DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE ENANTIOSELECTIVE PREPARATION OF FINERENONE INTERMEDIATE COMPOUND

We, LEE PHARMA LIMITED,
a company incorporated under the companies act, 1956 having address at
Sy.No: 257 & 258/1; Door No: 11-6/56-C; Opp: IDPL Factory; Moosapet; Balanagar (Post); Hyderabad, Telangana; 500037- India.

The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of mineralocorticoid receptor (MR) antagonists.

The present invention specifically relates to an improved process for the preparation of Finerenone and salts thereof.

The present invention relates to a process for the preparation of Finerenone intermediate compound of Formula (I) or salts thereof,

Formula (I)

The present invention also relates to a chiral Brønsted acid catalyzed asymmetric transfer hydrogenation of a compound of Formula (II) for the preparation of Finerenone intermediate compound of Formula (I) with high enantio-selectivity and yield.
Formula (II)

BACKGROUND OF THE INVENTION
Finerenone is a potent, selective, and orally available nonsteroidal mineralocorticoid receptor (MR) antagonist to control deleterious effects on the kidneys, blood vessels, and heart for the management of cardiovascular and renal diseases such as heart failure and diabetic nephropathy (Chem. Med. Chem. 2012, 7(8), 1385-1403). Finerenone is approved by USFDA under the brand name of Kerendia in the year of 2021 and by EU and IN in the following year, 2022. Finerenone’s chemical name is (4S)­4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, and has the following chemical structure.
Formula (III)

Bayer’s US 8,436,180 B2 discloses the compound, (4S)­4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide and salts thereof, and its use for the treatment and/or prophylaxis of diseases, especially cardiovascular disorders are shown by determining the inhibitory MR activity, MR selectivity, possible binding activity to the L-type Calcium Channel, and Cardiovascular Effect. This patent also discloses the preparation process of Finerenone by synthesizing racemic mixture followed optical resolution using chiral phase HPLC. Further, detailed study on syntheses, biological activities and comparative studies, is published in Chem. Med. Chem. 2012, 7(8), 1385-1403. The process is given below, schematically.

Bayer’s US 10,336,749 B2 discloses the preparation process of Finerenone by synthesizing racemic mixture from nitrile aldehyde compound with reduced steps and good yield followed optical resolution using chiral phase HPLC. The improved process is disclosed as given below schematically.

As the compound, (4S)­4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, is an important isomer, various resolution procedures for API or intermediate compounds have been developed that are suitable for industrial production and yielding high purity API. The basic and important step in the Finerenone preparation process is separation of stereo-selective isomer of precursor or Finerenone compound itself from the racemic mixture. Although chromatographic separation offers a relatively good yield and optically pure compounds, the operation costs, consumption of high energy and huge amount of solvents make difficult for industrial application. Hence, various techniques and/or resolution processes are tried for industrial friendly, cost-effective, simple and pure production.

Bayer’s US 2021/0163474 A1 discloses the optical resolution process by dissolving the racemic mixture of 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide and aromatically or hetero aromatically substituted derivatives of tartaric acid, whereas classical resolving agents that including (+)-tartaric acid also failed to form the salt formation. This application also discloses the trials for the formation of Finerenone diastereomeric salt using very strong inorganic and organic mineral acids such as chiral sulfonic acids or phosphonic acids, but failed to achieve high yields. For example, the cyclic phosphoric ester, chlocyphos, reaction with Finerenone racemate gives a diastereomeric salt in which S-isomer is present with an enantiomeric excess of only 44% e.e. Hence, aromatically or hetero aromatically substituted derivatives of tartaric acid are highly suitable for forming diastereomeric salts from Finerenone racemate that aids ease the resolution process. The process is given below, schematically.

The disadvantage associated with the above process are:
- Low yields due to final stage resolution
- 50% unwanted isomer losing in final stage which is essentially carried over from all the stages
- Cumbersome operations to make final racemic Finerenone followed by resolution

Bayer’s WO 2021/074077 A1 discloses a process with the aid of enzymatic methods to synthesize suitable chiral derivatives which can be used for the synthesis of Finerenones. This application specifically discloses a process for the production of acyloxymethyl esters of (4S)-(4-cyano- 2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxylic acid by chiral resolution of its racemic mixture using a hydrolase (fipase, esterase, amidases or proteases). It is further disclosed the process for the preparation of acyloxymethyl esters of Finerenone precursor compound, resolution using enzymes, saponification and conversion into Finerenone, as given below schematically.

