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

Abstract

The present invention relates to an improved process for the preparation of (4S)­4-(4- cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carboxamide represented by the following structural formula-1, which is referred to as Finerenone. Formula­1 The present invention also relates to a process for the preparation of crystalline form of Finerenone.

Description

[0001] Improved process for the preparation of (4S)-4-(4-cvano-2-methoxyphenyl)-5-ethoxy- 2,8-dimethyl-l,4-dihvdro-l,6-naphthyridine-3-carboxamide

[0002] Related Application:

[0003] This application claims the benefit of priority of our Indian patent application number 202341078471 filed on 18 November 2023, 202341084756 filed on 12 December 2023, 202441008069 filed on 06 February 2024 and 202441016561 filed on 07 March 2024, which are incorporated herein by reference.

[0004] Field of the Invention:

[0005] The present invention relates to an improved process for the preparation of (4S)-4-(4- cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1 ,4-dihydro- 1 ,6-naphthyridine-3- carboxamide represented by the following structural formula- 1, which is referred to as Finerenone.

[0006] Formula- 1

[0007] The present invention also relates to a process for the preparation of crystalline form of Finerenone.

[0008] Background of the Invention:

[0009] Finerenone is a non-steroidal and selective mineralocorticoid receptor antagonist. The steroidal hormones, aldosterone and cortisol, are natural ligands of the mineralocorticoid receptor. Overactivation of the mineralocorticoid receptor contributes to organ damage found in CKD, HF and hypertension, through mediation of pro-inflammatory and pro-fibrotic effects, as well as via sodium retention and endothelial dysfunction. Finerenone is approved by United States Federal Drug Administration (USFDA) as KERENDIA tablet for oral administration is 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).

[0010] U.S patent US8436180 B2 discloses Finerenone or a salt. This patent also discloses a process for the preparation of Finerenone.

[0011] U.S patent USRE49575 E discloses crystalline form of polymorph I of Finerenone and process for preparation thereof.

[0012] Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and / or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid-state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.

[0013] Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances.

[0014] Brief description of the Invention:

[0015] The present invention relates to an improved process for the preparation of Finerenone of formula- 1.

[0016] Brief description of Drawings:

[0017] Figure-1: Illustrates the PXRD pattern of crystalline form of Finerenone. Figure-2: Illustrates the PXRD pattern of crystalline form of compound of formula-6b(i). Figure-3: Illustrates the PXRD pattern of crystalline form of compound of formula-6(i).

[0018] Detailed description of the Invention:

[0019] As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, 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, 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, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyro nitrile 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, 1, 2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol, monoethyl ether, cyclohexanol, benzyl alcohol or glycerol and the like; “polar solvents” such as water or mixtures thereof.

[0020] The “suitable base” as used in the present invention is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; triethyl amine, methyl amine, ethylamine, 1,8-diaza bicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiiso propylamide (LDA), n-butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine, diisopropylethylamine, N- methylmorpholine, N-ethylmorpholine, piperidine, dimethylamino pyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1-methyl imidazole, 1,2,4-triazole, 1,4- diazabicyclo[2.2.2]octane (DABCO) or mixtures thereof.

[0021] As used herein the term “acid” in the present invention refers to inorganic acid and organic acid; inorganic acid is selected from such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid and the like; organic acid such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, trifluoromethane sulfonic acid, p -toluenesulfonic acid, tartaric acid, mandelic acid, malic acid, oxalic acid, formic acid, ascorbic acid, phosphorous acid, maleic acid, succinic acid, malonic acid, oxalic acid, dibenzoyl tartaric acid, lactic acid, cinnamic acid and the like.

[0022] The “chiral acid” as used in the present invention is selected from L-(+) tartaric acid, D-(-) tartaric acid, (+)-dibenzoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-di-p- toluoyl-D-tartaric acid, and (-)-di-p-toluoyl-L-tartaric acid.

[0023] The “coupling agent” as used in the present invention is selected from PyBOP, BOP, TBTU, EDCI, HATU, HBTU, HCTU, DCC, CDI, DIC, isobutylchloroformate, pivaloyl chloride, oxalyl chloride, thionyl chloride, 1 -propanephosphonic acid, EDC.HC1, HOBt, DMAP, HO At, HOCt, HOSu, BOMI, BDMP, BMPI or CMPI and the like.

[0024] The term “enantiopure” as used herein in the present invention means that a compound has an enantiomeric excess of at least 80%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99%.

[0025] The term “enantiopure” as used herein in the present invention means that an enantiomer is present with a purity of at least 99% enantiomeric excess, preferably in a purity of 99.5-100% enantiomeric excess.

[0026] The “ * ” denotes a mixture of (S) and (R) isomers of the compounds described in the present invention.

[0027] In the first embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1, comprising one or more reaction steps of the following synthetic scheme.

[0028]

[0029] In the first aspect of the first embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1, comprising one or more reaction steps of the following synthetic scheme.

[0030] In the second aspect of the first embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1 , comprising one or more reaction steps of the following synthetic scheme.

[0031] In the second embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1 , comprising one or more reaction steps of the following synthetic scheme. In the first aspect of the second embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1 , comprising one or more reaction steps of the following synthetic scheme.

[0032] In the second aspect of the second embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1 , comprising one or more reaction steps of the following synthetic scheme. In the third embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1 , comprising one or more reaction steps of the following synthetic scheme.

[0033] Chiral acid /

[0034] Diastereomers separation

[0035] Formula- 1

[0036] In the fourth embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1 , one or more reaction steps of the following synthetic scheme. In the fifth embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1, comprising one or more reaction steps of the following synthetic scheme.

[0037] Formula- 1

[0038] In the first aspect of the fifth embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1, which comprises: a) reacting compound of formula- 18 with hydroxylamine hydrochloride in the presence of DIBAL-H in a suitable solvent to provide compound of formula- 17; b) reacting compound of formula- 17 with (+)-dibenzoyl-D-tartaric acid in a suitable solvent to compound of formula- 16a; c) converting compound of formula- 16a to compound of formula- 15 in the presence of suitable base in a suitable solvent; and d) converting compound of formula- 15 to Finerenone of formula- 1 in the presence of acid.

[0039] In the process of the first aspect of the fifth embodiment, wherein the suitable solvent used in steps a) to c) is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof; the suitable base used in step-c) is selected from inorganic base or organic base; the suitable acid used in step-d) is selected from inorganic acid or organic acid

[0040] In the sixth embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1 , comprising one or more reaction steps of the following synthetic scheme.

