DESC:“NOVEL PROCESS FOR THE PREPARATION OF FINERENONE”

FIELD OF THE INVENTION

The present invention relates to a novel process for preparing Finerenone from the compound of formulae (IV), (VI), (VII), and (VIII).

BACKGROUND OF THE INVENTION

Finerenone, sold under the brand name Kerendia, which is a nonsteroidal anti-mineralocorticoid that is under study for the treatment of chronic heart failure. Kerendia is indicated to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, nonfatal myocardial infarction, and hospitalization for heart failure in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D).

Finerenone, sold under the brand name Kerendia, is a nonsteroidal mineralocorticoid antagonist approved for the treatment of chronic kidney disease (CKD) associated with type 2 diabetes (T2D). Kerendia is indicated to reduce the risk of sustained estimated glomerular filtration rate (eGFR) decline, end-stage kidney disease, cardiovascular death, nonfatal myocardial infarction, and hospitalization for heart failure in adult patients with CKD and T2D.

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 was first described in example 4 and 5 of US 8436180, wherein the process is disclosed by the compound of formula (X) converts into the compound of formula (XI) in presence of NaIO4 / OsO4 / Ph(Et)3NCl / H2O. The compound of formula (XI) is reacted with the compound of formula (XII) in presence of AcOH / piperidine and MDC to get the compound of formula (XIII). The compound of formula (XIII) is reacted with the compound of formula (V) in presence of IPA to get the compound of formula (XIV). The compound of formula (XIV) is reacted with triethyl orthoformate in presence of conc. H2SO4 to get the compound of formula (XV). The compound of formula (XV) undergoes hydrolysis in presence of H2O / NaOH to get the compound of formula (IXa). The compound of formula (IXa) converts into racemic Finerenone (Ia) in presence of EtOAc / CDI / DMF / NH3 and H2O and followed by resolution with chiral HPLC to get Finerenone (I).

Finerenone was first described in examples 4 and 5 of US 8436180. The process involves converting the compound of formula (X) into the compound of formula (XI) in the presence of NaIO4, OsO4, Ph(Et)3NCl, and H2O. The compound of formula (XI) is then reacted with the compound of formula (XII) in the presence of AcOH, piperidine, and MDC to obtain the compound of formula (XIII). This compound is subsequently reacted with the compound of formula (V) in the presence of IPA to yield the compound of formula (XIV). The compound of formula ( (XIV) is then reacted with Triethyl orthoformate in concentrated H2SO4 to the compound of formula (XV). Finally, hydrolysis of the compound of formula (XV) in the presence of H2O and NaOH affords the compound of formula (IXa). This compound is then converted to racemic Finerenone (Ia) and, followed by resolution with chiral HPLC to obtain Finerenone (I).

The process is schematically shown as below:

Scheme 1

The processes described in scheme 1 achieve resolution after obtaining Finerenone racemate, their overall yield is uneconomical. This process also employs chiral HPLC resolution, which further increases the production cost and makes them unsuitable for large-scale industrial production.

CN 114605410 A of Zhejiang Chemtrue disclosed a process for the preparation of Finerenone (I) involves several steps. Firstly, the compound of formula (XI) is reacted with the compound of formula (XVI) in the presence of IPA/AcOH and piperidine to obtain the compound of formula (XVII). Subsequently, the compound of formula (XVII) is reacted with the compound of formula (V) in the presence of toluene and p-TSA to afford the compound of formula (XVIII). This intermediate then undergoes a reaction with triethyl orthoformate in the presence of DMF/H2SO4 to yield the compound of formula (XIX), which is undergoes hydrolysis in the presence of potassium trimethylsiliconate to provide the compound of formula (IXa). Finally, the compound of formula (IXa) is reacted with CDI, followed by amidation in the presence of 25% NH3. H2O to obtain racemic Finerenone (Ia). The resolution of racemic Finerenone (Ia) is achieved with D-dibenzoyl tartaric acid in the presence of S2O8-2/ZrO2/Al2O3 ultimately yielding Finerenone (I).
The process is schematically shown as below:

Scheme 2

The processes described in scheme 2, resolution occurred after obtaining Finerenone racemate, the total yield is uneconomical, the production cost of this method is very high, Not suitable for industrialized mass production.

