WO2024075139A1 - A process for preparation of finerenone and intermediates thereof - Google Patents

A process for preparation of finerenone and intermediates thereof Download PDF

Info

Publication number
WO2024075139A1
WO2024075139A1 PCT/IN2023/050906 IN2023050906W WO2024075139A1 WO 2024075139 A1 WO2024075139 A1 WO 2024075139A1 IN 2023050906 W IN2023050906 W IN 2023050906W WO 2024075139 A1 WO2024075139 A1 WO 2024075139A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
acid
solvents
solvent
Prior art date
Application number
PCT/IN2023/050906
Other languages
French (fr)
Inventor
Nagaraju Chakilam
Ramprasad Achampeta Kodanda
Pradeep Rebelli
Rafeeq Mohammad
Ramulu GUMMADI
Original Assignee
Maithri Drugs Private Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Maithri Drugs Private Limited filed Critical Maithri Drugs Private Limited
Publication of WO2024075139A1 publication Critical patent/WO2024075139A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present application relates to an improved process for the preparation of Finerenone and its intermediates thereof, is represented by the following structural formula-I
  • Finerenone is a non-steroidal mineralocorticoid receptor antagonist (MRA) developed by Bayer Health Care Pharmaceuticals, having the chemical name as (4S) 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1 ,4-dihydro- 1 ,6-naphthyridine-3-carboxamide is approved for the treatment for heart failure in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes with the brand name of Kerendia as capsule, oral for 10 mg, 20 mg in USA.
  • MRA mineralocorticoid receptor antagonist
  • Finerenone is a chiral compound, finerenone and process for its preparation is first reported in US8436180B2.
  • the said patent reported isolation of finerenone specified isomer from preparative chiral HPLC methods, which is not suitable for industrial purposes.
  • the US patent US10392384B2 reported a process for preparation of finerenone by electro chemical methods.
  • the US patent US10336749B2 reported a process for preparation of finerenone by using various reagents and solvents.
  • W02021074078A1 reported chiral resolution processes of finerenone, its intermediates thereof by using various chiral reagents and process for preparation thereof.
  • the present invention provides an improved process for preparation of finerenone and intermediates thereof and free from other impurities or isomers and nitroso amine impurities.
  • the present invention involves cost effective key starting material, reagents and solvents, and suitable industrial production.
  • the first aspect of the present invention is to provide a resolution process for compound of formula-5.
  • the second aspect of the present invention is to provide a resolution a resolution process for compound of formula-6.
  • the third aspect of the present invention is to provide a process for the preparation of Finerenone compound of formula-I
  • the fourth aspect of the present invention is to provide a process for the preparation of Finerenone compound of formula-I
  • Figure 1 Illustrates the PXRD pattern of crystalline Form of di-p-toluoyl-L-tartaric acid salt of (S)-4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4- dihydro- 1 ,6-naphthyridine-3-carboxylate
  • suitable solvent refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3 -dioxane, 1,4-dioxane, furan, 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, 1 ,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate,
  • suitable base refers to inorganic or organic base.
  • Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, di
  • suitable reducing reagents are selected from Lithium aluminium hydride, sodium borohydride, BF3 etherate solution, Pd/C, Ray-nickel;
  • suitable chiral reagents refers to L-tartaric acid, D-tartaric acid, camphorsulphonic acid, di-para-toluoyl-L-tartaric acid ,di-para-toluoyl -D-tartaric acid, Phenylalanine, D-(-)-a-Phenylglycine, L-(+)-a-Phenylglycine, D(-) -Phenyl glycinamide, S-(+)mandelicacid, R-(-)mandelicacid, L-(+)tartaric acid, D-(-) tartaric acid, L-malicacid, D-malic acid, D-(+)-maleicacid, (-)- nap
  • the first aspect of the present invention is to provide resolution of a compound of formula-5.
  • the suitable chiral reagents are selected from the list that is mentioned in the description.
  • the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvent, ether solvents, ketone solvents, nitrile solvents, polar aportic solvents, polor protic solvents, alcohol solvents, polar solvent like acetic acid, water or any mixture thereof; suitable temperature: 10-100°C;
  • the preferred embodiment of the present invention provides a resolution of Compound of formula-5b.
  • the second aspect of the present invention is to provide a resolution of Compound of formula-6.
  • the suitable chiral reagents are selected from the list that is mentioned in the description.
  • the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvent, ether solvents, ketone solvents, nitrile solvents, polar aportic solvents, polor protic solvents, alcohol solvents, polar solvent like acetic acid, water or any mixture thereof; suitable temperature: 10-150°C;
  • the preferred embodiment of the present invention provides a resolution of compound of formula-6b.
  • the third aspect of the present invention is to provide a process for the preparation of compound of formula-I.
  • the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, ketone solvents, polar aportic solvent, alcohol solvents, polor protic solvent, acetic acid, water or any mixture thereof; suitable temperature: 10-180°C;
  • suitable reagents are piperidine, morpholine, triethyl amine, diethyl amine, acetic acid and mixture thereof; step-b) specifically alcohol solvents; step-c) suitable reagents are triethyl orthoformate, triethyl orthoacetate, chloroethane, bromo ethane, iodo ethane; step-d)
  • suitable chiral reagents are selected from the list that is mentioned in the description.
