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

Abstract

An improved process is described for the industrial production of (4S)-4-(4-cyano-2- methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide, a compound known by the trade name Finerenone, having the Formula (I) below.

Description

[0001] DESCRIPTION of the industrial invention entitled:

[0002] PROCESS FOR THE PREPARATION OF (4S)-4-(4-CYANO-2-METHOXYPHENYL)-5- ETHOXY-l,4-DIHYDRO-2,8-DIMETHYL-l,6-NAPTHYRIDINE-3-CARBOXAMIDE

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to the field of processes for synthesizing active ingredients for pharmaceutical use, and in particular to a process for preparing on an industrial scale the compound (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-l,4-dihydro- 2, 8-dimethyl-l,6-naphthyridine-3 -carboxamide, also known by the trade name Finerenone.

[0005] BACKGROUND ART

[0006] The compound (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-l,4-dihydro-2,8- dimethyl-l,6-naphthyridine-3 -carboxamide, generally indicated by the name Finerenone which will also be used in the following description, has the structure shown below:

[0007] The compound is identified with CAS Registry Number 1050477-31-0 and belongs to the class of mineralocorticoid receptor antagonists, Finerenone is an active ingredient used in the preparation of drugs to reduce the risk of prolonged decline in estimated glomerular filtration rate (eGFR), end-stage renal disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D).

[0008] The therapeutic use of Finerenone was authorized for the first time in the USA in the form of the drug KERENDIA (Finerenone 10 and 20 mg tablets) by Bayer Healthcare. Finerenone, described for the first time in patent EP 2,132,206 Bl, is characterized by the presence of a stereocenter; the structure of the two enantiomers is shown below with the indication (arrow) of the stereocenter and the related configuration:

[0009] Of the two possible enantiomers, the S enantiomer (left in the image above) is the one used in pharmaceutical preparations.

[0010] In patent EP 2,132,206 Bl, the separation of the two enantiomers is obtained by chromatographic resolution on a preparative column, operating on the racemic mixture of Finerenone obtained by non-enantioselective chemical synthesis.

[0011] This purification method is certainly useful at the laboratory level when small quantities of product are to be obtained, but it is not acceptable for industrial -scale production due to operating costs, complexity of the technique and the use of plants and solvents.

[0012] EP 3,174,875 Bl describes another route of synthesis of Finerenone, more applicable at an industrial level, which leads to obtaining a polymorph of the compound, called polymorph I.

[0013] Application WO 2023 / 223188 Al proposes, for separating the non-active enantiomer from the active one, salifying with a chiral acid the racemic mixture of 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-l,4-dihydro-2,8-dimethyl-l,6-naphthyridine-3-carboxylic acid, a synthetic precursor of Finerenone. The structure of the two enantiomers of this acid is shown below:

[0014] The same racemic mixture of acids is obtained through the procedure described in the article “Discovery of BAY 94-8862: A Nonsteroidal Antagonist of the Mineralocorticoid Receptor for the Treatment of Cardiorenal Diseases”, L. Barfacker et al., ChemMedChem

[0015] 2012 7(8) 1385-1403.

[0016] For brevity, in the rest of the description 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-l,4- dihydro-2,8-dimethyl-l,6-naphthyridine-3 -carboxylic acid will also be indicated with the term “carboxylic acid 1”, specifying each time whether it is the racemic mixture or one of the two enantiomers.

[0017] In the process of WO 2023 / 223188 Al, the racemic mixture indicated above, containing both the precursor acid of the pharmacologically active enantiomer of Finerenone, i.e., the S isomer of the acid, and the R isomer of the same compound, is treated with a chiral acid which generates the corresponding diastereoisomeric salts which are separated by filtration, exploiting the different solubility of such salts. The salt formed by the chiral acid and the desired enantiomer (S enantiomer) is then treated with bases so as to free the acid in the form of S enantiomer, which is then transformed into Finerenone.