The present invention provides an alternative preparative routes for Finerenone, which for example, use reactants are less expensive and/or easier to handle, consume smaller amounts of reagents, eco-friendlier to provide a higher yield and good purity of product.

The present invention provides an alternative preparative route for Finerenone that utilizes less expensive and/or easier-to-handle reagents, requires smaller quantities, and, resulting in higher yields and improved product purity.

SUMMARY OF THE INVENTION

The present invention relates to a novel process for the preparation of Finerenone from the compound of formulae (IV), (VI), (VII) and (VIII).

One aspect of the present invention provides a novel process for the preparation of Finerenone (I), comprising the steps of:

a) reacting the compound of formula (II) with the compound of formula (III) in the presence of a base and an organic solvent to yield the compound of formula (IV);

b) reacting the compound of formula (IV) with the compound of formula (V) in the presence of an organic solvent at suitable temperature to yield the compound of formula (VI);

c) separating the desired isomer from the diastereomeric mixture of compound (VI) to yield compound VII.

d) reacting the compound of formula (VII) with triethyl ortho acetate or triethyl ortho formate in the presence of an organic solvent to yield the compound of formula (VIII);

e) hydrolyzing the compound of formula (VIII) in the presence of an acid yields the compound of formula (IX);

f) reacting the compound of formula (IX) with CDI in the presence of DMAP and an organic solvent, followed by amidation yields Finerenone (I).

In another aspect, the present invention provides the compound of formula (IV), (VI), (VII) and (VIII):

In another aspect, the present invention provides the compounds of formulae (IV), (VI), (VII), and (VIII) are used for the preparation of Finerenone (I)

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel process for the preparation of Finerenone from the compound of formulae (IV), (VI), (VII) and (VIII).

One embodiment of the present invention provides a novel process for the preparation of Finerenone (I), comprising the steps of:

a) reacting the compound of formula (II) with the compound of formula (III) in the presence of a base and an organic solvent to yield the compound of formula (IV);

b) reacting the compound of formula (IV) with the compound of formula (V) in the presence of an organic solvent at suitable temperature to yield the compound of formula (VI);

c) separating the desired isomer from the diastereomeric mixture of compound (VI) to yield compound VII.

d) reacting the compound of formula (VII) with triethyl ortho acetate or triethyl ortho formate in the presence of an organic solvent to yield the compound of formula (VIII);

e) hydrolyzing the compound of formula (VIII) in the presence of an acid yields the compound of formula (IX);

f) reacting the compound of formula (IX) with CDI in the presence of DMAP and an organic solvent, followed by amidation yields Finerenone (I).

According to one embodiment of the present invention, the compound of formula (II) is reacted with the compound of formula (III) in the presence of a base and an organic solvent to yield the compound of formula (IV). This compound (IV) is then reacted with the compound of formula (V) in an organic solvent at a suitable temperature to yield the compound of formula (VI). The diastereomeric mixture of compound (VI) is separated to obtain a single isomer or the desired isomer, compound (VII). This isomer is then reacted with triethyl orthoacetate or triethyl ortho formate in an organic solvent to yield the compound of formula (VIII). Finally, the compound of formula (VIII) is hydrolyzed in the presence of an acid to yield the compound of formula (IX). This compound (IX) reacts with CDI in the presence of DMAP and an organic solvent, followed by a reaction with an amidating agent to yield Finerenone (I).

The invention also relates to a process for separating a mixture of enantiomers. This process involves contacting the mixture, in a suitable solvent, with at least one resolving agent. The process of the present invention achieves this separation by first racemizing the racemate into its individual enantiomers. This racemization step can be carried out in a suitable organic solvent and in the presence of a base.

According to an embodiment of the present invention, wherein the resolving agent is selected from tartaric acid, dibenzoyl-L-tartaric acid, mandelic acid, (+)-di-p-toluoyl-d-tartaric acid, (-)-di-p-toluoyl-d-tartaric acid, diisopropyl D-(-)-tartrate, D-(+)-malic acid, dimethyl L-(+)-tartrate and L-valine.

