DESC:Field of the Invention:
The present application relates to an improved process for the preparation of Finerenone and its intermediate’s thereof, is represented by the following structural formula-I

Formula-I
Background of the Invention:
Finerenone is a non-steroidal mineralocorticoid receptor antagonist (MRA) developed by Bayer Health Care Pharmaceuticals, having the chemical name as (4S)¬ 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide and is approved for the treatment of heart failure in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes with the brand name of Kerendia as capsule, for oral use in 10 mg, 20 mg strengths in USA on 09-Jul-2021. The drug is also approved in Europe on 16-Feb-2022 and in Japan on 28-Mar-2022.
Finerenone is a chiral compound, finerenone and process for its preparation is first reported in US8436180B2. The said patent reported isolation of finerenone specific isomer from preparative chiral HPLC methods, which is not suitable for industrial purposes.
The US patent US103922384B2 reported a process for preparation of finerenone by electro chemicals methods.
The US patent US10336749B2 reported a process for preparation of finerenone by using various reagents and solvents.
The PCT application publication WO2019206909A1, WO2021074072A1 and WO2021074078A1 were reported chiral resolution processes of finerenone, its intermediates thereof by using various chiral reagents and process for preparation thereof .
There are other processes are reported for finerenone and intermediates thereof by using different starting materials, reagents and solvents.
Based on drawbacks in the prior art process, there is a need for providing an improved process for the preparation of finerenone, which involves simple experimental procedures, well suited to industrial production, which avoids the use of column chromatography, chiral HPLC purification, and which affords highly pure finerenone.
The present invention provides an improved process for preparation of finerenone and intermediates thereof and free from other impurities or isomers. The present invention involves by using cheap and easily available key starting material, reagents and solvents, which are efficient, industrially viable and cost effective.
Brief Description:
The first aspect of the present invention is to provide a process for the preparation of Finerenone compound of formula-I.
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline Form of di-p-toluoyl-L-tartaric acid salt of (S)-4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate
Figure 1: Illustrates the PXRD pattern of crystalline Form of di-p-toluoyl-L-tartaric acid salt of (S)-4-methoxybenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxy ethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are selected from Lithium aluminium hydride, sodium borohydride, BF3 etherate solution, Pd/C, Ray-nickel; The term “suitable chiral reagents” refers to L-tartaric acid, D-tartaric acid, camphorsulphonic acid, di-para-toluoyl-L-tartaric acid ,di-para-toluoyl -D-tartaric acid, Phenylalanine, D-(-)-a-Phenylglycine, L-(+)-a-Phenylglycine, D(-) -Phenyl glycinamide, S-(+)mandelicacid, R-(-)mandelicacid, L-(+)tartaric acid, D-(-) tartaric acid, L-malicacid, D-malic acid, D-(+)-maleicacid, (-)- naproxen, (+)-naproxen, (1R)-(-) camphor sulfonic acid, (1S)-(+)- camphor sulfonic acid, (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)-bromo camphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L-tartaricacid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)-dipara-tolyl-D-tartaric acid, (-)-dipara tolyl-L-tartaric acid, L(-)-pyro glutamic acid, L(+)- pyroglutamic acid, (-)-lacticacid, L-lysine, D-lysine , (2R,3R)-2,3-bis(phenyl sulfonyloxy) succinic acid, (2S,3S)-2,3-bis(phenylsulfonyloxy)succinic acid, benzenesulfonyl derivatives of tratartic acid and mixtures thereof;
The first aspect of the present invention is to provide a process for the preparation of Compound of formula-1.

[I]
Comprising of
a) reacting the compound of formula-1 with compound of formula-2

in presence of suitable solvent and reagents to provide compound of formula-3,

b)reacting the compound of formula-3 with compound of formula-4 with suitable reagent , solvent to provide compound of formula-5

c)reacting the compound of formula-5 with suitable reagent, suitable solvent to provide compound of formula-6,

d) treating compound of formula-6 with suitable chiral reagent, solvents to provide compound of formula-8.

