) with sodium hydroxide solution to give the compound of the formula (purple) and this compound of the formula (purple) then first reacted in THF as solvent with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane heated under reflux for 16-24 hours and then mixed with a THF / water mixture. Preferred in the context of the present invention is a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine- 3-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) is mixed with halogen esters of the general formula (V), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl,

X represents chlorine or bromine, to form racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Formula (II), where R stands for methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) by resolution using a hydrolase ) -5-ethoxy-2,8-dimethyl-l, 4-dihydro- l, 6-naphthyridine-3-carboxylic acid of the formula (Ha), in which

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and this in a THF / water mixture (2: 1) with sodium hydroxide to give the compound of the formula (purple), saponified and this compound of the formula ( purple) then first reacted in THF as a solvent with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane heated under reflux for 16-24 hours and then mixed with a THF / water mixture.

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl,

X stands for bromine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula ( II), where

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy- 2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and this in a THF / water mixture (2: 1) with sodium hydroxide to give the compound of the formula (purple), saponified and this compound of the formula ( purple) then first reacted in THF as a solvent with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane heated under reflux for 16-24 hours and then mixed with a THF / water mixture.

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl,

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy- 2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, transferred, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple), saponified and this compound of the formula (purple) then in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts 4- (Dimethylamino) pyridine reacted, after addition of hexamethyldisilazane, heated under reflux for 16-24 hours and then treated with a THF / water mixture.

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl,

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple), saponified and this compound of the formula (purple) is then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane heated under reflux for 16-24 hours and then with a THF / Water mixture added. Preferred in the context of the present invention is a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine- 3-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) is mixed with halogen esters of the general formula (V), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl,

X represents chlorine or bromine, to form racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Formula (II), where R stands for methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano) by resolution using lipase AK from Pseudomonas fluorescens -2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, transferred, and this in a THF / water

Mixture (2: 1) with sodium hydroxide solution to form the compound of the formula (purple), saponified and this compound of the formula (purple) is then first reacted in THF as a solvent with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine adding Hexamethyldisilazane heated under reflux for 16-24 hours and then treated with a THF / water mixture.

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl,

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) - by resolution using lipase AK from Pseudomonas fluorescens 5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and this in a THF / water mixture (2: 1) with sodium hydroxide to give the compound of the formula (purple), saponified and this compound of the formula ( purple) then first reacted in THF as a solvent with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane, heated under reflux for 16-24 hours and then treated with a THF / water mixture. Preferred in the context of the present invention is a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine- 3-carboxamide of the formula (Ia)

(Ia), characterized in that the racemic acid of the formula (III)

(III), with halogen esters of the general formula (V) where R stands for methyl, X represents chlorine or bromine, to form racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Formula (II)

(P), R represents methyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-l, by resolution of the racemate using a hydrolase, 4-dihydro- l, 6-naphthyridine-3-carboxylic acid of the formula (Ha)

R stands for methyl, transferred, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple)

(Illa), saponified and this compound of the formula (purple) is then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane, heated under reflux for 16-24 hours and then mixed with a THF / water mixture.

(Ia), characterized in that the racemic acid of the formula (III)

(III), with halogen esters of the general formula (V)

(V), where

R stands for methyl,

X stands for bromine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula ( II)

(P), R represents methyl, and this is converted by resolution using a hydrolase into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro- 1,6-naphthyridine-3-carboxylic acid of the formula (Ha)

(Ha),

R represents methyl, converted, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple)

(Illa), saponified and this compound of the formula (purple) is then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding Hexamethyldisilazane heated under reflux for 16-24 hours and then treated with a THF / water mixture.

(Ia), characterized in that the racemic acid of the formula (III)

(III). with halogen esters of the general formula (V)

(V), in which

R stands for methyl,

(II),

R represents methyl, converts, and this by resolution using a lipase, in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro- 1,6-naphthyridine-3-carboxylic acid of the formula (Ha)

(Ha), R represents methyl, converted, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple)

(IHa), saponified and this compound of the formula (purple) then in THF as a solvent first with 1,1-

Carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine reacted, after adding hexamethyldisilazane, heated under reflux for 16-24 hours and then treated with a THF / water mixture.