[0018] The sequence of transformations of WO 2023 / 223188 Al can therefore be outlined as follows:

[0019] 1. Formation of diastereoisomeric salts by reaction of carboxylic acid 1 with a chiral acid —> 2. Separation of diastereoisomeric salts by filtration —> 3. Treatment of the salt of the S enantiomer with a base and liberation of the acid —> 4. Transformation of the S enantiomer of the salt into Finerenone — 5. Purification of Finerenone.

[0020] This series of operations certainly represents an improvement with respect to what is described in EP 2,132,206 Bl. In the course of their experiments, however, the present inventors have observed that the isomers of carboxylic acid 1 and the salts thereof have a high tendency to decarboxylation in solution, as shown in the following diagram:

[0021] This undesired reaction causes a decrease in the reaction yield, making this process not optimal for industrial-scale production.

[0022] It is an object of the present invention to provide a simple Finerenone preparation process, which maximizes reaction yields and of real industrial applicability.

[0023] SUMMARY OF THE INVENTION

[0024] This object is achieved by the present invention, with a process comprising the following steps: a) forming, in a solution, the diastereoisomeric salts of the racemic mixture of 4-(4- cyano-2-methoxyphenyl)-5-ethoxy- 1 ,4-dihydro-2, 8-dimethyl- 1 ,6-naphthyridine-

[0025] 3 -carboxylic acid with a chiral acid; b) separating the salt of the S isomer of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-l,4- dihydro-2,8-dimethyl-l,6-naphthyridine-3-carboxylic acid by filtration; c) direct formation of Finerenone from the salt obtained in step b).

[0026] In a second aspect the invention relates to the purification of crude Finerenone, obtainable by the process described above or by processes of the prior art.

[0027] DETAILED DESCRIPTION OF THE INVENTION

[0028] In the process of the invention, steps a) and b) are analogous to steps 1 and 2 indicated above of the process of WO 2023 / 223188 Al, but the subsequent transformation into Finerenone takes place in a single step with respect to the two steps of WO 2023 / 223188 Al. This allows decreasing the time in which the 4-(4-cyano-2-methoxyphenyl) -5-ethoxy- l,4-dihydro-2,8-dimethyl-l,6-naphthyridine-3-carboxylic acid isomers remain in solution, and thus reducing the extent of the decarboxylation reaction reported above, increasing the yield compared to the process of WO 2023 / 223188 Al. The process of the present invention can be summarized by the following diagram:

[0029] Carboxylic acid 1 racemate

[0030] Diastereoisomeric salts separation

[0031] In the above diagram, "• AC" indicates the salt of an enantiomer of carboxylic acid 1 with a chiral acid.

[0032] The starting point of the process of the invention is the racemic mixture of 4-(4-cyano- 2-methoxyphenyl)-5-ethoxy-l,4-dihydro-2,8-dimethyl-l,6-naphthyridine-3-carboxylic acid, which can be obtained as described in the ChemMedChem article above or in product patent EP 2,132,206 Bl.

[0033] Step a) of the process is the salification of said racemic mixture with a chiral acid. This step can be carried out with any chiral acid; preferably the chiral acid is selected from L-(+) tartaric acid, D-(-) tartaric acid, (+)-dibenzoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid and (-)-di-p-toluoyl-L-tartaric acid; the preferred acid is (+)- dibenzoyl-D-tartaric acid. Even though the starting substrate is a racemic mixture of a compound defined as acid, it has two basic functions in the naphthyridine part of the molecule, which allow salification with acids.

[0034] The salification reaction is conducted at a temperature between 30 and 55 °C in a dimethylformamide (DMF) / water mixture in a DMF : water volume ratio between 0.8: 1.2 and 1.2:0.8, and preferably 1 : 1 (v / v).

[0035] The total volume of the solvent in milliliters is between 10 and 15 times, preferably 13 times, the weight in grams of the initial racemic acid mixture.

[0036] The molar ratio between the chiral acid and the starting racemic mixture is 0.9: 1.1; preferably this ratio is 0.95.