e)deprotecting of compound of formula-8 with suitable reagent, solvent to provide compound-9
f) reacting compound of formula-9 with a source of ammonia, suitable solvent to provide compound of formula-I,
g) optionally purifying the compound of formula-I using suitable solvents to provide pure compound of formula-I.
Wherein in step-a), b), c) ,d), e) and f) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvent, ether solvents, toluene, acetone, polar aprotic solvent, polar protic solvent, alcohol solvent, water or any mixture thereof; suitable temperature: 10-100°C;
Wherein in step-a) suitable reagents are piperidine, morpholine, diethylamine, acetic acid and mixture thereof; step-b) specifically alcohol solvents; step-c) suitable reagents are triethyl orthoformate, triethyl orthoacetate, chloroethane, bromoethane, iodo ethane, diethyl sulfate; step-d) suitable chiral reagents are selected from L-tartaric acid, D-tartaric acid, camphor sulphonic acid, di-para-toluoyl-L-tartaric acid, di-para-toluoyl-D-tartaric acid, dibenzoyl-L-tartaric acid, dibenzoyl-D-tartaric acid, Phenylalanine, Phenylglycine, Phenyl glycinamide, S-(+)mandelicacid, R-(-)mandelicacid, L-malicacid, D-malic acid, D-(+)-maleicacid, (-)- naproxen, (+)-naproxen, (1R)-(-) camphor sulfonic acid, (1S)-(+)- camphor sulfonic acid, (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)-bromo camphor-10-sulfonic acid, L(-)-pyro glutamic acid, L(+)- pyroglutamic acid, (-)-lacticacid, L-lysine, D-lysine, (2R,3R)-2,3-bis(phenyl sulfonyloxy)succinic acid, (2S,3S)-2,3-bis(phenylsulfonyloxy) succinic acid, benzenesulfonyl derivatives of tartaric acid and mixtures thereof;
and mixtures thereof;
e) suitable reagents are selected from palladium catalyst, ammonium formate, acetic acid, HCl, HBr, trifluoroacetic acid and mixture thereof;
f) suitable reagents are selected form Carbonyldiimidazole, EDC HCl, hexamethyldisilazane, ammonia (g) aq.ammonia, ammonium chloride, ammonium carbonate and mixture thereof;
The preferred embodiment of the present invention provides a process for the preparation of compound of formula-I.
Comprising of
a) reacting the compound of formula-1 with compound of formula-2b in presence of acetic acid, piperidine in isopropanol

to provide compound of formula-3b,

b) reacting the compound of formula-3b with compound of formula-4 in ethylene glycol to provide compound of formula-5b,

c) reacting the compound of formula-5b with triethylorthoacetate, sulfuric acid in DMF to provide compound of formula-6b,
d) treating compound of formula-6b with di-p-toluoyl-L-tartaric acid in acetonitrile, water to provide compound of formula-6A, further treating with sodium hydroxide in water to provide compound of formaul-8b,

e) deprotecting the compound of formula-8b with palladium hydroxide in tetrahydrofuran under hydrogen gas pressure to provide compound of formula-9,
f) reacting the compound of formula-9 with carbonyldiimidazole, ammonia in tetrahydo furan, to provide compound of formula-I.
g) purifying the compound of formula-I in isopropanol, methanol,water to provide pure compound of formula-I
The other aspect of the present invention is to provide resolution of Compound of formula-5.

Comprising of:
Treating the compound of formula-5 with suitable chiral reagent, solvents to provide compound of formula-7.
The suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvent, ether solvents, toluene, acetone, polar aprotic solvent, polar protic solvent, alcohol solvent, water or any mixture thereof; suitable temperature: 10-100°C;
The other aspect of the present invention is to provide a resolution of Compound of formula-6.

Comprising of:
Treating the compound of formula-6 with suitable chiral reagent, solvents to provide compound of formula-8.
The suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvent, ether solvents, toluene, acetone, polar aprotic solvent, polar protic solvent, alcohol solvent, water or any mixture thereof; suitable temperature: 10-100°C;
The other embodiment of the preparation of compound of formula-8b by the chemical resolution of compound of formula-6b.
Comprising of:
a)Treating the compound of formula-6b with di-p-toluoyl-L-tartaric acid in acetonitrile, water provide compound of formula-6A (((S)-4-methylbenzyl 4-(4-cyano-2-methoxy phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate di-p-toluoyl -L-tartaric acid salt),
b) treating the compound of formula-6A with sodium hydroxide in water to provide compound of formula-8b (((S)-4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate).

