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

Abstract

An improved process 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 commonly known as Finerenone, having the formula below, is described: Finerenone

Description

Title of the invention: Process for the preparation of (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide FIELD OF THE INVENTION

[0001] The present invention relates to the field of processes for the synthesis of active ingredients for pharmaceutical use, and in particular a process for the industrial-scale preparation of the compound (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide, also known by the common name Finerenone. STATE OF THE ART

[0002] The compound (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide, generally designated by the usage name Finerenone which will also be used in the remainder of this description, has the following structure: Finerenone

[0003] The compound is identified by 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 medicaments 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).

[0004] The therapeutic use of Finerenone was first authorized in the United States in the form of the drug KERENDIA (10 and 20 mg Finerenone tablets) from Bayer Healthcare.

[0005] Finerenone, first described in patent EP 2,132,206 B1, 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 its corresponding configuration: ON CM

[0006] Of the two possible enantiomers, the S enantiomer (on the left in the image above) is the one used in pharmaceutical preparations.

[0007] In patent EP 2,132,206 B1, the separation of the two enantiomers is obtained by chromatographic resolution on a preparative column by operating on the racemic mixture of Finerenone obtained by non-enantioselective chemical synthesis.

[0008] This purification method is certainly useful at the laboratory level when it is necessary to obtain small quantities of product, but it is not acceptable for industrial scale production due to operating costs, complexity of the technique and use of facilities and solvents.

[0009] EP 3,174,875 B1 describes another route for the synthesis of Finerenone, more applicable at the industrial level, which leads to the production of a polymorph of the compound, called polymorph I.

[0010] Application WO 2023 / 223188 A1 proposes, for the separation of the non-active enantiomer from the active enantiomer, to salify with a chiral acid the racemic mixture of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid, a synthetic precursor of Finerenone. The structure of the two enantiomers of this acid is shown below:

[0011] The same racemic mixture of acids is obtained by 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. Bârfacker et al., ChemMedChem 2012 7(8) 1385-1403.

[0012] For the sake of brevity, in the remainder of the description, 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid will also be referred to as "carboxylic acid 1", specifying on a case-by-case basis whether it is the racemic mixture or one of the two enantiomers.

[0013] In the process of WO 2023 / 223188 A1, the aforementioned racemic mixture, containing both the precursor acid of the pharmacologically active enantiomer of Finerenone, namely 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 these salts. The salt formed by the chiral acid and the desired enantiomer (S-enantiomer) is then treated with bases in order to release the acid in the form of the S-enantiomer, which will then be transformed into Finerenone.

[0014] The sequence of transformations of WO 2023 / 223188 A1 can therefore be schematized as follows: 1 - Formation of diastereoisomeric salts by reaction of carboxylic acid 1 with a chiral acid —> 2. Separation of the diastereoisomeric salts by filtration —> 3. Treatment of the S-enantiomer salt with a base and liberation of the acid —> 4. Transformation of the S-enantiomer of the salt into Finerenone —> 5. Purification of Finerenone. This series of operations certainly represents an improvement over what is described in EP 2,132,206 Bl. During their experiments, the present inventors have however observed that the isomers of carboxylic acid 1 and their salts have a strong tendency to decarboxylate in solution, as illustrated in the following diagram:

[0015] This undesirable reaction results in a decrease in reaction yield, making this process non-optimal for industrial scale production.

[0016] An objective of the present invention is to provide a simple process for the preparation of Finerenone, which maximizes reaction yields and has real industrial applicability. SUMMARY OF THE INVENTION

[0017] This objective is achieved by the present invention, with a method which comprises the following steps: - formation, in a solution, of 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; - separation by filtration of the salt of the S isomer of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid; - direct formation of Finerenone from the salt obtained in step b).

[0018] In a second aspect, the invention relates to the purification of crude Finerenone, obtainable by the method described above or by prior art methods. DETAILED DESCRIPTION OF THE INVENTION

[0019] In the process of the invention, steps a) and b) are analogous to the above-mentioned steps 1 and 2 of the process of WO 2023 / 223188 A1, but the subsequent transformation to Finerenone is carried out in a single step compared to the two steps of WO 2023 / 223188 A1. This makes it possible to decrease the time during which the isomers of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid remain in solution, and thus to reduce the extent of the above-mentioned decarboxylation reaction, thus increasing the yield compared to the process of WO 2023 / 223188 A1.