According to an embodiment of the present invention, wherein base is selected from triethylamine, tert-butylamine, pyridine, piperidine, diazabicycloundecane (DBU), sodium hydride, sodium hydroxide, potassium hydroxide, ammonia;

According to an embodiment of the present invention, wherein the suitable solvent is selected sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; alcohols such as methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, tert-butanol; nitriles such as acetonitrile and propionitrile; ether solvent such as tetrahydrofuran, diisopropylether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, methyl tert-butyl ether, dioxane; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; and aromatic hydrocarbons such as toluene, anisole, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone, 2-pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; water; cyclohexane and N-methyl-2-pyrrolidone and or mixtures thereof.

According to an embodiment of the present invention, wherein the acid selected from but not limited to "inorganic acids" such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, perchloric acid, carbonic acid; and "organic acids" such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, capric acid, oxalic acid, malonic acid, maleic acid, fumaric acid, lactic acid, succinic acid, citric acid, uric acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, salicylic acid, oleic acid, octanoic acid, stearic acid, mandelic acid, adepic acid, pivalic acid, camphorsulfonic acid, substituted/unsubstituted alkyl/aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and or mixtures thereof.

According to an embodiment of the present invention, wherein the an amidating agent is selected from, ammonia (NH3), ammonia water (NH3.H2O), ammonium hydroxide (NH4OH), hexamethyldisilazane (HMDS), ammonium carbonate (NHCO3) and formamide (HCONH2).

In Another embodiment, the present invention provides the compound of formula (IV), (VI), (VII) and (VIII):

In another embodiment, the present invention provides the compounds of formulae (IV), (VI), (VII), and (VIII) are used for the preparation of Finerenone (I)

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.
EXAMPLES

Example-1: Preparation of compound (IV)

4-Formyl-3-methoxybenzonitrile (33.8 g, 0.21 mol), MDC (300 mL), piperidine (1.86 g, 0.021 mol), and N-norbornen-5-yl-acetoecetate (0.231 mol) were added to a reaction flask at 25-30°C. The reaction mixture was then heated to 40°C and maintained for 4-5 hours. The solvent was distilled, and MTBE/heptane was added to the reaction mass. Drying at 55°C yielded the titled compound.

Example-2: Preparation of compound (VI)

2-butanol (200 mL) and toluene (200 mL) were added to the reaction flask at 25-30°C. Following this, compound IV (14.07 g, 0.042 mol), 4-amino-5-methylpyridin-2-alcohol (5 g, 0.04 mol), and p-toluenesulfonic acid (1.44 g, 0.0084 mol) were added to the flask. The mixture was heated to reflux for 16 hours, resulting in a large amount solid. The reaction mixture was then cooled to 5-10°C and stirred for 30 minutes. It was then filtered with suction, and the filter cake was rinsed with 2-butanol and dried at 55°C to yield the desired compound (VI).

Example-3: Preparation of compound (VII)

Racemate compound (VI) (200 g, 494.5 mmol) and dibenzoyl-D-tartaric acid (237.5 g, 1.05 eq.) were added to a reaction flask containing 5400 ml of ethanol at 25-30°C. The mixture was heated to 50°C for 60 minutes and stirred for 4 hours. It was then cooled to 20°Cover two hours. After overnight cooling, the diastereomeric salt precipitated out. This was filtered off, dried (209 g), and the measurement gave an enantiomeric excess of 97% e.e. for compound (VII).

Example-4: Preparation of compound (VIII)

Compound VII (15.4 g (0.035 mol), N-methyl-2-pyrrolidone (80g), mol) of triethyl orthoacetate (7.8 g (0.053) and 0.35 g (0.0035 mol) of sulfuric acid were added to the reaction flask. The resulting mixture was heated to 120°C for 4 hours. After completion of the reaction, it was cooled to room temperature. Water and methanol (10 g) were then added dropwise to the mixture, which was stirred for 30 minutes. A yellow solid product precipitated. This product was dried at 55°C to yield the titled compound (VIII).