The present invention is a process for the preparation of finerenone described in the schematic representation in scheme-I

General description of compounds of formula as mentioned in the scheme-1

R Formula-2 Formula-3 Formula-5 Formula-6 Formula-7 Formula-8
H 2a 3a 5a 6a 7a 8a
Me 2b 3b 5b 6b 7b 8b
OMe 2c 3c 5c 6c 7c 8c
CN 2d 3d 5d 6d 7d 8d
Cl 2e 3e 5e 6e 7e 8e
Br 2f 3f 5f 6f 7f 8f

The present invention provides an alternative process for the preparation of finerenone as described in scheme-II

The present invention is an alternative process for the preparation of finerenone as described in the scheme-III

The other aspect of the present invention is compound of:

Wherein R’ represents: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, phenoxy, nitro, cyano, amido; Wherein R represents: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, phenoxy, nitro, cyano, amido.
The process for the preparation of finerenone developed by the present inventor produces highly pure compound and with good yield. All the related substances and residual solvents are controlled well within the limits as suggested by ICH guidelines and most of the related substances are controlled in non-detectable levels.
The compound of formula-I produced by the process of the present invention is
having purity of greater than 99.0 % , preferably greater than 99.5% by HPLC / chiral HPLC.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of the compound of formula-2b (4-methylbenzyl 3-oxo butanoate).
A round bottom flask was charged with 2,2,6-trimethyl-4H-1,3-dioxin-one (500 g), toluene (5 L) and 4-methylbenzyl alcohol (430 g) at 25-35°C and stirred for 10 min. The reaction mixture was heated to 105-115°C and stirred for 5 hr. Cooled the reaction mass to 20-30°C, charged with water and stirred for 10-15 min and separated the two layers and taken organic layer into another RBF and charged with water and separated. The organic layer was dried over sodium sulphate, distilled off the solvent completely to get the title compound.
Yield: 683 g
Example-2: Preparation of the compound of formula -3b (4-Methylbenzyl 2-(4-cyano-2-methoxy benzylidene) -3-oxobutanoate.
A round bottom flask was charged with 4-formyl-3-methoxybenzonitrile (200 g), formula-2b (281.5 g), isopropanol (1L), acetic acid (14.9 g) and piperidine (21.13 g) at 25-35°C and stirred for 6 hr. The precipitated solid was filtered and dried to get the title compound.
Yield: 358 g
Example-3: Preparation of the compound of formula -5b
A round bottom flask was charged with formula-3b (200 g), n-butanol (600 ml), 4-amino-5-methylpyridin-2(1H)-one (50 g) and heated to 115-120°C and stirred for 20 hr. The reaction mixture was distilled off completely, charged with isopropanol and water and stirred at 25-35°C for 30 min. The resulting solvent was evaporated and, cooled to 25-35°C, filter the solid over Buchner funnel and wash the wet compound with isopropanol, dried the solid to get the title compound.
Example-4: Preparation of the compound of formula-6b (4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate)
A round bottom flask was charged with triethylortho acetate (535 g), formula-5b (200.0 g), NMP (300 mL) and sulphuric acid (22 g) at 30±5°C and heated the reaction mass to 125-130°C and stirred for 3 hr. Cooled the reaction mass to 50-60°C, slowly added water over a period of 1 hr. Further, cooled the reaction mass to 5±5°C and stirred for 30 minutes at same temperature. Filtered the obtained solid, washed with water and dried to obtain the title compound.
Yield: 184 g.
Example-5: Preparation of the compound of formula-6b (4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate)
A round bottom flask was charged with triethylortho formate (366 g), formula-5b (150.0 g), NMP (225 mL) and sulphuric acid (16.14 g) at 30±5°C and heated the reaction mass to 125-130°C and stirred for 3 hr. Cooled the reaction mass to 50-60°C, slowly added water over a period of 1 hr. Further, cooled the reaction mass to 5±5°C and stirred for 30 minutes at same temperature. Filtered the obtained solid, washed with water and dried to obtain the title compound.
Yield: 130 g.
Example-6: Preparation of the compound of formula-8b ((S)-4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate).