(Ia), characterized in that the racemic acid of the formula (III)

(III), with halogen esters of the general formula (V) where R stands for methyl,

X stands for bromine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula ( II) R stands for methyl, converts, and this by resolution using a lipase, in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine -3 -carboxylic acid of the formula (Ha)

(purple), saponified and this compound of the formula (purple) is then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane, heated under reflux for 16-24 hours and then mixed with a THF / water mixture. Preferred in the context of the present invention is a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine- 3-carboxamide of the formula (Ia)

(Ia), characterized in that the racemic acid of the formula (III)

(III), with halogen esters of the general formula (V) in which

R represents methyl, X represents chlorine or bromine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (II) where R stands for methyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1 by resolution of the racemate using lipase AK from Pseudomonas fluorescens , 4-dihydro- l, 6-naphthyridine-3-carboxylic acid of the formula (Ha) in which R represents methyl, converted, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple)

(Ia), characterized in that the racemic acid of the formula (III)

X stands for bromine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula ( II) in which R represents methyl, converts, and this by resolution using lipase AK from Pseudomonas fluorescens, in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1, 4-dihydro- l, 6-naphthyridine-3-carboxylic acid of the formula (Ha)

(Ha), where

(purple), saponified and this compound of the formula (purple) is then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane heated under reflux for 16-24 hours and then with a THF / Water mixture added. Preferred in the context of the present invention is a process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine- 3-carboxamide of the formula (Ia), characterized in that the racemic acid of the formula (III) with halogen esters of the general formula (V), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl,

X represents chlorine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula ( II), where R stands for methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) - by resolution using a hydrolase 5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and this in a THF / water mixture (2: 1) with sodium hydroxide to give the compound of the formula (purple), saponified and this compound of the formula ( purple) then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding Hexamethyldisilazane heated under reflux for 16-24 hours and then treated with a THF / water mixture.

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, X represents chlorine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1 , 4-dihydro-l, 6- naphthyridine-3-carboxylic acid of the formula (II), where

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and converts this into the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy- 2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha), where R is methyl, ethyl and isopropyl, n-butyl or n-pentyl, and this is converted into a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple), saponified and this compound of the formula (purple) then in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine converts, after the addition of Hexamethyldisilazane heated under reflux for 16-24 hours and then treated with a THF / water mixture.

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl,

X represents chlorine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula ( II), where

(Ia), characterized in that the racemic acid of the formula (III)

(III), with halogen esters of the general formula (V) where R stands for methyl, X represents chlorine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula ( II)

(P),

(Ia), characterized in that the racemic acid of the formula (III)

X represents chlorine, to racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula ( II) in which R represents methyl, converts, and this by resolution using lipase AK from Pseudomonas fluorescens, in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1, 4-dihydro- l, 6-naphthyridine-3-carboxylic acid of the formula (Ha) in which

(purple), saponified and this compound of the formula (purple) is then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane, heated under reflux for 16-24 hours and then with a THF / Water mixture added. The reaction takes place in organic solvents such as dimethylformamide, dimethylacetamide, NMP, acetonitrile, THF, DMSO, sulfolane, acetone, 2-butanone in the presence of an organic or inorganic base such as triethylamine, tributylamine, pyridine, potassium carbonate, cesium carbonate, sodium carbonate, potassium hydrogen carbonate, Sodium hydrogen carbonate, fithium hydroxide. The reaction takes place at 0.degree. C. to 80.degree. C., preferably at 20.degree.-60.degree. C., particularly preferably at 20.degree.-40.degree. The crude products obtained after working up are purified by crystallization

The preparation of the acid (III) is described in WO 2016/016287 A1 (example 6).

The preparation of the halogen esters (V) is analogous to that in G Sosnovsky, NUM Rao, SW Fi, HM Swartz, J. Org. Chem. 1988, 54, 3667 and NP Mustafaev, MA Kulieva, KN Mustafaev, TN Kulibekova, GA Kakhramanova , MR Safarova, NN Novotorzhina, Russ. J. Org. Chem. 2012, 49, 198 carried out synthesis described.

In addition, the invention also relates to the use of a hydrolase in a process for preparing a compound according to formula (Ha).

In one embodiment, the invention relates to the use of a hydrolase in a process for the preparation of a compound of the formula (Ha) by resolution of the compound (II).

In a further embodiment, the invention relates to the use of a hydrolase in a process for the preparation of a compound of the formula (Ha) by resolution of the compound (II), where the Process corresponds to one of the embodiments of the process for the preparation of a compound of formula (Ha) explained above.

The invention also relates to the use of a hydrolase in a process for the preparation of a compound according to formula (Ia). In one embodiment, the invention relates to the use of a hydrolase for the preparation of a compound of the formula (Ia), the process corresponding to one of the embodiments of the process for the preparation of a compound of the formula (Ia) explained above.

