DESC:FIELD OF THE INVENTION
The present invention relates to novel, commercially viable and industrially advantageous processes for the preparation of Finerenone or a pharmaceutically acceptable salt thereof using novel intermediates with high yield and purity.

BACKGROUND OF THE INVENTION
U.S. Patent No. 8,436,180B2 (hereinafter referred to as the US‘180 patent) discloses novel substituted 4-aryl-1,4-dihydro-1,6-naphthyridine-3-carboxamide derivatives, processes for their preparation, and their use as medicaments for the treatment and/or prophylaxis of diseases, especially cardiovascular disorders. Among them, Finerenone, chemically named (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, is a non-steroidal mineralocorticoid receptor antagonist (MRA) indicated to reduce the risk of sustained eGFR decline, end stage kidney 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). Finerenone is represented by the following structural formula I:

Finerenone was developed by Bayer Healthcare Pharmaceuticals Inc., and it has been approved by Regulatory Authorities in several countries including United States, European Union, Canada, China, Australia, Brazil, Japan, India, Korea and Israel. Finerenone is sold under the brand name KERENDIA® and it is orally administered as tablets containing 10 mg and 20 mg of Finerenone.
Various processes for the preparation of Finerenone and its intermediates are described in U.S. Patent Nos. US8436180B2, US10059707B2, US10336749B2, US10392384B2; U.S. Patent Application Publication Nos. US20210163474A1, US20220153699A1, US20220153701A1; PCT Publication Nos. WO2021074072 A1, WO2021074078 A1, WO2021254896 A1, WO2021074079 A1, WO2021074077 A1; Indian Patent Application Nos. IN 202141053315A, IN 202241026903A, and IN202341004626A; and Angewandte Chemie, International Edition (2020), 59(51), 23107-23111.
As per the information disclosed in the European Public Assessment Report, Finerenone was examined for polymorphism and pseudo-polymorphism by instrumental methods of analysis, crystallization experiments from different solvents and from the melt. Finerenone was found to exist in one modification (designated as Modification I or Polymorph I). The identity of Polymorph I is determined by XRPD. An amorphous form can exist at room temperature. In addition, existence of isomorphic solvates with different solvents was observed. The solvates are not stable at room temperature. The crystalline Polymorph I of Finerenone is the thermodynamically stable polymorph, which is characterized by an XRPD, IR and Raman spectral data in the U.S. Patent No. US10,059,707B2 and US10,336,749B2.
The synthetic routes of Finerenone and its intermediates were first described in the US’180 patent. According to the US’180 patent, Finerenone is prepared by a process comprising the following reaction steps: (i) 4-Formyl-3-methoxybenzonitrile is reacted with 2-Cyanoethyl 3-oxobutanoate in presence of piperidine, acetic acid in anhydrous dichloromethane solvent to obtain a residue, which is purified by silica gel column chromatography to produce 2-Cyanoethyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate as a mixture of E/Z isomers; (ii) the resulting intermediate is reacted with 4-amino-5-methylpyridin-2(1H)-one in 2-propanol under reflux temperature overnight to produce 2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate; (iii) the resulting intermediate is reacted with triethyl orthoformate in presence of concentrated sulfuric acid to obtain a crude product, which is purified by silica gel column chromatography to obtain a residue followed by crystallization from ethyl acetate/diethyl ether to produce 2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate; (iv) the resulting intermediate compound was dissolved in 1,2-dimethoxyethane/water, followed by the addition of 1N NaOH solution and diethyl ether to produce 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid; (v) the resulting intermediate compound is reacted with 1,1’-carbonyl diimidazole in ethyl acetate to produce an intermediate compound, followed by reacting with ammonia to obtain a residue and then purified by preparative HPLC to obtain 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (racemic Finerenone); and (vi) the racemic Finerenone is fractionated into its enantiomers on the preparative scale by chiral phase HPLC to obtain Finerenone which is an (S)-isomer [Example 5, specific rotation (chloroform, 589nm, 19.7°C., c=0.38600g/100ml): -148.8°; a single crystal X-ray structural analysis revealed an S-configuration]. The synthesis of Finerenone disclosed in the US’180 patent is depicted below in Scheme-1:

U.S. Patent No. US 10,336,749B2 (hereinafter referred to as the US’749 patent) discloses a process for producing Finerenone, which is depicted in the below Scheme-2:

As per the process described in the US’707 patent, Finerenone is produced by a process comprising the following steps: (i) 4-Formyl-3-methoxybenzonitrile is reacted with 3-oxobutanamide in presence of piperidine, glacial acetic acid in dichloromethane solvent to produce (2E/2Z)-2-(4-Cyano-2-methoxybenzylidene)-3-oxobutanamide (ii) the resulting intermediate compound is reacted with 4-amino-5-methylpyridone in 2-butanol solvent to produce 4-(4-Cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxamide; (iii) the resulting intermediate is reacted with triethyl orthoacetate in dimethyl acetamide in presence of concentrated sulphuric acid to produce 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (racemic Finerenone); (iv) the racemic Finerenone is dissolved in a mixture of 60:40 methanol/acetonitrile, the resulting solution was chromatographed by means of an SMB system on a stationary phase: Chiralpak AS-V, 20 µm to produce (S)-isomer of Finerenone, which is then added to a mixture of 40: 60 acetonitrile/methanol and filtered through a filter catridge and subsequently sufficiently concentrated at 250 mbar such that the solution is still stirrable, followed by the addition of ethanol, denatured with toluene and distilled again at 250 mbar up to the limit of stirrability (re distillation in ethanol) and then regular work up procedure to produce crystalline polymorph I of Finerenone.
The processes for the preparation of Finerenone and intermediates thereof disclosed in the prior art are associated with several disadvantageous like column chromatographic purifications, and separation of isomers by chiral HPLC.
A need still remains for novel, improved, commercially viable and industrially advantageous processes for the preparation of Finerenone and its intermediates to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.

SUMMARY OF THE INVENTION
The object of the present invention is to provide novel, commercially viable and industrially advantageous processes for the preparation of Finerenone or a pharmaceutically acceptable salt thereof using novel intermediate compounds with high yield and high purity.
The present inventors have found that Finerenone of formula I or a pharmaceutically acceptable salt thereof can be prepared with high yield and high purity by using the following reaction steps: (i) 4-Formyl-3-methoxy-benzonitrile of formula II is reacted with a substituted-benzyl-3-oxobutanoate compound of formula III in presence of an acid and/or a base in a suitable solvent to produce 2-(4-Cyano-2-methoxy-benzylidene)-3-oxo-butyric acid substituted-benzyl ester of formula IV; (ii) reacting the compound of formula IV with 4-amino-5-methyl-2(1H)-pyridinone of formula V or a salt thereof in the presence of an acid in a suitable solvent to produce 4-(4-Cyano-2-methoxy-phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-[1,6]naphthyridine-3-carboxylic acid substituted-benzyl ester of formula VI or a salt thereof; (iii) reacting the compound of formula VI or a salt thereof with a suitable alkylating agent in presence of catalytic amount of an acid in a suitable solvent to produce 4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid substituted-benzyl ester of formula VII or a salt thereof; (iv) reacting the compound of formula VII or a salt thereof with a suitable resolving agent in a suitable solvent, followed by treatment with a suitable base, to produce (S)-4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid substituted-benzyl ester of formula VIII or a salt thereof; (v) deprotection of the compound of formula VIII or a salt thereof with a suitable deprotecting agent in a suitable solvent to produce (S)-4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of formula IX or a salt thereof; and (vi) converting the compound of formula IX or a salt thereof into Finerenone of formula I or a pharmaceutically acceptable salt thereof. The synthesis of Finerenone as per the present invention is depicted below in Scheme-3:

wherein the radical ‘R’ in the compounds of formula III, IV, VI, VII and VIII is selected from the group consisting of para, ortho and meta- substituted C1 to C5 alkoxy; para-NO2, o-NO2, m-NO2, p-Cl, o-Cl, m-Cl, p-Br, o-Br and m-Br.
In a preferred embodiment, the synthesis of Finerenone as per the present invention is depicted below in Scheme-4:


According to the synthesis of Finerenone depicted in Scheme-4, Finerenone of formula I or a pharmaceutically acceptable salt thereof is prepared in high yield and high chemical and chiral purity by the following reaction steps: (i) 4-Formyl-3-methoxy-benzonitrile of formula II is reacted with 4-Methoxybenzyl-3-oxobutanoate of formula IIIa in presence of an acid and/or a base in a suitable solvent to produce (E)-2-(4-Cyano-2-methoxy-benzylidene)-3-oxo-butyric acid 4-methoxy-benzyl ester of formula IVa; (ii) reacting the compound of formula IVa with 4-amino-5-methyl-2(1H)-pyridinone of formula V or a salt thereof in the presence of an acid in a suitable solvent to produce 4-(4-Cyano-2-methoxy-phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-[1,6]naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester of formula VIa or a salt thereof; (iii) reacting the compound of formula VIa or a salt thereof with a suitable alkylating agent in presence of catalytic amount of an acid in a suitable solvent to produce 4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester of formula VIIa or a salt thereof; (iv) reacting the compound of formula VIIa or a salt thereof with a suitable resolving agent in a suitable solvent, followed by optional treatment with a suitable base, to produce (S)-4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester of formula VIIIa or a salt thereof; (v) deprotection of the compound of formula VIIIa or a salt thereof with a suitable deprotecting agent in a suitable solvent to produce (S)-4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of formula IX or a salt thereof; and (vi) converting the compound of formula IX or a salt thereof into Finerenone of formula I or a pharmaceutically acceptable salt thereof.
The process for the preparation of Finerenone or a pharmaceutically acceptable salt thereof disclosed in the present invention has the following advantages over the processes disclosed in the prior art:
(i) the process involves the use of novel intermediate compounds;
(ii) the process avoids the use of tedious and cumbersome column chromatographic purifications;
(iii) the process produces the product with high yield;
(iv) the process produces the product with high chemical and high chiral purity.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a process for the preparation of Finerenone of formula I:

or a pharmaceutically acceptable salt thereof; which comprises:
(a) reacting 4-formyl-3-methoxy-benzonitrile of formula II:

with a substituted-benzyl-3-oxobutanoate of formula III:

wherein the radical ‘R’ is selected from the group consisting of para, ortho and meta- substituted C1 to C5 alkoxy; p-NO2, o-NO2, m-NO2, p-Cl, o-Cl, m-Cl, p-Br, o-Br and m-Br;
in the presence of a suitable acid and/or a suitable base in a solvent to produce 2-(4-cyano-2-methoxy-benzylidene)-3-oxo-butyric acid substituted benzyl ester of formula IV:

wherein the radical R is as defined hereinabove for formula III;
(b) reacting the compound of formula IV with 4-amino-5-methyl-2(1H)-pyridinone of formula V:


or a salt thereof,
in the presence of an acid in a solvent to produce the 4-(4-Cyano-2-methoxy-phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-[1,6]naphthyridine-3-carboxylic acid substituted benzyl ester of formula VI:

or a salt thereof, wherein the radical R is as defined hereinabove;
(c) reacting the compound of formula VI or a salt thereof with an alkylating agent in the presence of an acid in a solvent to produce the 4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid substituted benzyl ester of formula VII:

or a salt thereof, wherein the radical R is as defined hereinabove;
(d) resolving the racemic compound of formula VII or a salt thereof by reacting with a suitable resolving agent in a first solvent to produce a diastereomeric salt of the compound of formula VIII, and neutralizing the desired diastereomeric salt by treatment with a suitable base in a second solvent to produce the enantiomerically pure (S)-4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid substituted benzyl ester of formula VIII:

or a salt thereof, wherein R is as defined hereinabove;
(e) deprotection of the compound of formula VIII or a salt thereof with a suitable deprotecting agent in a solvent to produce (S)-4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of formula IX:

or a salt thereof; and
(f) conversion of the compound of formula IX or a salt thereof into highly pure Finerenone of formula I or a pharmaceutically acceptable salt thereof.
The term “pharmaceutically acceptable salt” of the compound of formula I as prepared according to the present invention may include pharmaceutically acceptable acid addition salts.
The term ‘salt’ of the compounds of formulae V, VI, VII and VIII as used or prepared according to the present invention may include acid addition salts.
The term ‘salt’ of the compound of formula IX as used or prepared according to the present invention may include acid addition salts and/or base addition salts.
Exemplary acid addition salts of the compounds prepared according to the present invention may include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, oxalic acid, fumaric acid, maleic acid and benzoic acid.
Base addition salts may be derived from an organic or an inorganic base. For example, the base addition salts are derived from alkali or alkaline earth metals such as sodium, calcium, potassium and magnesium; ammonium salt, organic amines such as methylamine, ethylamine, tert-butylamine, diethylamine, diisopropylamine, and the like.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term “room temperature” refers to a temperature of about 20ºC to about 35ºC, and specifically to a temperature of about 25ºC to about 30ºC.
Unless otherwise specified, the solvent used for work-up, isolation, purification and/or recrystallization of the compounds obtained by the processes described in the present invention is selected from the group consisting of water, an alcohol, an ether, an ester, an aliphatic hydrocarbon solvent, an aromatic hydrocarbon solvent, a halogenated hydrocarbon, a nitrile solvent, a ketone, a polar aprotic solvent, and mixtures thereof.
Specifically, the solvent used for work-up, isolation, purification and/or recrystallization of the compounds obtained by the processes described herein is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, propyl acetate, butyl acetate, acetone, 2-butanone, methyl isobutyl ketone, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, acetonitrile, dimethylformamide, dimethylacetamide, and mixtures thereof.
Unless otherwise specified, the carbon treatment is carried out by the methods known in the art, for example, by stirring the reaction mass/solution with finely powdered carbon at a temperature of about 25°C to the reflux temperature of the solvent used for at least 5 minutes, preferably for about 10 minutes to about 2 hours; and filtering the resulting mixture through hyflo bed to obtain a filtrate containing compound by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
Unless otherwise specified, the term ‘base’ as used herein includes, but is not limited to inorganic bases such as carbonates, bicarbonates, hydroxides of alkali metals or alkaline earth metals; and organic bases such as alkoxides, acetates, amines and amides.
Exemplary inorganic bases include, but are not limited to, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium amide, potassium amide, ammonia, and mixtures thereof.
Exemplary organic bases include, but are not limited to alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert.butoxide, amines such dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine, tert-butyl amine, N-methylmorpholine, 1-methylimidazole, piperidine, pyridine, piperazine, 4-dimethylaminopyridine (DMAP), and mixtures thereof.
Unless otherwise specified, the term ‘acid’ as used herein is an inorganic acid or organic acid. Exemplary acids as used herein include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, , propionic acid, lactic acid, , tartaric acid, malic acid, succinic acid, citric acid, oxalic acid, fumaric acid, maleic acid, trifluoroacetic acid and benzoic acid.
In one embodiment, the compounds of formulae III, IV, VI, VII and VIII wherein the radical ‘R’ is selected from the group consisting of p-OCH3, p-OC2H5, p-NO2, p-Cl and p-Br; preferably R is p-OCH3 or p-NO2; and most preferably R is p-OCH3.
In another embodiment, the most preferable intermediate compounds of formulae III, IV, VI, VII and VIII prepared according to the present invention are the compounds of formulae IIIa, IVa, VIa, VIIa and VIIIa:
(E)-2-(4-Cyano-2-methoxy-benzylidene)-3-oxo-butyric acid 4-methoxy-benzyl ester (formula IVa):
4-(4-Cyano-2-methoxy-phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-[1,6] naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester (formula VIa);
4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester of formula VIIa; and
(S)-4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester of formula VIIIa.
The solvents used for reaction in steps (a), (b), (c), (d), (e) and/or (f) of the present invention may include, but are not limited to, water, an alcohol, a ketone, a halogenated solvent, a hydrocarbon solvent, an ester, an ether, a nitrile, a polar aprotic solvent, and mixtures thereof.
Exemplary solvents used for reaction in the steps (a), (b), (c), (d), (e) and/or (f) of the present invention may include, but are not limited to, water, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, 2-butanol, tert-butanol, acetone, 2-butanone, methyl isobutyl ketone, dichloromethane, dichloroethane, chloroform, cyclohexane, toluene, xylene, ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, tert-butyl methyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethylsulfoxide, and mixtures thereof.
In one embodiment, the solvent used for reaction in step-(a) is selected from the group consisting of methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, 2-butanol, tert-butyl alcohol and mixtures thereof. A most specific solvent used in step-(a) is isopropyl alcohol or ethanol.
In another embodiment, the acid used in step-(a) is selected from the group of acids as described hereinabove. Specifically, the acid used in step-(a) selected from the group consisting of acetic acid, trifluoroacetic acid, methane sulfonic acid or p-toluene sulfonic acid. A most specific acid used in step-(a) is acetic acid.
In another embodiment, the base used in step-(a) is an organic base or an inorganic base selected from the group as described hereinabove. Specifically, the base used in step-(a) is triethylamine, piperidine, piperazine or 1-methylimidazole. A most specific base used in step-(a) is piperidine.
In another embodiment, the reaction in step-(a) is carried out at about 15°C to the reflux temperature of the solvent used, and most specifically at about 25°C to about 50°C. In another embodiment, the reaction in step-(a) is carried out for about 4 hours to about 40 hours, and more specifically for about 10 hours to about 30 hours.
The reaction mass containing the 2-(4-Cyano-2-methoxy-benzylidene)-3-oxo-butyric acid substituted-benzyl ester of formula IV obtained in step-(a) may be subjected to usual work up methods such as washing, quenching, extraction, pH adjustment, evaporation, layer separation, decolorization, carbon treatment, filtration, or a combination thereof. The reaction mass containing the compound of formula IV may be used directly (in situ) in the next step to produce the compound of formula VI or the compound of formula IV may be isolated and/or recrystallized and then used in the next step.
In another embodiment, the solvent used for work-up, isolation, purification and/or recrystallization of the compound of formula IV obtained in step-(a) is selected from the group of solvents as described hereinabove.
In another embodiment, the compound of formula IV obtained in step-(a) is isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, filtration, drying, or a combination thereof.
In one embodiment, the solvent used in step-(b) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-butanol, 2-butanol, tert-butyl alcohol and mixtures thereof. A most specific solvent used in step-(b) is 2-butanol.
In another embodiment, the acid used in step-(b) is selected from the group of acids as described hereinabove. Specifically, the acid used in step-(b) selected from the group consisting of acetic acid, trifluoroacetic acid, methane sulfonic acid or p-toluene sulfonic acid. A most specific acid used in step-(b) is acetic acid.
In another embodiment, the reaction in step-(b) is carried out at about 20°C to the reflux temperature of the solvent used, and specifically at about 25°C to the reflux temperature of the solvent medium used in the reaction. The reaction time may vary from about 4 hours to about 40 hours, and specifically from about 5 hours to about 30 hours.
The reaction mass containing the 4-(4-Cyano-2-methoxy-phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-[1,6]naphthyridine-3-carboxylic acid substituted benzyl ester of formula VI obtained in step-(b) may be subjected to usual work up methods as described hereinabove.
In one embodiment, the reaction mass containing the compound of formula VI obtained in step-(b) may be used directly (in situ) in the next step to produce the compound of formula VII or the compound of formula VI or a salt thereof may be isolated and/or recrystallized and then used in the next step.
In another embodiment, the compound of formula VI or a salt thereof obtained in step-(b) is isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove, and then used in the next step.
In another embodiment, the solvent used for work-up, isolation, purification and/or recrystallization of the compound of formula VI or a salt thereof obtained in step-(b) is selected from the group of solvents as described hereinabove.
In one embodiment, the alkylating agent used in step-(c) is selected from the group consisting of triethyl orthoacetate, triethyl orthoformate, ethyl bromide, ethyl iodide and diethyl sulphate. A most specific alkylating agent used in step-(c) is triethyl orthoformate.
In another embodiment, the solvent used in step-(c) is selected from the group consisting of 1-methyl-2-pyrrolidone, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide and mixtures thereof. A most specific solvent used in step-(c) is N,N-dimethylacetamide.
In another embodiment, the acid used in step-(c) is selected from the group of acids as described hereinabove. Specifically, the acid used in step-(c) selected from the group consisting of acetic acid, trifluoroacetic acid, sulfuric acid and hydrochloric acid. A most specific acid used in step-(c) is sulfuric acid.
In another embodiment, the reaction in step-(c) is carried out at a temperature of about 60°C to the reflux temperature of the solvent used, and specifically at a temperature of about 90°C to 100°C. The reaction time may vary from about 2 hours to about 10 hours, specifically from about 3 hours to about 8 hours.
The reaction mass containing the 4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid substituted benzyl ester of formula VII or a salt thereof obtained in step-(c) may be subjected to usual work up methods as described hereinabove.
In one embodiment, the reaction mass containing the compound of formula VII obtained in step-(c) may be used directly (in situ) in the next step to produce the compound of formula VIII or a salt thereof; or the compound of formula VII or a salt thereof may be isolated and/or recrystallized and then used in the next step.
In another embodiment, the compound of formula VII or a salt thereof obtained in step-(c) is isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove and then used in the next step.
In another embodiment, the solvent used for work-up, isolation, purification and/or recrystallization of the compound of formula VII or a salt thereof obtained in step-(c) is selected from the group of solvents as described hereinabove.
In one embodiment, the resolving agent used in step-(d) is a chiral substituted tartaric acid ester derivative of formula X:

wherein the radical ‘P’ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, chloro, bromo, fluoro, iodo, nitro, cyano, methoxy, ethoxy and propoxy. Preferably, the ‘P’ in the chiral substituted tartaric acid ester derivative of formula X is selected from the group consisting of methyl, hydrogen, chloro and nitro.
A most preferable chiral substituted tartaric acid ester derivative of formula X used in step-(d) is dibenzoyl L-(-)-tartaric acid or di-p-toluoyl L-(-)-tartaric acid.
In another embodiment, the resolution of the compound of formula VII in step-(d) is carried out by using a suitable hydrolase as per the enzymatic resolution methods known in the art, for example, as per the methods disclosed in the PCT Publication No. WO2021/074077A1.
In another embodiment, the first solvent used in step-(d) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, 2-butanol, tert-butyl alcohol, dichloromethane, acetone, 2-butanone, methyl isobutyl ketone and mixtures thereof. Specifically, the first solvent used in step-(d) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, acetone, 2-butanone, methyl isobutyl ketone and mixtures thereof. A most specific first solvent used in step-(d) is 2-butanone.
In another embodiment, the second solvent used in step-(d) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, 2-butanol, tert-butyl alcohol, dichloromethane, acetone, 2-butanone, methyl isobutyl ketone and mixtures thereof. Specifically, the second solvent used in step-(d) is selected from the group consisting of water, dichloromethane and mixtures thereof.
In another embodiment, the base used in step-(d) is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert.butoxide, sodium amide, potassium amide, ammonia, triethylamine, diisopropylamine, butylamine, N,N-diisopropylethylamkine and mixtures thereof. A most specific base used in step-(d) is aqueous sodium carbonate or aqueous sodium bicarbonate solution.
In another embodiment, the reaction with resolving agent in step-(d) is carried out at a temperature of about 30°C to the reflux temperature of the solvent used, specifically at a temperature of about 50°C to about 80°C. The reaction time may vary from about 2 hours to about 30 hours, specifically from about 4 hours to about 25 hours.
In another embodiment, the neutralization with the base in step-(d) is carried out at a temperature of below about 40°C, specifically at a temperature of about 20°C to about 35°C.
The reaction mass containing the enantiomerically pure (S)-4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid substituted benzyl ester of formula VIII obtained in step-(d) may be subjected to usual work up methods as described hereinabove.
In one embodiment, the reaction mass containing the compound of formula VIII obtained in step-(d) may be used directly (in situ) in the next step to produce the compound of formula IX or a salt thereof; or the compound of formula VIII or a salt thereof may be isolated and/or recrystallized and then used in the next step.
In another embodiment, the compound of formula VIII or a salt thereof obtained in step-(d) is isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove and then used in the next step.
In another embodiment, the solvent used for work-up, isolation, purification and/or recrystallization of the compound of formula VIII or a salt thereof obtained in step-(d) is selected from the group of solvents as described hereinabove.
The deprotection in step-(e) is performed by subjecting the compound of Formula VIII or a salt thereof to hydrolysis, hydrogenolysis, or a combination thereof.
In one embodiment, the deprotection in step-(e) is carried out by reacting the compound of Formula VIII or a salt thereof with a suitable deprotecting agent such as an acid or a base, potassium trimethyl siliconate, triethylsilane, or a combination thereof.
In another embodiment, the deprotection in step-(e) is carried out by subjecting the compound of Formula VIII or a salt thereof to hydrogenolysis under hydrogen pressure or in the presence of a hydrogen source using a metal catalyst such as zinc, Raney nickel, palladium, palladium on carbon, platinum and the like. A most specific hydrogenating agent used for deprotection in step-(e) is palladium on carbon under hydrogen pressure.
In another embodiment, the deprotection in step-(e) is carried out by hydrolysis of the compound of formula VIII or a salt thereof using a suitable acid or a base.
The acid used for deprotection in step-(e) is selected from the group consisting of hydrochloric acid, sulphuric acid, hydrobromic acid and trifluoro acetic acid.
The base used for deprotection in step-(e) is selected from the group consisting of collidine, 2,6-lutidine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.
For example, the acid used may be in the form of aqueous solutions or in the form of a solution in an organic solvent. The organic solvent used for dissolving the acid is selected from the group consisting of ethanol, methanol, isopropyl alcohol, ethyl acetate, diethyl ether, dimethyl ether and acetone.
In another embodiment, the deprotection in step-(e) is carried out by reacting the compound of formula VIII or a salt thereof with trifluoro acetic acid in the presence or absence of a hydrogen source such as triethylsilane.
In one embodiment, the solvent used for deprotection in step-(e) is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, tert-butanol, dichloromethane, dichloroethane, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof.
Specifically, the solvent used in step-(e) is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, tert-butanol, dichloromethane, ethyl acetate, tetrahydrofuran, and mixtures thereof. A most specific solvent used in step-(e) is methanol or tetrahydrofuran or a mixture thereof.
In one embodiment, the reaction in step-(e) is carried out at a temperature of about 20°C to about 50°C, and specifically at a temperature of about 25°C to about 35°C. The reaction time may vary from about 30 minutes to about 24 hours, specifically from about 1 hour to about 8 hours.
The reaction mass containing the enantiomerically pure ((S)-4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of formula IX or a salt thereof obtained in step-(e) may be subjected to usual work up methods as described hereinabove.
In one embodiment, the reaction mass containing the compound of formula IX obtained in step-(e) may be used directly (in situ) in the next step to produce the compound of formula I or a pharmaceutically acceptable salt thereof; or the compound of formula IX or a salt thereof may be isolated and/or recrystallized and then used in the next step.
In another embodiment, the compound of formula IX or a salt thereof obtained in step-(e) is isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove and then used in the next step.
In another embodiment, the solvent used for work-up, isolation, purification and/or recrystallization of the compound of formula IX or a salt thereof obtained in step-(e) is selected from the group of solvents as described hereinabove.
In one embodiment, the conversion of the compound of formula IX or a salt thereof into Finerenone of formula I or a pharmaceutically acceptable salt thereof in step-(f) can be can be carried out by the process described herein, or by the methods known in the art.
In another embodiment, the conversion in step-(f) is carried out by reacting the compound of formula IX or a salt thereof with carbonyldiimidazole followed by treatment aqueous ammonia in a suitable solvent.
In one embodiment the solvent used in step-(f) is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, tert-butanol, dichloromethane, dichloroethane, ethyl acetate, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof.
Specifically, the solvent used in step-(f) is selected from the group consisting of ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof. A most specific solvent used in step-(f) is N,N-dimethylformamide.
In another embodiment, the conversion in step-(f) can be carried out at a temperature of about 20°C to about 120°C, specifically at a temperature of about 25°C to about 90°C. The reaction time may vary from about 2 hours to about 30 hours; preferably from about 5 hours to about 25 hours.
The reaction mass containing the Finerenone of formula I or a pharmaceutically acceptable salt thereof obtained in step-(f) may be subjected to usual workup methods such as washing, quenching, extraction, pH adjustment, evaporation, layer separation, decolorization, carbon treatment, filtration, or a combination thereof.
In one embodiment, the Finerenone of formula I or a pharmaceutically acceptable salt thereof obtained in step-(f) is isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the Finerenone of formula I or a pharmaceutically acceptable salt thereof obtained in step-(f) is selected from the group as described hereinabove.
In one embodiment, the solvent used for work up, isolation and/or recrystallization of Finerenone of formula I or a pharmaceutically acceptable salt thereof is water, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, acetonitrile, dichloromethane, methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, tert-butyl alcohol, C1-C5 alcohols, acetone, 2-butanone, methyl isobutyl ketone, diethyl ether, diisopropyl ether, methyl tert-butyl ether and mixtures thereof.
The intermediate compounds of formulae III, IV, VII, VIII and IX or a salt thereof and the highly pure Finerenone of Formula I or a pharmaceutically acceptable salt obtained by the processes described herein are further dried, under reduced pressure and/or at atmospheric pressure, at a temperature of about 30°C to about 120°C, specifically at a temperature of about 50°C to about 110°C. In another embodiment, the drying is carried out for any desired time period that achieves the desired result, specifically for a period of about 15 minutes to 30 hours, more specifically for a period of about 30 minutes to 15 hours.
Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art. The drying can be carried out in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure or at atmospheric pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
The highly pure Finerenone or a pharmaceutically acceptable salt thereof obtained by the process disclosed herein has a chemical purity of greater than about 99%, specifically greater than about 99.5%, and more specifically greater than about 99.9% as measured by HPLC. For example, the chemical purity of the highly pure Finerenone obtained by the processes disclosed herein is about 99.5% to about 99.99% as measured by HPLC.
The highly pure Finerenone, obtained by the process disclosed herein has an enantiomeric purity of greater than about 99.5%, specifically greater than about 99.8%, and most specifically greater than about 99.9% as measured by chiral HPLC method.
In one embodiment, the highly pure Finerenone obtained by the process disclosed herein is a crystalline form. In another embodiment, the highly pure Finerenone obtained by the process disclosed herein is an amorphous form.
According to another aspect, there is provided a novel intermediate compound, (E)-2-(4-Cyano-2-methoxybenzylidene)-3-oxobutyric acid substituted-benzyl ester of formula IV:

wherein the radical ‘R’ is selected from the group consisting of para, ortho and meta- substituted C1 to C5 alkoxy; p-NO2, o-NO2, m-NO2, p-Cl, o-Cl, m-Cl, p-Br, o-Br and m-Br. Specifically, the radical ‘R’ is selected from the group consisting of p-OCH3, p-NO2, p-Cl and p-Br.
In one embodiment, a specific compound of formula IV is (E)-2-(4-Cyano-2-methoxybenzylidene)-3-oxobutyric acid 4-methoxy-benzyl ester of formula IVa (Formula IV, wherein R is p-OCH3):

According to another aspect, there is provided a novel intermediate compound, 4-(4-Cyano-2-methoxyphenyl)-1,4,5,6-tetrahydro-2,8-dimethyl-5-oxo-1,6-naphthyridine-3-carboxylic acid substituted-benzyl ester, of formula VI:

or a salt thereof, wherein the radical ‘R’ is selected from the group consisting of para, ortho and meta- substituted C1 to C5 alkoxy; p-NO2, o-NO2, m-NO2, p-Cl, o-Cl, m-Cl, p-Br, o-Br and m-Br. Specifically, the radical ‘R’ is selected from the group consisting of p-OCH3, p-NO2, p-Cl and p-Br.
In one embodiment, a specific compound of formula VI is 4-(4-Cyano-2-methoxyphenyl)-1,4,5,6-tetrahydro-2,8-dimethyl-5-oxo-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester of formula VIa (Formula VI, wherein R is p-OCH3):

or a salt thereof.
According to another aspect, there is provided a novel intermediate compound, 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid substituted-benzyl ester of formula VII:

or a salt thereof, wherein the radical ‘R’ is selected from the group consisting of para, ortho and meta- substituted C1 to C5 alkoxy; p-NO2, o-NO2, m-NO2, p-Cl, o-Cl, m-Cl, p-Br, o-Br and m-Br. Specifically, the radical ‘R’ is selected from the group consisting of p-OCH3, p-NO2, p-Cl and p-Br.
In one embodiment, a specific compound of formula VII is 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester of formula VIIa (Formula VII, wherein R is p-OCH3):

or a salt thereof.
According to another aspect, there is provided a novel intermediate compound, (S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid substituted-benzyl ester of formula VIII:

or a salt thereof, wherein the radical ‘R’ is selected from the group consisting of para, ortho and meta- substituted C1 to C5 alkoxy; p-NO2, o-NO2, m-NO2, p-Cl, o-Cl, m-Cl, p-Br, o-Br and m-Br. Specifically, the radical ‘R’ is selected from the group consisting of p-OCH3, p-NO2, p-Cl and p-Br.
In one embodiment, a specific compound of formula VIII is (S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester of formula VIIIa (Formula VIII, wherein R is p-OCH3):

or a salt thereof.
According to another aspect of the present invention, there is provided the use of the novel intermediate compounds of formulae III, IV, VI, VII and/or VIII or a salt thereof in the synthesis of Finerenone of Formula I or a pharmaceutically acceptable salt.
According to another aspect of the present invention, there is provided the use of the novel intermediate compounds of formulae IIIa, IVa, VIa, VIIa and/or VIIIa or a salt thereof in the synthesis of Finerenone of Formula I or a pharmaceutically acceptable salt.
Further encompassed herein is the use of the highly pure Finerenone or a pharmaceutically acceptable salt thereof obtained by the processes disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier/excipient.
A specific pharmaceutical composition of highly pure Finerenone or a pharmaceutically acceptable salt thereof obtained by the processes disclosed herein is a solid dosage form, preferably a Tablet dosage form.
In another aspect, the highly pure Finerenone made by the processes disclosed herein for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 200 microns, specifically about 2 microns to about 150 microns, and most specifically about 4 microns to about 100 microns.
In another aspect, the highly pure Finerenone made by the processes disclosed herein for use in the pharmaceutical compositions, has a D50 particle size of less than or equal to about 100 microns, specifically about 2 microns to about 80 microns, and most specifically about 3 microns to about 50 microns.
In another embodiment, the particle sizes of the highly pure Finerenone obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
The term “micronization” used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term “micron” or “µm” both are equivalent and refer to “micrometer” which is 1x10–6 meter.
As used herein, “crystalline particles” means any combination of single crystals, aggregates and agglomerates.