[0037] Step b) of the process of the invention is the separation of the diastereoisomeric salts obtained in step a) by filtration, exploiting the different solubility of the two salts. To carry out this step, the solution deriving from step a) is brought from room temperature to about 50 °C in a time between 30 minutes and two hours, and maintained at this temperature for a time between 30 minutes and three hours; the salt soluble in these conditions is that formed by the R enantiomer of carboxylic acid 1, which therefore remains in the solution, while the salt of the S enantiomer is collected on the filter.

[0038] Step c) is the direct transformation of the salt of the S enantiomer of 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-l,4-dihydro-2,8-dimethyl-l,6-naphthyridine-3-carboxylic acid into Finerenone. This is the characteristic step of the process of the present invention, which distinguishes it from the process of WO 2023 / 223188 Al, in which the acid is liberated from the salt before the transformation into Finerenone; a synthetic step is thereby eliminated, in which a certain percentage of product decarboxylation would not be avoidable, and it is thus possible to obtain the aforementioned overall yield advantages.

[0039] The direct transformation of the diastereoisomer salt of the S enantiomer of the acid into Finerenone can be divided into three operations: c. l) activating the carboxylic function of the S enantiomer of 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-l,4-dihydro-2,8-dimethyl-l,6-naphthyridine-3- carboxylic acid with 1,1 -carbonyldiimidazole and 4-dimethylaminopyridine (DMAP); c.2) reacting with hexamethyldisilazane (HDMS); c.3) quenching the reaction.

[0040] Operation c. l) is carried out directly on the diastereoisomer salt separated in step b), where the compound of interest has configuration S. The 1,1 -carbonyldiimidazole compound activates the carbonyl function of the compound, while DMAP functions as a catalyst for this reaction. The molar ratio between the three reagents of this operation, i.e., diastereoisomer salt, 1,1 -carbonyldiimidazole and DMAP is 1 / 3- / 0.1-M13. This operation is carried out at a temperature between 15 and 35 °C, preferably at 25 °C, for a time between 20 minutes and 2 hours, in a solvent selected from dimethylformamide (DMF) and, preferably, tetrahydrofuran (THF).

[0041] Operation c.2) is carried out by reacting the activated species obtained in operation c. l) with HDMS at a temperature between 40 °C and the reflux temperature of the reaction mixture; preferably operating under reflux conditions. The molar ratio between the activated species obtained in operation c.l) and HDMS is 1 :10 -^18; the reaction time is between 1 and 8 hours, preferably between 6 and 7 hours.

[0042] Operation c.3), of quenching the reaction, is carried out by adding water to the reaction mixture of operation c.2) in an amount between 0.5 and 20 volumes, preferably 7 volumes in mL, with respect to the weight of the diastereoisomer salt in grams at a temperature between 0 and 40 °C; then the system is heated to a temperature between 40 °C and the reflux temperature (preferably operating under reflux). The mixture thus obtained is kept under stirring for a time between 10 minutes and 2 hours, preferably about one hour.

[0043] Confirming the indication above regarding the improvement of the process yield by operating according to the invention with respect to the teachings of WO 2023 / 223188 Al, the inventors carried out an experimental comparison of the two procedures, obtaining the following results:

[0044] - in the case of the process of WO 2023 / 223188 Al, starting from the diastereoisomeric salt with (+)-dibenzoyl-D-tartaric acid, the salt is first released to provide the S enantiomer of carboxylic acid, with a yield of 92.2% and obtaining a product with a purity of 90.3%; the second step is the conversion of the S isomer of carboxylic acid thus obtained to crude Finerenone, a step which has a yield of 53.8% and leads to obtaining a product with a purity of 99.6%;

[0045] - operating according to the present invention, the formation of Finerenone directly from the salt between (+)-D-dibenzoyl tartaric acid and the S isomer of 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-l,4-dihydro-2,8-dimethyl-l,6-naphthyridine-3-carboxylic acid has a yield of 86%, with HPLC purity of 98.3%.