A round bottom flask was charged with acetone (1.25L) and formula-6b (250.0 g) were heated to 50±5 °C stirred for 30 min. Charged with di-p-toluoyl-L-tartaric acid monohydrate (200.0 g) to the reaction mixture at 30±5°C and stirred for 3 hr. Filtered the obtained solid and washed with ethanol (28.0 ml) and dried. The wet compound was charged with acetone and heated to 45-55°C stirred for 30 min and cooled to 25-35°C and stirred for 1 hr. filtered the solid and was charged with water adjusted the pH to 11-12 with aq. NaOH solution at 30±5°C and stirred for 30 min at same temperature. Filtered the obtained solid, washed with water (56.0 ml) and dried the material to obtain the title compound.
Yield: 10 g; chiral purity > 99 %
Isolated solid di-p-toluoyl-L-tartaric acid salt of (S)-4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate PXRD depicted in figure-1
Example-7: Preparation of the compound of formula-9.
A round bottom flask under stirring was charged with tetrahydrofuran (1L), formula-8b (50.0 g) and palladium carbon (2.0 g) at 30±5°C and stirred under hydrogen pressure 1.0 kg/cm3 at 50±5°C for 4 hr. Filtered the mass and washed with THF and distilled off the mass completely and charged with water. Adjusted the pH to 11-12 with aq.NaOH solution and charged with MTBE and stirred for 30 min. separated the organic layer and aqueous layer pH was adjusted to 3-4 with Con. HCl and stirred for 1 hr. The obtained solid was filtered and dried to obtain the title compound.
Yield: 31.5 g.
Example-8: Preparation of the compound of formula-I.
A round bottom flask was charged with formula-9 (42 g), THF (210 ml) under nitrogen atmosphere at 30±5°C. Cooled the reaction mass to 15-20°C and added 1, 1-carbonyl di imidazole (36 g) followed by dimethyl amino pyridine (1.35 g) and stirred for 5 hr. The reaction mixture was purged with ammonia gas till the pH of the reaction mixture attained ~10 and with continues heating 50-60°C stirred form 12 hr. Cooled the reaction mass to 15-20°C charged with water, dichloromethane and stirred for 30 min. The organic layer separated and dried evaporated to get the crude compound. The obtained compound was stirred in ethanol for 1 hr at 55-65°C, filtered the obtained solid and dried to get the title compound.
Yield: 32 g; chiral purity >99.5 %
Example-9: Preparation of the compound of formula -2c (4-Methoxybenzyl 3-oxobutanoate)
A round bottom flask was charged with 2,2,6-trimethyl-4H-1,3-dioxin-one (300 g) toluene (3000 ml) 4-methoxybenzyl alcohol (291.88 g) at 25-35°C and stirred for 5-10 min at 25-35°C. The reaction mass heated to reflux and maintained for 5 hr. Cooled the reaction mass to 20-30°C, charged with water at 20-30°C and stirred for 10-15 min at same temperature. Separated the two layers and taken organic layer into another RBF and charged with water and separated. The organic layers was dried over sodium sulphate, distilled off the solvent under vacuum and dried to get the title compound.
Yield: 469 g
Example-10: Preparation of the compound formula -3c (4-Methoxybenzyl 2-(4-cyano-2-methoxy benzylidene)-3-oxobutanoate.
A round bottom flask was charged with 4-formyl-3-methoxybenzonitrile (200 g), isopropanol (1000 ml), acetic acid (14.9 g) and piperidine (21.13 g) at 25-35°C and stirred for 5-10 min. The reaction mixture was charged with formula-2c (303.37 g) at 25-35°C and maintained till the reaction complete. Filtered the solid and washed with isopropanol and dried the solid to get the title compound.
Yield: 400 g
Example-11: Preparation of the compound formula -5c
A round bottom flask was charged with formula-3c (250 g), n-butanol (750 ml), 4-amino-5-methylpyridin-2(1H)-one (59.43 g) and heated to reflux for 20 hrs. Distilled off the solvent under vacuum, the reaction mixture was charged with isopropanol and water and heated to 105-115°C and stirred for 30 min. Cooled the reaction mass to 25-35°C, filtered the solid and washed the wet compound with isopropanol, dried the solid to get the title compound.
Yield: 153 g
Example-12: Preparation of the compound formula -6c