The following examples are given only to illustrate the present invention. However, they should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES
Example 1
Preparation of 4-Methoxybenzyl-3-oxobutanoate
2,2,6-Trimethyl-4H-1,3-dioxin-4-one (100 g), 4-Methoxybenzyl alcohol (106.9 g) and toluene (500 ml) were taken into a reaction flask at room temperature. The resulting solution was heated to 97-103°C and then stirred for about 8 hours at the same temperature. After completion of reaction, the solvent was distilled off completely under vacuum at a temperature below about 60°C to produce 165 g of 4-Methoxybenzyl-3-oxobutanoate as a liquid (Purity by HPLC: 98%).

Example 2
Preparation of (E)-2-(4-Cyano-2-methoxybenzylidene)-3-oxobutyric acid 4-methoxy-benzyl ester
Isopropanol (1000 ml,), Acetic acid (5.5 g, 0.089 moles), Piperidine (7.6 g, 0.089 moles) and 4-Formyl-3-methoxy benzonitrile (72.35 g, 0.449 moles) were taken into a reaction flask at 25-35°C and the resulting mixture was stirred for 5-10 minutes at the same temperature. To the resulting mass, a solution of 4-Methoxybenzyl-3-oxobutanoate (100 g, 0.449moles) in isopropyl alcohol (200 ml) was added at 25-35°C and the resulting mass was stirred for about 24 hours at the same temperature. After completion of reaction, the resulting mass was cooled to 0-6°C and stirred for about 3 hours at the same temperature. The solid obtained was filtered off and washed with chilled isopropanol (100 ml). The resulting wet compound was dried under vacuum at 60°C to produce 125 g (76.2%) of (E)-2-(4-Cyano-2-methoxybenzylidene)-3-oxobutyric acid 4-methoxy-benzyl ester as a yellow colour solid [Purity by HPLC 99.0%].

Example 3
Preparation of 4-(4-Cyano-2-methoxyphenyl)-1,4,5,6-tetrahydro-2,8-dimethyl-5-oxo-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester
(E)-2-(4-Cyano-2-methoxybenzylidene)-3-oxobutyric acid 4-methoxy-benzyl ester (100 g, 0.273 moles), 2-butanol (500 ml), 4-Amino-5-methoxypyridin-2-(1H)-one (33.9 g, 0.273 moles), and acetic acid (6.5 g, 0.109 moles) were taken into a reaction flask at 100-110°C and the resulting mixture was stirred for about 40 hours at the same temperature. After completion of reaction, the resulting mass was cooled to 0-5°C and stirred for about 3 hours. The solid was filtered off and washed with chilled 2-butanol (100 ml). The resulting wet compound was dried under vacuum at 55-60°C to get 95 g (73.6%) of 4-(4-Cyano-2-methoxyphenyl)-1,4,5,6-tetrahydro-2,8-dimethyl-5-oxo-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester as a yellow colour solid [Purity by HPLC: 97.0%].

Example 4
Preparation of 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester
4-(4-Cyano-2-methoxyphenyl)-1,4,5,6-tetrahydro-2,8-dimethyl-5-oxo-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester (100 g, 0.212 moles), N,N-Dimethylacetamide (600 ml), Triethyl orthoformate (123 g, 0.958 moles) and sulfuric acid (5.0 g, 0.051 moles) were charged into a reaction flask at 25-35°C. The resulting mixture was heated to 100-110°C and stirred for about 3 hours at the same temperature. After completion of reaction, the resulting mass was cooled to 50-60°C and water (1200 ml) was added at the same temperature. The resulting mass was stirred for 30-40 minutes at 50-60°C. Then the reaction mass was cooled to room temperature and stirred for 40 minutes at the same temperature. The reaction mass was further cooled to 10-15°C and stirred for about 2 hours and the resulting solid was filtered off and washed with water (200 ml). The resulting wet compound was dried under vacuum at 55-60°C to produce 95 g (89.7%) of 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester as a yellow colour solid [Purity by HPLC: 95%].

Example 5
Preparation of (S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester
4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester (100 g, 0.20 moles) and 2-butanone (1500 ml) were taken into a reaction flask at 25-35°C. The resulting mass was heated to 60-70°C, followed by the addition of Di-p-toluyl-L-tartaric acid (77.25 g, 0.20 moles) at the same temperature. The resulting mass was stirred for about 4 hours at 60-70°C. Then the reaction mass was gradually cooled to 20-25°C and stirred for 19 hours at the same temperature. The solid was filtered off and washed with 2-butanone (100 ml). The resulting wet compound was dried under vacuum at 40-45°C for 2 hours. The above compound was dissolved in dichloromethane (1500 ml) in RB flask then aq. sodium bicarbonate solution (24.0g sodium bicarbonate dissolved in 300.0 ml of water) was added. Reaction mass was stirred for 30 minutes and layers were separated. Aq. layer was again extract with dichloromethane (500 ml) and layers were separated. Combined organic layer was washed with water (500 ml), layers were separated. The organic layer was distilled for the complete removal of the solvent at a temperature of below 40°C. 2-Butanone (750 ml) was added to the resulting mass and heated to 60-70°C. To the resulting mass, Di-p-toluyl-L-(-)-tartaric acid (38.65 g) was added at 60-70°C and the resulting mass was stirred for about 4 hours at the same temperature. The resulting mass was cooled to 20-25°C and then stirred for 19 hours at the same temperature. Solid was dried under vacuum at 40-45°C for 2 hrs. The above compound and dichloromethane (750 ml) were taken in RB flask then aq. sodium bicarbonate solution (12.0g sodium bicarbonate was dissolved in 150 ml of water) was added. Reaction mass was stirred for 30 min at 25-35°C and layers were separated. Aq. layer was extracted with dichloromethane (225 ml) and layers were separated. Combined organic layer was washed with water (225 m) and layers were separated. Solvent was distilled off under reduced pressure below 40°C to obtain to produce 30 g of (S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester [Chemical Purity by HPLC: 99.5%; Enantiomeric Purity by HPLC: 99.5%].

Example 6
Preparation of (S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid
(S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester (100 g), tetrahydrofuran (2000 ml) and 10% Pd/C (10 g) were charged in an autoclave at 25-30°C. To the resulting mixture, nitrogen pressure of 2-3 Kg/Cm2 was applied at 25-30°C followed by stirring the mass for 5-10 minutes at the same temperature. The nitrogen pressure was released and then hydrogen pressure of 2-3 Kg/Cm2 was applied at 25-30°C followed by stirring the mass for 5-10 minutes at the same temperature. The hydrogen pressure was released and a further hydrogen pressure of 4-5 Kg/Cm2 was applied at 25-30°C followed by stirring the mass for about 5 hours at the same temperature. After completion of reaction, catalyst was filtered with the help of tetrahydrofuran (50 ml). Solvent from the filtrate was distilled off completely under vacuum at below 45°C to produce 75 g of (S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid as pale yellow colour solid.