[0046] Step c) described above can also be applied to a mixture of diastereoisomeric salts of carboxylic acid 1 obtained by a process other than that of steps a) and b) above.

[0047] In the second aspect thereof, the invention relates to the purification of crude Finerenone. The purification method described below can be applied to the crude Finerenone obtained from steps a)-c) described above, and thus represent a step d) of an overall process, or it can be applied to crude Finerenone obtained by any known method, for example those described in patent documents EP 2,132,206 Bl, EP 3,174,875 Bl and WO 2023 / 223188 Al, or in the cited ChemMedChem article.

[0048] Drying an API (active ingredient of a pharmaceutical formulation) is a fundamental step in a synthesis process which is intended to provide a pharmaceutical grade product, as the maximum permissible content of water and / or residual solvents of the synthesis process is regulated by international guidelines.

[0049] In the course of their research, the inventors found that drying the Finerenone obtained was poorly reproducible, and in some cases a satisfactory drying was obtained, while in other cases the content of residual solvents did not decrease below the limits imposed by the ICH- Q3C international guidelines despite the drying process being prolonged over time and acting by increasing temperature and degree of vacuum.

[0050] As real examples of this inconsistent and unreproducible behavior, in some preparations the inventors obtained Finerenone which had pharmaceutical grade but overly high solvent content; in particular, Finerenone crystallized from ethanol after vacuum drying at 65 °C for 16 h showed a residual solvent content of 7110 ppm (starting content 8200 ppm), or Finerenone crystallized from acetone after vacuum drying at 55 °C for 16 h showed a solvent content of 15505 ppm (starting content 17289 ppm). Instead in other cases, the Finerenone crystallized from ethanol or acetone dried easily and the residual solvent content was in line with the limits of international guidelines, despite operating milder drying conditions than the above cases.

[0051] This behavior is generally due to the formation of different solid forms, each of which has different solvent retention properties. However, the investigations carried out by the inventors in this regard provided a negative answer: the starting polymorph was always the same, corresponding to polymorph I of EP 3,174,875 Bl.

[0052] Therefore, the inventors developed a Finerenone purification procedure which reproducibly leads to a reduced solvent content in the compound, lower than the limits imposed by the ICH-Q3C international guidelines. The Finerenone treated in the purification process of the invention can be crude (derived directly from a synthesis process) or the product of a first crystallization.

[0053] The purification process comprises a crystallization of Finerenone powders, crude or resulting from a previous crystallization, and leads to powders containing residual solvents in limited amounts; the process is characterized by the following steps:

[0054] 1. hot dissolution of Finerenone in solvent;

[0055] 2. slow cooling of the solution to a temperature of 20-30 °C;

[0056] 3. distillation of a fraction between 20 and 30% by volume of the solvent with mild heating (35 < T < 45 °C) so as to obtain an onset of crystallization of Finerenone;

[0057] 4. cooling the suspension obtained in step 3 to 20-30 °C and stirring for at least 1 hour;

[0058] 5. repeating the procedure of steps 3 and 4 until the massive precipitation of Finerenone is obtained;

[0059] 6. filtering the solid obtained and washing thereof with the crystallization solvent;

[0060] 7. drying Finerenone under reduced pressure at at least 40 °C for at least 3 hours.

[0061] In carrying out steps 1 to 7 above, the following conditions are applied:

[0062] - the amount of solvent used in step 1 is such that the result of step 2 is a solution; this condition can easily be verified in advance with a few orientation tests;

[0063] - the Finerenone which begins to crystallize in step 3 acts as a crystallization seed in the following steps; in step 3 most of the Finerenone remains in solution;

[0064] - step 4 preferably has a duration between 1 and 3 hours;

[0065] - as step 5, the procedure of steps 3 and 4 is preferably repeated twice.

[0066] By operating as described above, Finerenone is always obtained with a solvent content less than the limits set by the ICH guidelines.

[0067] The invention will be further described by the following experimental part.

