DESC:Title of the Invention
An improved process for the preparation of Finerenone and its intermediates.

Field of the Invention
The present invention relates to an improved process for the preparation of Finerenone compound of Formula I.

The present invention also relates to novel intermediate compounds of Formula II, III IV, V & VI which are used in the preparation of Finerenone.

The present invention also relates to process for the preparation of novel intermediate compounds of Formula II, III, IV, V&VI.

Background of the Invention
Finerenone having a chemical name 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8- dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide is represented with structure as follows:

Finerenone is a non-steroidal antagonist of the mineral corticoid receptor and can be used as an agent for the prophylaxis and/or treatment of cardiovascular and renal diseases such as heart failure and diabetic nephropathy.

Finerenone and its process first disclosed in US 8,436,180 further its process for preparation is also disclosed in US 10,399,977. US 2018237414, US 10336749, US 10392384, US 2021163474, AU2020230965, AU2020233169, WO 2021074078 A1. The process disclosed in references is unsuitable for large-scale process, with very high expensive reagents and not commercially viable process.

Therefore, it would be desirable and of paramount importance to have a process for the preparation of Finerenone compound of Formula I, by employing inexpensive, readily available, easy to handle reagents. It would also be desirable to have a process that can be readily scaled up and which does not require a special purification step, thereby making it more suitable for industrial scale preparation.

Summary of the Invention

The present invention provides a cost effective, novel and an efficient process for the preparation of Finerenone compound of Formula I with higher yields and better purity.

The main embodiment of the present invention provides an improved process for the preparation of Finerenone compound of Formula I.

which comprises:
i) condensation of 4-Bromo-2-methoxybenzaldehyde with 3-Oxobutanamide

in presence of solvent and base to obtained compound of Formula II;

ii) condensation of compound of Formula II with KSM II in presence of solvent to obtained compound of Formula III;

iii) reduction of compound of Formula III in the presence of acid and solvent to obtained compound of Formula IV;

iv) alkylation of compound of Formula IV with ethyl iodide in presence of acid and solvent to obtained compound of Formula V;

v) resolution of compound of Formula V with resolution agent in presence of solvent to obtained compound of Formula VI;

vi) cyanation of compound of Formula VI with cyanation reagent to obtained Finerenone of compound of Formula I.

In yet another embodiment, the present invention relates to process for the preparation of novel intermediate compound of Formula II.

which comprises:
i) condensation of 4-Bromo-2-methoxybenzaldehyde with 3-Oxobutanamide

in presence of solvent and base to obtained compound of Formula II.
In yet another embodiment, the present invention relates to a process for the preparation of novel intermediate compound of Formula III.

which comprises:
i) condensation of compound of Formula II with of KSM II in presence of solvent to obtained compound of Formula III.

In yet another embodiment, the present invention relates to a process for the preparation of novel intermediate compound of Formula IV.

which comprises:
i) dehydration of compound of Formula III;

in the presence of acid and solvent to obtained compound of Formula IV.
In yet another embodiment, the present invention relates to a process for the preparation of novel intermediate compound of Formula V;

which comprises:
i) alkylation of compound of Formula IV;

in the presence of acid to obtained compound Formula V.

In yet another embodiment, the present invention relates to a process for the preparation of novel intermediate compound of Formula VI;

which comprises:
i) resolution of compound of Formula V;

in the presence of acid to obtained compound of Formula VI.

In yet another embodiment, the present invention relates to novel intermediates of the compound of Formula II, III, IV, V and VI which are used in the preparation of Finerenone of compound of Formula I.

Detailed Description of the Invention

Accordingly, the present invention provides an improved process for the preparation of Finerenone having the structural Formula I.

The main embodiment of the present invention provides an improved process for the preparation of Finerenone, which is outlined in below Scheme I:

In step-i), condensation of 4-Bromo-2-methoxybenzaldehyde with 3-oxobutanamide in the presence of solvent, base and acid to obtained compound of Formula II.

The reaction temperature may range from 20 °C to 35 °C and preferably at a temperature in the range from 25°C to 30 °C. The duration of the reaction may range from 3 to 7 hours, preferably for a period of 4 to 6 hours.

In step-ii), condensation of compound of Formula II with KSM II in presence of solvent to obtained compound of Formula III.