[0041]

[0042] Formula- 1

[0043] In the seventh embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1, comprising one or more reaction steps of the following synthetic scheme.

[0044]

[0045] Finerenone

[0046] Formula- 1 wherein R is selected from substituted or unsubstituted aryl or heteroaryl group.

[0047] In the first aspect of the seventh embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1 , comprising one or more reaction steps of the following synthetic scheme.

[0048] Finerenone

[0049] Formula- 1

[0050] In the eighth embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1 , comprising one or more reaction steps of the following synthetic scheme.

[0051] wherein Ri is selected from hydrogen or Ci-6 alkyl.

[0052] In the ninth embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1 , comprising one or more reaction steps of the following synthetic scheme.

[0053]

[0054] Formula- 1 wherein R2 and R3 are selected from hydrogen, chiral auxiliary group, substituted or unsubstituted Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Ci-10 alkoxy, C6-20 aryloxy, arylcarbonyl, Ci-10 alkylcarbonyl, Ci-10 haloalkyl, Ci-10 alkylsulfonyl, arylsulfonyl, substituted or unsubstituted C2-10 alkylcarbonyloxy, substituted or unsubstituted C7-20 arylcarbonyloxy, substituted or unsubstituted Ci-10 alkoxycarbonyl, substituted or unsubstituted C7-20 aryloxycarbonyl, substituted or unsubstituted Ce-is arylene, acrylates, -C(0)NR4, -0C(0)NR4, -SO2NR4, -C(O)NR4OR4, substituted or unsubstituted C3-10 alicyclic group, substituted or unsubstituted 4-10 membered heterocyclic group containing heteroatoms selected from N, P, S or O, substituted or unsubstituted 4-10 membered heterocyclylalkyl group containing heteroatoms selected from N, P, S or O, a substituted or unsubstituted Ce-io aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted 5-10 membered heteroaryl containing heteroatoms selected from N, P, S or O; substituted or unsubstituted 5-10 membered heteroarylalkyl containing heteroatoms selected from N, P, S or O; the chiral auxiliary group is selected from the following groups having a chiral structure: substituted or unsubstituted Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Ci-10 alkoxy, C6-20 aryloxy, arylcarbonyl, Ci-10 alkylcarbonyl, Ci-10 haloalkyl, Ci-10 alkylsulfonyl, arylsulfonyl, substituted or unsubstituted C2-10 alkylcarbonyloxy, substituted or unsubstituted C7-20 arylcarbonyloxy, substituted or unsubstituted Ci-10 alkoxycarbonyl, substituted or unsubstituted C7-20 aryloxycarbonyl, substituted or unsubstituted Ce-is arylene, acrylates, -C(O)NR4, -OC(O)NR4, -SO2NR4, - C(O)NR4OR4, substituted or unsubstituted C3-10 alicyclic group, substituted or unsubstituted 4-10 membered heterocyclic group containing heteroatoms selected from N, P, S or O, substituted or unsubstituted 4-10 membered heterocyclylalkyl group containing heteroatoms selected from N, P, S or O, a substituted or unsubstituted Ce-io aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted 5-10 membered heteroaryl containing heteroatoms selected from N, P, S or O; substituted or unsubstituted 5-10 membered heteroarylalkyl containing heteroatoms selected from N, P, S or O; R is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; provided that at least one of R2 and R3 is other than hydrogen.

[0055] In the first aspect of the ninth embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1, which comprises: a) reacting compound of formula-4 with compound of general formula-8 in the presence of suitable coupling agent in a suitable solvent to provide compound of general formula-7, and

[0056] Formula-4

[0057] Formula-7 wherein R2 and R3 are as defined above. b) converting compound of general formula-7 to Finerenone.

[0058] In the process of the first aspect of the ninth embodiment, the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar- aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof; the suitable coupling agent is selected from PyBOP, BOP, TBTU, EDCI, HATU, HBTU, HCTU, DCC, CDI, DIC, isobutylchloroformate, pivaloyl chloride, oxalyl chloride, thionyl chloride, 1-propanephosphonic acid, EDC.HC1, HOBt, DMAP, HO At, HOCt, HOSu, BOMI, BDMP, BMPI or CMPI and the like.

[0059] In an embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1, which comprises: a) reacting compound of formula-4 with compound of formula-8a in the presence of suitable coupling agent in a suitable solvent to provide compound of formula-7a, and u - b) converting compound of general formula-7 to Finerenone. wherein suitable coupling agent and suitable solvent are as defined above. In the second aspect of the ninth embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1, which comprises: a) reacting compound of general formula-7 with suitable chiral acid in a suitable solvent to provide compound of general formula-6a, and wherein R2 and R3 are as defined above. b) converting compound of general formula-6a to Finerenone.

[0060] In the process of the second aspect of the ninth embodiment, the suitable chiral acid is selected from L-(+) tartaric acid, D-(-) tartaric acid, (+)-dibenzoyl-D-tartaric acid, (-)- dibenzoyl -L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, and (-)-di-p-toluoyl-L-tartaric acid; the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

[0061] In an embodiment, the present invention provides a process for the preparation of

[0062] Finerenone of formula- 1, which comprises: a) reacting compound of formula-7a with chiral acid to provide compound of formula- 6b; b) converting compound of formula-6b to Finerenone of formula- 1

[0063] In the third aspect of the ninth embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1, which comprises: a) converting compound of general formula-6a to compound of general formula-6 in the presence of suitable base in a suitable solvent, and wherein R2 and R3 are as defined above. b) converting compound of general formula-6 to Finerenone.

[0064] In the process of the third aspect of the ninth embodiment, wherein the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar- aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof; the suitable base is selected from inorganic base or organic base.

[0065] In an embodiment, the present invention provides a process for the preparation of

[0066] Finerenone of formula- 1, which comprises: a) converting compound of formula-6b to compound of formula-6(i) in the presence of suitable base, and b) converting compound of formula-6(i) to Finerenone of formula- 1. wherein suitable base is as defined above.

[0067] In the fourth aspect of the ninth embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1, which comprises converting compound of general formula-6 to Finerenone of formula- 1 in the presence of suitable acid or suitable catalyst.

[0068] Formula- 1 wherein R2 and R3 are as defined above. wherein the suitable acid is selected from inorganic acid or organic acid; suitable catalyst is selected from Pt / C, Pt / AFCh, Pd / C, Pd(OH)2 / C and the like.

[0069] In an embodiment, the present invention provides a process for the preparation of

[0070] Finerenone of formula- 1, which comprises converting compound of formula-6(i) to

[0071] Finerenone of formula- 1 in the presence of suitable acid or suitable catalyst.