  • suitable reagents are selected form palladium catalyst, palladium hydroxide, Ray-Ni, ammonium formate, acetic acid, HC1, HBr, trifluoroacetic acid and mixture thereof; f) suitable reagents are selected form carbonyldiimidazole, EDC-HC1, hexamethyl disilazane, ammonia (g) aq. ammonia, ammonium chloride, ammonium carbonate and mixture thereof;
  • the preferred embodiment of the present invention provides a process for the preparation of compound of formula-I.
  • the fourth aspect of the present invention is to provide a process for the preparation of compound of formula-I.
  • the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, ketone solvents, polar aportic solvent, polor protic solvents, alcohol solvents, acetic acid, water or any mixture thereof; suitable temperature: 10-150°C;
  • step-a) The suitable chiral reagents are selected from the list that is mentioned in the description.
  • step-b) suitable reagents are triethyl orthoformate, triethyl orthoacetate, chloroethane, bromo ethane, iodo ethane; sulfuric acid, HC1, step-c) suitable reagents are selected form palladium catalyst, ammonium formate, acetic acid, HC1, HBr, trifluoroacetic acid and mixture thereof;
  • suitable reagents are selected form carbonyldiimidazole, EDC-HC1, hexamethyl di silazane, ammonia (g) aq.ammonia, ammonium chloride, ammonium carbonate and mixture thereof;
  • finerenone obtained according to the present invention having the following impurities racemic or specific isomers are having less than 0.15 % by HPLC.
  • the compound of formula-I produced by the process of the present invention is having purity of greater than 99.0 % , preferably greater than 99.5% by HPLC / chiral HPLC.
  • Compound of formula-I produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • Example-1 Preparation of 2-chloro-5-methylpyridine-l-oxide.
  • Example-2 Preparation of 2-chloro-5-methyl-4-nitropyridine-l-oxide.
  • Example-6 Preparation of the compound of formula-1.
  • Example-7 Preparation of the compound of formula-3 (benzyl 2-(4-cyano-2- methoxy benzylidene)-3-oxobutanoate).
  • a round botom flask was charged with formula- 1 (100 g), acetic acid (7.44 g), isopropanol (500 ml) and piperidine (10.55 g) stirred for 5-10 min at 30 ⁇ 5°C.
  • Example-8 Preparation of the compound of formula-5 (benzyl 4-(4-cyano-2- methoxyphenyl)-2,8-dimethyl-5-oxo-l,4,5,6-tetrahydro-l,6-naphthyridine-3- carboxylate).
  • Example-9 Preparation of the compound of formula-6 (benzyl 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate).
  • a round botom flask was charged with triethylortho acetate (82.7 g), formula-5 (30.0 g), NMP (45 g) and sulphuric acid (3.33 g) at 30 ⁇ 5°C and heated the reaction mass to 125- 130°C and stirred for 3 hr. Cooled the reaction mass to 50-60°C, slowly added water (180 mL over a period of 1 hr. Further, cooled the reaction mass to 5 ⁇ 5°C and stirred for 30 minutes at same temperature. Filtered the obtained solid and washed with water and dried to obtain the title compound.
  • Example-10 Preparation of the compound of formula-8 ((S)-benzyl 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate).
  • a round botom flask was charged with ethanol (420 ml.), purified water (140 ml), and formula-6 (28.0 g) at 30 ⁇ 5 °C stirred for 10-15 min.
  • Example-11 Preparation of the compound of formula-7 ((S)-benzyl 4-(4-cyano-2- methoxyphenyl)-5-hydroxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate).
  • Example-12 Preparation of the compound of formula-8 ((S)-benzyl 4-(4-cyano-2- methoxy phenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate).
  • a round botom flask was charged with triethylortho acetate (15 g), formula-7 (5 g), NMP (8.2 g) and sulphuric acid (0.6 g) at 30 ⁇ 5°C and heated the reaction mass to 125-130°C and stirred for 3 hr. Cooled the reaction mass to 50-60°C, slowly added water (30 mL over a period of 1 hr). Further, cooled the reaction mass to 5 ⁇ 5°C and stirred for 30 minutes at same temperature. Filtered the obtained solid, washed with water and dried to obtain the title compound.
  • Example-13 Preparation of the compound of formula-9 (S)-4-(4-cyano-2-methoxy phenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3-carboxylic acid.
  • Example-17 Preparation of the compound of formula -3b (4-Methylbenzyl 2-(4- cyano-2-methoxy benzylidene) -3-oxobutanoate.
  • Example-18 Preparation of the compound of formula -5b (4-methylbenzyl 4-(4- cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-l,4,5,6-tetrahydro-l,6-naphthyridine-
  • Example-19 Preparation of the compound of formula-6b (4-methylbenzyl 4-(4- cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate)
  • a round bottom flask was charged with tri ethylortho acetate (535 g), formula-5b (200.0 g), NMP (300 mL) and sulphuric acid (22 g) at 30 ⁇ 5°C and heated the reaction mass to 125-130°C and stirred for 3 hr. Cooled the reaction mass to 50-60°C, slowly added water over a period of 1 hr. Further, cooled the reaction mass to 5 ⁇ 5°C and stirred for 30 minutes at same temperature. Filtered the obtained solid, washed with water and dried to obtain the title compound.