[0068] METHODS, INSTRUMENTS AND MATERIALS

[0069] SEM: Electron microscopy was performed using a JEOL JSM-IT200 scanning electron microscope (SEM) using a tungsten thermionic electron source. The instrument has a Everhart- Thornley-type secondary electrons (SED) detector, a backscattered electrons (BED) detector, and a X-ray detector for EDX microanalysis. The samples were deposited as is on carbon adhesive film, metallized with gold, and observed in high vacuum mode to maximize resolution. The images were acquired using an electron acceleration voltage of 20 kV, a probe current of 50, and the SED detector.

[0070] HPLC: Method for chiral analysis of salified and non-salified 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-l,4-dihydro-2,8-dimethyl-l,6-naphthyridine-3-carboxylic acid intermediates R and S.

[0071] Mobile phase: Ammonium acetate 1.44 g / L in H2O brought to pH = 6.0 ± 0.1 / Acetonitrile 50:50 v / v

[0072] Chromatographic conditions:

[0073] Column: CHIRALPAK QD-AX, 150 x 4.6 mm; 5.0 pm

[0074] Flow: 0.7 mL / minute

[0075] Detector: UV 255 nm (360 / 4 nm bandwidth)

[0076] Injection volume: 5 pL

[0077] Temperature: 25 °C

[0078] Isocratic: 25'

[0079] Concentration: 1.0 g / L in mobile phase

[0080] Analytical method for the chiral analysis of Finerenone

[0081] Determined by liquid chromatography (Ph Eur 2.2.29). Solvent: Acetonitrile

[0082] Mobile phase: Acetonitrile / MTBE 90: 10 (v / v)

[0083] Reference solution: in a 20 mL flask, accurately weigh 20 mg of Finerenone Working STD. Bring to volume with the solvent.

[0084] Enantiomer reference solution: in a 20 mL flask, accurately weigh 20 mg of Finerenone Enantiomer STD. Bring to volume with the solvent.

[0085] Sample solution: in a 20 mL flask, accurately weigh 20 mg of test sample. Bring to volume with the solvent.

[0086] Chromatographic conditions:

[0087] Column: CHIRALPAK IA, 250 x 4.6 mm; 5.0 pm

[0088] Flow: 0.8 mL / minute

[0089] Detector: 255 nm

[0090] Injection volume: 5 pL

[0091] Temperature: 25 °C

[0092] Procedure, inject 5 pL of solvent and record the chromatogram for 25’ (acquisition method: FIN method D or FIN02). Inject the solutions according to the current procedures.

[0093] The compounds are identified based on the relative retention times thereof:

[0094] Method for the HPLC control of Finerenone

[0095] Mobile phase A '. KH2PO4 0.66 g / L + K2HPO4 0.58 g / L in 1 L of water at pH 7.2

[0096] Mobile phase B: Acetonitrile

[0097] Gradient:

[0098] Chromatographic conditions:

[0099] Column: Kinetex C8, 150 x 4.6 mm; 2.6 m

[0100] Flow: 0.8 mL / minute

[0101] Detector: 232 / 255 nm

[0102] Injection volume: 5 pL

[0103] Temperature: 35 °C

[0104] Concentration: 0.2 g / L in mobile phase A - ACN 70:30 (v / v)

[0105] TLC

[0106] MERCK: TLC silica gel 60 F254 Aluminum sheets 20 x 20 cm, code 1.0554.0001.

[0107] TLC detectors

[0108] 1. Cerium phosphomolybdate: 25 g of phosphomolybdic acid and 10 g of cerium (IV) sulfate are dissolved in 600 mL of H2O. 60 mL of 98% H2SO4 are added, then bring to 1 L with H2O. The plate is impregnated with solution then heated until the products are detected.

[0109] 2. UV lamp at 254 nm and 366 nm.

[0110] The water used in the experimental descriptions is to be understood as pure water unless otherwise indicated.