A round bottom flask was charged with formula-5c (30 g), triethylorthoacetate (83 g), NMP (45 ml) and sulphuric acid (3.33 g) at 25-35°C and heated the reaction mass to 125-130°C for 3 hr. Cooled the reaction mass to 50-56°C and slowly added water (180 ml) at 50-56°C over a period of 1 hr. Cooled the reaction mass to 0-10°C and maintained for 30 min. Filtered the solid and washed with water and dried the solid to get the title compound.
Yield: 30.0 g
Example-13: Preparation of the compound of formula-6c
A round bottom flask was charged with triethylortho formate (370 g), formula-5c (150.0 g), NMP (250 mL) and sulphuric acid (18 g) at 30±5°C and heated the reaction mass to 125-130°C and stirred for 3 hr. Cooled the reaction mass to 50-60°C, slowly added water over a period of 1 hr. Further, cooled the reaction mass to 5±5°C and stirred for 30 minutes at same temperature. Filtered the obtained solid, washed with water and dried to obtain the title compound.
Yield: 125 g.
Example-14: Preparation of the compound formula -8c
A round bottom flask was charged with formula-6c (190 g), ethanol (1000 mL), water (1900 mL) and stirred the reaction mass for 10-15 min at 25-35°C. The reaction mixture was charged with di-p-toluoyl-L-tartaric acid monohydrate (146.81 g) at 25-35°C, stirred at the same temperature for 24 hr. Filtered the solid and washed the wet solid with ethanol. The above wet material was charged into another RBF and charged with water , adjusted the reaction mass pH to 11.5 with aq.NaOH solution at 25-35°C and maintained for 30 min. Filtered the solid and washed the wet solid with water and dried to get the title compound.
Yield: 74 g
Isolated solid di-p-toluoyl-L-tartaric acid salt of (S)-4-methoxylbenzyl 4-(4-cyano-2-methoxy phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate PXRD depicted in figure-2
Example-15: Preparation of the compound formula -9
A round bottom flask was charged with a compound of formula-8c (10 g), tetrahydrofuran (200 ml), water (1 ml) at 25-35°C and heated the reaction mass for 45-55°C and maintained for 15 min. The reaction mixture was charged with Pd/C (1 g) , purged the hydrogen gas into the reaction mass at 45-55°C and maintained for 4 hr. Filtered the reaction mass through hyflow bed and washed with tetrahydrofuran (20 ml) and distilled off the reaction mass completely. The obtained solid was charged with water, and adjust pH of the reaction mass with aq.NaOH (10 %) to 11.5 at 25-35°C and charge the reaction mass with dichloromethane at 25-35°C and stirred for 20 min. Separated the two layers and washed aqueous layer with dichloromethane, the aqueous layer pH was adjusted to 3-4 with Con. HCl at 25-35°C and stirred for 60 min. Filtered the solid and washed with water, dried to get the title compound.
Yield: 6 g
Example-16: Preparation of the compound formula -9
A round bottom flask was charged with formula-8c (1.0 mol), methanol (15 vol) and Pd/C (1 g) heated the reaction mass for 45-55°C and under the hydrogen gas into the reaction mass maintained for 4 hr. Filtered the mass through hyflow bed and washed with methanol (1 vol). Distilled off the reaction mass completely and obtained solid was charged with water (5 vol), aq.NaOH solution (10%) and stirred for 15-20 min, washed the reaction mass with methylene chloride (5 vol). The two layers are separated and the aqueous layer pH was adjusted to 4.5 with dil.HCl and stirred for 60 min. Filtered the solid and washed with water and dried to get the title compound.
Example-17: Preparation of the compound formula-I
A round bottom flask was charged with formula-9 (10 g), THF (50 ml) under nitrogen atmosphere at 25-35°C and cooled the reaction mass to 15-20°C. The reaction mass is charged with 1,1-carbonyl diimidazole (8.5 g) at 15-20°C and followed by catalytic amount of DMAP (0.3 g). Ammonia gas was purged until pH is attained to 10.2 to the reaction mixture and heated to 50-60°C, maintained the reaction mass for 36 hr. Cool the reaction mass to 15-20°C and maintain for 1 hr. Filtered the solid and washed the wet solid with chilled THF and dried the solid to get the title compound.
Yield: 7 g
Example-18: Preparation of the compound of formula-IIa (N-benzyl-3-oxobutanamide).
