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 IV, VI, VII & VIII used in the preparation of Finerenone compound of Formula I

wherein X is selected from group consisting of tert-butyloxycarbonyl (Boc), Toluenesulfonyl (Tosyl), Acetyl (or) Benzyl chloroformate (Cbz).

The present invention also relates to process for the preparation of intermediate compounds of Formula IV, VI, VII & VIII

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. US’180 further discloses process for crystallizing Finerenone in 1:1 ratio of dichloromethane: methanol.

Finerenone and 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. A In the disclosed process synthesis described is unsuitable for a further 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.

In one aspect, the present invention relates to the novel intermediates of the compound of Formula IV, VI, VII & VIII which are useful in the preparation of Finerenone compound of Formula I.

wherein X is selected from group consisting of tert-butyloxycarbonyl (Boc), Toluenesulfonyl (Tosyl), Acetyl (or) Benzyl chloroformate (Cbz).

In another aspect, the present invention also relates to process for the preparation of intermediate compounds of Formula IV, VI, VII & VIII.

In another aspect, the present invention provides an improved process for the preparation of Finerenone compound of Formula I.


which comprises:
i) condensation of compound of Formula II

with compound of Formula III

in presence of suitable solvent and base to obtained compound of Formula IV;
wherein X is selected from group consisting of tert-butyloxycarbonyl (Boc), Toluenesulfonyl (Tosyl), Acetyl (or) Benzyl chloroformate (Cbz).

ii) condensation of compound of Formula IV with compound of Formula V

in the presence of suitable solvent to obtained compound of Formula VI;

iii) alkylation of compound of Formula VI in the presence of suitable solvent to obtained compound of Formula VII;

iv) resolution of compound of Formula VII in presence of suitable acid to obtained compound of Formula VIII;

v) amine deprotection of compound of Formula VIII to obtained compound of Formula I.

In another aspect, the present invention also relates to process for the preparation of novel intermediate compound of Formula IV;

which comprises: condensation compound of Formula II with compound of Formula III

in the presence of suitable solvent and base to obtained compound Formula-IV.

In another aspect, the present invention also relates to process for the preparation of novel intermediate compound of Formula VI;

which comprises: condensation compound of Formula IV with compound of FormulaV;

in the presence of suitable solvents to obtained compound Formula VI.

In another aspect, the present invention also relates to process for the preparation of novel intermediate compound of Formula VIII;

which comprises: alkylation of compound of Formula VI in the presence of suitable solvent to obtained compound Formula VII.

In another aspect, the present invention also relates to process for the preparation of novel intermediate compound of Formula VIII;

which comprises: resolution of compound of Formula VIII in the presence of suitable acid to obtained compound of Formula I.

Detailed Description of the Invention
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 dimethylacetamide, dimethylformamide, formamide (or) N-Methylformamide, “chloro solvents” such as dichloromethane, chloroform, ethylene chloride (or) carbon tetrachloride, “alcohol solvents” such as ethanol, isopropanol, isobutanol (2-butanol), 2-amyl alcohol, cyclohexanol, methanol, tert-butanol (or) n-pentanol, “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 Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid (or) benzoic acid.

Bases used throughout the invention is selected from the group consisting of pyridine. Imidazole, methylamine, triethylamine, pyridine, piperidine.

Accordingly, the present invention provides an improved process for the preparation of Finerenone compound of 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:

Scheme-I

In step-i), condensation of compound of Formula II with compound of Formula III in the presence of suitable solvent and base to obtained compound of Formula IV.

In step-ii), condensation of compound of Formula IV with compound of Formula-V in presence of suitable solvent to obtained compound of Formula VI.

In step-iii), alkylation compound of Formula VI in the presence of suitable solvent to obtained compound of Formula VII.

In step-iv), resolution of compound of Formula VII with suitable acid to obtained compound of Formula VIII and

In step-v), amine deprotection of compound of Formula VIII to obtained compound of Formula I.

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 tert-butyl(3-oxobutanoyl) carbamate

3-Oxobutanamide was dissolved in dichloromethane and triethylamine followed by DMAP and Boc2O to the reaction mass. The reaction mixture was stirred up to completion of reaction solvent was removed. Residue was purified by flash column chromatography to obtained compound tert-butyl(3-oxobutanoyl) carbamate.

Example 2: Process for the preparation of Finerenone

Stage-I: Process for the preparation of tert-butyl (2-(4-cyano-2-methoxybenzyl) -3-oxobutanoyl)carbamate

4-Formyl-3-methoxy benzonitrile, tert-butyl(3-oxobutanoyl) carbamate (obtained from above example 1) and piperidine was dissolved in anhydrous DCM and stirred under reflux with a water trap overnight. The volatile compounds are removed by rota vapour and the residue is purified by column chromatography to obtain tert-butyl (2-(4-cyano-2-methoxybenzyl)-3-oxobutanoyl)carbamate of E/Z isomers.