  • Example-20 Preparation of the compound of formula-6b (4-methylbenzyl 4-(4- cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate)
  • a round bottom flask was charged with triethylortho acetate (267 g), formula-5b (100.0 g), dimethylformamide (300 mL), sulphuric acid (10.76 g) and triethylamine (4.44) at 30 ⁇ 5°C and heated the reaction mass to 110-120°C and stirred for 10 hr. Gradually, cooled the reaction mass to 25-35°C, charged n-heptane and water and stirred for 1 hr at same temperature Filtered the precipitated solid and washed with water to get the wet compound. Further, the wet compound was charged in a mixture of isopropanol and water stirred for 2 hr. Filtered the solid compound and washed with isopropanol and dried to get the title compound.
  • Example-21 Preparation of the compound of formula-6b (4-methylbenzyl 4-(4- cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate)
  • Example-22 Preparation of the compound of formula-8b ((S)-4-methylbenzyl 4-(4- cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate).
  • Example-23 Preparation of the compound of formula-8b ((S)-4-methylbenzyl 4-(4- cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate).
  • a round bottom flask was charged with acetonitrile (800 mL), water and formula-6b (100.0 g) were heated to 25-35 °C stirred for 30 min. Charged with di-p-toluoyl-L-tartaric acid monohydrate (44 g) to the reaction mixture at 25-35 °C and stirred for 2 hr at 70- 80°C. Filtered the obtained solid and washed with acetonitrile and dried. The wet compound was charged with acetonitrile, water (1:5) and heated to 70-80°C stirred for 2.5 hr and cooled to 25-35°C and stirred for 2 hr.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present application relates to an improved process for the preparation of finerenone and intermediates thereof, which is represented by the following structural formula-I.

Description

“A PROCESS FOR PREPARATION OF FINERENONE AND INTERMEDIATES
THEREOF”
Related applications:
This application claims the benefit of priority of our Indian patent application numbers IN202241057129 filed on 06-0ct-2022 and IN202341015807 filed on 09-March-2023, the contents of which are incorporated herein by reference.
Field of the Invention:
The present application relates to an improved process for the preparation of Finerenone and its intermediates thereof, is represented by the following structural formula-I
Figure imgf000003_0001
Background of the Invention:
Finerenone is a non-steroidal mineralocorticoid receptor antagonist (MRA) developed by Bayer Health Care Pharmaceuticals, having the chemical name as (4S) 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1 ,4-dihydro- 1 ,6-naphthyridine-3-carboxamide is approved for the treatment for heart failure in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes with the brand name of Kerendia as capsule, oral for 10 mg, 20 mg in USA.
Finerenone is a chiral compound, finerenone and process for its preparation is first reported in US8436180B2. The said patent reported isolation of finerenone specified isomer from preparative chiral HPLC methods, which is not suitable for industrial purposes.
The US patent US10392384B2 reported a process for preparation of finerenone by electro chemical methods. The US patent US10336749B2 reported a process for preparation of finerenone by using various reagents and solvents.
The PCT applications W02019206909A1, WO2021074072 A2 and
W02021074078A1 reported chiral resolution processes of finerenone, its intermediates thereof by using various chiral reagents and process for preparation thereof.
There are other processes are reported for finerenone and intermediates thereof by using different starting materials, reagents and solvents.
Based on drawbacks in the prior art process and certain limitations, there is a need for providing an improved process for the preparation of finerenone, which involves simple experimental procedures, well suited to industrial production, which avoids the use of column chromatography purification, and which affords highly pure finerenone.
The present invention provides an improved process for preparation of finerenone and intermediates thereof and free from other impurities or isomers and nitroso amine impurities. The present invention involves cost effective key starting material, reagents and solvents, and suitable industrial production.
Brief Description:
The first aspect of the present invention is to provide a resolution process for compound of formula-5.
The second aspect of the present invention is to provide a resolution a resolution process for compound of formula-6.
The third aspect of the present invention is to provide a process for the preparation of Finerenone compound of formula-I
The fourth aspect of the present invention is to provide a process for the preparation of Finerenone compound of formula-I
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of crystalline Form of di-p-toluoyl-L-tartaric acid salt of (S)-4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4- dihydro- 1 ,6-naphthyridine-3-carboxylate
Detailed Description: As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3 -dioxane, 1,4-dioxane, furan, 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, 1 ,2-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), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile 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-ethoxy ethanol, diethylene glycol, 1, 2, or 3-pentanol, neopentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing reagents are selected from Lithium aluminium hydride, sodium borohydride, BF3 etherate solution, Pd/C, Ray-nickel; The term “suitable chiral reagents” refers to L-tartaric acid, D-tartaric acid, camphorsulphonic acid, di-para-toluoyl-L-tartaric acid ,di-para-toluoyl -D-tartaric acid, Phenylalanine, D-(-)-a-Phenylglycine, L-(+)-a-Phenylglycine, D(-) -Phenyl glycinamide, S-(+)mandelicacid, R-(-)mandelicacid, L-(+)tartaric acid, D-(-) tartaric acid, L-malicacid, D-malic acid, D-(+)-maleicacid, (-)- naproxen, (-t-)-naproxen, (IR)-(-) camphor sulfonic acid, (lS)-(+)- camphor sulfonic acid, (lR)-(+)-bromocamphor-10- sulfonic acid, (lS)-(-)-bromo camphor- 10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-) -Dibenzoyl-L-tartaricacid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate, (+)-dipara-toluoyl-D-tartaric acid, (-)-dipara toluoyl-L- tartaric acid, L(-)-pyro glutamic acid, L(+)- pyroglutamic acid, (-)-lacticacid, L-lysine, D-lysine , (2R,3R)-2,3-bis(phenyl sulfonyloxy)succinic acid, (2S,3S)-2,3- bis(phenylsulfonyloxy) succinic acid, benzenesulfonyl derivatives of tratartic acid and mixtures thereof;
The first aspect of the present invention is to provide resolution of a compound of formula-5.