Example 7
Preparation of (S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid
(S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester (100 g), methanol (2000 ml) and 10% Pd/C (10 g) were charged in an autoclave at 25-30°C. To the resulting mixture, nitrogen pressure of 2-3 Kg/Cm2 was applied at 25-30°C followed by stirring the mass for 5-10 minutes at the same temperature. The nitrogen pressure was released and then hydrogen pressure of 2-3 Kg/Cm2 was applied at 25-30°C followed by stirring the mass for 5-10 minutes at the same temperature. The hydrogen pressure was released and a further hydrogen pressure of 4-5 Kg/Cm2 was applied at 25-30°C followed by stirring the mass for about 5 hours at the same temperature. After completion of reaction, catalyst was filtered with the help of methanol (50 ml). The solvent was distilled off completely from the filtrate under vacuum at below 45°C to produce (S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid.

Example 8
Preparation of Finerenone
(S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid (100 g, 0.263 moles), N,N-dimethylformamide (1000 ml) and carbonyl diimidazole (85.6 g, 0.527 moles) were taken into a reaction flask at room temperature and the resulting mass was stirred for about 18 hours. After completion of reaction, 25% aqueous ammonia solution (840 ml) was added to the reaction mass at 25-30°C. The resulting mass was heated to 95-100°C and stirred for about 2 hours at the same temperature. After completion of reaction, the reaction mass was cooled to 25-30°C and water (1500 ml) and ethyl acetate (1500 ml) were added and stirred for 25-35 minutes. Layers were separated and aq. layer was again extracted with ethyl acetate (1500 ml. The combined organic layer was washed with water (1500 ml). The organic layer was separated and the solvent was distilled completely under vacuum at a temperature of below about 45°C to obtain Finerenone crude compound. The resulting crude was leached with the solvent mixture of acetonitrile (100 ml) and methyl-tert-butyl ether (400 ml) and then filtered. The resulting solid was crystallized from ethanol to afford pure Finerenone [Chemical Purity by HPLC: 99.9%; Enantiomeric Purity by HPLC: 99.98%].

Example 9
Preparation of 4-Nitrobenzyl-3-oxobutanoate
2,2,6-Trimethyl-4H-1,3-dioxin-4-one (100 g, 0.703 moles), 4-Nitrobenzyl alcohol (118.5 g, 0.773 moles) and toluene (500 ml) taken into a reaction flask at 25-35°C. The resulting solution was heated to 97-103°C and stirred for 6 hours at the same temperature. After completion of reaction, the solvent was distilled off completely under vacuum at a temperature of below about 60°C to get 165 g of 4-nitrobenzyl-3-oxobutanoate as an oily compound.

Example 10
Preparation of (E)-2-(4-Cyano-2-methoxybenzylidene)-3-oxobutyric acid 4-nitro-benzyl ester
4-Formyl-3-methoxy benzonitrile (68.0 g, 0.421 moles), isopropanol (300 ml), acetic acid (5.1 g) and Piperidine (7.1 g) were taken into a reaction flask at 25-35°C and the resulting mixture was stirred for 5 to 10 minutes at the same temperature. To the resulting mass, a solution of 4-Nitrobenzyl-3-oxobutanoate (100 g, 0.421 moles) in isopropanol (200 ml) was added at 25-35°C and the resulting mass was stirred for 24 hours at the same temperature. After completion of reaction, the resulting mass was cooled to 0-6°C and stirred for about 3 hours and solid was filtered off and washed with chilled isopropanol (100 ml). The resulting wet compound was dried under vacuum at 54-60°C to obtain 125 g of (E)-2-(4-Cyano-2-methoxybenzylidene)-3-oxobutyric acid 4-nitro-benzyl ester.

Example 11
Preparation of 4-(4-Cyano-2-methoxyphenyl)-1,4,5,6-tetrahydro-2,8-dimethyl-5-oxo-1,6-naphthyridine-3-carboxylic acid 4-nitro-benzyl ester
(E)-2-(4-Cyano-2-methoxybenzylidene)-3-oxobutyric acid 4-nitro-benzyl ester (100 g, 0.263 moles), 2-Butanol (500 ml), 4-Amino-5-methoxypyridin-2-(1H)-one (32.6 g, 0.263 moles) and acetic acid (6.3 g) were taken into a reaction flask at 25-30°C and the resulting mixture was stirred for about 24 hours at the same temperature. After completion of reaction, the resulting mass was cooled to 0-5°C and stirred for about 3 hours and solid was filtered off and washed with chilled 2-butanol (100 ml). The resulting wet compound was dried under vacuum at 55-60°C to produce 90 g of 4-(4-Cyano-2-methoxyphenyl)-1,4,5,6-tetrahydro-2,8-dimethyl-5-oxo-1,6-naphthyridine-3-carboxylic acid 4-nitro-benzyl ester.

Example 12
Preparation of 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid 4-nitro-benzyl ester
4-(4-Cyano-2-methoxyphenyl)-1,4,5,6-tetrahydro-2,8-dimethyl-5-oxo-1,6-naphthyridine-3-carboxylic acid 4-nitro-benzyl ester (100 g, 0.205 moles), N,N-Dimethyl acetamide (600 ml), Triethyl orthoformate (120 g, 0.929 moles) and sulphuric acid (4.85 g) were charged into a reaction flask at room temperature. The resulting mixture was heated to 100-110°C and stirred for about 3 hours at the same temperature. After completion of reaction, the resulting mass was cooled to 50-60°C followed by the addition of water (1200 ml) at the same temperature. The resulting mass was stirred for 30-40 minutes at 50-60°C. The resulting mass was cooled to 25-35°C and stirred for 40 minutes at the same temperature. The resulting mass was further cooled to 10-15°C and stirred for about 2 hours at the same temperature, the resulting solid was filtered off and washed with water (200 ml) to yield 95 g of 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid 4-nitro-benzyl ester.
,CLAIMS:We Claim:
1. A process for the preparation of Finerenone of formula I:

or a pharmaceutically acceptable salt thereof; which comprises:
(a) reacting 4-formyl-3-methoxy-benzonitrile of formula II:

with a substituted-benzyl-3-oxobutanoate of formula III:

wherein the radical ‘R’ is selected from the group consisting of para, ortho and meta- substituted C1 to C5 alkoxy; p-NO2, o-NO2, m-NO2, p-Cl, o-Cl, m-Cl, p-Br, o-Br and m-Br;
in the presence of a suitable acid and/or a suitable base in a solvent to produce
2-(4-cyano-2-methoxy-benzylidene)-3-oxo-butyric acid substituted benzyl ester
of formula IV:

wherein the radical ‘R’ is as defined hereinabove for formula III;
(b) reacting the compound of formula IV with 4-amino-5-methyl-2(1H)-pyridinone of formula V:


or a salt thereof,
in the presence of an acid in a solvent to produce the 4-(4-Cyano-2-methoxy-phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-[1,6]naphthyridine-3-carboxylic acid substituted benzyl ester of formula VI:

or a salt thereof, wherein the radical ‘R’ is as defined hereinabove;
(c) reacting the compound of formula VI or a salt thereof with an alkylating agent
in the presence of an acid in a solvent to produce the 4-(4-Cyano-2-methoxy
phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-[1,6]naphthyridine-3-carboxylic
acid substituted benzyl ester of formula VII:

or a salt thereof, wherein the radical ‘R’ is as defined hereinabove;
(d) resolving the racemic compound of formula VII or a salt thereof by reacting with
a suitable resolving agent in a first solvent to produce a diastereomeric salt of
the compound of formula VIII, and neutralizing the desired diastereomeric salt by treatment with a suitable base in a second solvent to produce the enantiomerically pure (S)-4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-[1,6]naphthyridine-3-carboxylic acid substituted benzyl ester of formula VIII:

or a salt thereof, wherein the radical ‘R’ is as defined hereinabove;
(e) deprotection of the compound of formula VIII or a salt thereof with a suitable deprotecting agent in a solvent to produce (S)-4-(4-Cyano-2-methoxy-phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of formula IX:

or a salt thereof; and
(f) conversion of the compound of formula IX or a salt thereof into highly pure Finerenone of formula I or a pharmaceutically acceptable salt thereof.

2. The process as claimed in claim 1, wherein the solvent used for reaction in step-(a) is selected from the group consisting of methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, 2-butanol, tert-butyl alcohol and mixtures thereof; wherein the acid used in step-(a) selected from the group consisting of acetic acid, trifluoroacetic acid, methane sulfonic acid or p-toluene sulfonic acid; wherein the base used in step-(a) is triethylamine, piperidine, piperazine or 1-methylimidazole; wherein solvent used in step-(b) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-butanol, 2-butanol, tert-butyl alcohol and mixtures thereof; wherein the acid used in step-(b) is selected from the group consisting of acetic acid, trifluoroacetic acid, methane sulfonic acid or p-toluene sulfonic acid; wherein the alkylating agent used in step-(c) is selected from the group consisting of triethyl orthoacetate, triethyl orthoformate, ethyl bromide, ethyl iodide and diethyl sulphate; wherein the acid used in step-(c) is selected from the group consisting of acetic acid, trifluoroacetic acid, sulfuric acid and hydrochloric acid; wherein the chiral substituted tartaric acid ester derivative of formula X used in step-(d) is dibenzoyl L-(-)-tartaric acid or di-p-toluoyl L-(-)-tartaric acid; wherein the first solvent used in step-(d) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, 2-butanol, tert-butyl alcohol, dichloromethane, acetone, 2-butanone, methyl isobutyl ketone and mixtures thereof; wherein the second solvent used in step-(d) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, 2-butanol, tert-butyl alcohol, dichloromethane, acetone, 2-butanone, methyl isobutyl ketone and mixtures thereof; wherein the base used in step-(d) is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert.butoxide, sodium amide, potassium amide, ammonia, triethylamine, diisopropylamine, butylamine, N,N-diisopropylethylamkine and mixtures thereof; wherein the deprotection in step-(e) is performed by hydrogenolysis under hydrogen pressure using a metal catalyst such as zinc, Raney nickel, palladium, palladium on carbon, platinum and the like; wherein the solvent used for deprotection in step-(e) is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, tert-butanol, dichloromethane, dichloroethane, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof; wherein the conversion in step-(f) is carried out with carbonyl diimidazole followed by treatment aqueous ammonia in a suitable solvent; and wherein the the solvent used in step-(f) is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, tert-butanol, dichloromethane, dichloroethane, ethyl acetate, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof.

3. The process as claimed in claim 2, wherein the solvent used for reaction in step-(a) is isopropyl alcohol; wherein the acid used in step-(a) is acetic acid; wherein the base used in step-(a) is piperidine; wherein the solvent used in step-(b) is 2-butanol; wherein the acid used in step-(b) is acetic acid; wherein the alkylating agent used in step-(c) is triethyl orthoformate; wherein the acid used in step-(c) is sulfuric acid; wherein the chiral substituted tartaric acid ester derivative of formula X used in step-(d) is di-p-toluoyl L-(-)-tartaric acid; wherein the first solvent used in step-(d) is 2-butanone; wherein the second solvent used in step-(d) is selected from the group consisting of water, dichloromethane and mixtures thereof; wherein the base used in step-(d) is aqueous sodium bicarbonate solution; wherein the hydrogenating agent used for deprotection in step-(e) is palladium on carbon under hydrogen pressure; and wherein the solvent used in step-(e) is methanol, tetrahydrofuran; wherein the solvent used in step-(f) is N,N-dimethylformamide.

4. A novel intermediate compound, (E)-2-(4-Cyano-2-methoxybenzylidene)-3-oxobutyric acid substituted-benzyl ester of formula IV:

wherein the radical ‘R’ is selected from the group consisting of para, ortho and meta- substituted C1 to C5 alkoxy; p-NO2, o-NO2, m-NO2, p-Cl, o-Cl, m-Cl, p-Br, o-Br and m-Br.

5. A novel intermediate compound, (E)-2-(4-Cyano-2-methoxybenzylidene)-3-oxobutyric acid 4-methoxy-benzyl ester of formula IVa:

6. A novel intermediate compound, 4-(4-Cyano-2-methoxyphenyl)-1,4,5,6-tetrahydro-2,8-dimethyl-5-oxo-[1,6]-naphthyridine-3-carboxylic acid substituted-benzyl ester, of formula VI:

or a salt thereof, wherein the radical ‘R’ is selected from the group consisting of para, ortho and meta- substituted C1 to C5 alkoxy; p-NO2, o-NO2, m-NO2, p-Cl, o-Cl, m-Cl, p-Br, o-Br and m-Br.

7. A novel intermediate compound, 4-(4-Cyano-2-methoxyphenyl)-1,4,5,6-tetrahydro-2,8-dimethyl-5-oxo-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester of formula VIa:

or a salt thereof.

8. A novel intermediate compound, 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid substituted-benzyl ester of formula VII:

or a salt thereof, wherein the radical ‘R’ is selected from the group consisting of para, ortho and meta- substituted C1 to C5 alkoxy; p-NO2, o-NO2, m-NO2, p-Cl, o-Cl, m-Cl, p-Br, o-Br and m-Br.

9. A novel intermediate compound, 4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester of formula VIIa:

or a salt thereof.

10. A novel intermediate compound, (S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid substituted-benzyl ester, of formula VIII:

or a salt thereof, wherein the radical ‘R’ is selected from the group consisting of para, ortho and meta- substituted C1 to C5 alkoxy; p-NO2, o-NO2, m-NO2, p-Cl, o-Cl, m-Cl, p-Br, o-Br and m-Br.

11. A novel intermediate compound, (S)-4-(4-Cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylic acid 4-methoxy-benzyl ester, of formula VIIIa:

or a salt thereof.