[0020] The method of the present invention can be summarized by the following diagram:

[0021] In the scheme above, “• AC” indicates the salt of one enantiomer of carboxylic acid 1 with a chiral acid.

[0022] The starting point of the process of the invention is the racemic mixture of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid, which can be obtained as described in the ChemMedChem article mentioned above or in the product patent, EP 2,132,206 Bl.

[0023] 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 chosen 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 if the starting substrate is a racemic mixture of a compound defined as an acid, this has two basic functions in the naphthyridine part of the molecule, which allow salification with acids.

[0024] The salification reaction is carried out 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).

[0025] 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.

[0026] The molar ratio between the chiral acid and the starting racemic mixture is 0.9:1.1; preferably, this ratio is equal to 0.95.

[0027] 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 from step a) is brought from room temperature to approximately 50°C in a time of between 30 minutes and two hours, and maintained at this temperature for a time of between 30 minutes and three hours; the salt soluble under these conditions is that formed by the R enantiomer of the carboxylic acid 1, which therefore remains in the solution, while the salt of the S enantiomer is collected on the filter.

[0028] Step c) is the direct transformation of the salt of the S-enantiomer of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-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 A1, in which the acid is liberated from the salt before the transformation into Finerenone; in this way, a synthesis step is eliminated in which a certain percentage of decarboxylation of the product would not be avoidable, and it is thus possible to obtain the mentioned advantages of overall yield.

[0029] The direct transformation into Finerenone of the diastereoisomeric salt of the S enantiomer of the acid can be subdivided into three operations: - activation of the carboxylic function of the S-enantiomer of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid with 1,1-carbonyldiimidazole and 4-dimethylaminopyridine (DMAP); - reaction with hexamethyldisilazane (HMDS); - stopping the reaction.

[0030] Operation c1) is carried out directly on the diastereoisomeric salt separated in step b), in which the compound of interest has an S configuration. The 1,1-carbonyldiimidazole compound activates the carbonyl function of the compound, while DMAP has a catalyst function for this reaction. The molar ratio between the three reactants of this operation, namely the diastereoisomeric salt, 1,1-carbonyldiimidazo le and DMAP, is 1 / 3^4 / 0.1^-0.3. 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 chosen between dimethylformamide (DMF) and, preferably, tetrahydrofuran (THF).

[0031] Operation c.2) is carried out by reacting the activated species obtained in operation c1) with HMDS at a temperature between 40°C and the reflux temperature of the reaction mixture; the operation is preferably carried out under reflux conditions. The molar ratio between the activated species obtained in operation c1) and HMDS is 1:10^18; the reaction time is between 1 and 8 hours, preferably between 6 and 7 hours.

[0032] Operation c.3), of stopping the reaction, is carried out by adding water to the reaction mixture of operation c.2) in an amount of between 0.5 and 20 volumes, preferably 7 volumes in ml, relative to the weight of the diastereoisomeric 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 (it is preferable to operate at reflux). The mixture thus obtained is kept stirring for a period of between 10 minutes and 2 hours, preferably about one hour.

[0033] To confirm what is indicated above concerning the improvement in the yield of the method operating according to the invention compared to the teachings of WO 2023 / 223188 A1, the inventors carried out an experimental comparison of the two procedures, obtaining the following results: - in the case of the process of WO 2023 / 223188 A1, starting from the diastereoisomeric salt with (+)-dibenzoyl-D-tartaric acid, the deblocking of the salt is first carried out to provide the S-enantiomer of the 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 the carboxylic acid thus obtained into crude Finerenone, a step which has a yield of 53.8% and leads to obtaining a product with a purity of 99.6%; - by 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 an HPLC purity of 98.3%.

[0034] Step c) described above can also be applied to a mixture of diastereoisomeric salts of carboxylic acid 1 obtained by a process different from that of steps a) and b) described above.