Figure imgf000006_0001
Comprising of:
Treating the compound of formula-5 with suitable chiral reagent, solvents to provide compound of formula-7.
The suitable chiral reagents are selected from the list that is mentioned in the description. The suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvent, ether solvents, ketone solvents, nitrile solvents, polar aportic solvents, polor protic solvents, alcohol solvents, polar solvent like acetic acid, water or any mixture thereof; suitable temperature: 10-100°C;
The preferred embodiment of the present invention provides a resolution of Compound of formula-5b.
Comprising of: a) Treating 4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-l,4,5,6- tetrahydro-l,6-naphthyridine-3-carboxylate the compound of formula-5b with di-p- toluoyl-L-tartaric acid in acetonitrile, water to provide compound of formula-5A (di-p- toluoyl-L-tartaric acid salt of (R)-4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-2,8- dimethyl-5-oxo- 1 ,4,5 ,6-tetrahydro- 1 ,6-naphthyridine-3-carboxylate). b) treating the compound of formula-5A with sodium hydroxide in water to provide (S)- 4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo- 1,4,5, 6-tetrahydro- l,6-naphthyridine-3-carboxylate the compound of formula-7b.
The second aspect of the present invention is to provide a resolution of Compound of formula-6.
Figure imgf000007_0001
Comprising of:
Treating the compound of formula-6 with suitable chiral reagent, solvents to provide compound of formula- 8.
The suitable chiral reagents are selected from the list that is mentioned in the description. The suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvent, ether solvents, ketone solvents, nitrile solvents, polar aportic solvents, polor protic solvents, alcohol solvents, polar solvent like acetic acid, water or any mixture thereof; suitable temperature: 10-150°C;
The preferred embodiment of the present invention provides a resolution of compound of formula-6b.
Figure imgf000008_0001
Comprising of: a) Treating the compound of formula-6b with di-p-toluoyl-L-tartaric acid in acetonitrile and water to provide compound of formula-6A (((S)-4-methylbenzyl 4-(4-cyano-2- methoxy phenyl)-5-ethoxy-2,8-dimethyl- 1 ,4-dihydro- 1 ,6-naphthyridine-3-carboxylate di- p-toluoyl-L-tartaric acid salt). b) treating the compound of formula-6A with sodium hydroxide in water to provide compound of formula-8b (((S)-4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy- 2, 8-dimethyl- 1 ,4-dihydro- 1 ,6-naphthyridine-3-carboxylate).
The third aspect of the present invention is to provide a process for the preparation of compound of formula-I.
Comprising of a) reacting the compound of formula- 1 with compound of formula-2
Figure imgf000008_0002
in presence of suitable solvent and reagents to provide compound of formula-3,
Figure imgf000009_0001
b) reacting the compound of formula-3 with compound of formula-4 with suitable reagent, solvent to provide compound of formula-5,
Figure imgf000009_0002
c) reacting the compound of formula-5 with suitable reagent, suitable solvent to provide compound of formula-6, purifying the compound in suitable solvent, d) treating compound of formula-6 with suitable chiral reagent, solvents to provide compound of formula-8,
Figure imgf000009_0003
e) deprotecting of compound of formula-8 with suitable reagent, solvent to provide compound of formula-9, f) reacting compound of formula-9 with source of ammonia, suitable reagent and solvent to provide compound of formula-I, g) optionally purifying the compound of formula-I using suitable solvents to provide pure compound of formula-I.
Wherein in step-a), b), c) ,d), e) and f) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, ketone solvents, polar aportic solvent, alcohol solvents, polor protic solvent, acetic acid, water or any mixture thereof; suitable temperature: 10-180°C;
Wherein step-a) suitable reagents are piperidine, morpholine, triethyl amine, diethyl amine, acetic acid and mixture thereof; step-b) specifically alcohol solvents; step-c) suitable reagents are triethyl orthoformate, triethyl orthoacetate, chloroethane, bromo ethane, iodo ethane; step-d) The suitable chiral reagents are selected from the list that is mentioned in the description. e) suitable reagents are selected form palladium catalyst, palladium hydroxide, Ray-Ni, ammonium formate, acetic acid, HC1, HBr, trifluoroacetic acid and mixture thereof; f) suitable reagents are selected form carbonyldiimidazole, EDC-HC1, hexamethyl disilazane, ammonia (g) aq. ammonia, ammonium chloride, ammonium carbonate and mixture thereof;
The preferred embodiment of the present invention provides a process for the preparation of compound of formula-I.