Bayer’s US 10,392,384 B2 discloses a process that enables conversion of by-product, (R)-isomer, after chromatographic separation into racemic mixture using oxidation followed by electrochemical reduction. Further, the racemic mixture is subjected to another enantiomeric separation to obtain Finerenone that helps economically and environmentally by avoiding wastage of (R)-isomer by-product. The process is given below schematically.

Bayer’s WO 2021/074079 A1 discloses a photochemical process for producing racemic (4R,4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxamide of formula (I) from the enantiomers (S) or (R) by irradiating with light in a suitable solvent, or solvent mixture, in the presence of a base. This technique also discloses the conversion of (R) isomer into racemic mixture upon irradiation of light and further resolution of obtained racemic mixture using existing processes (chromatographic or resolution agents) for the preparation of (S)-isomer, that again converted into Finerenone.

Above methods are disclosing the preparation of racemic mixture followed by resolution process using either Chiral HPLC or resolving agents because only (S)-enantiomer is pharmacological active. Further, these methods require excess stages to obtain enantioselective compound and other isomer is not of use. Hence, enantioselective preparation methods are focused. As Angew. Chemie Int. Ed. 2006, 45, 3683-3686 discloses the organocatalytic transfer hydrogenation of quinolines and their application in the synthesis of highly enantioselective synthesis of alkaloids, efforts have been initiated to avoid the formation of (R)-isomer compound as well as to develop industrial friendly process.

Bayer’s WO 2021/254896 A1 discloses the enantioselective preparation of Finerenone using asymmetric transfer hydrogenation, which involves the partial transfer hydrogenation of a naphthyridine using a chiral phosphoric acid catalyst with a Hantzsch ester. Detailed study is published in Angew. Chem. Int. Ed. 2020, 59, 23107-23111 over the catalyst screening, temperature dependent inter-conversion of atropisomers of stating materials, enantioselectivity during the reduction process to optimize the conditions for partial transfer hydrogenation. The optimized process is as given below schematically.


Teva’s WO 2023/205164 A1 discloses a process for the preparation of Finerenone which also involves use of Hantzsch ester and a chiral phosphoric acid catalyst. The process is shown in the scheme given below:

In order to improve the yield, product purity, usage of environmental friendly reagents, cost effective and industrial friendly process, different methods have been tried for enantioselective preparation process at different stages of the Finerenone production process. It is convenient to prepare the enantioselective intermediate compound and subsequent product preparation.

Here, inventors tried to synthesize (S)-enantiomer compound of Formula (I) to avoid resolution process and subsequent conversion of the compound into Finerenone. The process has simple operations, which can be used in bigger batch sizes, with specific / selective isomer preparation in high yields

The process of the present invention enables the use of highly safe, stable, cost-effective, eco-friendly preparation process of Finerenone precursor compound. These features make the process of the invention highly suitable for industrial scale up production.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of Finerenone or salts thereof.

Another objective of the present invention is to provide an improved process for the preparation of Finerenone intermediate compound of Formula (I) or salts thereof,
Formula (I)

Still another objective of the present invention is to provide a chiral Brønsted acid catalyzed asymmetric transfer hydrogenation of a compound of Formula (II) for the preparation of Finerenone intermediate compound of Formula (I) with highly enantio-selectivity and yield.
Formula (II)

Another objective of the present invention is to provide the preparation of the compound of formula (I) by means of chiral phosphoric acid catalyzed Hantzsch ethylester reduction of the compound of formula (II).

Still another preferred objective of the present invention is to provide an improved process for the preparation of Finerenone of Formula (III) or its pharmaceutically acceptable salts using intermediate compound of Formula (I) or its salts thereof.
Formula (III)

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of Finerenone intermediate compound of Formula (I), used in the preparation of Finerenone or salts thereof.
Formula (I)

In another embodiment, the present invention provides an improved process for the preparation of Finerenone intermediate compound of Formula (I) using a chiral Brønsted acid catalyzed asymmetric transfer hydrogenation process.