[0072] Formula- 1

[0073] In the tenth embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1, which comprises: a) reacting compound of formula-4 with compound of general formula-8 in the presence of suitable coupling agent in a suitable solvent to provide compound of general formula-6, and wherein R2 and R3 are as defined above. b) converting compound of general formula-6 to Finerenone of formula- 1.

[0074] In the process of the tenth embodiment, the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof; the suitable coupling agent is selected from PyBOP, BOP, TBTU, EDCI, HATU, HBTU, HCTU, DCC, CDI, DIC, isobutylchloroformate, pivaloyl chloride, oxalyl chloride, thionyl chloride, 1 -propane phosphonic acid, EDC.HC1, HOBt, DMAP, HOAt, HOCt, HOSu, BOMI, BDMP, BMPI or CMPI and the like.

[0075] In the first aspect of the tenth embodiment, the present invention provides a process for the preparation of Finerenone of formula- 1, which comprises: a) reacting compound of formula-4 with compound of formula-8a in the presence of suitable coupling agent in a suitable solvent to provide compound of formula-6(i), and b) converting compound of formula-6(i) to Finerenone of formula- 1. wherein suitable coupling agent and suitable solvent are as defined above. Finerenone of formula- 1 obtained according to the present invention is having Acid impurity, Amide pyridine impurity, Diamide impurity, Phenylethylamide impurity, Desethoxy impurity, Cyanoethyl ethoxy impurity, Enantiomer impurity, Dimethoxy impurity and

[0076] In the eleventh embodiment, the present invention provides a crystalline form of Finerenone of formula- 1, is characterized by its X-ray powder diffraction (PXRD) pattern having 2 theta values at about 14.0, 17.1, 18.9, 25.5 and 26.3 ± 0.2 degrees.

[0077] In the first aspect of the eleventh embodiment, the present invention provides a crystalline form of Finerenone of formula- 1, is further characterized by its X-ray powder diffraction (XRD) pattern having 2 theta values at about 11.3, 13.3, 14.9, 15.3, 15.9, 19.7, 20.4, 20.7, 22.8 and 23.8 ± 0.2 degrees.

[0078] In the second aspect of the eleventh embodiment, the present invention provides a crystalline form of Finerenone of formula- 1, is further characterized by the X-ray powder diffraction (PXRD) pattern as illustrated in Figure- 1.

[0079] In the twelfth embodiment, the present invention provides a process for the preparation of crystalline form of Finerenone, which comprises: a) dissolving Finerenone in acetic acid and water, and b) isolating the crystalline form of Finerenone.

[0080] In the process of the twelfth embodiment, optionally the solution obtained in step-a) can be filtered to make it particle free.

[0081] In the process of the twelfth embodiment, adding aqueous ammonia to the solution obtained in step-a), then adding water to the mixture and isolating the crystalline form of Finerenone or adding an alcohol solvent to the solution obtained in step-a), followed by adding an aqueous ammonia then adding water to the mixture and isolating the crystalline form of Finerenone or the solution obtained in step-a) is adding to a mixture of an alcohol solvent and an aqueous ammonia, followed by adding water and then isolating the crystalline form of Finerenone.

[0082] In the process of the twelfth embodiment, wherein the alcohol solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol and tert-butanol.

[0083] In the thirteenth embodiment, the present invention provides a process for the preparation of crystalline form of Finerenone, which comprises: a) dissolving Finerenone in dichloromethane, b) adding n-heptane to the solution obtained in step-a); and c) isolating the crystalline form of Finerenone.

[0084] In the process of the thirteenth embodiment, optionally the solution obtained in step-a) can be filtered to make it particle free. In the process of the thirteenth embodiment, adding water to the mixture obtained in step-b) and isolating the crystalline form of Finerenone.

[0085] In the fourteenth embodiment, the present invention provides a process for the preparation of crystalline form of Finerenone, which comprises: a) contacting or suspending Finerenone in methanol; b) adding dichloromethane and ethyl acetate to the mixture obtained in step- a); and c) isolating the crystalline form of Finerenone.

[0086] In the fifteenth embodiment, the present invention provides a crystalline form of compound of formula-6b(i).

[0087] In the sixteenth embodiment, the present invention provides a crystalline form of compound of formula-6b(i), is characterized by its X-ray powder diffraction (PXRD) pattern having 2 theta values at about 3.5, 3.9, 6.4, 7.8, 12.5 and 14.2 ± 0.2 degrees.

[0088] In the first aspect of the sixteenth embodiment, the present invention provides a crystalline form of compound of formula-6b(i), is further characterized by the X-ray powder diffraction (PXRD) pattern as illustrated in Figure-2.

[0089] In the seventeenth embodiment, the present invention provides a process for the preparation of crystalline form of compound of formula-6b(i), which comprises: a) contacting compound of formula-6b(i) with acetone; and b) isolating crystalline form of compound of formula-6b(i). In the process of the seventeenth embodiment, adding acetone to the compound of formula-6b(i) and heating the mixture to a temperature ranging from 40-60°C followed by isolating the crystalline form of compound 6b(i) from the mixture by cooling it to 25-30°C.

[0090] In the eighteenth embodiment, the present invention provides a crystalline form of compound of formula-6(i).

[0091] Formula-6(i)

[0092] In the nineteenth embodiment, the present invention provides a crystalline form of compound of formula-6(i), is characterized by its X-ray powder diffraction (PXRD) pattern having 2 theta values at about 6.7, 8.5, 9.4, 10.8, 11.8, 14.9 and 21.6± 0.2 degrees.

[0093] In the first aspect of the nineteenth embodiment, the present invention provides a crystalline form of compound of formula-6(i), is further characterized by the X-ray powder diffraction (PXRD) pattern as illustrated in Figure-3.

[0094] In the twentieth embodiment, the present invention provides a process for the preparation of crystalline form of compound of formula-6(i), which comprises: a) contacting compound of formula-6(i) with n-heptane; and b) isolating crystalline form of compound of formula-6.

[0095] In the twenty-first embodiment, Finerenone obtained according to the present invention has a particle size distribution of D90 less than about 150 pm, preferably less than about 100 pm, more preferably less than about 50 pm.

[0096] In the process of the present invention, isolating the crystalline forms of Finerenone or its intermediates can be carrying out by any methods known in the art for e.g. isolated by any of the techniques selected from but not limited to decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.

[0097] In the process of the present invention, the crystalline forms of Finerenone or its intermediates can be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carrying out at atmospheric pressure or under reduced pressure at temperature of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperature. The drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

[0098] Crystalline form of Finerenone prepared according to the present invention can be further micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that can be used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization can be performed before drying, or after the completion of drying of the product.