Comprising of a) reacting the compound of formula- 1 with compound of formula-2b in presence of acetic acid, piperidine in isopropanol
Figure imgf000010_0001
to provide compound of formula-3b,
Figure imgf000011_0001
b) reacting the compound of formula-3b with compound of formula-4 in ethylene glycol to provide compound of formula-5b,
Figure imgf000011_0002
c) reacting the compound of formula-5b with triethylorthoacetate, sulfuric acid in DMF to provide compound of formula-6b, d) treating compound of formula-6b with di-p-toluoyl-L-tartaric acid in acetonitrile, water to provide compound of formula-6A, further treating with sodium hydroxide in water to provide compound of formaul-8b,
Figure imgf000011_0003
e) deprotecting the compound of formula-8b with palladium hydroxide in tetrahydrofuran under hydrogen gas pressure to provide compound of formula-9, f) reacting the compound of formula-9 with carbonyldiimidazole, ammonia in tetrahydo furan, to provide compound of formula-I. g) purifying the compound of formula-I in ethanol to provide pure compound of formula- I
The fourth aspect of the present invention is to provide a process for the preparation of compound of formula-I.
Comprising of a) chiral resolution of the compound of formula-5 with suitable chiral reagent, solvent to provide compound of formula-7, b) reacting the compound of formula-7 with suitable reagent, solvent to provide compound of formula- 8, c) deprotecting of compound of formula-8 with suitable reagent, solvent to provide compound of formula-9, d) reacting compound of formula-9 with source of ammonia, suitable reagents, solvent to provide compound of formula-I, e) optionally purifying the compound of formula-I using suitable solvents to provide pure compound of formula-I.
Wherein in step-a), b), c), d) and e) the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, ketone solvents, polar aportic solvent, polor protic solvents, alcohol solvents, acetic acid, water or any mixture thereof; suitable temperature: 10-150°C;
Wherein step-a) The suitable chiral reagents are selected from the list that is mentioned in the description. step-b) suitable reagents are triethyl orthoformate, triethyl orthoacetate, chloroethane, bromo ethane, iodo ethane; sulfuric acid, HC1, step-c) suitable reagents are selected form palladium catalyst, ammonium formate, acetic acid, HC1, HBr, trifluoroacetic acid and mixture thereof; d) suitable reagents are selected form carbonyldiimidazole, EDC-HC1, hexamethyl di silazane, ammonia (g) aq.ammonia, ammonium chloride, ammonium carbonate and mixture thereof; In another embodiment, finerenone obtained according to the present invention having the following impurities racemic or specific isomers are having less than 0.15 % by HPLC.
Figure imgf000013_0001
The process for the preparation of finerenone developed by the present inventors produces highly pure compound and with good yield. All the related substances and residual solvents are controlled well within the limits as suggested by ICH guidelines and most of the related substances are controlled in non-detectable levels.
The compound of formula-I produced by the process of the present invention is having purity of greater than 99.0 % , preferably greater than 99.5% by HPLC / chiral HPLC.
Compound of formula-I produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The process of the present invention can be represented schematically as follows:
Figure imgf000014_0001
An alternative process for the preparation of compound of formula-I as follows.
Figure imgf000015_0001
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples:
Example-1: Preparation of 2-chloro-5-methylpyridine-l-oxide.
A round bottom flask was charged with acetic acid (1250 g) and 2-chloro-5- methylpyridine (500 g) and stirred for 15 min. Cooled the reaction mass to 0-5°C, slowly added hydrogen peroxide (1050 mL) and raised the temperature to 60-65°C and stirred for 20 hr. Cooled the reaction mass to 25-35°C, charged with water and adjusted the reaction mass pH to 8.5-9.0. and stirred for 30 min. The reaction mass was extracted with methylene dichloride (1200 mL x 2) and separated the organic and aqueous layers. The combined organic methylene dichloride layer was evaporated and dried to obtain the title compound.
Yield: 542 g
Example-2: Preparation of 2-chloro-5-methyl-4-nitropyridine-l-oxide.
A round bottom flask was charged with 2-chloro-5-methylpyridine-l -oxide (500 g) and cone, sulfuric acid (784.1 g) at 5-10°C and stirred for 30 min. The nitration mixture (Fuming nitric acid 701.7 g + 1029.9 g sulphuric acid) was slowly added into to the above reaction mixture in about 2.5 hr and heated the mixture to 60-70°C maintained the stirring for 4 hr. Cooled the reaction mass to room temperature, quenched with ice cold water (5 L) slowly and stirred for 1 hr at same temperature. Filtered the precipitated solid and washed with water and dried to obtain the title compound.
Yield: 450 g
Example-3: Preparation of 2-chloro-5-methylpyridin-4-amine.
A round bottom flask was charged with 2-chloro-5-methyl-4-nitropyridine-l-oxide (100 g) and acetic acid (500 mL) and cooled to 15-20°C, charged iron powder (201 g) slowly in 3-4 lots. The reaction mass was heated to 100°C and maintained for 1 hr. Cooled the reaction mass to room temperature, charged with ethyl acetate and stirred for 2 min and filtered. The filtrate solution pH was adjusted to 11-12 by using sodium hydroxide solution and stirred for 30 min. Separated the both layers, the aqueous layer was extracted with ethyl acetate , the combined organic layer was dried over sodium sulphate and evaporated to get the title compound.