Stage-II): Process for the preparation of tert-butyl (4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carbonyl)carbamate

2-(4-cyano-2-methoxybenzilidene)-3-oxobutanamide (obtained from above stage I) was dissolved in 2-propanol and 4- amino-6-methylpyridin-2(1H)-one and stirred at reflux temperature overnight. After cooling the precipitate is filtered off, washed with diethyl ether, and dried under vacuum to obtain tert-butyl (4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6naphthyridine-3-carbonyl)carbamate.

Stage-III): Process for the preparation of tert-butyl (4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbonyl)carbamate

Tert-butyl (4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthyridine-3-carbonyl)carbamate (obtained from above stage II) was dissolved in dimethoxy ethane/water and mixed with 1N sodium hydroxide solution and stirred at room temperature overnight. The reaction mixture is mixed with diethyl ether and water. The organic phase is separated off and the aqueous phase is adjusted to pH with 1N HCl. The resulting solution is stirred and the precipitated solid is filtered by filtration. The precipitate is washed with water and diethyl ether. Drying in vacuum to obtain tert-butyl
(4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3 -carbonyl)carbamate.

Stage-IV): Process for the preparation of tert-butyl (S)-(4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbonyl) carbamate

Racemic Finerenone (obtained from above stage III) was dissolved in mixture consisting ethanol and water at room temperature. (+)-O, O-debenzoyl -D-tartaric acid were added using a funnel for solids, subsequently rinsing with mixture consisting of ethanol: water. The resulting suspension was heated and then stirred. Subsequently using a cooling ramp, the mixture was cooled and stirred at the temperature overnight. The suspension was filtered off via a frit, rinsing once with mixture containing ethanol and water and sucked dried. Dry and weight to obtain colourless crystalline powder. At room temperature, compound was dissolved in ethanol: water the pH is adjusted. Subsequently, an aqueous sodium phosphate solution was added dropwise, and the pH was adjusted. The mixture was stirred at room temperature. Subsequently an aqueous sodium phosphate solution was added dropwise for and pH was adjusted. The mixture was heated to an internal temperature and stirred at this temperature. The mixture was cooled and stirred at the temperature. The crystals are filtered and washed with mixture containing ethanol: water and twice with water to obtain colour less crystalline powder.

Curd product prepared above was dissolved in ethanol and then heated to reflux. On heating, the product went into solution. Stirring was continued at this temperature for one hour. The solution was filtered off through a heated pressure filter and the pressure filter was rinsed with ethanol. The solvent was then distilled off to the point where the final volume of that 4-fold had been achieved. The mixture was then cooled to room temperature than stirred to an internal temperature. The product was filtered off and rinsed once with ethanol. The wet material was dried under vacuum to produce colourless crystalline powder.

Stage-V): Process for the preparation of Finerenone

Boc-protected finerenone (obtained from above stage-IV) was dissolved in TFA and DCM. Stir the mixture at room temperature. Concentrate the reaction mixture in vacuo to obtain a residue. Dissolve the resulting crude product in EtOAc. Wash the resulting crude product with NaOH (aq) till pH = 9. Extract the organics with EtOAc. Dry the organics over Na2SO4 and concentrate to obtain the product.
,CLAIMS:1. An improved process for the preparation of Finerenone compound of Formula I,

wherein the process comprises:
i) condensation of compound of Formula II,

with compound of Formula III,

in presence of suitable solvent and base to obtained compound of Formula IV,

ii) condensation of compound of Formula IV with compound of Formula V

in the presence of suitable solvent to obtained compound of Formula VI,

iii) alkylation of compound of Formula VI in the presence of suitable solvent and base to obtained compound of Formula VII,

iv) resolution of compound of Formula VII in presence of suitable acid to obtained compound of Formula VIII,

v) deprotection of compound of Formula VIII to obtained compound of Formula I.


2. A process for the preparation of novel intermediate compound of Formula IV.

which comprises:
i. condensation of compound of Formula II

with compound of Formula III

in the presence of suitable solvent and base to obtained compound Formula IV.

3. A process for the preparation of novel intermediate compound of Formula VI.

which comprises:
i) Condensation of compound of Formula IV,

with compound of Formula V,

in the presence of suitable solvents to obtained compound Formula VI.

4. A process for the preparation of novel intermediate compound of Formula VII.

which comprises:

i) alkylation of compound of Formula VI,

in the presence of suitable solvent to obtained compound Formula VII.

5. A process for the preparation of novel intermediate compound of Formula VIII

wherein the process comprises:
i) resolution of compound of Formula VII,

in the presence of suitable acid to obtained compound Formula VIII.
6. The process according to claims 1 to 5, wherein the base is selected from the group comprising pyridine. Imidazole, methylamine, triethylamine, pyridine or piperidine.

7. The process according to claims 1to 5, wherein the solvent is selected from a group comprising dimethylacetamide, dimethylformamide, formamide (or) N-Methylformamide, dichloromethane, chloroform, ethylene chloride (or) carbon tetrachloride, ethanol, isopropanol, isobutanol (2-butanol), 2-amyl alcohol, cyclohexanol, methanol, tert-butanol (or) n-pentanol, water, formic acid, acetic acid, 2-methoxyethanol or mixtures.

8. The process according to claim 1to 5, wherein the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid (or) benzoic acid.

9. A novel intermediate of the compound of Formulas IV, VI, VII & VIII