[0099] In the twenty-second embodiment, the present invention provides novel intermediate compounds represented by the following structural formulae.

[0100] wherein the chiral acid is selected from L-(+) tartaric acid, D-(-) tartaric acid, (+)- dibenzoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, and (- )-di-p-toluoyl-L-tartaric acid. The above mentioned novel intermediate compounds are useful in the preparation of Finerenone of formula- 1.

[0101] In an embodiment, the compound of formula 6 of the present invention is the enantiomerically enriched (S)-isomer.

[0102] In an aspect of the present invention, provides Finerenone having chiral purity of about 99.90% ee; preferably of about 99.95% ee; more preferably of about 99.98% ee; most preferably of about 99.99% ee as measured by chiral HPLC method.

[0103] In an embodiment, Finerenone obtained according to the present invention is enantiopure.

[0104] The compounds of formulae 4, 8, 11, 14, 18, 22, 26 or 26a, 27 or 27a, 31, 36, 37 and 38 used in the present invention are synthesized from any of the known prior art processes.

[0105] Finerenone of formula- 1 obtained according to the present invention can be purified using a suitable solvent selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

[0106] In another embodiment, the present invention provides pharmaceutical composition comprising crystalline form of Finerenone and one or more pharmaceutically acceptable excipients. wherein, the excipient can be selected from those reported in Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems 2006.

[0107] In yet another embodiment, pharmaceutical composition comprising crystalline form of Finerenone and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used.

[0108] As used herein, the term "pharmaceutical compositions" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

[0109] P-XRD Method of Analysis: PXRD analysis of compounds of the present invention was carried out by using BRUKER / D8 ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.037min. PSD method of Analysis: Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 3000 instrument.

[0110] The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation of the scope of the invention.

[0111] Examples:

[0112] Example-1: Preparation of compound of formula-35.

[0113] Ethanol (400.0 ml) was added to compound of formula-37 (100.0 gm) at 25-30°C. Piperidine (13.21 gm) and acetic acid (37.23 gm) were added to the mixture at 25-30°C. Compound of formula-36 (125.15 gm) was added lot wise to the mixture at 25-30°C and stirred for 8 hours. Cooled the mixture to 15-20°C and stirred for 2 hours. Filtered the solid and washed with ethanol. Dichloromethane (500.0 ml) was added to the obtained compound at 25-30°C and stirred for 10 minutes. n-Heptane (1000.0 ml) was added to the mixture at 25- 30°C and stirred for 2 hours. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 161.0 gm.

[0114] Example-2: Preparation of compound of formula-34. n-Propanol (500.0 ml) was added to compound of formula-38 (50.0 gm) at 25-30°C. Compound of formula-35 (156.2 gm) was added to the mixture at 25-30°C and stirred for 10 minutes. Heated the mixture to 90-95°C and stirred for 11 hours. Cooled the mixture to 25- 30°C and stirred for 1 hours. Filtered the solid, washed with n-propanol and dried to get the title compound. Yield: 144.0 gm.

[0115] Example-3: Preparation of compound of formula-33.

[0116] N,N-Dimethyl acetamide (550.0 ml) was added to compound of formula-34 (110.0 gm) at 25-30°C. Triethyl orthoformate (201.5 gm) was added to the mixture at 25-30°C and stirred for 10 minutes. Sulfuric acid (5.33 gm) was slowly added to the mixture at 25-30°C. Heated the mixture to 90-95°C and stirred for 20 hours. Cooled the mixture to 60-65°C. Water (1100.0 ml) was added to the mixture at 60-65°C and stirred for 2 hours. Cooled the mixture to 25-30°C and stirred for 2 hours. Filtered the solid, washed with water and dried to get the title compound. Yield: 102.0 gm. Example-4: Preparation of compound of formula-4.

[0117] Acetone (1500.0 ml) and water (750.0 ml) was added to compound of formula-33 (150.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to 10-15°C. Pre-cool aqueous sodium hydroxide solution was slowly added to the mixture at 10-15°C and stirred for 4 hours. Toluene (375.0 ml) was added to the mixture at 10-15°C. Raised the temperature of the mixture to 25-30°C and stirred for 10 minutes. Layers were separated. Toluene (375.0 ml) was added to the aqueous layer at 25-30°C and stirred for 10 minutes. Layers were separated. Toluene (375.0 ml) was added to the aqueous layer at 25-30°C and stirred for 10 minutes. Layers were separated. Cooled the aqueous layer to 5-10°C. Hydrochloric acid solution was added to the aqueous layer at 5-10°C and stirred for 2 hours. Filtered the solid and washed with water. To the obtained compound was added to acetone (750.0 ml) at 25- 30°C and stirred for 45 minutes. Filtered the solid and washed with acetone to get the title compound. Yield: 168.0 gm.

[0118] Example-5: Preparation of compound of formula-7a.

[0119] Tetrahydrofuran (1350.0 ml) was added to compound obtained in exemple-4 at 25- 30°C and stirred for 10 minutes. N,N'-carbonyldiimidazole (168.72 gm) was added lot wise to the mixture at 25-30°C. 4-(Dimethylamino)pyridine (4.23 gm) was added to the mixture at 25- 30°C and stirred for 2 hours. Cooled the mixture to 20-25°C. A mixture of compound of formula-8a (126.07 ml), tetrahydrofuran (675. 0 ml) and water (675.0 ml) was slowly added lot wise to the mixture at 20-25°C. Raised the temperature of the mixture to 60-65°C and stirred for 10 hours. Cooled the mixture to 25-30°C. Water (675.0 ml) was added to the mixture at 25-30°C and stirred for 15 minutes. Ethyl acetate (1350.0 ml) was added to the mixture at 25-30°C and stirred for 15 minutes. Layers were separated and aqueous layer extracted with ethyl acetate. Combined the total organic layers. Hydrochloric acid solution was added to the organic layer at 25-30°C and stirred for 15 minutes. Layers were separated. Aqueous sodium bicarbonate solution was added to the organic layer at 25-30°C and stirred for 15 minutes. Layers were separated. Aqueous sodium chloride solution was added to the organic layer at 25-30°C and stirred for 15 minutes. Layers were separated. Distilled off the solvent completely from the organic layer under vacuum at below 40°C and co-distilled with ethyl acetate to get the title compound. Yield: 190.0 gm. Example-6: Preparation of compound of formula-6b(i).