Yield: 72 g. Example-4: Preparation of 4-amino-5-methylpyridin-2-ol
A round bottom flask was charged with 2-chloro-5-methylpyridin-4-amine (255 g), ethylene glycol (220 mL) at room temperature. Potassium hydroxide (228 g) was added slowly to the reaction mixture and heated to 130°C and stirred for 26 hr. Cooled the reaction mass to room temperature, adjusted the pH to 7 by using cone. Hydrochloric acid and extraction was performed by n-butanol (2550 mL). Separated the organic and aqueous layers, the organic layer was dried over sodium sulphate and distilled-off the solvent completely. The obtained compound was charged with isopropanol and stirred for 1 hr, filtered the solid and dried to obtain title compound.
Yield: 201 g.
Example-5: Preparation of 4-(dibromomethyl)-3-methoxybenzonitrile.
A round bottom flask was charged with chloroform (1000 ml), 3-methoxy-4-methyl benzonitrile (500 g) at 30±5°C. Charged AIBN (16.73 g) and N-bromo succinamide (1.2 kg) to the reaction mass at 30±5°C and heated to 60-70°C stirred for 2 hr. Cooled the reaction mass to room temperature and charged with water (2500 ml) and separated the organic and aqueous layers. The organic layer was washed with water (2500 ml) and dried over sodium sulphate. The organic layer was distilled off completely and dried to get the title compound.
Yield: 983 g.
Example-6: Preparation of the compound of formula-1.
A round bottom flask was charged with 4-(dibromomethyl)-3-methoxybenzonitrile (983 g), sodium carbonate (683.33 g in water) and water (4920 mL) the reaction mass was heated to 90-95°C stirred at same temperature for 9 hr. The reaction mixture was cooled to 25±5°C, filtered the solid compound and dried. The wet compound was charged with isopropanol (1.5 L) heated to 80-85°C and stirred for 1 hr. Cooled the reaction mass to 25-30°C, filtered the obtained solid and dried to get the title compound.
Yield: 364 g.
Example-7: Preparation of the compound of formula-3 (benzyl 2-(4-cyano-2- methoxy benzylidene)-3-oxobutanoate). A round botom flask was charged with formula- 1 (100 g), acetic acid (7.44 g), isopropanol (500 ml) and piperidine (10.55 g) stirred for 5-10 min at 30±5°C. Charged the reaction mass with a solution of benzyl-3-oxobutanoate compound of formula-2 (119.17 g) in isopropanol (100 ml) and stirred for 6 hr at same temperature. Filtered the obtained solid, and washed with isopropanol dried to get the title compound.
Yield: 163 g.
Example-8: Preparation of the compound of formula-5 (benzyl 4-(4-cyano-2- methoxyphenyl)-2,8-dimethyl-5-oxo-l,4,5,6-tetrahydro-l,6-naphthyridine-3- carboxylate).
A round botom flask was charged with n-butanol (500 ml), formula-3 (50.0 g), formula-4 (13.0 g) at 30±5°C and further heated to 110-120°C and stirred for 20 hr. Distilled off the solvent completely, charged with isopropanol (200 ml) and water (100 ml) at 110-120°C for 1 hr. Distilled-off the solvent, again charged with isopropanol (250 ml) stirred for 1 hr and distilled off the solvent under vacuum and filtered the solid and washed with isopropanol (100 mL) and dried the material to obtain the title compound Yield: 35 g.
Example-9: Preparation of the compound of formula-6 (benzyl 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate).
A round botom flask was charged with triethylortho acetate (82.7 g), formula-5 (30.0 g), NMP (45 g) and sulphuric acid (3.33 g) at 30±5°C and heated the reaction mass to 125- 130°C and stirred for 3 hr. Cooled the reaction mass to 50-60°C, slowly added water (180 mL over a period of 1 hr. Further, cooled the reaction mass to 5±5°C and stirred for 30 minutes at same temperature. Filtered the obtained solid and washed with water and dried to obtain the title compound.
Yield: 30.0 g.
Example-10: Preparation of the compound of formula-8 ((S)-benzyl 4-(4-cyano-2- methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate). A round botom flask was charged with ethanol (420 ml.), purified water (140 ml), and formula-6 (28.0 g) at 30±5 °C stirred for 10-15 min. Charged with di-p-toluoyl-L-tartaric acid monohydrate (23.0 g) to the reaction mixture at 30±5°C and stirred for 24 hr. Filtered the obtained solid and washed with ethanol (28.0 ml) and dried. The wet compound was charged with water (104 mL), adjusted the pH to 11.5 with aq. NaOH solution at 30±5°C and stirred for 30 min at same temperature. Filtered the obtained solid, washed with water (56.0 ml) and dried the material to obtain the title compound. Yield: 10 g; chiral purity > 99 %
Example-11: Preparation of the compound of formula-7 ((S)-benzyl 4-(4-cyano-2- methoxyphenyl)-5-hydroxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate).