Example-5: Preparation of compound (IX)

Compound VIII (14.4 g, 0.0308 mol), anisole (80 ml), and trifluoroacetic acid (7.88 g, 0.0616 mol) were added to a reaction flask at 25-30°C. The reaction mixture was maintained at 30°C for 8 hours. Ethyl acetate (80ml) was added for layer separation, and the pH was adjusted to 5–6 with concentrated hydrochloric acid, which precipitated the solid. Recrystallization with methanol (20 mL) yielded an off-white solid, which was dried to obtain the desired titled compound as an off-white product.

Example-6: Preparation of compound (I)

Compound (IX) (30 g, 79.13 mmol), 1,1-carbodiimidazole (17.96 g, 110.8 mmol), THF (150 ml) and DMAP (956 mg, 7.82 mmol) were added to the reaction flask at 20°C. The obtained reaction mixture was stirred at 20°C for one hour, then heated to 50°C for 2.5 hours. Followed by the addition of ammonium hydroxide (55.7 g, 0.345 mol) to the mixture, which was then heated to reflux for 22 hours. The reaction mixture was cooled to 0°C and stirred for one hour. The product was filtered off, washed with THF and water and then, dried at 70°C under vacuum to yield the titled product.

,CLAIMS:We Claim,

1. A novel process for the preparation of Finerenone (I), comprising the steps of:
a) reacting the compound of formula (II) with the compound of formula (III) in the presence of a base and an organic solvent to yield the compound of formula (IV);

b) reacting the compound of formula (IV) with the compound of formula (V) in the presence of an organic solvent at suitable temperature to yield the compound of formula (VI);

c) separating the desired isomer from the diastereomeric mixture of compound (VI) to yield compound VII.

d) reacting the compound of formula (VII) with triethyl ortho acetate or triethyl ortho formate in the presence of an organic solvent to yield the compound of formula (VIII);

e) hydrolyzing the compound of formula (VIII) in the presence of an acid yields the compound of formula (IX);

f) reacting the compound of formula (IX) with CDI in the presence of DMAP and an organic solvent, followed by amidation yields Finerenone (I).

2. The process as claimed in claim 1, wherein base is selected from triethylamine, tert-butylamine, pyridine, piperidine, diazabicycloundecane (DBU), sodium hydride, sodium hydroxide, potassium hydroxide, ammonia;
3. The process as claimed in claim 1, wherein the suitable solvent is selected from dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, isobutanol, acetonitrile, tetrahydrofuran, diisopropylether, methyl tert-butyl ether, dioxane, N,N-dimethylformamide, toluene, anisole, heptane, xylene, ethylacetate, isopropyl acetate, acetone, chloroform, dichloromethane, water, cyclohexane and N-methyl-2-pyrrolidone and or mixtures thereof.

4. The process as claimed in claim 1, wherein the acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, succinic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid or mixtures thereof.

5. The process as claimed in claim 1, wherein the an amidating agent is selected from, ammonia (NH3), ammonia water (NH3.H2O), ammonium hydroxide (NH4OH), hexamethyldisilazane (HMDS), ammonium carbonate (NHCO3) and formamide (HCONH2).

6. The process as claimed in claim 1, The process is characterized in that the mixture of enantiomers is contacted in a suitable solvent with at least one resolving agent. And also the process of the present invention accomplishes this by racemization of the racemate into enantiomer. The racemization step can be carried out in the suitable organic solvent and base.

7. The process as claimed in claim 1 and 6, wherein the resolving agent is selected from tartaric acid, dibenzoyl-L-tartaric acid, mandelic acid, (+)-di-p-toluoyl-d-tartaric acid, (-)-di-p-toluoyl-d-tartaric acid, diisopropyl D-(-)-tartrate, D-(+)-malic acid, dimethyl L-(+)-tartrate and L-valine.

8. The compound of formula (IV), (VI), (VII) and (VIII):

9. The compound of formula (IV), (VI), (VII) and (VIII) as claimed in claim 7, used for the preparation of Finerenone (I).