[0111] The organic solvents used in the experimental descriptions are to be understood as "technical" grade unless otherwise indicated.

[0112] The reagents and catalysts used in the experimental descriptions are to be understood as being of commercial quality unless otherwise indicated.

[0113] EXAMPLE 1

[0114] This Example relates to the resolution of 4-(4-cyano-2-methoxyphenyl) -5 -ethoxy- 1,4- dihydro-2,8-dimethyl-l,6-naphthyridine-3 -carboxylic acid racemate by formation of a salt with (+)-D-dibenzoyl tartaric acid according to the invention.

[0115] S enantiomeric salt carboxylic acid 1 with D-dibenzoyltartrate

[0116] 2.5 kg of water are loaded in a reactor and DMF (2.5 L) is slowly added while maintaining the temperature < 40 °C. The solution is cooled to 25 °C. 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-l,4-dihydro-2,8-dimethyl-l,6-naphthyridine-3-carboxylic acid racemate (0.375 kg), (+)-D-dibenzoyl tartaric acid (0.354 kg), and the previously prepared water and DMF solution are loaded in a second reactor. It is heated to 50 °C in 1 h and kept under stirring for another 30 min at the same temperature. The suspension is filtered at 50 °C by washing with a solution of water and DMF (1 / 1 v / v = 1.125 L / 1.125 L). 1.487 kg of wet crude product are recovered (corresponding to about 800 g of dry product, calculated based on a loss in weight of an aliquot of wet product).

[0117] Chiral HPLC analysis shows an isomer R content = 19%.

[0118] 5.15 kg of water is loaded in a reactor and DMF (5.15 L) is slowly added while maintaining the temperature < 40 °C. The solution is cooled to 25 °C. Half of the DMF / water solution is loaded in another reactor and the wet crude product is added. The loading hopper is washed with the remaining DMF / water solution. It is heated to 50 °C in 1 hour and kept under stirring for another 60 min at the same temperature. The suspension is filtered at 50 °C by washing with 2.6 L of water.

[0119] 1.005 kg of wet product is recovered (corresponding to about 500 g of dry product calculated based on an aliquot weight loss).

[0120] Chiral HPLC analysis shows an R isomer content = 6.2%.

[0121] The previous procedure is repeated on the wet product, using a total of 2.66 kg of water and 2.66 L of DMF.

[0122] The suspension is filtered at 50 °C by washing with 2.3 L of water.

[0123] 0.932 kg of the wet purified product is recovered (corresponding to about 490 g of dry product calculated based on an aliquot weight loss).

[0124] Chiral HPLC analysis shows an R isomer content = 4.9%.

[0125] The previous procedure is repeated on the wet product, using a total of 2.43 kg of water and 2.43 L of DMF. The suspension is filtered at 50 °C by washing with 2.14 L of water.

[0126] 0.766 kg of wet purified product is recovered.

[0127] Chiral HPLC analysis shows an R isomer content = 3.9%.

[0128] The wet product is dried at 50 °C for 8 hours to obtain 0.462 kg of product which is loaded in a reactor with acetone (9.25 L).

[0129] It is stirred at 25 °C for 30 min and the suspension is filtered by washing with 1.2 L acetone. The wet product is dried at 50 °C for 8 hours recovering 0.309 kg of the chiral salt.

[0130] Chiral HPLC analysis shows an R isomer content = 3.1%.

[0131] EXAMPLE 2

[0132] This example relates to obtaining crude Finerenone according to the process of the invention.

[0133]

[0134] S enantiomer salt carboxylic acid 1 with D-dibenzoyltartrate

[0135] 20.20 g of the chiral salt obtained in Example 1 is loaded in a flask under a nitrogen atmosphere and tetrahydrofuran (140 mL) is added. 1,1-carbonyl imidazole (15.54 g) and DMAP (0.669 g) are added to the suspension and stirred at 25 °C for 30 min. Hexamethyldisilazane (57.1 mL) is added and heated to 60 °C. After 2.5 h, further hexamethyldisilazane (22.8 mL, 4 equivalents) is added and stirred at 60 °C for a further 4 hours.