A round botom flask was charged with ethanol (380 ml.), purified water (110 ml), and formula-5 (25.0 g) at 30±5 °C stirred for 10-15 min. Charged with di-p-toluoyl-L-tartaric acid monohydrate (20.0 g) to the reaction mixture at 30±5°C and stirred for 24 hr. Filtered the obtained solid and washed with ethanol (20.0 ml) and dried. The wet compound was charged with water (90 mL), adjusted the pH to 11.5 with aq. NaOH solution at 30±5°C and stirred for 30 min at same temperature. Filtered the obtained solid, washed with water (46.0 ml) and dried the material to obtain the title compound. Yield: 8.5 g. chiral purity > 99 %
Example-12: Preparation of the compound of formula-8 ((S)-benzyl 4-(4-cyano-2- methoxy phenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate).
A round botom flask was charged with triethylortho acetate (15 g), formula-7 (5 g), NMP (8.2 g) and sulphuric acid (0.6 g) at 30±5°C and heated the reaction mass to 125-130°C and stirred for 3 hr. Cooled the reaction mass to 50-60°C, slowly added water (30 mL over a period of 1 hr). Further, cooled the reaction mass to 5±5°C and stirred for 30 minutes at same temperature. Filtered the obtained solid, washed with water and dried to obtain the title compound.
Yield: 4.5 g.
Example-13: Preparation of the compound of formula-9 (S)-4-(4-cyano-2-methoxy phenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3-carboxylic acid.
A round botom flask under stirring was charged with methanol (100 ml), formula-8 (10.0 g) and palladium carbon (2.0 g) at 30±5°C and stirred under hydrogen pressure 1.0 kg/cm3 at 30±5°C for 4 hr. Filtered the mass and washed with methanol (10 ml) and distilled off the mass completely and dried to obtain the title compound
Yield: 5.2 g.
Example-14: Preparation of the compound of formula-L
A round botom flask was charged with formula-9 (10.0 g), THF (50 ml) under nitrogen atmosphere at 30±5°C. Cooled the reaction mass to 15-20°C and added 1, 1 -carbonyl di imidazole (8.5 g) followed by dimethyl amino pyridine (0.3 g) and stirred for 5 hr. The reaction mixture was purged with ammonia gas till the pH of the reaction mixture atained ~10 and stirred for 36 hr. cooled the reaction mass to 15-20°C, stirred for 1 hr filtered the solid obtain and washed with THF and dried to obtain the title compound. Yield: 7.0 g; chiral purity >99.5 %
Example-15: Preparation of 4-amino-5-methylpyridin-2-ol
A round botom flask was charged with 2-chloro-5-methylpyridin-4-amine (120 g), xylene (120 mL) at room temperature. Potassium hydroxide (120 g) was added slowly to the reaction mixture and heated to 125-135°C and stirred for 22-26 hr at same temperature. Cooled the reaction mass to room temperature, adjust the pH to 7.5 by using cone. Hydrochloric acid and stirred for 2h. Filtered the unwanted solid and washed with methanol. The filtrate solution was distilled off completely and co-distilled with toluene to get the residue compound. The residue compound was charged with methanol and heated to 55-35° and stirred for 1 hr at same temperature. Distilled off the reaction mixture completely and resulting compound was stirred in isopropanol for 1 hr and resulting solid was filtered and dried to get the title compound.
Yield: 108 g.
Example-16: Preparation of the compound of formula-2b (4-methylbenzyl 3-oxo butanoate).
A round botom flask was charged with 2,2,6-trimethyl-4H-l,3-dioxin-one (500 g), toluene (5 L) and 4-methylbenzyl alcohol (430 g) at 25 -35 °C and stirred for 10 min. The reaction mixture was heated to 105-115°C and stirred for 5 hr. Cooled the reaction mass to 20-30°C, charged with water and stirred for 10-15 min and separated the two layers and taken organic layer into another RBF and charged with water and separated. The organic layer was dried over sodium sulphate, distilled off the solvent completely to get the title compound.
Yield: 683 g
Example-17: Preparation of the compound of formula -3b (4-Methylbenzyl 2-(4- cyano-2-methoxy benzylidene) -3-oxobutanoate.
A round bottom flask was charged with 4-formy 1-3 -methoxybenzonitrile (200 g), formula-2b (281.5 g), isopropanol (IL), acetic acid (14.9 g) and piperidine (21.13 g) at 25-35°C and stirred for 6 hr. The precipitated solid was filtered and washed with a mixture of isopropanol and methanol dried to get the title compound.
Yield: 358 g
Example-18: Preparation of the compound of formula -5b (4-methylbenzyl 4-(4- cyano-2-methoxyphenyl)-2,8-dimethyl-5-oxo-l,4,5,6-tetrahydro-l,6-naphthyridine-
3-carboxylate)
A round bottom flask was charged with formula-3b (100 g), ethylene glycol (300 ml) and
4-amino-5-methylpyridin-2(lH)-one (31.97 g) and heated to 105-125°C and stirred for 14 hr at same temperature. The reaction mixture was gradually cooled and charged with isopropanol and stirred at 25 -35 °C for 30 min. The resulting compound was filtered and washed with isopropanol and dried to get the title compound.