[0035] In its second aspect, the invention relates to the purification of crude Finerenone. The purification procedure described below can be applied to crude Finerenone obtained by steps a)-c) described above, and therefore represent a step d) of an overall process, or can be applied to crude Finerenone obtained according to any known method, such as for example those described in patent documents EP 2,132,206 B1, EP 3,174,875 B1 and WO 2023 / 223188 A1, or in the cited ChemMedChem article.

[0036] The drying of an API (active ingredient of a pharmaceutical formulation) is a fundamental step in a synthesis process aimed at providing a pharmaceutical quality product, because the maximum admissible content of water and / or residual solvents in the synthesis process is regulated by international directives.

[0037] During their research, the inventors found that the drying of the Finerenone obtained was not very reproducible, and in certain cases satisfactory drying was obtained, while in other cases the residual solvent content did not decrease. not below the limits imposed by the international ICH-Q3C guidelines despite the extension of the drying process and the increase in temperature and vacuum level.

[0038] As real examples of this inconsistent and non-reproducible behavior, the inventors obtained in some preparations Finerenone which had a pharmaceutical quality but too high a solvent content; in particular, Finerenone crystallized from ethanol after drying under vacuum at a temperature of 65 °C for 16 h showed a residual solvent content of 7110 ppm (initial content 8200 ppm), or Finerenone crystallized by acetone after drying under vacuum at 55 °C for 16 h showed a solvent content of 15505 ppm (initial content 17289 ppm). In other cases, however, Finerenone crystallized by ethanol or acetone dried easily and the residual solvent content was in accordance with the limits of international guidelines, even when operating under milder drying conditions than in the above cases.

[0039] This behavior is generally due to the formation of different solid forms, each having different solvent retention properties. The investigations carried out by the inventors in this regard, however, provided a negative answer: the starting polymorph was always the same, corresponding to polymorph I of EP 3,174,875 Bl.

[0040] The inventors have therefore developed a procedure for purifying Finerenone which reproducibly leads to a reduced solvent content in the compound, below the limits imposed by the international ICH-Q3C guidelines. The Finerenone treated in the purification procedure of the invention can be crude (derived directly from a synthesis process) or the product of a first crystallization.

[0041] The purification procedure comprises a crystallization of Finerenone powders, crude or deriving from a previous crystallization, and leads to powders containing residual solvents in limited quantity; the procedure is characterized by the following steps: - dissolution of Finerenone in a hot solvent; - slow cooling of the solution to a temperature of 20-30 °C; - distillation of a fraction between 20 and 30% by volume of the solvent with moderate heating (35 < T < 45 °C) so as to obtain the start of crystallization of Finerenone; - cooling to 20-30°C of the suspension obtained in step 3 and stirring for at least 1 hour; - repeating the procedure of steps 3 and 4 until massive precipitation of Finerenone is obtained; - filtration of the solid obtained and its washing with the crystallization solvent; - drying of Finerenone under reduced pressure at at least 40°C for at least minus 3 hours.

[0042] In carrying out steps 1 to 7 indicated above, the following conditions are applied: - the amount of solvent used in step 1 is such that the result of step 2 is a solution; this condition can be easily verified beforehand with some orientation tests; - the Finerenone that 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; - step 4 preferably lasts between 1 and 3 hours; - as step 5, the procedure of steps 3 and 4 is preferably repeated two times.

[0043] By operating as described above, Finerenone is always obtained with a solvent content lower than the limits provided for by the ICH guidelines.

[0044] The invention will be described in more detail through the experimental part which follows. METHODS, INSTRUMENTS AND MATERIALS

[0045] SEM: Electron microscopy was performed using a JEOL JSM-IT200 scanning electron microscope (SEM) that utilizes a tungsten thermionic electron source. The instrument has Everhart-Thomley secondary electron detectors (SED), backscattered electron detectors (BED), and X-ray detectors for EDX microanalysis. Samples were deposited as-is on a carbon adhesive film, metallized with gold, and observed in high vacuum mode to maximize resolution. Images were acquired using an electron accelerating voltage of 20 kV, a probe current of 50, and the SED detector.