[0136] The temperature is lowered to 0 °C and water is added (140 mL), maintaining the temperature < 30 °C. It is heated at 70 °C for 1 h and allowed to spontaneously return to 25 °C. The mixture is left under stirring for 16 h. Water is added (140 mL) and stirred for 30 min. The tetrahydrofuran is distilled, and the system is cooled to 0 / 5 °C. Abundant precipitation is observed. Toluene (50 mL) is added and is stirred 1 h at 0 / 5 °C.

[0137] The solid is filtered by washing with water and then with toluene.

[0138] The product is dried under vacuum at 50 °C, recovering 8.95 g of crude Finerenone of HPLC purity equal to 98.32%.

[0139] EXAMPLE 3 (Comparative)

[0140] This example relates to obtaining pure Finerenone according to a purification process not of the invention.

[0141] Crude Finerenone Pure Finerenone

[0142] 8.95 g of crude Finerenone obtained in Example 2 is loaded in a flask, ethanol (200 mL) is added, the system is heated to 85 °C and stirred until total dissolution.

[0143] The solution is filtered hot, 80% of the volume of the solvent is distilled under reduced pressure in about 15 minutes (solid formation is already noted) and the resulting suspension is stirred at 25 °C for 2 h.

[0144] The solid is filtered by washing with ethanol and dried under vacuum at constant weight at 50 °C to obtain Finerenone (7.6 g).

[0145] HPLC: purity 99.79%; R isomer = 0.5%, S isomer = 99.5%.

[0146] The above procedure is repeated using 7.57 g of Finerenone and 182 mL of ethanol to obtain 6.83 g of Finerenone.

[0147] Chiral HPLC: purity 99.69%; R isomer = 0.05%, S isomer = 99.95%.

[0148] Residual solvents: ethanol 8200 ppm (ICH limit: 5000 ppm).

[0149] The sample subjected to further drying under reduced pressure and at T = 65 °C for 16 hours showed a residual ethanol content of 7110 ppm, above the limits allowed by the pharmacopoeia.

[0150] EXAMPLE 4 (Comparative)

[0151] This example relates to obtaining pure Finerenone according to a purification process not of the invention.

[0152] 5.95 g of Finerenone obtained in Example 3 is loaded in a flask, and 190 mL of acetone is added. It is heated to 65 °C until complete dissolution. Approximately 80% of the acetone is distilled under reduced pressure in about 15 minutes. Solid formation is already noted. It is stirred for 1 hour at 0 °C and the solid is filtered by washing with acetone (3 mL). It is dried under vacuum at 50 °C at constant weight, obtaining 5.24 g of Finerenone containing a limited amount of ethanol (45 ppm) but 15505 ppm of acetone, above the ICH limit of 5000 ppm.

[0153] EXAMPLE 5 (of the invention) This example relates to obtaining pure Finerenone according to the purification process of the invention.

[0154] 5.15 g of Finerenone obtained in Example 4 are loaded in a flask and 155 mL of acetone are added. It is heated to 70 °C and stirred until complete dissolution. The temperature is allowed to cool spontaneously to 25 °C (no precipitate is observed). Approximately 25% of the solvent is distilled at T = 40 °C under vacuum (slightly opalescent solution). It is stirred for 1 hour at 25 °C.

[0155] The distillation is repeated another two times, leaving the final suspension under stirring at 25 °C for 2.5 h.

[0156] The solid is filtered by washing with acetone. It is dried under vacuum at 50 °C for 4 h to obtain 4.11 g of Finerenone.

[0157] HPLC: 100% purity, R isomer not detected.

[0158] Residual solvents: 1000 ppm acetone (ICH limit: 5000 ppm).