A round bottom flask was charged with 2,2,6-trimethyl-4H-1,3-dioxin-one (100 g), toluene (1 L) and benzylamine (75.3 g) at 25-35°C and stirred for 10 min. The reaction mixture was heated to 105-115°C and stirred for 5 hr. Cooled the reaction mass to 20-30°C, charged with water and stirred for 10-15 min and separated the two layers and taken organic layer into another RBF and charged with water and separated. The organic layer was dried over sodium sulphate, distilled off the solvent completely to get the title compound.
Yield: 91 g
Example-19: Preparation of the compound of formula -IIIa (N-benzyl-2-(4-cyano-2-methoxy benzylidene) -3-oxobutanamide.
A round bottom flask was charged with 4-formyl-3-methoxybenzonitrile (40 g), compound of formula-IIa (52.1 g), isopropanol (1L), acetic acid (2.9 g) and piperidine (4.2 g) at 25-35°C and stirred for 9 hr. The precipitated solid was filtered and washed with water dried to get the title compound.
Yield: 20 g
Example-20: Preparation of the compound of formula -IVa
A round bottom flask was charged with a compound of formula-IIIa (20 g), n-butanol (60 ml), 4-amino-5-methylpyridin-2(1H)-one (5.1 g) and heated to 115-120°C and stirred for 20 hr. Butanol was distilled off completely from the reaction mixture charged with isopropanol and water, stirred at for 30 min. The resulting solution was concentrated and, cooled to 25-35°C, filtered the solid and washed the wet compound with isopropanol and dried the solid to get the title compound.
Yiels: 22 g
Example-21: Preparation of the compound of formula-Va
A round bottom flask was charged with triethylortho acetate (55 g), a compound of formula-IVa (20.0 g), NMP (30 mL) and sulphuric acid (2.2 g) at 30±5°C and heated the reaction mass to 125-130°C and stirred for 3 hr. Cooled the reaction mass to 50-60°C, slowly added water over a period of 1 hr. Further, cooled the reaction mass to 5±5°C and stirred for 1 hr at same temperature. Filtered the obtained solid, washed with water and dried to obtain the title compound ; Yield: 15 g.
Example-22: Preparation of the compound of formula-VIa
A round bottom flask was charged with acetone (75 mL) and a compound of formula-Va (15.0 g) were heated to 50±5 °C stirred for 30 min. Charged with di-p-toluoyl-L-tartaric acid monohydrate (12.36 g) to the reaction mixture at 30±5°C and stirred for 6 hr. Filtered the obtained solid and washed with acetone and dried. The wet compound was charged with acetone and heated to 45-55°C stirred for 30 min and cooled to 25-35°C and stirred for 1 hr. Filtered the solid and was charged with water, adjusted the pH to 11.5 with aq. NaOH solution at 30±5°C and stirred for 30 min at same temperature. Filtered the obtained solid, washed with water and dried the material to obtain the title compound.
Yield: 5 g; chiral purity > 99 %
Example-23: Preparation of the compound formula -I
A round bottom flask was charged with a compound of formula-VIa (5 g), THF (100 mL) and Pd/C (0.15%) g) heated the reaction mass for 45-55°C and under the hydrogen gas into the reaction mass maintained for 4 hr. Filtered the mass through hyflow bed and washed with THF, distilled off the reaction mass completely and obtained solid was charged with water, aq.NaOH solution (10%) and stirred for 15-20 min, washed the reaction mass with MTBE. The two layers are separated and the aqueous layer pH was adjusted to 4.5 with dil.HCl and stirred for 60 min. Filter the obtained solid and wash with water and dried to get the title compound ; Yield: 3.2 g; chiral purity > 99 %
Example-24: Preparation of the compound of formula -3b (4-Methylbenzyl 2-(4-cyano-2-methoxy benzylidene) -3-oxobutanoate.
A round bottom flask was charged with 4-formyl-3-methoxybenzonitrile (200 g), formula-2b (281.5 g), isopropanol (1L), acetic acid (14.9 g) and piperidine (21.13 g) at 25-35°C and stirred for 6 hr. The precipitated solid was filtered and washed with a mixture of isopropanol and methanol dried to get the title compound.
Yield: 358 g
Example-25: Preparation of the compound of formula -5b (4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate)
A round bottom flask was charged with formula-3b (100 g), ethylene glycol (300 ml) and 4-amino-5-methylpyridin-2(1H)-one (31.97 g) and heated to 105-125°C and stirred for 14 hr at same temperature. The reaction mixture was gradually cooled and charged with isopropanol and stirred at 25-35°C for 30 min. The resulting compound was filtered and washed with isopropanol and dried to get the title compound.