Yet another embodiment, converting Formula (II) to Formula (II-a) and converting Formula (II-a) to Formula (I) using chiral phosphoric acid catalyzed Hantzsch ethylester reduction.
Formula (II-a)

Yet another embodiment, the present invention provides an improved process for the preparation of Finerenone intermediate compound of Formula (I) using chiral phosphoric acid catalyzed Hantzsch ethylester reduction of the compound of formula (II).

Formula (II)

In another embodiment, the present invention also provides an improved process for the preparation of the compound of formula (I) using chiral phosphoric acid catalysts such as formula (IVa), formula (IVb) and formula (IVc)

where R represents a substituted or unsubstituted phenyl, a substituted or unsubstituted aryl or polyaryl, or triphenylsilyl group, in which phenyl and substituted or unsubstituted aryl or polyaryl may be substituted by 1-3 substituents selected independently of one another from the group consisting of straight or branched C1-C4 alkyl, cyclohexyl, trifluoromethyl, hydroxyl, C1-C4 alkoxy, mono-C1-C4 alkylamino or di- C1-C4 alkylamino and fluorine.

In another embodiment, the present invention also provides an improved process for the preparation of the compound of formula (I) using Hantzsch ester of general formula (V).

where R1 represents straight or branched C1-C6 alkyl or benzyl.

In another embodiment, the present invention also provides the use of compounds, a chiral phosphoric acid of Formula (IVa) or Formula (IVa) or mixture of the both and Hantzsch ester of general formula (V), in the preparation of Finerenone of Formula (III) or its pharmaceutically acceptable salts.
Formula (III)

DETAILED DESCRIPTION OF THE INVENTION
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

In a specific embodiment, reduction of compound of Formula (II) is carried out using Hantzsch ester of general formula (V)

where R1 represents straight or branched C1-C6 alkyl or benzyl, preferably methyl, ethyl or butyl, diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and dibutyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate, and in the presence of chiral phosphoric acid catalyst of the general formula (IVa), formula (IVb) and formula (IVc)

where R represents a substituted or unsubstituted phenyl, a substituted or unsubstituted aryl or polyaryl, or triphenylsilyl group, in which phenyl and substituted or unsubstituted aryl or polyaryl may be substituted by 1-3 substituents selected independently of one another from the group consisting of straight or branched C1-C4 alkyl, cyclohexyl, trifluoromethyl, hydroxyl, C1-C4 alkoxy, mono-C1-C4 alkylamino or di- C1-C4 alkylamino and fluorine, preferably 9-anthracenyl, (S)-3,3'-Bis-(9-anthracenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate.

The reaction is carried out in the presence of a solvent, selected from alcohols such as Ethyl Acetate, Acetic Anhydride, DMF, DMA, NMP (1-methyl-2-pyrrolidone), acetonitrile, NMP with dimethyl sulphate, methanol, ethanol, propanol, n-butanol, 2-butanol, isopropanol, and the like, with n-butanol being the preferred alcohol. Alternatively, the solvent can be an ether, such as dimethyl ether, diethyl ether, methyl ethyl ether, tetrahydrofuran (THF), 2-methyl-THF, methyl tert-butyl ether (MTBE), or the like, with THF being the preferred ether.

The reaction is conducted at a temperature ranging from 80°C to 130°C for a duration of 10 to 70 hours. Upon completion, the solids corresponding to the compound of Formula (I) are filtered and dried to obtain the final product.

In another embodiment, the present invention provides a process for the preparation of Finerenone intermediate, comprising converting Formula (II) to Formula (II-a) and converting Formula (II-a) to Formula (I) using chiral phosphoric acid catalyzed Hantzsch ethylester reduction.
Formula (II-a)

In another embodiment, the present invention provides a process for the preparation of Finerenone of formula (III) which comprises converting compound of formula (I) prepared by the process of the present invention. The process comprises:

(a) converting compound of formula (I) to compound of formula (VI)
Formula (VI)
using a with a trialkyl ortho ester reagent, an acid in a solvent;
(b) hydrolyzing the compound of formula (VI) to acid compound of formula (VII)
Formula (VII)

using a base and in a solvent.
(c) converting the acid compound of formula (VII) to Finerenone of formula (III) using carbonyl diimidazole, ammonia solution in a solvent.

The trialkyl orthoester is selected from trialkyl orthoformate, trialkyl orthoacetate, specifically trimethyl orthoformate (TMOF), triethyl orthoacetate, triethyl orthopropionate.