The following paragraphs 1 to 10 represent further embodiments of the invention:

1. A process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula ( Ha)

(Ha), where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, by resolution of (II)

(P), where R stands for a linear or branched C1-C25 ketone, which is optionally substituted by an aromatic radical, using a hydrolase. 2. The method according to paragraph 1, characterized in that

3. The method according to paragraph 1 or 2, characterized in that R stands for methyl,

4. The method according to paragraph 1, 2 or 3, characterized in that the hydrolase used is a lipase.

5. The method according to paragraph 4, characterized in that lipase AK from Pseudomonas fluorescens is used.

6. Process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro- 1,6-naphthyridine-3-carboxamide of the formula ( Ia)

(Ia), characterized in that the racemic acid of the formula (III) in which

7. The method according to paragraph 6, characterized in that

R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, and

X stands for bromine. 8. The method according to paragraph 6 or 7, characterized in that

R is methyl, and

X stands for bromine.

9. The method according to paragraph 6, 7 or 8, characterized in that lipase is used for the resolution.

10. The method according to paragraph 9 gekennzeicnet that for the resolution lipase AK from

Pseudomonas fluorescens is used. Paragraphs 1 to 10

The following paragraphs 1 to 10 represent further embodiments of the invention.

(II), where R is a linear or branched C1-C25 chain, optionally with an aromatic

Residue is substituted using a hydrolase.

2 Method according to paragraph 1, characterized in that R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl. Process according to paragraph 1 or 2, characterized in that R stands for methyl,. Method according to paragraph 1, 2 or 3, characterized in that the hydrolase used is a lipase. . Method according to paragraph 4, characterized in that lipase AK from Pseudomonas fluorescens is used. . Process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (Ia) (Ia), characterized in that the racemic acid of the formula (III)

(III), with halogen esters of the general formula (V) in which

R stands for a linear or branched C1-C25 ketone, which is optionally substituted by an aromatic radical,

X stands for chlorine or bromine, to form racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Formula (II)

(II), where R is a linear or branched C1-C25 ketone, optionally with an aromatic

Rest is substituted, converts, and this by resolution using a hydrolase in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-l, 6-naphthyridine-3-carboxylic acid of the formula (Ha) where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, converted, and this in a THF / water mixture (2: 1) with sodium hydroxide to give the compound of the formula (purple)

(purple), saponified and this compound of the formula (purple) is then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding hexamethyldisilazane, heated under reflux for 16-24 hours and then mixed with a THF / water mixture. Method according to paragraph 6, characterized in that

X stands for bromine.

8. The method according to paragraph 6 or 7, characterized in that

R is methyl, and

X stands for bromine.

10. The method according to paragraph 9, characterized in that lipase AK from Pseudomonas fluorescens is used for the resolution.

Paragraphs (1) to (27)

The following paragraphs (1) to (27) represent further embodiments of the invention: (1) Process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl- l, 4-dihydro-l, 6-naphthyridine-3-carboxylic acid of the formula (Ha)

(Ha), where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, by resolution of (II) where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, using a hydrolase.

(2) The method according to paragraph 1, wherein in the compound according to formula (Ha)

R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, and where in the compound according to formula (II)

R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl.

(3) Process according to paragraph 1 or 2, wherein in the compound according to formula (Ha)

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and where in the compound according to formula (II)

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl. (4) Process according to paragraph 1, 2 or 3, wherein in the compound according to formula (Ha)

R stands for methyl, and where in the compound according to formula (II) R is methyl.

(5) The method according to any one of paragraphs 1 to 4, wherein the hydrolase used is a lipase.

(6) Method according to one of paragraphs 1 to 5, wherein the lipase is selected from lipase type VII from Candida rugosa, lipase from Candida rugosa, Amano lipase M, from Mucor javanicus, Amano lipase PS from Burkholderia cepacian, Amano lipase PS-IM , Lipase from Aspergillus niger lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica B, lipase from Candida antarctica A, lipase from Aspergillus oryzae, lipase from Humicola insolens, lipase from Candida antarctinos B, lipase from Thermomyces lanug Rhizomucor miehei, lipase from Candida antarctica and lipase from pig liver.

(7) Method according to one of paragraphs 1 to 6, wherein the lipase is Lipase AK from Pseudomonas fluorescens.

(8) Process according to one of paragraphs 1 to 7, wherein the resolution is carried out in a single-phase system.

(9) Process according to one of paragraphs 1 to 7, wherein the resolution is carried out in a two-phase system.

(10) The method according to any one of paragraphs 1 to 9, wherein the resolution is carried out in an aqueous buffer.

(11) The method according to any one of paragraphs 1 to 10, wherein the racemate resolution is carried out in an aqueous buffer selected from sodium phosphate, potassium phosphate and mixtures thereof.

(12) Process according to one of paragraphs 1 to 11, wherein the racemate resolution is carried out at a pH between pH 7.0 and pH 10, between pH 7 and 8, or at pH 7.

(13) Process according to one of paragraphs 1 to 12, wherein the racemate resolution is carried out in a water-miscible or immiscible organic solvent.