Yield: 108 g
Example-26: Preparation of the compound of formula-6b (4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate)
A round bottom flask was charged with triethylortho acetate (267 g), formula-5b (100.0 g), dimethylformamide (300 mL), sulphuric acid (10.76 g) and triethylamine (4.44) at 30±5°C and heated the reaction mass to 110-120°C and stirred for 10 hr. Gradually, cooled the reaction mass to 25-35°C, charged n-heptane and water and stirred for 1 hr at same temperature Filtered the precipitated solid and washed with water to get the wet compound. Further, the wet compound was charged in a mixture of isopropanol and water stirred for 2 hr. Filtered the solid compound and washed with isopropanol and dried to get the title compound ; Yield: 105 g.
Example-27: Preparation of the compound of formula-8b ((S)-4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate).
A round bottom flask was charged with acetonitrile (800 mL), water and formula-6b (100.0 g) were heated to 25-35 °C stirred for 30 min. Charged with di-p-toluoyl-L-tartaric acid monohydrate (44 g) to the reaction mixture at 25-35 °C and stirred for 2 hr at 70-80°C. Filtered the obtained solid and washed with acetonitrile and dried. The wet compound was charged with acetonitrile, water (1:5) and heated to 70-80°C stirred for 2.5 hr and cooled to 25-35°C and stirred for 2 hr. Filtered the solid and washed with acetonitrile to get DPTTA salt of compound. The wet compound was charged with water and adjusted the pH to 11.5 with aq. NaOH solution at 25-35°C and stirred for 2hr at same temperature. Filtered the obtained solid, and dried to obtain the title compound.
PXRD of the isolated solid of di-p-toluoyl-L-tartaric acid salt of (S)-4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate is depicted in figure-1; Yield: 42.5 g; chiral purity by HPLC> 99 %: R-isomer <0.2 %
Example-28: Preparation of the compound of formula-I.
An autoclave was charged with tetrahydrofuran (2L), formula-8b (100.0 g) and palladium hydroxide (10.0 g) at 35-45°C and stirred under hydrogen pressure 4.0 kg/cm3 at 35-45°C for 6 hr. Cooled the reaction mixture, Filtered the mass and washed with tetra hydrofuran and distilled off the mass completely and co-distilled with toluene. The obtained compound was charged with toluene and stirred for 1 hr, the resulting solid was filtered and washed with toluene and dried to get the wet crude compound-9.
A round bottom flask was charged with formula-9, THF (500 ml) under nitrogen atmosphere at 30±5°C. Cooled the reaction mass to 15-20°C and charged 1, 1-carbonyl di imidazole (50.31 g) followed by dimethyl amino pyridine (2.5 g) and stirred for 5 hr. The reaction mixture was purged with ammonia gas till the pH of the reaction mixture attained ~9 and with continues heating 50-60°C stirred form 12 hr. Cooled the reaction mass to 15-20°C and distilled-off , the obtained crude was charged with water (500 mL) and stirred for 1 hr. Filtered the reaction mixture and washed with water to get the wet compound. The wet compound was stirred in a mixture of isopropanol, water for 1 h at 60-70°C. Further, the reaction mixture was cooled to 25-35°C and stirred for 3 hr and filtered the solid compound and washed with water and dried to get the title compound.
Yield: 50 g; chiral purity >99.5 %; R- isomer <0.15 %
Example-29: purification of compound of formula-I.
A round bottom flask was charged with formula-I (100 g), isopropanol (250 mL) and water (100 ml) heated to 55-65° and stirred for 1 hr. Cooled the reaction mixture to 25-35°C, and stirred for 2 hr and filtered the compound and washed with isopropanol. The wet compound was charged with methanol (1.5L) and heated to 40-50°C and stirred for 30 min and charged with activated carbon and filtered through hyflow bed and washed with methanol. The filtrate layer was cooled to 10-20°C, and charged with water (1.5 L) and stirred for 2 hr. Filtered the obtained compound and washed with water and dried to get the title compound.
Yield: 12.6 g; chiral purity >99.8 %; R- isomer <0.1 %