The acid as used herein is selected from inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, polyphosphoric acid; organic acid selected from formic acid, acetic acid, propionic acid, citric acid and oxalic acid, TsOH or mixture thereof.

The base as used herein is selected from inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, Lithium hexamethyldisilazide, Sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisopropylamide), triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like.

The solvent as used herein is selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof.

The term “salts” as used herein refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenylsubstituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like.

In another preferred embodiment, a process for the preparation of compound of Formula (III) which yields the compounds with high chemical purity.

In yet another preferred embodiment, the present invention provides use of intermediate compounds of Formula (I) in the preparation of Finerenone or its salts. The intermediate formed in the present invention may or may not be isolated. Any of the above reactions may be carried out in-situ reactions to obtain compound of Formula (III).

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES

Example 1: Preparation of 2-Cyanoethyl 4-(4-cyano-2-methoxy phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate:
4-Formyl-3-methoxybenzonitrile (100 grams, 0.620 mmol), 2-cyanomethyl-3-oxobutanoate (133 grams, 0.85mmol), acetic acid (3.72 grams, 0.062 mmol), Piperidine (5.27 grams, 0.061 mmol) and ethanol (450 ml) were added into the flask. Reaction mass was stirred for 12 to 15 hours at 25-30°C. After reaction completion, filtered and washed with ethanol (50 ml). Wet material dried under vacuum at 55-65°C to yield 2-cyanoethyl-2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate.

2-cyanomethyl-2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate material, 4-amino-5-methyl-pyridin-2(1H)-one (58.0 grams, 0.46 mmol) and isopropyl alcohol (1500 ml) were added into the autoclave. Reaction mass was heated to 100-105° for 24 to 28 hours. After reaction completion, cooled to 25-30°C, then filtered, washed with IPA (100 ml). Wet material dried under vacuum at 50-55°C to get 2-Cyanoethyl 4-(4-cyano-2-methoxy phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (160 grams, Purity = ~ 99%, Yield ~ 64%).

'H-NMR: 2.03 (s, 3H), 2.36 (s, 3H), 2.80 (m, 2H), 3.75 (s, 3H), 4.04 (m, 1H), 4.11(m, 1H), 5.23 (s, 1H), 6.85 (s, 1H), 7.25 (m, 1H), 7.31 (m, 2H), 8.19 (s, 1H), 10.78 (s, 1H); [M+H]+: 405.17).

Example 2: Preparation of 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl -5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate:
2-Cyanoethyl 4-(4-cyano-2-methoxy phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (110.00 grams, 0.27 mmol), n-Butanol (1100 mL) and nitric acid (37.2 grams, 0.40 mmol) were added into the flask. The reaction heated to 100-105°C for 2-4 hours. After reaction completion, cooled to 25-30°C, then add water (1100 mL) and cooled to 0-5°C, stir for 2 hours. Filtered the reaction mass and washed with water (100 ml). Wet material dried under vacuum at 50-55°C to get 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (70 grams, Purity = ~ 98%, yield: 68%).

'H-NMR: 2.26 (s, 3H), 2.76-2.60 (m, 5H), 3.68 (s, 3H), 4.15-4.0 (m, 2H), 7.13-7.11 (d, 1H), 7.40-7.34 (q, 2H), 7.45 (s, 1H), 11.15-11.14 (d, 1H). Mass: [M+H]+: 403.13

Example 3: Preparation of 2-Cyanoethyl (S)-4-(4-cyano-2-methoxy phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate:

Example 3a: 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (100 gr, 0.24 mmol), (S)-3,3'-Bis-(9-anthracenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (11 gr, 15.7 mmol) (chiral phosphoric acid catalyst) as catalyst in n-Butanol (3 Lit) and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (314 gr, 1.24 mmol) to single neck RBF. The reaction stirred at 115-120°C in an oil bath for 48-60 hours. Then, the reaction was cooled to room temperature to get crude 2-Cyanoethyl (S)-4-(4-cyano-2-methoxy phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (47 gr, Purity = ~ 98%, yield: 48.4 %).