(14) The method according to one of paragraphs 1 to 13, wherein the racemate resolution in water-miscible organic solvents selected from the group consisting of ethanol, methanol, n-butanol, isopropanol, acetone, THF, DMF, DMSO, tert .-Butyl methyl ether, cyclopentyl methyl ether, 1,4-dioxanes, 2-methyl-THF, toluene and mixtures thereof. (15) The method according to any one of paragraphs 1 to 14, wherein the resolution is carried out in a solvent combination selected from the group consisting of

• 2-Methl-THF / potassium phosphate buffer pH 7;

• 10% DMSO / 90% 50 mM potassium phosphate buffer pH 7; 20% tert-butyl methyl ether / 80% 50 mM potassium phosphate buffer pH 7;

• Water, saturated tert-butyl methyl ether / various buffers pH 7 - pH 7.5;

• 50% cyclopentyl methyl ether / 50% 50 mM K-phosphate buffer pH 7;

• 1: 1 w / w Triton X-100, 1.5% DMF / 98.5% 50 mM potassium phosphate buffer pH 7 - pH 8; and

• Water saturated 1,4-dioxane / various buffers pH 7 - pH 7.5 is carried out.

(16) Process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula (Ia)

(Ia), characterized in that the racemic acid of the formula (III) where R stands for a linear or branched C1-C25 ketone, optionally with an aromatic

Radical is substituted,

(P), where R stands for a linear or branched C1-C25 ketene, which is optionally substituted by an aromatic radical, and converts this by resolution using a hydrolase in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha)

(Da), where R stands for a linear or branched C1-C25 ketone, optionally with an aromatic

Rest is substituted, transferred, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple)

(purple), saponified and this compound of the formula (purple) then in THF as a solvent first with 1,1-

(17) The method according to paragraph 16, wherein in the compound according to formula (V)

X stands for bromine, and where in the compound according to formula (II)

R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl or n-pentyl n-hexyl, and where in the compound according to formula (Ha)

R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl or n-pentyl.

(18) The method according to paragraph 16 or 17, wherein in the compound according to formula (V)

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and

X stands for bromine, and where in the compound according to formula (II)

R stands for methyl, ethyl and isopropyl, n-butyl or n-pentyl, and where in the compound according to formula (Ha)

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl.

(19) Process according to one of paragraphs 16 to 18, wherein in the compound according to formula (V) R stands for methyl, and X stands for bromine, and wherein in the compound according to formula (II) R stands for methyl, and where in the compound according to formula (Ha)

R is methyl.

(20) The method according to any one of paragraphs 8 to 11, wherein in formula (V) X is chlorine and R is as defined in one of paragraphs 16 to 19, and where in the compound according to formula (II) R is like one of the paragraphs

16 to 19 is defined, and where in the compound according to formula (Ha) R is defined as one of paragraphs 16 to 19.

(21) Method according to one of paragraphs 16 to 20, wherein lipase is used for the resolution.

(22) Method according to one of paragraphs 16 to 21, wherein the lipase is selected from lipase type VII from Candida rugosa, lipase from Candida rugosa, Amano lipase M, from Mucor javanicus, Amano lipase PS from Burkholderia cepacian, Amano lipase PS-IM , Lipase from Aspergillus niger lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica B, lipase from Candida antarctica A, lipase from Aspergillus oryzae, lipase from Humicola insolens, lipase from Candida Antarctinos B, lipase from Thermomyces lanug Rhizomucor miehei, lipase from Candida Antarctica and lipase from pig liver.

(23) The method according to any one of paragraphs 16 to 22, wherein the lipase is lipase AK from Pseudomonas fluorescens.

(24) Use of a hydrolase in a process for the preparation of a compound of the formula (Ha) by resolution of the compound (II). (25) Use according to paragraph 24, the process for the preparation of the compound according to formula (Ha) according to one of paragraphs 1 to 15 being defined.

(25) Use of a hydrolase in a process for the preparation of a compound of the formula (Ia).

(26) Use according to paragraph 25, the process for the preparation of the compound according to formula (Ia) according to one of paragraphs 16 to 22 being defined. (27) Use according to paragraph 25 or 26, wherein the process for the preparation of the compound according to formula

(Ia) is defined according to one of paragraphs 16 to 22 and further comprises the process for preparing the compound according to formula (Ha) according to one of paragraphs 1 to 15. Experimental part

Abbreviations and acronyms:

Examples

Table 3 below shows the structures of the compounds found in the HPLC. The assignment of the retention times in HPLC is given below.

Table 3

Analytical method for testing the content of impurities and enantiomeric purity at the Finerenone stage, crude (Ia).