[0120] Ethyl acetate (1500.0 ml) was added to compound obtained in example-5 at 25-30°C and stirred for 15 minutes. (-)-Di-p-toluoyl-L-tartaric acid (100.48 gm) was added to the mixture at 25-30°C and stirred for 15 minutes. Raised the temperature of the mixture to 45- 50°C and stirred for 4 hours. Cooled the mixture to 25-30°C and stirred for 2 hours. Filtered the solid and washed with ethyl acetate. To the obtained compound was added to acetone (1350.0 ml) at 25-30°C. Raised the temperature of the mixture to 45-50°C and stirred for 2 hours. Cooled the mixture to 25-30°C and stirred for 90 minutes. Filtered the solid and washed with acetone. To the obtained compound was added to acetone (1350.0 ml) at 25- 30°C. Raised the temperature of the mixture to 45-50°C and stirred for 2 hours. Cooled the mixture to 25-30°C and stirred for 2 hour. Filtered the solid, washed with acetone and dried to get the title compound. Yield: 105.8 gm; Purity by HPEC: 99.58%.

[0121] The PXRD pattern of the obtained compound is illustrated in figure-2.

[0122] Example-7: Preparation of compound of formula-6(i).

[0123] Water (500.0 ml) and dichloromethane (1000.0 ml) was added to compound of formula-6b(i) (100.0 gm) at 25-30°C and stirred for 15 minutes. Aqueous ammonia solution (100.0 ml) was slowly added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated. Dichloromethane (300.0 ml) was added to the aqueous layer at 25-30°C and stirred for 15 minutes. Layers were separated and combined the total organic layers. Distilled off the solvent completely from the organic layer under vacuum at below 40°C and codistilled with n-heptane. n-Heptane (400.0 ml) was added to the obtained compound at 25- 30°C and stirred for 45 minutes. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 52.2 gm.

[0124] Example-8: Preparation of Finerenone.

[0125] Fluorobenzene (500.0 ml) was added to compound obtained in example-7 at 25-30°C and stirred for 10 minutes. Cooled the mixture to -15°C to -10°C. Sulfuric acid (250.0 ml) was slowly added to the mixture at -15°C to -10°C and stirred for 5 hours. To the mixture was slowly added to the pre-cooled mixture of aqueous ammonia (1000.0 ml) and methanol (500.0 ml) at -70°C to -65°C. Raised the temperature of the mixture to 25-30°C and stirred for 10 minutes. Water (100.0 ml) was added to the mixture at 25-30°C and stirred for 1 hour. Filtered the solid and washed with water. Water (100.0 ml) was added to the obtained compound at 25- 30°C and stirred for 1 hour. Filtered the solid, washed with water and dried. Ethyl acetate (80.0 ml) was added to the obtained compound at 25-30°C and stirred for 15 minutes. Methanol (16.0 ml) and acetonitrile (16.0 ml) was added to the mixture at 25-30°C. Raised the temperature of the mixture to 45-50°C and stirred for 1 hour. Cooled the mixture to 25-30°C and stirred for 1 hour. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 23.2 gm. Purity by HPLC: 99.63 %; Acid impurity: Not detected; Amide pyridine impurity: 0.02%; Diamide impurity: 0.09%; Phenylethylamide impurity: 0.08%; Desethoxy impurity: Not detected; Cyanoethyl ethoxy impurity: Not detected; Dimethoxy impurity: 0.08%; Fluorobenzene: 0.02%. Chiral Purity: 99.99%; Enantiomer impurity: Not detected. The PXRD pattern of the obtained compound is illustrated in figure- 1.

[0126] Example-9: Preparation of crystalline form of Finerenone.

[0127] Finerenone (350.0 gm) was added to a pre-cooled mixture of water (1575.0 ml) and acetic acid (1575.0 ml) at 5-10°C and stirred for 10 minutes. Filtered the mixture through 0.2 micron filter paper and washed with pre-cooled acetic acid solution. To the obtained filtrate was slowly added to the pre-cooled mixture of aqueous ammonia (2450.0 ml), water (4900.0 ml) and methanol (350.0 ml) at 10-15°C. A mixture of aqueous ammonia (350.0 ml) and water (700.0 ml) was added to the mixture at 10-15°C and stirred for 90 minutes. Filtered the solid and washed with water. To the obtained compound was added to the pre-cooled water (3500.0 ml) at 10-15°C and stirred for 90 minutes. Filtered the solid, washed with water and dried to get the title compound. Yield: 315.0 gm. Purity by HPEC: 99.78 %; Acid impurity: Not detected; Amide pyridine impurity: 0.01%; Diamide impurity: 0.02%; Phenylethylamide impurity: 0.02%; Desethoxy impurity: Not detected; Cyanoethyl ethoxy impurity: Not detected; Dimethoxy impurity: 0.09%; Fluorobenzene: Not detected. Chiral Purity: 99.99%; Enantiomer impurity: Not detected.

[0128] Particle size distribution: D90: 25.86 pm; D50: 12.48 pm; D10: 3.69 pm; The PXRD pattern of the obtained compound is illustrated in figure- 1.

[0129] Example-10: Preparation of crystalline form of compound of formula-6(i).

[0130] Water (2500.0 ml) and dichloromethane (5000.0 ml) was added to compound of formula-6b(i) (500.0 gm) at 25-30°C and stirred for 20 minutes. Aqueous ammonia solution (500.0 ml) was slowly added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated. Dichloromethane (1500.0 ml) was added to the aqueous layer at 25-30°C and stirred for 30 minutes. Layers were separated and combined the total organic layers. Distilled off the solvent completely from the organic layer under vacuum at below 40°C and codistilled with n-heptane. n-Heptane (2000.0 ml) was added to the obtained compound at 25- 30°C and stirred for 1 hour. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 262.0 gm.

[0131] The PXRD pattern of the obtained compound is illustrated in figure-3.

[0132] Example- 11: Preparation of compound of formula-17.

[0133] Dichloromethane (750.0 ml) and hydroxylamine hydrochloride (27.54 gm) was added to compound of formula-18 (50.0 gm) at 25-30°C and stirred for 10 minutes. Cooled the mixture to -20°C to -15°C. DIBAL-H (93.96 gm) was slowly added to the mixture at -20°C to -15°C and stirred for 3 hours. To the mixture was slowly added to the pre-cooled hydroxylamine hydrochloride solution at 5-10°C and stirred for 15 minutes. Raised the temperature of the mixture to 25-30°C. Aqueous ammonia solution was slowly added to the mixture at 25-30°C. Filtered the solid and washed with dichloromethane. Methanol was added to the obtained compound at 25-30°C and stirred for 9 hours. Filtered the solid and washed with methanol. Distilled off the solvent completely from the filtrate under vacuum at below 45°C. n-Heptane (250.0 ml) was added to the obtained compound at 25-30°C and stirred for 1 hour. Filtered the solid, washed with n-heptane and dried to get the title compound. Yield: 49.0 gm.