The reaction temperature may range from 80 °C to 95 °C and preferably at a temperature in the range from 85°C to 90 °C. The duration of the reaction may range from 45 to 55 hours, preferably for a period of 48 to 50 hours.

In step-iii), dehydration of compound of Formula III in the presence of suitable acid and solvent to obtained compound of Formula IV.

The reaction temperature may range from 80 °C to 95 °C and preferably at a temperature in the range from 85°C to 90 °C. The duration of the reaction may range from 7 to 15 hours, preferably for a period of 8 to 10 hours.

In step-iv), alkylation of compound of Formula IV with alkylating reagent in presence of acid (or) base and solvent to obtained compound of Formula V.

The reaction temperature may range from 20 °C to 35 °C and preferably at a temperature in the range from 25°C to 30 °C. The duration of the reaction may range from 20 to 30 hours, preferably for a period of 24 to 26 hours.

In step-v), resolution of compound of Formula V with suitable resolution agent in presence of solvent and base to obtained compound of Formula VI.

The reaction temperature may range from 60 °C to 80 °C and preferably at a temperature in the range from 70 °C to 75 °C. The duration of the reaction may range from 2 to 4 hours, preferably for a period of 3 to 3.5 hours.

In step-vi), cyanation of compound of Formula VI with cyanation reagent in presence of base and suitable solvent to obtained Finerenone of compound of Formula I.

The reaction temperature may range from 75 °C to 95 °C and preferably at a temperature in the range from 80 °C to 90 °C. The duration of the reaction may range from 8 to 15 hours, preferably for a period of 10 to 12 hours.

Unless otherwise stated, the following terms used in the specification have the meanings given below:

Solvents used throughout the invention is selected from the group consisting of amide solvents such as N,N-dimethylacetamide, N,N-dimethylformamide, formamide (or) N-Methylformamide; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride; ether solvents such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; hydrocarbon solvents such as pentane, hexane, heptane, 1,2-Dimethoxy ethane, 1,4-dioxane, xylene, toluene; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol, isobutanol (2-butanol), 2-amyl alcohol, cyclohexanol, tert-butanol, 1-Propanol, 2-Propanol, n-pentanol; ester solvents such as ethyl acetate, isopropyl acetate; nitrile solvents such as acetonitrile, propionitrile; ketone solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; polar solvents such as water, formic acid, acetic acid, 2-methoxyethanol or mixtures thereof.

Acids used throughout the invention is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, sulphurous acid, p-Toluenesulfonic acid, phosphorus oxychloride, nitric acid, nitrous acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Bases used throughout the invention is selected from the group consisting of Piperidine, Pyrrolidine, Triethyl amine, Pyridine, Ethylene diamine, DBU, Imidazole, methylamine, lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), rubidium hydroxide (RbOH) and caesium hydroxide (CsOH), sodium hydride, potassium hydride, NaOEt, n-butyllithium, tert-butyllithium, sodium phosphate, potassium phosphate, ammonia, sodium carbonate, cesium carbonate, silver carbonate or potassium carbonate.

Catalyst used throughout the invention is selected from the group consisting of Palladium acetate, Tetrakis (triphenyl phosphine) palladium, [1,1'-Bis(diphenylphosphino)ferrocene] dichloropalladium(II).

Reducing agent is selected from the group consisting of sodium borohydride (NaBH4), potassium borohydride (KBH4), lithium borohydride (LiBH4) or hydrogen.

Alkylating reagent is selected from the group consisting of Ethyl iodide, Ethyl bromide, Diethyl sulfate, Diethyl carbonate, Trimethyl ortho formate or Triethyl orthoacetate.

Cyanation reagent is selected from the group consisting of Sodium cyanide, Zinc cyanide, Potassium cyanide, Trimethyl silyl cyanide, Potassium hexacyano ferrate trihydrate or Copper cyanide.

Resolving agent is selected from the group consisting of (+)-O,O-dibenzoyl-D-tartaric acid, (S)-(+)-mandelic acid, (2R,3R)-(+)-tartaric acid and (lR)-(-)-camphor-l0-sulfonic acid.

While the present invention has been described in terms of its specific embodiments, 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. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.

EXPERIMENTAL PORTION:

The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.

EXAMPLES:

Example 1: Process for the preparation of (Z)-2-(4-Bromo-2-methoxy benzylidene)-3-oxobutanamide.