,CLAIMS:We claim:
1.An improved process for finerenone the compound of formula-I.

[I]
Comprising of
a)reacting the compound of formula-1 with compound of formula-2

in presence of suitable solvent and reagents to provide compound of formula-3,

b)reacting the compound of formula-3 with compound of formula-4 with suitable reagent, solvent to provide compound of formula-5

c)reacting the compound of formula-5 with suitable reagent, suitable solvent to provide compound of formula-6, purifying the compound in suitable solvent,
d) treating compound of formula-6 with suitable chiral reagent, solvents to provide compound of formula-8,

e)deprotecting of compound of formula-8 with suitable reagent, solvent to provide compound-9, purifying the compound in suitable solvent,
f) reacting compound of formula-9 with source of ammonia, suitable reagent, solvent to provide compound of formula-I,
g) optionally purifying the compound of formula-I using suitable solvents to provide pure compound of formula-I.
2. A process according to any proceeding claims the suitable solvents as per the above claims wherein in the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, nitrile solvents, ketone solvents, polar aportic solvent, alcohol solvents , polor protic solvents, acetic acid, water or any mixture thereof; suitable temperature: 10-150°C;
3. A process according to any proceeding claims the suitable reagents are wherein step-a) suitable reagents are piperidine, morpholine, triethyl amine, diethylamine, acetic acid and mixture thereof; step-b) specifically alcohol solvents; step-c) suitable reagents are triethyl orthoformate, triethyl orthoacetate, chloroethane, bromoethane, iodo ethane;
e) suitable reagents are selected form palladium catalyst, palladium hydroxide, ammonium formate, acetic acid, HCl, HBr, trifluoroacetic acid and mixture thereof;
f) suitable reagents are selected from carbonyldiimidazole, EDC- HCl, hexamethyl disilazane, ammonia (g), aq. ammonia, ammonium chloride, ammonium carbonate and mixture thereof;
4. A process according to any proceeding claims wherein in the suitable chiral reagents include L-tartaric acid, D-tartaric acid, camphor sulphonic acid, di-para-toluoyl-L-tartaric acid, di-para-toluoyl-D-tartaric acid, dibenzoyl-L-tartaric acid, dibenzoyl-D-tartaric acid, Phenylalanine, Phenylglycine, Phenyl glycinamide, S-(+)mandelicacid, R-(-) mandelic acid, L-malicacid, D-malic acid, D-(+)-maleicacid, (-)- naproxen, (+)-naproxen, (1R)-(-) camphor sulfonic acid, (1S)-(+)- camphor sulfonic acid, (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)-bromo camphor-10-sulfonic acid, L(-)-pyro glutamic acid, L(+)- pyroglutamic acid, (-)-lacticacid, L-lysine, D-lysine, (2R,3R)-2,3-bis(phenyl sulfonyloxy)succinic acid, (2S,3S)-2,3-bis(phenylsulfonyloxy)succinic acid, benzene sulfonyl derivatives of tartartic acid and mixtures thereof;
5. An improved process for finerneone the compound of formula-I.
Comprising of
a)reacting the compound of formula-1 with compound of formula-2b in presence of acetic acid, piperidine in isopropanol

to provide compound of formula-3b,

b)reacting the compound of formula-3b with compound of formula-4 in ethylene glycol to provide compound of formula-5b,
c)reacting the compound of formula-5b with triethylorthoacetate, sulfuric acid in dimethyl formamide to provide compound of formula-6b, purifying in alcohol solvent,

d) treating compound of formula-6b with di-p-toluoyl-L-tartaric acid in acetonitrile and water to provide compound of formula-6A, further treating with sodium hydroxide in water to provide compound of formula-8b,
e) deprotecting the compound of formula-8b with palladium hydroxide in tetrahydrofuran under hydrogen pressure to provide compound of formula-9,

f) reacting the compound of formula-9 with carbonyl diimidazole, ammonia in tetra hydofuran, to provide compound of formula-I.
g) purifying the compound of formula-I in isopropanol, methanol, water to provide the compound of formula-I
6. A process for the preparation of compound of formula-8b by the chemical resolution of compound of formula-6b.

Comprising of:
a)Treating the compound of formula-6b with di-p-toluoyl-L-tartaric acid in acetonitrile, water provide compound of formula-6A (((S)-4-methylbenzyl 4-(4-cyano-2-methoxy phenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate di-p-toluoyl -L-tartaric acid salt),
b) treating the compound of formula-6A with sodium hydroxide in water to provide compound of formula-8b (((S)-4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate).
7. Finerenone obtained according to the preceding claims is having purity of at least about 95%; preferably of at least about 97%; more preferably of at least about 98%; most preferably of at least about 99.9% as measured by HPLC; Finerenone obtained according to the preceding claims is having R-isomer, N-ethyl impurity, R-isomer of finerenone, des-ethyl impurity, aromatization impurity are less than 0.15% as measured by HPLC.

Dated this day 07 Mar-2024.

Authorized Signatory
(Chakilam Nagaraju)
Maithri Drugs Private Limited
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