[0134] Example-12: Preparation of compound of formula-16a.

[0135] Ethanol (250.0 ml) was added to compound of formula-17 (25.0 gm) at 25-30°C and stirred for 15 minutes. Water (87.5 ml) was added to the mixture at 25-30°C and stirred for 10 minutes. (+)-Dibenzoyl-D-tartaric acid (11.86gm) was added to the mixture at 25-30°C and stirred for 10 minutes. Raised the temperature of the mixture to 70-75°C and stirred for 3 hours. Cooled the mixture to 40-45°C. Filtered the solid and dried to get the title compound. Yield: 16.4 gm.

[0136] Example-13: Preparation of purification of compound of formula-16a. A mixture of ethanol (105.0 ml) and water (35.0 ml) was added to compound of formula-16a (10.0 gm) at 25-30°C and stirred 10 minutes. Raised the temperature of the mixture to 70-75°C and stirred for 2 hours. Cooled the mixture to 40-45°C. Filtered the solid and dried. A mixture of ethanol (105.0 ml) and water (35.0 ml) was added to the obtained compound at 25-30°C. Raised the temperature of the mixture to 70-75°C and stirred for 1 hour. Cooled the mixture to 40-45°C. Filtered the solid and dried to get the title compound. Yield: 6.9 gm.

[0137] Example-14: Preparation of compound of formula-15.

[0138] Water (35.0 ml) and dichloromethane (65.0 ml) was added to compound of formula- 16a (6.5 gm) at 25-30°C and stirred for 15 minutes. Aqueous ammonia solution (35.0 ml) was added to the mixture at 25-30°C and stirred for 20 minutes. Layers were separated. Sodium sulfate was added to the organic layer at 25-30°C. Distilled off the solvent completely from the organic layer under vacuum at below 45°C. Yield: 4.0 gm.

[0139] Example-15: Preparation of Finerenone.

[0140] Fumaric acid (17.5 ml) was added to compound of formula-15 (3.5 gm) at 25-30°C and stirred for 10 minutes. Sodium formate (1.5 gm) was slowly added to the mixture at 25- 30°C and stirred for 10 minutes. Raised the temperature of the mixture to 100-105°C and stirred for 1 hour. Cooled the mixture to 25-30°C. To the mixture was added to sodium bicarbonate solution at 5-10°C. Ethyl acetate (70.0) was added to the mixture at 5-10°C. Layers were separated. Distilled off the solvent completely from the organic layer under reduced pressure at 45°C and co-distilled with methyl tertiary butyl ether to get the title compound. Yield: 2.8 gm.

[0141] Example-16: Preparation of crystalline form of Finerenone.

[0142] Finerenone (20.0 gm) was dissolved in water (100.0 ml) and acetic acid (100.0 ml) at 10-15°C and stirred for 15 minutes. Filtered the mixture through 0.2 micron filter paper and washed with water. Aqueous ammonia solution (100.0 ml) was added to the filtrate at 10- 15°C and stirred for 1 hour. Filtered the solid and washed with water. To the obtained compound was added to water (200.0) at 10-15°C and stirred for 30 minutes. Filtered the solid, washed with water and dried to get the title compound. Yield: 17.5 gm.

[0143] The PXRD pattern of the obtained compound is illustrated in figure- 1. Example-17: Preparation of crystalline form of Finerenone.

[0144] Finerenone (20.0 gm) was dissolved in dichloromethane (700.0 ml) at 10-15°C and stirred for 15 minutes. Filtered the mixture through 0.2 micron filter paper and washed with dichloromethane. To the obtained solution was added to n-heptane (100.0 ml) at 10-15°C and stirred for 30 minutes. Filtered the solid and washed with n-heptane. To the obtained compound was added to water (200.0 ml) at 10-15°C and stirred for 1 hour. Filtered the solid, washed with water and dried to get the title compound. Yield: 15.0 gm. The PXRD pattern of the obtained compound is illustrated in figure- 1.

[0145] Example-18: Preparation of crystalline form of Finerenone.

[0146] Methanol (75.0 ml) was added to Finerenone (5.0 gm) at 25-30°C and stirred for 15 minutes. Dichloromethane (75.0 ml) and ethyl acetate (375.0 ml) were added to the mixture at 25-30°C. Distilled off the solvent from the mixture at below 30°C under vacuum. Filtered the solid, washed with diethyl ether and dried to get the title compound. Yield: 4.2 gm. The PXRD pattern of the obtained compound is illustrated in figure- 1.

[0147] Example-19: Preparation of crystalline form of Finerenone.

[0148] Finerenone (5.0 gm) was dissolved in water (22.5 ml) and acetic acid (22.5 ml) at 5- 10°C and stirred for 20 minutes. Filtered the mixture through 0.2 micron filter paper and washed with diluted acetic acid solution. Pre-cooled methanol (5.0 ml) was added to the filtrate at 5-10°C. Aqueous ammonia (50.0 ml) and water (50.0 ml) was slowly added to the mixture at 5-10°C and stirred for 2 hour. Filtered the precipitated solid and washed with water. To the obtained compound was added to water (25.0 ml) at 10-15°C and stirred for 2 hours. Filtered the solid, washed with water and dried to get the title compound.

[0149] Yield: 4.46 gm. The PXRD pattern of the obtained compound is illustrated in figure- 1.

[0150] Example-20: Preparation of crystalline form of Finerenone.

[0151] Finerenone (650.0 gm) was dissolved in water (2925.0 ml) and acetic acid (2925.0 ml) at 5-10°C and stirred for 20 minutes. Filtered the mixture through 0.2 micron filter paper and washed with pre-cooled acetic acid solution. Pre-cooled methanol (650.0 ml) was added to the filtrate at 5-10°C. Aqueous ammonia (6500.0 ml) and water (6500.0 ml) was slowly added to the mixture at 5-10°C and stirred for 2 hour. Filtered the solid and washed with water. To the obtained compound was added to water (6500.0 ml) at 10-15°C and stirred for 2 hours. Filtered the solid, washed with water and dried to get the title compound. Yield: 584.0 gm. Particle size distribution [PSD]: D90: 4.55 pm; D50: 2.32 pm; DIO: 1.14 pm.

[0152] Example-21: Preparation of compound of formula-6(i).