To a mixture of 4-Bromo-2-methoxy benzaldehyde (450 grams) in IPA (1350 mL) was added to 3-Oxobutanamide (254 grams), Piperidine (17.8 grams) and Acetic acid (12.5 mL). Then the reaction mixture was stirred 4-6 hours at ambient temperature, monitor the reaction progress by using TLC, after completion of reaction cooled to 0-10 oC and stirred for another 1-2 hours. The precipitated material was filtered through Buckner funnel and washed with chilled IPA (220 mL) and dried at below 50 oC to afford (Z/E)-2-(4-bromo-2-methoxybenzylidine)-3-oxobutanamide.

Yield: 90%

Example 2: Process for the preparation of 4-(4-Bromo-2-methoxyphenyl)-2,5-dihydroxy-2,8-dimethyl-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carboxamide

To a mixture of (Z/E)-2-(4-bromo-2-methoxybenzylidine)-3-oxobutanamide (100 grams) (Obtained from above Example 1) in IPA (1500 mL) was added to 4-amino-5-methylpyridin-2-ol (35.5 grams). Then the reaction mixture was stirred for 48-50 hours at 85-90 oC, monitoring the progress of the reaction by TLC, after completion of reaction cooled to 0-10 oC and stirred for another 1-2 hours. The precipitated material was filtered through Buckner funnel and washed with chilled IPA (150 mL) and dried at below 55 oC to afford 4-(4-bromo-2-methoxyphenyl)-2,5-dihydroxy-2,8-dimethyl-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carboxamide.
Yield: 75%
Example 3: Process for the preparation of 4-(4-Bromo-2-methoxyphenyl)-5-dihydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

To a mixture of 4-(4-Bromo-2-methoxyphenyl)-2,5-dihydroxy-2,8-dimethyl-1,2,3,4-tetrahydro-1,6-naphthyridine-3-carboxamide (50 grams) (Obtained from above Example 2) in DMF (350 mL) and Toluene (350 mL) was added to phosphoric acid (10 mL). Then the reaction mixture was stirred for 8-10 hours at 85-90 oC, monitoring the reaction progress by using TLC, after completion of reaction cooled to 50-60 oC and distilled out the reaction solvent under reduced pressure to obtained residue was added water (250 mL) at ambient temperature then heated to 40-50oC and maintained at the same temperature for 30 minutes. Cooled to 25-30 oC and the precipitated material was filtered through buckner funnel, washed with water (25 mL) and dried at below 55oC to afford 4-(4-bromo-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide.
Yield: 65%

Example 4: Process for the preparation of 4-(4-Bromo-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide.

To a mixture of 4-(4-Bromo-2-methoxyphenyl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (30 grams) (Obtained from above Example 3) in methanol (375 mL), dichloromethane (375 mL) was added to silver carbonate (71 grams) followed by ethyl iodide (21 mL). Then the reaction mixture was stirred for 24-26 hours at ambient temperature, monitoring the reaction progress by using TLC, after completion of reaction filtered through celite bed and washed with methanol (60 mL). The filtrate was distilled out under reduced pressure to obtained residue was added IPA (75 mL) and stirred for 1-2 hours at 25-30 oC. Precipitated material was filtered through Buckner funnel, washed with IPA (30 mL) and dried at below 55 oC to afford 4-(4-bromo-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

Yield: 85%

Example 5: Process for the preparation of 4(S)-4-(4-Bromo-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide.

To a mixture of 4-(4-bromo-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (25 grams) (obtained from above example 4) in ethanol (187.5 mL) and water (62.5 mL) was added to (+)-O,O-dibenzoyl-D-tartaric acid (11.4 grams). Then the reaction mixture was heated to 70-75 oC and maintained for 3-3.5 hours, monitoring the reaction progress by using TLC after completion of reaction cooled to 25-30 oC and maintained for 12-14 hours at same temperature. Filtered the solid and washed with ethanol (37.5 mL) and water (12.5 mL) mixture. Finally dried the sample under reduced pressure at below 50 oC to obtained salt compound.

To the obtained above salt was added to mixture of ethanol (50 mL) and water (200 mL) at ambient temperature and adjusted the pH: 7-7.1 by using aqueous sodium phosphate solution then stirred for 30 minitues at same temperature. The reaction mixture was heated to 40-50 oC then maintained for 3 hours. After 3 hours the reaction was cooled to 25 oC and stirred for 1-1.5 hours. The formed precipitate was filtered through Buckner funnel and washed with mixture of ethanol (10 mL) and water (40 mL). Dried the sample at below 50 oC to obtained (4S)-4-(4-bromo-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide.