Content and organic RT (min) RRT impurities Finerenone (Ia) 5.2 1.00

Contamination A 3.3 0.53 Contamination B 3.7 0.60 Contamination C 3.9 0.62 Contamination D 1.4 0.70 Contamination E 3.5 0.89 Contamination F 3.6 0.91 Contamination G 5.8 1.10 Contamination H 7.6 1.23 Impurity K 10.4 1.68

Device: Ultra high-performance liquid chromatograph (with a pressure range of up to 1200 bar with thermostated column oven and UV detector

Column: YMC Triart C8

Lengths: 100 mm, inner diameter: 3.0 mm, grain size: 1.9 pm

Max pressure: 1000 bar

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

Eluant: A: 0.1% TFA in water; B: acetonitrile Gradient: time (min) A (%) B (%)

Enantiomeric purity RRT

RT (min)

Method a

Device: high-performance liquid chromatograph with thermostated column oven and UV detector

Pillar: Chiralpak IA

Length: 250 mm, inner diameter: 4.6 mm, particle size: 5.0 pm

Max pressure: 300 bar

Conditions: 40 ° C; 0.8 mL / min; 5 pL (20 ° C); 255nm / 6nm

Eluent: A: acetonitrile; B: methyl tert-butyl ether (MTBE)

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

10

Enantiomeric purity

Method B.

RT (min) RRT Finerenone (Ia) 5.7 1.00

Enantiomer (Ib) 6.8 1.19

Device / detector: high-performance liquid chromatograph with thermostated column oven, UV detector and data evaluation system

Measurement wavelength: 252 nm Oven temperature: 40 ° C column: Chiralpak IC

Length: 150 mm, inner diameter: 4.6 mm, grain size: 3 pm Mobile phase:

A: 50% buffer 20mM NH ₄ OAc pH 9 B: 50% acetonitrile flow: 1 mL / min.

Running time: 8 min.

Equilibration: not necessary, isocratic. Sample solvent: superplasticizer

Test solution: approx. 0.5 mg / mL of the substance racemate, dissolve with sample solvent. Reference solution: A reference solution is prepared analogous to the test solution

Injection volume: 10 pL

The measured values for the determination of enantiomers given in the following examples were all determined according to method B. Some values, especially the batches produced in the pilot plant, were measured using method A for comparison and provided comparable results.

The HPLC analysis data given in the following examples with regard to purity and content for the end product Finerenone, pure (Ia) only relate to impurities which are present in the product at> 0.05%. This is essentially impurity E. All other impurities shown in the table above are typically <0.05%. The structure of such impurities was determined by isolation from enriched mother liquors.

HPLC conditions / methods

Method (C) YMC Hydrosphere C 18 150 * 4.6 mm, 3.0 pm 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 C 18 150 * 4.6 mm, 3.0 pm

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 C 18

150 * 2mm, 3.0pm

35 ° C, 0.22 ml / min, 255 nm, 6 nm

Solution A: 0.58 g ammonium hydrogen phosphate and 0.66 g ammonium dihydrogen phosphate in 1 L 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) Column: Nucleodur C18 Gravity, 50x3 mm, 1.8 mih, 45 ° C, 1.2 mL / min, 210 nm, 1.2 nm; Solvent A: aqueous 0.1% formic acid solution Solvent B: acetonitrile 0.1% formic acid solution 0 ’: 80% A; 20% B 1.3 ': 20% A; 80% B 2 ': 20% A; 80% B

2.5 ': 80% A; 20% B method (G)

RT (min) RRT

Acyloxymethyl ester (IIAa) approx. 9.9 1.00 Acyloxymethyl ester (IIAb) approx. 11.4 1.15

Column: Chiralpak AD-H, 250x4.6 mm, 5 pm, 40 ° C, 2 mL / min, 207 nm, 6 nm; Solvent A: n-heptane

Solvent B: ethanol + 0.1% diethylamine solution 0 ': 95% A; 5% B

16 ': 95% A; 5% B 16. G: 10% A; 90% B 20 ': 10% A; 90% B equilibration: 10 min

Example 1 The following racemic acyloxy esters of the general formula (II) were synthesized in 10-15 mg on a parallel synthesis equipment * and characterized by mass spectroscopy:

* Acid (III) was stirred together with a bromine ester (V AF) in DMF and potassium carbonate at 40 ° C. The solid was filtered off and the filtrate was chromatographed directly for purification and then isolated by freeze-drying. Example 2