[0046] HPLC: Method for the chiral analysis of salified and non-salified 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3 carboxylic acid R and S intermediates.

[0047] Mobile phase: Ammonium acetate 1.44 g / l in H2O brought to pH = 6.0 ± 0.1 / Acetonitrile 50:50 v / v

[0048] Chromatographic conditions: Column: CHIRALPAK QD-AX, 150 x 4.6 mm; 5.0 qm Flow rate: 0.7 ml / minute Detector: UV 255 nm (bandwidth 360 / 4 nm) Injection volume: 5 ql Temperature: 25°C Isocratic: 25' Concentration: 1.0 g / 1 in mobile phase

[0049] Analytical method for the chiral analysis of Finerenone It is determined by liquid chromatography (Ph Eur 2.2.29). Solvent: Acetonitrile

[0050] Mobile phase: Acetonitrile / MTBE 90:10 (v / v)

[0051] Reference solution: in a 20 ml graduated flask, accurately weigh 20 mg of Finerenone Working STD. Make up to volume with the solvent.

[0052] Enantiomer Reference Solution: In a 20 ml graduated flask, accurately weigh 20 mg of Finerenone Enantiomer STD. Make up to volume with the solvent.

[0053] Sample solution: in a 20 ml graduated flask, accurately weigh 20 mg of the sample being analyzed. Make up to volume with the solvent.

[0054] Chromatographic conditions: Column: CHIRALPAK IA, 250 x 4.6 mm; 5.0 sqm Flow rate: 0.8 ml / minute Detector: 255 nm Injection volume: 5 ql Temperature: 25°C

[0055] Procedure: Inject 5 ql of solvent and record the chromatogram for 25' (acquisition method: FIN method D or FIN02). Inject the solutions according to the procedures in force.

[0056] Compounds are identified based on their relative retention times: Name TRR TR Enantiomer R 0.78 8.9 Enantiomer S 1 11.4

[0057] Method for the HPLC control of Finerenone Mobile phase A: KH2PO4 0.66 g / L + K2HPO4 0.58 g / l in 1 l of water at pH 7.2 Mobile phase B: Acetonitrile

[0058] Gradient: Time (minutes) Mobile phase A Mobile phase B Comment 0 70 30 1.5 70 30 isocratic 16 25 75 linear gradient 20 25 75 isocratic 20.1 70 30 linear gradient 30 70 30 reconditioning

[0059] Chromatographic conditions: Column: Kinetex C8, 150 x 4.6 mm; 2.6 p.m. Flow rate: 0.8 ml / minute Detector: 232 / 255 nm Injection volume: 5 ft Temperature: 35°C Concentration: 0.2 g / 1 in mobile phase A - ACN 70:30 (v / v)

[0060] CCM MERCK: Pure Silica Gel CCM 60 F254 Aluminum Sheets 20 x 20 cm, Ref. 1.0554.0001.

[0061] CCM Detectors 1. Cerium phosphomolybdate: Dissolve 25 g of phosphomolybdic acid and 10 g of cerium (IV) sulfate in 600 ml of H2O. Add 60 ml of 98% H2 SO4 and dilute to 11% with H2O. The plate is soaked in the solution and then heated until the products are detected. 2. UV lamp at 254 nm and 366 nm.

[0062] Water used in experimental descriptions should be understood as pure water unless otherwise indicated.

[0063] Organic solvents used in experimental descriptions should be understood as being of “technical” quality unless otherwise indicated.

[0064] The reagents and catalysts used in the experimental descriptions should be understood to be of commercial quality unless otherwise indicated. EXAMPLE 1

[0065] This Example relates to the resolution of the raceme of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3 carboxylic acid by formation of a salt with (+)-D-dibenzoyl tartaric acid according to the invention. Acids 1 recipe § b) 2-acetane t sal ènantkswère S caitcKy^ce 1 with

[0066] In a reactor, charge 2.5 kg of water and slowly add DMF (2.5 l) while maintaining the temperature < 40 °C. Cool the solution to 25 °C. In a second reactor, charge the raceme of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3 carboxylic acid (0.375 kg), (+)-D-dibenzoyl tartaric acid (0.354 kg), and the solution of water and DMF prepared previously. Heat at 50 °C for 1 h and keep stirring for another 30 min at the same temperature. Filter the suspension at 50 °C while washing with a solution of water and DMF (1 / 1 v / v = 1.125 l / 1.125 l).