Claims

CLAIMS1. A process for preparing (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-l,4-dihydro-2, 8-dimethyl-l,6-naphthyridine-3 -carboxamide (Finerenone), comprising the following steps: a) forming, in a solution, the diastereoisomeric salts of the racemic mixture of 4-(4- cyano-2-methoxyphenyl)-5-ethoxy- 1 ,4-dihydro-2, 8-dimethyl- 1 ,6-naphthyridine-3 -carboxylic acid with a chiral acid; b) separating the salt of the S isomer of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-l,4- dihydro-2,8-dimethyl-l,6-naphthyridine-3-carboxylic acid by filtration; c) direct formation of Finerenone from the salt obtained in step b).

2. A process according to claim 1, wherein said chiral acid is selected from L-(+) tartaric acid, D-(-) tartaric acid, (+)-dibenzoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid and (-)-di-p-toluoyl-L-tartaric acid.

3. A process according to any one of claims 1 or 2, wherein step a) is carried out at a temperature between 30 and 55 °C, in a dimethylformamide (DMF) / water mixture in volume ratio DMF:water between 0.8:1.2 and 1.2:0.8, with a total volume of solvent in milliliters between 10 and 15 times the weight in grams of said racemic mixture, and with a molar ratio between the chiral acid and the starting racemic mixture between 0.9: 1.1.

4. A process according to any one of the preceding claims, wherein in step b) the solution deriving from step a) is brought to about 50 °C in a time between 30 minutes and two hours, and maintained at this temperature for a time between 30 minutes and three hours.

5. A process according to any one of the preceding claims, wherein step c) is carried outwith the following operations: c. l) activating the carboxylic function of the S enantiomer of 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-l,4-dihydro-2,8-dimethyl-l,6-naphthyridine-3- carboxylic acid with 1,1 -carbonyldiimidazole and 4-dimethylaminopyridine (DMAP); c.2) reacting with hexamethyldisilazane (HDMS); c.3) quenching the reaction.

6. A process according to claim 5, wherein in operation c.l) the molar ratio between diastereoisomer salt, 1,1 -carbonyldiimidazole and DMAP is 1 / 3- / O.1^-0.3, and said operation is carried out at a temperature between 15 and 35 °C, for a time between 20 minutes and 2 hours, in a solvent chosen from dimethylformamide (DMF) and tetrahydrofuran (THF).

7. A process according to any one of claims 5 and 6 wherein step c.2) is carried out with a molar ratio between the activated species obtained in step c. l) and HDMS between 1 : 10 and 1 : 18, at a temperature between 40 °C and the reflux temperature of the reaction mixture, for a reaction time between 1 and 8 hours.

8. A process according to any one of claims 5 to 7, wherein operation c.3) is carried out by adding water to the mixture deriving from operation c.2) in an amount between 0.5 and 20 volumes in mL with respect to the weight of the diastereoisomer salt in grams at a temperature between 0 and 40 °C, then bringing the system to a temperature of between 40 °C and the reflux temperature, and keeping the obtained mixture under stirring for a time between 10 minutes and 2 hours.

9. A process for purifying of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-l,4-dihydro- 2, 8-dimethyl-l,6-naphthyridine-3 -carboxamide (Finerenone), crude or resulting from a previous crystallization, comprising the following steps:

1. hot dissolution of Finerenone in solvent;2. slow cooling of the solution to a temperature of 20-30 °C;3. distillation of a fraction between 20 and 30% by volume of the solvent with mild heating (35 < T < 45 °C) so as to obtain an onset of crystallization of Finerenone;4. cooling the suspension obtained in step 3 to 20-30 °C and stirring for at least 1 hour;5. repeating the procedure of steps 3 and 4 until the massive precipitation of Finerenone is obtained;6. filtering the solid obtained and washing thereof with the crystallization solvent;7. drying the Finerenone under reduced pressure at at least 40 °C for at least 3 hours.

10. A process according to claim 9, wherein:- the amount of solvent employed in step 1 is such that the result of step 2 is a solution;- step 4 has a duration between 1 and 3 hours;- as step 5, the procedure of steps 3 and 4 is repeated twice.

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