Screening results

The potential of several hydrolases was tested for the kinetic resolution of the racemic acyloxy esters (II A-F). The racemic starting material was dissolved in an organic solvent such as DMSO, tert-butyl methyl ether, cyclopentyl methyl ether, 1,4-dioxane, DMF or 2-methyl-THF and passed through a buffered aqueous solution (pH 7) of an enzyme. The following lipases were used: lipase AK from Pseudomonas fluorescens, lipase type VII from Candida rugose, lipase from Candida rugose, Amano-lipase M, from Mucor javanicus, Amano-lipase PS, from Burkholderia cepacia, Amano-lipase PS-IM, lipase from Aspergillus niger, lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida antarctica B, lipase from Candida antarctica A, lipase from Aspergillus oryzae, lipase from Humicola insolens, lipase from Candida antarctica B, immobilized (lanug from Thermomyusces B, immobilized ), Lipase from Rhizomucor miehei (immobilized), lipase from Candida antarctica in acrylic resin or lipase from pig liver. The resulting two-phase system was stirred at 22 ° to 36 ° C. until a degree of conversion of almost 50% was reached. The separation of the product and the enantiomerically enriched substrate was carried out by means of base acid extraction. Treatment of the organic layer with 5% aqueous potassium phosphate solution separates the desired enantiomerically enriched residual ester from the acid and carries out a chromatographic enantiomeric excess determination (method G).

The enantiomeric excesses (ee) achieved are usually between 70% e.e. up to 91% e.e .; the 4R enantiomer is preferably saponified.

For a further upscaling of the reaction, (±) -Acetoxymethyl-4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (IIA) because it showed the best results in screening. In principle, the other esters (II B-F) would also be suitable for suitable upscaling.

Example 3a

Acetoxymethyl- (4S, 4R) -4- (4-cyano-2-methoxy-phenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine- 3-carboxylate (IIA)

57.68 g (152.024 mmol) of racemic (4S, 4R) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (III ) 46.51 g (304.049 mmol) of bromomethyl acetate (VA) and 42.02 g (304.05 mmol) of potassium carbonate were placed in 288 ml of dimethylacetamide and stirred at 20 ° C. for 20 h (complete conversion according to TLC, ethyl acetate / heptane 1: 1, R _f (ester = 0.18)). The reaction mixture is filtered (separation of the salts) and the filter residue is washed with 400 ml of ethyl acetate. The filtrate is twice with 400 ml of water and then washed with 200 ml of saturated aqueous sodium chloride solution. The organic phase was evaporated to dryness in vacuo and the residue from 200 ml tert. Butyl methyl ether / 50 ml of ethanol recrystallized.

Yield: 27.04 g (39% of theory); A further 20 g of material could be isolated from the mother liquor.

MS (ES +): 452 [M + H] ⁺ ,

Ή-NMR (500 MHz, DMSO-ri ₆ ): d = 1.10 (t, J = 7.09 Hz, 3 H), 1.96 (s, 3 H), 2.16 (s, 3 H), 2.42 (s, 3 H ), 3.75 (s, 3 H), 3.99 - 4.11 (m, 2 H), 5.32 (s, 1 H), 5.56 - 5.64 (m, 2 H), 7.21 - 7.27 (m, 2 H), 7.31 ( s, 1 H), 7.61 (s, 1 H), 8.50 (s, 1 H) ppm.

Example 3b

Acetoxymethyl (4S) -4- (4-cyano-2-methoxy-phenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (Ha: R = Me))

Lipase AK from Pseudomonas fluorescens (22.5 g, 21,000 U / g), potassium phosphate buffer (2.1 1, 50 mM, pH 7.0) and a solution of racemic (±) -acetoxymethyl- (4S, 4R) - 4 (4-Cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (ILA) (15 g, 33,224 mmol) in 2-methyltetrahydrofuran (2-Me-THL, 0.9 1) submitted. The resulting two-phase mixture was stirred for 7 days at 28.5 ° C. and 110 rpm (emulsion). Additional amounts of enzyme were added after 2, 3 and 4 days for a total of 45 g (1: 3 w / w substrate / enzyme). After a conversion of 55% (enantiomerically enriched ester (Ha: R = Me; 92% ee)) the reaction was stopped by adding sodium chloride (150 g) and extracted with 2-MeTHF (2 ^c 11). The organic phases were combined with 2 l of a 5% strength aqueous potassium phosphate solution at 0 ° C. and stirred for 40 min. The organic phase was separated off, dried with sodium sulfate, filtered and concentrated to dryness in vacuo.

An orange oil (8.34 g) was obtained. The crude reaction product was purified by flash chromatography on silica gel using a solvent gradient (15% EtOAc / heptane - 100% EtOAc). 4.78 g (32% of theory) of a white solid are obtained.

Enantiomer excess: 91% ee (method G) t _R (HPLC method F): 1.1 min;

MS (ES +): 452 [M + H] ⁺ , Ή-NMR (500 MHz, DMSO-r ₆ ): d = 1.10 (t, J = 7.09 Hz, 3 H), 1.96 (s, 3 H), 2.16 (s, 3 H), 2.42 (s, 3 H ), 3.75 (s, 3 H), 3.99 - 4.10 (m, 2 H), 5.31 (s, 1 H), 5.56 - 5.64 (m, 2 H), 7.21 - 7.28 (m, 2 H), 7.31 ( s, 1 H), 7.61 (s, 1 H), 8.49 (s, 1 H) ppm.