[0067] Recover 1.487 kg of wet raw product (corresponding to approximately 800 g of dry product, calculated based on a weight loss of an aliquot of wet product).

[0068] According to chiral HPLC analysis, the R-isomer content is 19%.

[0069] In a reactor, charge 5.15 kg of water and slowly add DMF (5.15 l) while maintaining the temperature < 40 °C. Cool the solution to 25 °C. Charge half of the DMF / water solution into another reactor and add the wet crude product. Wash the charging hopper with the remaining DMF / water solution. Heat at 50 °C for 1 hour and keep stirring for another 60 min at the same temperature. Filter the suspension at 50 °C while washing with 2.6 l of water.

[0070] 1.005 kg of wet product are recovered (corresponding to approximately 500 g of dry product calculated based on a loss in weight of an aliquot).

[0071] According to chiral HPLC analysis, the R-isomer content is 6.2%.

[0072] On the wet product, the previous procedure is repeated using a total of 2.66 kg of water and 2.66 l of DMF.

[0073] Filter the suspension at 50°C, washing with 2.3 l of water.

[0074] Recover the wet purified product 0.932 kg (corresponding to approximately 490 g of dry product calculated based on a weight loss of an aliquot).

[0075] According to chiral HPLC analysis, the R-isomer content is 4.9%.

[0076] On the wet product, the previous procedure is repeated using a total of 2.43 kg of water and 2.43 l of DMF. Filter the suspension at 50 °C, washing with 2.14 l of water.

[0077] Recover 0.766 kg of wet purified product.

[0078] According to chiral HPLC analysis, the R-isomer content is 3.9%.

[0079] Dry the wet product at 50°C for 8 hours to obtain 0.462 kg of product which is loaded into a reactor with acetone (9.25 l).

[0080] Stir at 25°C for 30 min and filter the suspension, washing with acetone, 1.2 L. The wet product is dried at 50°C for 8 hours to recover 0.309 kg of the chiral salt.

[0081] According to chiral HPLC analysis, the R isomer content is 3.1%. EXAMPLE 2

[0082] This example relates to the production of crude Finerenone according to the procedure of the invention. !L LJ Jk j I <7^0 OH L CDLTHF OJO"" -----------------*- YJ TO H! î II 3) water. HAT YV HQ s YNW' X. J? .-C | IJ 1 Crude Finerenone arid enantiomeric salt S carboxylic acid 1 with D-dibenzoylmethane

[0083] In a flask under nitrogen, charge 20.20 g of the chiral salt obtained in Example 1 and add tetrahydrofuran (140 ml). Add 1,1-carbonylimidazole (15.54 g) and DMAP (0.669 g) to the suspension and stir at 25 °C for 30 min. Add hexamethyldisilazane (57.1 ml) and heat to 60 °C. After 2.5 h, add further hexamethyldisilazane (22.8 ml, 4 equivalents) and stir at 60 °C for another 4 h.

[0084] Lower the temperature to 0 °C, add water (140 ml) while maintaining the temperature < 30 °C. Heat at 70 °C for 1 h and allow it to return spontaneously to 25 °C. Leave stirring for 16 h. Add water (140 ml) and stir for 30 min. Distill the tetrahydrofuran and cool to 0 / 5 °C. Abundant precipitation is observed. Add toluene (50 ml) and stir for 1 h at 0 / 5 °C.

[0085] Filter the solid by washing with water then with toluene.

[0086] The product is dried under vacuum at 50°C to recover 8.95 g of crude Finerenone with an HPLC purity of 98.32%. EXAMPLE 3 (Comparison)

[0087] This example relates to the obtaining of pure Finerenone according to a non-inventive purification procedure. Raw finerenone Pure finerenone

[0088] In a flask, charge 8.95 g of the crude Finerenone obtained in Example 2, add ethanol (200 ml), heat to 85 °C and stir until completely dissolved.