Example 3b: 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (5 gr, 0.012 mmol), (S)-3,3'-Bis-(9-anthracenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (0.55 gr, 0.785 mmol) (chiral phosphoric acid catalyst) as catalyst in 2-butanol (160 ml) and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (15.7 gr, 0.062 mmol) to single neck RBF. The reaction stirred at 100-110°C in an oil bath for 60-70 hours. Then, the reaction was cooled to room temperature to get crude 2-Cyanoethyl (S)-4-(4-cyano-2-methoxy phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (2.2 gr, Purity = ~ 96%, yield: 45.8%)..

Example 3c: 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (10 gr, 0.024 mmol), (S)-3,3'-Bis-(9-anthracenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (1.1 gr, 1.57 mmol) (chiral phosphoric acid catalyst) as catalyst and dibutyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (32.5 gr, 0.105mmol) in THF (350 ml) to a RBF under reflux. The reaction stirred at 80-85°C in an oil bath for 30-40 hours. Then, the reaction was cooled to room temperature to get 2-Cyanoethyl (S)-4-(4-cyano-2-methoxy phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (4.8 gr, Purity = ~ 95%, yield: 48%).

Example 3d: 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-5,6-dihydro-1,6-naphthyridine-3-carboxylate (20 gr, 0.048 mmol), (S)-3,3'-Bis-(9-anthracenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (2.2 gr, 3.14 mmol) (chiral phosphoric acid catalyst) as catalyst and dibutyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (65 gr, 0.21 mmol) in n-Butanol (600 ml) to single neck RBF. The reaction stirred at 120-130°C in an oil bath for 55-65 hours. Then, the reaction was cooled to room temperature to get 2-Cyanoethyl (S)-4-(4-cyano-2-methoxy phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (9.5 gr, Purity = ~ 97%, yield: 47.5%).

Example 4: Preparation of 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylate:
2-Cyanoethyl (S)-4-(4-cyano-2-methoxy phenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carboxylate (50 grams, 0.123m mol), triethyl orthoacetate (120 grams, 0.67), Dimethyl Formamide (400 mL) were added followed by sulphuric acid (3.65 grams, 0.037 mmol) into the flask. Reaction mass was heated to 110-115°C for 2 to 3 hours. After reaction completion, cooled to room temperature and water (550 mL) added, stirred for 2 hours, filtered and washed with water (100ml), wet material dried under vacuum at 50-55°C to get 2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylate (49.5 grams, Purity = ~ 98%, Yield ~ 92%).

'H-NMR: 1.22 (t, 3H, J=7.05), 2.16 (s, 3H), 2.47 (s, 3H), 2.63 (m, 2H), 3.79 (s, 3H), 4.16 (q, 2H, J=7.51), 4.22 (m, 2H), 5.48 (s, 1H), 6.13 (s, 1H), 7.04 (d, 1H, J=1.14), 7.16 (dd, 1H, J=8.48, 0.69), 7.42 (d, 1H, J=7.81), 7.65 (s, 1H); [M+H]+: 433.17.

Example 5: Preparation of (S)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-ethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid:
2-cyanoethyl (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-1,4-dihydro-2,8-dimethyl-1,6-naphthyridine-3-carboxylate (30 grams, 0.069 mmol), 1,2-dimethoxyethane (240 mL) and water (300 mL) were added. To the reaction mass, Aq. Sodium hydroxide solution (4.16 grams, 0.104 mmol dissolved in 45 mL water) was added and stirred for 1 to 2 hours at room temperature. After reaction completion, extracted with Diethyl ether (450 ml) and Aq. Layer separated. Aq. Layer was adjusted to pH 3-4 by using diluted hydrochloric acid, filtered the solid and washed with water (30 mL), dried under vacuum at 50-55°C to get (S)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-ethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (24 grams, Purity = ~ 97%, Yield ~ 91%).

1H-NMR: 1.12 (t, 3H, J=6.97), 2.39 (s, 3H), 2.15 (s, 3H), 3.76 (s, 3H), 4.05 (m, 2H), 5.35 (s, 1H), 7.28 (m, 1H), 7.28 (m, 1H), 7.32 (s, 1H), 7.57 (s, 1H), 8.15 (s, 1H), 11.44 (s, 1H).
Mass: [M+H]+: 380.15.