Yield: 42.5%

Example 6: Process for the preparation of Finerenone.

To a mixture of (4S) 4-(4-bromo-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (10 grams) (obtained from above example 5) in THF (80 mL) and water (20 mL) was added to Potassium hydroxide (2.6 grams) and purged the reaction mixture with Nitrogen gas for 30 minitue then added Palladium acetate (0.26 grams), Tetrakis (triphenyl phosphino) palladium (2.6 grams ) and Potassium Hexacyano ferrate (II) tri hydrate (4.9 grams) sequentially to the above reaction mixture. The reaction mixture was heated to 80-90 oC and maintained for 10-12 hours by monitoring with TLC. After completion of the reaction, the reaction mixture was cooled to 25-30 oC and filtered through celite pad and washed with methanol (50 mL). The filtrate was distilled out under reduced pressure at 45-50 oC to obtained residue. To the obtained residue was added 2-Propanol (50 mL) then cooled to 0-10 oC and stirred for 1-2 hours. The formed precipitate material was filtered through Buckner funnel and washed with chilled 2-Propanol (25 mL). Dried under reduced pressure at below 55 oC to obtained (4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide.

Yield: 80%
,CLAIMS:1. An improved process for the preparation of Finerenone compound of Formula I.

which comprises:
i) condensation of 4-Bromo-2-methoxybenzaldehyde with 3- Oxobutanamide

in presence of solvent and base to obtained compound of Formula II;

ii) condensation of compound of Formula II with 4-amino-5-methylpyridin-2-ol of KSM II in presence of solvent to obtained compound of Formula III.

iii) reduction of compound of Formula III in the presence of acid and solvent to obtained compound of Formula IV;

iv) alkylation of compound of Formula IV with ethyl iodide in presence of acid and solvent to obtained compound of Formula V;

v) resolution of compound of Formula V with resolution agent in presence of solvent to obtained compound of Formula VI;

vi) cyanation of compound of Formula VI with cyanation reagent to obtained Finerenone of compound of Formula I.

2. The process as claimed in claim 1, wherein solvent is selected from the group consisting of dichloromethane, chloroform, ethylene chloride, carbon tetrachloride, methanol, ethanol, isopropanol, 1-Propanol, 2-Propanol, n-pentanol,tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether. N,N-dimethylacetamide, N,N-dimethylformamide, formamide or N-Methylformamide.

3. The process as claimed in claim 1, wherein acid is selected from the group consisting of hydrochloric acid, phosphoric acid, sulphurous acid, p-Toluenesulfonic acid or phosphorus oxychloride.

4. The process as claimed in claim 1, wherein base is selected from the group consisting Piperidine, Pyrrolidine, Triethyl amine, Pyridine, Ethylene diamine, DBU, Imidazole, methylamine, lithium hydroxide sodium hydroxide or potassium hydroxide

5. The process as claimed in claim 1, wherein catalyst is selected from the group consisting of Palladium acetate, Tetrakis (triphenyl phosphine) palladium or [1,1'-Bis(diphenylphosphino)ferrocene] dichloropalladium.

6. The process as claimed in claim 1, wherein reducing agent is selected from the group consisting of sodium borohydride (NaBH4), potassium borohydride lithium borohydride or hydrogen.

7. The process as claimed in claim 1, wherein Alkylating reagent is selected from the group consisting of Ethyl iodide, Ethyl bromide, Diethyl sulfate, Diethyl carbonate, Trimethyl ortho formate or Triethyl orthoacetate.

8. The process as claimed in claim 1, wherein Cyanation reagent is selected from the group consisting of Sodium cyanide, Zinc cyanide, Potassium cyanide, Trimethyl silyl cyanide, Potassium hexacyano ferrate trihydrate or Copper cyanide.

9. The process as claimed in claim 1, wherein Resolving agent is selected from the group consisting of (+)-O,O-dibenzoyl-D-tartaric acid, (S)-(+)-mandelic acid, (2R,3R)-(+)-tartaric acid or (lR)-(-)-camphor-l0-sulfonic acid.

10. A novel intermediates compound of compound of Formula II, III, IV, V and VI