[0153] Acetone (50.0 ml) was added to compound of formula-4 (5.0 gm) at 25-30°C and stirred for 10 minutes. N,N'-carbonyldiimidazole (7.47 gm) was added lot wise to the mixture at 25-30°C and stirred for 23 hours. A mixture of compound of formula-8a (4.97 gm) and water (25.0 ml) were added to the mixture at 25-30°C. 4-(Dimethylamino)pyridine (0.160 gm) was added to the mixture at 25-30°C and stirred for 20 minutes. Raised the temperature of the mixture to 45-50°C and stirred for 16 hours. Raised the temperature of the mixture to 60-65°C and stirred for 20 hours. Cooled the mixture to 25-30°C and stirred for 5 hours. Filtered the solid, washed with acetone and dried to get the title compound. Yield: 3.25 gm.

[0154] Example-22: Preparation of compound of formula-7b (R2: H and R3: Isopropyl).

[0155] Tetrahydrofuran (20.0 ml) was added to compound of formula-4 (2.0 gm) at 25-30°C and stirred for 15 minutes. N,N'-carbonyldiimidazole (0.9969 gm) and 4-(Dimethylamino) pyridine (0.0647 gm) were added to the mixture at 25-30°C. N,N'-carbonyldiimidazole (1.9938 gm) was added lot wise to the mixture at 25-30°C and stirred for 2 hours. Isopropyl amine (0.6266 gm) was added to the mixture at 25-30°C. Raised the temperature of the mixture to 50-55°C and stirred for 5 hours. Cooled the mixture to 25-30°C. Ethyl acetate (10.0 ml) and water (10.0 ml) were added to the mixture at 25-30°C and stirred for 15 minutes. Layers were separated and aqueous layer extracted with ethyl acetate. Combined the total organic layers. Distilled off the solvent completely from the organic layer under vacuum at below 45°C to get the title compound. Yield: 2.0 gm.

[0156] Example-23: Preparation of compound of formula-7c (R2: H and R3: Benzyl).

[0157] Tetrahydrofuran (20.0 ml) was added to compound of formula-4 (2.0 gm) at 25-30°C and stirred for 15 minutes. N,N'-carbonyldiimidazole (0.9969 gm) and 4-(Dimethylamino) pyridine (0.0647 gm) were added to the mixture at 25-30°C. N,N'-carbonyldiimidazole (1.9938 gm) was added lot wise to the mixture at 25-30°C and stirred for 2 hours. Benzylamine (4.0 ml) was added to the mixture at 25-30°C. Raised the temperature of the mixture to 50-55°C and stirred for 5 hours. Cooled the mixture to 25-30°C. Ethyl acetate (10.0 ml) and water (10.0 ml) were added to the mixture at 25-30°C and stirred for 30 minutes. Layers were separated and aqueous layer extracted with ethyl acetate. Combined the total organic layers. Distilled off the solvent completely from the organic layer under vacuum at below 45°C to get the title compound. Yield: 1.8 gm.

[0158] Example-24: Preparation of (2S)-isopropyl 2-(4-(4-cyano-2-methoxyphenyl)-5-ethoxy- 2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3-carboxamido)propanoate hydrochloride of formula-7d.

[0159] Tetrahydrofuran (20.0 ml) was added to compound of formula-4 (2.0 gm) at 25-30°C and stirred for 15 minutes. N,N'-carbonyldiimidazole (0.9969 gm) and 4-(Dimethylamino) pyridine (0.0647 gm) were added to the mixture at 25-30°C and stirred for 10 minutes. N,N'- carbonyldiimidazole (1.9938 gm) was added lot wise to the mixture at 25-30°C and stirred for 2 hours. To the obtained mixture was added to a mixture to tetrahydrofuran (10.0 ml), L- alanine isopropyl ester hydrochloride (1.0626 gm) and triethylamine (0.8095 gm) at 25-30°C and stirred for 10 minutes. Raised the temperature of the mixture to 50-55°C and stirred for 5 hours. Cooled the mixture to 25-30°C. Ethyl acetate (10.0 ml) and water (10.0 ml) were added to the mixture at 25-30°C and stirred for 20 minutes. Layers were separated and aqueous layer extracted with ethyl acetate. Combined the total organic layers. Distilled off the solvent completely from the organic layer under vacuum at below 45°C to get the title compound. Yield: 1.9 gm.

Claims

We Claim:

1. A process for the preparation of Finerenone of formula- 1, which comprises converting compound of formula-6 to Finerenone of formula- 1.Formula- 1 wherein R2 and R3 are selected from hydrogen, chiral auxiliary group, substituted or unsubstituted Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Ci-10 alkoxy, C6-20 aryloxy, arylcarbonyl, Ci-10 alkylcarbonyl, Ci-10 haloalkyl, Ci-10 alkylsulfonyl, arylsulfonyl, substituted or unsubstituted C2-10 alkylcarbonyloxy, substituted or unsubstituted C7-20 arylcarbonyloxy, substituted or unsubstituted Ci-10 alkoxycarbonyl, substituted or unsubstituted C7-20 aryloxycarbonyl, substituted or unsubstituted Ce-is arylene, acrylates, - C(0)NR4, -0C(0)NR4, -SO2NR4, -C(O)NR4OR4, substituted or unsubstituted C3-10 alicyclic group, substituted or unsubstituted 4-10 membered heterocyclic group containing heteroatoms selected from N, P, S or O, substituted or unsubstituted 4-10 membered heterocyclylalkyl group containing heteroatoms selected from N, P, S or O, a substituted or unsubstituted Ce-io aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted 5-10 membered heteroaryl containing heteroatoms selected from N, P, S or O; substituted or unsubstituted 5-10 membered heteroarylalkyl containing heteroatoms selected from N, P, S or O; the chiral auxiliary group is selected from the following groups having a chiral structure: substituted or unsubstituted Ci-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, Ci-10 alkoxy, C6-20 aryloxy, arylcarbonyl, Ci-10 alkylcarbonyl, Ci-10 haloalkyl, Ci-10 alkylsulfonyl, arylsulfonyl, substituted or unsubstituted C2-10 alkylcarbonyloxy, substituted or unsubstituted C7-20 arylcarbonyloxy, substituted or unsubstituted Ci-10 alkoxycarbonyl, substituted or unsubstituted C7-20 aryloxycarbonyl, substituted or unsubstituted Ce-is arylene, acrylates, -C(O)NR4, -0C(0)NR , -SO2NR4, -C(O)NR4OR4, substituted orunsubstituted C3-10 alicyclic group, substituted or unsubstituted 4-10 membered heterocyclic group containing heteroatoms selected from N, P, S or O, substituted or unsubstituted 4-10 membered heterocyclylalkyl group containing heteroatoms selected from N, P, S or O, a substituted or unsubstituted Ce-io aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted 5-10 membered heteroaryl containing heteroatoms selected from N, P, S or O; substituted or unsubstituted 5-10 membered heteroarylalkyl containing heteroatoms selected from N, P, S or O; R4 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; provided that at least one of R2 and R3 is other than hydrogen.