Example 6: Preparation of (S)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-ethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxamide:
(S)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-ethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (25 grams, 0.065mmol), Carbonyldiimidazole (CDI) (16 grams, 0.098 mmol) were followed by ethyl acetate (375 mL) and stirred for 20-24 hours. After reaction completion, the ethyl acetate distilled out under vacuum. Then DMF (300 mL) and liquor ammonia were added, further heated to 100-105°C for 1 to 2 hours. After reaction completion, the DMF was distilled out under vacuum. Ethyl acetate (125 mL) was added and heated to 45-50°C for 1 hour and cooled to room temperature, filtered the solid. Material dried under vacuum at 40-50°C to get (S)-4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-ethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxamide (20 grams, Purity = ~ 99%, Yield ~ 80%).

'H-NMR: 1.06 (t, 3H, J=6.50), 2.13 (s, 3H), 2.20 (s, 3H), 3.83 (s, 3H), 4.02 (m, 2H), 5.39 (s, IH), 6.79 (m, 2H), 7.16 (d, IH, J=7.36), 7.29 (d, IH, J=7.16), 7.38 (s, IH), 7.56 (s, IH), 7.71 (s, IH).
Mass: [M+H]+: 379.17. ,CLAIMS:We Claim:

1. A process for converting of Finerenone intermediate compound of Formula (I), comprising:
Formula (I)

Step (a): converting Formula (II) to Formula (II-a);
Step (b): converting Formula (II-a) to Formula (I) using chiral phosphoric acid catalyzed Hantzsch ethylester reduction.

Formula (II)

2. A compound of Formula (II-a)
Formula (II-a)

3. A process for the preparation of Finerenone of formula (III)
Formula (III)

converting compound of formula (I) prepared by the process of claim 1-2 which comprises:

(a) converting compound of formula (I) to compound of formula (VI)
Formula (VI)
using a with a trialkyl ortho ester reagent, an acid in a solvent;
(b) hydrolyzing the compound of formula (VI) to acid compound of formula (VII)
Formula (VII)

using a base and in a solvent.
(c) converting the acid compound of formula (VII) to Finerenone of formula (III) using carbonyl diimidazole, ammonia solution in a solvent.
4. The process as claimed in claim 1-3, wherein the chiral phosphoric acid catalyst is selected from formula (IVa), formula (IVb) and formula (IVc)

where R represents a substituted or unsubstituted phenyl, a substituted or unsubstituted aryl or polyaryl, or triphenylsilyl group, in which phenyl and substituted or unsubstituted aryl or polyaryl may be substituted by 1-3 substituents selected independently of one another from the group consisting of straight or branched C1-C4 alkyl, cyclohexyl, trifluoromethyl, hydroxyl, C1-C4 alkoxy, mono-C1-C4 alkylamino or di- C1-C4 alkylamino and fluorine, (S)-3,3'-Bis(9-anthracenyl)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate.

5. The process as claimed in claim 1-3 wherein the Hantzsch ester is of general formula (V).

where R1 represents straight or branched C1-C6 alkyl or benzyl, diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and dibutyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate.

6. The process as claimed in claim 1-3 wherein trialkyl orthoester is selected from trialkyl orthoformate, trialkyl orthoacetate, specifically trimethyl orthoformate (TMOF), triethyl orthoacetate, triethyl orthopropionate.

7. The process as claimed in claim 1-3 wherein acid is selected from inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, polyphosphoric acid; organic acid selected from formic acid, acetic acid, propionic acid, citric acid and oxalic acid, TsOH or mixture thereof.

8. The process as claimed in claim 1-3 wherein base is selected from inorganic base like alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or Silicon-based amides, such as sodium and potassium bis(trimethylsilyl)amide, Lithium hexamethyldisilazide, Sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisopropylamide), triethylamine, triethanolaminetributylamine, N-methylmorpholine, N,N-diisopropylethylamine, di-n-propylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, 1,4-diazabicycloundec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]-octane (DABCO) and the like.

9. The process as claimed in claim 1-3 wherein the solvent is selected from water or "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol or "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile or "ether solvents" such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, or “Amide solvents” such as formamide, DMF, DMAC, N-methyl-2-pyrrolidone, N-methylformamide, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone, haloalkanes such as dichloromethane, 1,2-dichloroethane and chloroform, “amine solvents” selected from diethylenetriamine, ethylenediamine, morpholine, piperidine, pyridine, quinoline, tributylamine, diisopropyl amine and/or mixtures thereof.

Dated this Twenty Eighth (28th) day of December, 2024
_______________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883