[0089] Filter the solution while hot, distill 80% of the volume of the solvent under reduced pressure in approximately 15 minutes (the formation of solid is already noted) and the resulting suspension is stirred at 25°C for 2 h.

[0090] Filter the solid, washing with ethanol, and dry under vacuum to constant weight at 50°C to obtain Finerenone (7.6 g).

[0091] HPLC: purity 99.79%; R isomer = 0.5%, S isomer = 99.5%.

[0092] Repeat the above procedure using 7.57 g of Finerenone and 182 ml of ethanol to obtain 6.83 g of Finerenone.

[0093] Chiral HPLC: purity 99.69%; R isomer = 0.05%, S isomer = 99.95%.

[0094] Residual solvents: ethanol 8200 ppm (ICH limit: 5000 ppm).

[0095] The sample subjected to further drying under reduced pressure and T = 65 °C for 16 hours had a residual ethanol content of 7110 ppm, higher than the limits authorized by the pharmacopoeia. EXAMPLE 4 (Comparison)

[0096] This example relates to the obtaining of pure Finerenone according to a non-inventive purification procedure.

[0097] In a flask, charge 5.95 g of the Finerenone obtained in Example 3 and add 190 ml of acetone. Heat to 65 °C until complete dissolution. Distill about 80% of the acetone under reduced pressure in about 15 minutes. The formation of solid is already noted. Stir for 1 hour at 0 °C and filter the solid, washing it with acetone (3 ml).

[0098] Dry under vacuum at 50°C to constant weight to obtain 5.24 g of Finerenone which contains a limited amount of ethanol (45 ppm) but 15505 ppm of acetone, above the ICH limit of 5000 ppm. EXAMPLE 5 (of the invention)

[0099] This example relates to the obtaining of pure Finerenone according to the purification procedure of the invention.

[0100] In a flask, charge 5.15 g of the Finerenone obtained in Example 4 and add 155 ml of acetone. Heat to 70 °C and stir until completely dissolved. Allow the temperature to cool spontaneously to 25 °C (no precipitate is observed).

[0101] Distill about 25% of the solvent at T = 40 °C under vacuum (slightly opalescent solution). Stir for 1 hour at 25 °C.

[0102] Repeat the distillation two more times, leaving the final suspension stirring at 25°C for 2.5 h.

[0103] Filter the solid, washing with acetone.

[0104] Dry under vacuum at 50°C for 4 h to obtain 4.11 g of Finerenone.

[0105] HPLC: 100% purity, R isomer not detected.

[0106] Residual solvents: 1000 ppm acetone (ICH limit: 5000 ppm).

Claims

Claims

1. A process for the preparation of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-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 by filtration the salt of the S isomer of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid; c. direct formation of Finerenone from the salt obtained in step b).

2. The method of 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. 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 a DMF:water volume ratio 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 method according to any one of the preceding claims, wherein in step b) the solution derived from step a) is brought to approximately 50°C in a time of between 30 minutes and two hours, and maintained at this temperature for a time of between 30 minutes and three hours.

5. A method according to any one of the preceding claims, wherein step c) is carried out by the following operations: cl) activation of the carboxylic function of the S-enantiomer of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid with 1,1-carbonyldiimidazole and 4-dimethylaminopyridine (DMAP); c.2) reaction with hexamethyldisilazane (HMDS); c.3) stopping the reaction.

6. A method according to claim 5, wherein in operation cl) the molar ratio between the diastereoisomeric salt, 1,1-carbonyldiimidazole and DMAP is 1 / 3^-4 / 0.1^-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 between dimethylformamide (DMF) and tetrahydrofuran (THF).

7. Process according to any one of claims 5 and 6, wherein operation c.2) is carried out with a molar ratio between the activated species obtained in operation c1) and the HMDS of between 1:10 and 1:18, at a temperature of between 40°C and the reflux temperature of the reaction mixture, for a reaction time of between 1 and 8 hours.

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

9. Process for the purification of (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxamide (Finerenone), crude or derived from a previous crystallization, comprising the following steps:

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

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