2. The process as claimed in claim 1, wherein converting compound of formula-6 to Finerenone is carried out in the presence of acid selected from inorganic acid or organic acid or catalyst selected from Pt / C, Pt / AhCh, Pd / C, Pd(OH)2 / C and the like.

3. A process for the preparation of Finerenone of formula- 1, which comprises: a) converting compound of formula-6a to compound of formula-6 in the presence of base in a solvent.wherein R2 and R3 are as defined above. b) converting compound of formula-6 to Finerenone of formula- 1.

4. The process as claimed in claim 3 wherein, the chiral acid is selected from L-(+) tartaric acid, D-(-) tartaric acid, (+)-dibenzoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)- di-p-toluoyl-D-tartaric acid, and (-)-di-p-toluoyl-L-tartaric acid; the base is selected frominorganic base or organic base; the solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, water and mixture thereof.

5. A process for the preparation of Finerenone of formula- 1, which comprises: a) reacting compound of formula-7 with chiral acid to provide compound of formula-6a.wherein R2 and R3 are as defined above. b) converting compound of formula-6a to Finerenone of formula- 1.

6. The process as claimed in claim 5 wherein, the chiral acid used in step-a) is selected from L-(+) tartaric acid, D-(-) tartaric acid, (+)-dibenzoyl-D-tartaric acid, (-)-dibenzoyl-L- tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, and (-)-di-p-toluoyl-L-tartaric acid.

7. A process for the preparation of Finerenone of formula- 1, which comprises: a) reacting compound of formula-4 with compound of formula-8 to provide compound of formula-7, andwherein R2 and R3 are as defined above.b) converting compound of formula-7 to Finerenone of formula- 1.

8. The process as claimed in claim 7, wherein reacting compound of formula-4 with compound of formula-8 is carried out in the presence of coupling agent selected from PyBOP, BOP, TBTU, EDCI, HATU, HBTU, HCTU, DCC, CDI, DIC, isobutyl chloroformate, pivaloyl chloride, oxalyl chloride, thionyl chloride, 1 -propane phosphonic acid, EDC.HC1, HOBt, DMAP, HOAt, HOCt, HOSu, BOMI, BDMP, BMPI or CMPI and the like.

9. The process as claimed in claim 7, wherein reacting compound of formula-4 with compound of formula-8 is carried out in a solvent selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, water and mixture thereof.

10. A process for the preparation of Finerenone of formula- 1, which comprises: a) reacting compound of formula-4 with compound of formula-8 to provide compound of formula-6, andwherein R2 and R3 are as defined above. b) converting compound of formula-6 to Finerenone of formula- 1.

11. The process as claimed in claim 10, wherein reacting compound of formula-4 with compound of formula-8 is carried out in the presence of coupling agent selected from PyBOP, BOP, TBTU, EDCI, HATU, HBTU, HCTU, DCC, CDI, DIC, isobutyl chloroformate, pivaloyl chloride, oxalyl chloride, thionyl chloride, 1 -propane phosphonic acid, EDC.HC1, HOBt, DMAP, HOAt, HOCt, HOSu, BOMI, BDMP, BMPI or CMPI andthe like.

12. The process as claimed in claim 10, wherein reacting compound of formula-4 with compound of formula-8 is carried out in a solvent selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, water and mixture thereof.

13. A process for the preparation of crystalline form of Finerenone, which comprises: a) dissolving Finerenone in acetic acid and water, and b) isolating the crystalline form of Finerenone.

14. The process as claimed in claim 13, wherein adding aqueous ammonia solution to the solution obtained in step-a), then adding water to the mixture and isolating the crystalline form of Finerenone.

15. The process as claimed in claim 13, wherein adding an alcohol solvent to the solution obtained in step-a), followed by adding an aqueous ammonia solution then adding water to the mixture and isolating the crystalline form of Finerenone.

16. The process as claimed in claim 13, wherein the solution obtained in step-a) is adding to a mixture of an alcohol solvent and an aqueous ammonia solution, followed by adding water and then isolating the crystalline form of Finerenone.

17. A crystalline form of compound of formula-6b(i).

18. A crystalline form of compound of formula-6b(i), is characterized by its X-ray powder diffraction (PXRD) pattern having 2 theta values at about 3.5, 3.9, 6.4, 7.8, 12.5 and 14.2 ± 0.2 degrees.

19. A process for the preparation of crystalline form of compound of formula-6b(i) as claimed in claim 18 comprising the steps of: a) contacting compound of formula-6b(i) with acetone; and b) isolating crystalline form of compound of formula-6b(i).

20. The process as claimed in claim 19, wherein adding acetone to the compound of formula- 6b(i) and heating the mixture to a temperature ranging from 40°C-60°C followed by isolating the crystalline form of compound 6b(i) from the mixture by cooling it to 25- 30°C.

21. A crystalline form of compound of formula-6(i).

22. A crystalline form of compound of formula-6(i), is characterized by its X-ray powder diffraction (PXRD) pattern having 2 theta values at about 6.7, 8.5, 9.4, 10.8, 11.8, 14.9 and 21.6± 0.2 degrees.

23. A process for the preparation of crystalline form of compound of formula-6(i) as claimed in claim 22 comprising the steps of: a) contacting compound of formula-6(i) with n-heptane; and b) isolating crystalline form of compound of formula-6(i).

24. A compounds of formulae 6, 6a and 7wherein R2 and R3 are as defined above. which are used in the process for the preparation of Finerenone of formula- 1. wherein the chiral acid is selected from L-(+) tartaric acid, D-(-) tartaric acid, (+)- dibenzoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, and (-)-di-p-toluoyl-L-tartaric acid.

25. Finerenone having a particle size distribution of D90 less than 150 pm, preferably less than 100 pm, more preferably less than 50 pm.

26. Finerenone having a purity of about 99.7% by HPLC.

27. A pharmaceutical composition comprising Finerenone according to any of the preceding claims and one or more pharmaceutically acceptable excipients.

28. The use of Finerenone according to any of preceding claims for the preparation of a medicament for 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).

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