There were 10 approaches, starting from 15g of racemic (±) -acetoxymethyl- (4S, 4R) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,4 , 6-naphthyridine-3-carboxylate (IIA) is enzymatically saponified and the crude products are combined. 46 g of material with 91% e.e. receive. This crude product was recrystallized from 120 ml of tert-butyl methyl ether / 30 ml of ethanol and 41 g of the optically pure ester (Ha: R = Me; e.e.%> 99%) were obtained.

This material was converted into Finerenone (Ia) in analogy to the method described in WO 2016/016287 A1. This is described in the following examples.

Example 3c

(4, S ') - (4-Cvano-2- 2.8-dimethyl-l .4-dihvdro- 1.6-naphthyridine-3-carboxylic acid (purple)

40.0 g (88.69 mmol) acetoxymethyl- (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro- 1,6-naphthyridine-3- carboxylate (Ha: R = Me)) were dissolved in a mixture of 240 ml of 1 THF and 120 ml of water and cooled to 0 ° C. A sodium hydroxide solution (prepared from 16.4 g (184.96 mmol) of 45% aqueous sodium hydroxide solution and 85 ml of water) was added dropwise to this solution at 0 ° C. over the course of 15 minutes and the mixture was stirred at 0 ° C. for 1.5 hours. It was extracted twice with 100 ml of methyl tert-butyl ether each time and once with 100 ml of ethyl acetate. The aqueous solution was adjusted to pH 7 at 0 ° C. with dilute hydrochloric acid (prepared from 37.1 g of 37% strength hydrochloric acid and 151 ml of water). The mixture was allowed to warm to 20 ° C. and an aqueous solution of 41 g of ammonium chloride in 110 ml of water was added. The mixture was stirred at 20 ° C. for 1 hour, the product was filtered off and washed twice with 30 ml of water each time and once with 80 ml of acetonitrile. It was dried at 40 ° C. in vacuo under an entrainment gas.

Yield: 30.6 g (91.0% of theory) of an almost colorless powder (very slight yellow tinge).

HPLC method E: RT: approx. 6.8 min.

MS (EIpos): m / z = 380 [M + H] ⁺

Ή-NMR (300 MHz, DMSO-d ₆ ): d = 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).

Example 3d (4, V) 4- (4-Cvano-2- 2.8-dimethyl-1.4-dihvdro-l .6-naphthyridine-3-carbo \ amide da)

30 g (79.13 mmol) (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (purple) and 17.96 g (110.8 mmol) 1,1-carbodiimidazole were initially charged in 150 ml THF and 956 mg (7.82 mmol) DMAP were added at 20 ° C. The mixture was stirred at 20 ° C. for one hour (gas evolution!) And then heated to 50 ° C. for 2.5 hours. 55.7 g (0.345 mol) of hexamethyldisilazane were added to this solution and the mixture was refluxed for 22 hours. A further 34 ml of THF were added and the mixture was cooled to 5 ° C. A mixture of 22 ml of THF and 15.7 g of water was metered in over 3 hours so that the temperature remained between 5 ° and 20 ° C. The mixture was then refluxed for one hour, then cooled via a ramp (3 hours) to 0 ° C. and stirred at this temperature for one hour. The product was filtered off and washed twice with 38 ml of THF each time and twice with 60 ml of water each time. It was dried in vacuo at 70 ° C. under an entrainer gas.

Yield: 27.67 g (92.5% of theory) of an almost colorless powder (very slight yellow tinge).

HPLC method D: RT approx. 6.7 min.

MS (EIpos): m / z = 379 [M + H] ⁺

Ή-NMR (300 MHz, DMSO-d ₆ ): d = 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).

Example 3e

Production of pure product (Ia = Fincrcnonc)

27.0 g of the crude product (Ia) prepared in Example 3d were suspended in 540 ml of ethanol, denatured toluene and then heated to reflux. The product went into solution. The mixture was subsequently stirred at this temperature for one hour. The solution was filtered off through a heated pressure filter (T = 75 ° C.), and the pressure filter was then rinsed with 7 ml of ethanol, denatured toluene. The solvent was then distilled off (approx. 444 ml were distilled off) until a final volume of approx. 4-fold (based on the substance used: 27.0 g × 4 ~ 110 ml) was reached. It was then cooled to an internal temperature of 23 ° C. (duration approx. 1.5 to 2 hours). The mixture was then stirred at an internal temperature of 3 ° C. for 2 hours. The product was filtered off and washed once with 100 ml of ethanol, toluene denatured. Moist yield: 28 g. The moist product was dried at 50 ° C. over the weekend (> 48 h) under vacuum (<100 mbar). Yield: 25.67 g (95.1% of theory) of a colorless crystalline powder, fine needle crystals.

Analytical results:

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

Ή-NMR (400 MHz, DMSO-d ₆ ): d = 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 (wide signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.69 (s, 1H) and small signals from the solvent DMSO and water at d = 2, 5-2, 6 and a very small peak at d = 3.38 (not assignable)

Modification: Mod A (as defined in WO2016 / 016287 Al)

Claims

1 process for the preparation of acyloxymethyl esters of (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha )

(Da), where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, by resolution of (II) where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, using a hydrolase.

2. The method according to claim 1, wherein in the compound according to formula (Ha)

R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl, and where in the compound according to formula (II) R for methyl, ethyl, n-propyl, iso-propyl, tert. Butyl, benzyl, n-butyl, n-pentyl or n-hexyl.

3. The method according to claim 1 or 2, wherein in the compound according to formula (Ha)

R stands for methyl, and where in the compound according to formula (II) R stands for methyl.

4. The method according to any one of claims 1 to 3, wherein the hydrolase used is a fipase, esterase, amidases or proteases.

5. The method according to any one of claims 1 to 4, wherein the hydrolase is a fipase.

6. The method according to any one of claims 1 to 5, wherein the fipase is selected from Fipase type VII from Candida rugosa, fipase from Candida rugosa, Amano lipase M, from Mucor javanicus, Amano lipase PS from Burkholderia cepacian, Amano lipase PS-IM, Fipase from Aspergillus niger, fipase from Thermomyces lanuginosus, fipase from Rhizomucor miehei, fipase from Candida antarctica B, fipase from Candida antarctica A, fipase from Aspergillus oryzae, fipase from Humicola insolens, fipase from Rhizomucorizus from Rhizomyizus, fipase from Candida antarctica B miehei, fipase from Candida antarctica and fipase from pig Feber.

7. The method according to any one of claims 1 to 6, wherein the fipase is Fipase AK from Pseudomonas fluorescens.

8. Process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula ( Ia) (Ia), characterized in that the racemic acid of the formula (III)

(III), with halogen esters of the general formula (V)

(V), where R stands for a linear or branched C1-C25 chain, optionally with an aromatic

Radical is substituted,

X stands for chlorine or bromine, to form racemic acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid Formula (II) (II), where R stands for a linear or branched C1-C25 chain, which is optionally substituted by an aromatic radical, and converts this by resolution using a hydrolase in the enantiomeric acyloxymethyl ester (4S) - (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of the formula (Ha)

(Ha), where R stands for a linear or branched C1-C25 ketone, which is optionally substituted by an aromatic radical, and this in a THF / water mixture (2: 1) with sodium hydroxide solution to the compound of the formula (purple )

(purple), saponified and this compound of the formula (purple) is then reacted in THF as a solvent first with 1,1-carbodiimidazole and catalytic amounts of 4- (dimethylamino) pyridine, after adding

Hexamethyldisilazane heated under reflux for 16-24 hours and then treated with a THF / water mixture.

9. The method according to claim 8, wherein in the compound according to formula (V)

X stands for bromine, and where in the compound according to formula (II)

10. The method according to claim 8 or 9, wherein in the compound of formula (V)

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl, and

X stands for bromine, and where in the compound according to formula (II)

R represents methyl, ethyl and isopropyl, n-butyl or n-pentyl.

11. The method according to any one of claims 8 to 10, wherein in the compound according to formula (V)

R is methyl, and

X stands for bromine, and where in the compound according to formula (II) R stands for methyl, and where in the compound according to formula (Ha) R is methyl.

12. The method according to any one of claims 8 to 11, wherein in the formula (V) X is chlorine and R is as defined in any one of claims 8 to 11, and wherein in the compound according to formula (II) R is as one of the claims 8 to 11, and wherein in the compound according to formula (Ha) R is defined as one of claims 8 to 11.

13. The method according to any one of claims 8 to 12, wherein for the resolution

Lipase is used, or the lipase is selected from lipase type VII from Candida rugosa, lipase from Candida rugosa, Amano lipase M, from Mucor javanicus, Amano lipase PS from Burkholderia cepacian, Amano lipase PS-IM, lipase from Aspergillus niger lipase from Thermomyces lanuginosus, lipase from

Rhizomucor miehei, lipase from Candida antarctica B, lipase from Candida antarctica A, lipase from Aspergillus oryzae, lipase from Humicola insolens, lipase from Candida Antarctica B, lipase from Thermomyces lanuginosus, lipase from Rhizomucor miehei, lipase from Candida Antarctica and pigs Liver, or - the lipase is lipase AK from Pseudomonas fluorescens.

14. Use of a hydrolase in a process for the preparation of a compound of the formula (Ha) by resolution of the compound (II).

15. Use of a hydrolase in a process for the preparation of a compound of the formula (Ia).