Yield: 108 g
Example-19: Preparation of the compound of formula-6b (4-methylbenzyl 4-(4- cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate)
A round bottom flask was charged with tri ethylortho acetate (535 g), formula-5b (200.0 g), NMP (300 mL) and sulphuric acid (22 g) at 30±5°C and heated the reaction mass to 125-130°C and stirred for 3 hr. Cooled the reaction mass to 50-60°C, slowly added water over a period of 1 hr. Further, cooled the reaction mass to 5±5°C and stirred for 30 minutes at same temperature. Filtered the obtained solid, washed with water and dried to obtain the title compound.
Yield: 184 g.
Example-20: Preparation of the compound of formula-6b (4-methylbenzyl 4-(4- cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate)
A round bottom flask was charged with triethylortho acetate (267 g), formula-5b (100.0 g), dimethylformamide (300 mL), sulphuric acid (10.76 g) and triethylamine (4.44) at 30±5°C and heated the reaction mass to 110-120°C and stirred for 10 hr. Gradually, cooled the reaction mass to 25-35°C, charged n-heptane and water and stirred for 1 hr at same temperature Filtered the precipitated solid and washed with water to get the wet compound. Further, the wet compound was charged in a mixture of isopropanol and water stirred for 2 hr. Filtered the solid compound and washed with isopropanol and dried to get the title compound.
Yield: 105 g.
Example-21: Preparation of the compound of formula-6b (4-methylbenzyl 4-(4- cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate)
A round bottom flask was charged with triethylortho formate (366 g), formula-5b (150.0 g), NMP (225 mL) and sulphuric acid (16.14 g) at 30±5°C and heated the reaction mass to 125-130°C and stirred for 3 hr. Cooled the reaction mass to 50-60°C, slowly added water over a period of 1 hr. Further, cooled the reaction mass to 5±5°C and stirred for 30 minutes at same temperature. Filtered the obtained solid, washed with water and dried to obtain the title compound.
Yield: 130 g.
Example-22: Preparation of the compound of formula-8b ((S)-4-methylbenzyl 4-(4- cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate).
A round bottom flask was charged with acetone (1.25L) and formula-6b (250.0 g) were heated to 50±5 °C stirred for 30 min. Charged with di-p-toluoyl-L-tartaric acid monohydrate (200.0 g) to the reaction mixture at 30±5°C and stirred for 3 hr. Filtered the obtained solid and washed with ethanol (28.0 ml) and dried. The wet compound was charged with acetone and heated to 45-55°C stirred for 30 min and cooled to 25-35°C and stirred for 1 hr. filtered the solid and was charged with water adjusted the pH to 11-12 with aq. NaOH solution at 30±5°C and stirred for 30 min at same temperature. Filtered the obtained solid, washed with water (56.0 ml) and dried the material to obtain the title compound, chiral purity > 99 %
Yield: 100 g; PXRD of the isolated solid of di-p-toluoyl-L-tartaric acid salt of (S)-4- methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl- 1 ,4-dihydro- 1 ,6- naphthyridine-3-carboxylate is depicted in figure- 1.
Example-23: Preparation of the compound of formula-8b ((S)-4-methylbenzyl 4-(4- cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-l,4-dihydro-l,6-naphthyridine-3- carboxylate).
A round bottom flask was charged with acetonitrile (800 mL), water and formula-6b (100.0 g) were heated to 25-35 °C stirred for 30 min. Charged with di-p-toluoyl-L-tartaric acid monohydrate (44 g) to the reaction mixture at 25-35 °C and stirred for 2 hr at 70- 80°C. Filtered the obtained solid and washed with acetonitrile and dried. The wet compound was charged with acetonitrile, water (1:5) and heated to 70-80°C stirred for 2.5 hr and cooled to 25-35°C and stirred for 2 hr. Filtered the solid and washed with acetonitrile to get DPTTA salt of compound. The wet compound was charged with water and adjusted the pH to 11.5 with aq. NaOH solution at 25-35°C and stirred for 2hr at same temperature. Filtered the obtained solid, and dried to obtain the title compound.
Yield: 42.5 g; chiral purity by HPLC> 99 %: R-isomer <0.2 %
Example-24: Preparation of the compound of formula-9.
An autoclave was charged with tetrahydrofuran (IL), formula- 8b (50.0 g) and palladium carbon (2.0 g) at 30±5°C and stirred under hydrogen pressure 1.0 kg/cm3 at 50±5°C for 4 hr. Filtered the mass and washed with THF and distilled off the mass completely and charged with water. Adjusted the pH to 11-12 with aq.NaOH solution and charged with MTBE and stirred for 30 min. separated the organic layer and aqueous layer pH was adjusted to 3-4 with Con. HC1 and stirred for 1 hr. The obtained solid was filtered and dried to obtain the title compound.
Yield: 31.5 g.
Example-25: Preparation of the compound of formula-9.
An autoclave was charged with tetrahydrofuran (1.5L), formula-8b (100.0 g) and palladium hydroxide (10.0 g) at 35-45°C and stirred under hydrogen pressure 4.0 kg/cm3 at 35-45°C for 6 hr. Cooled the reaction mixture, Filtered the mass and washed with tetra hydrofuran and distilled off the mass completely and co-distilled with toluene. The obtained compound was charged with toluene and stirred for 1 hr, the resulting solid was filtered and washed with toluene and dried to get the title compound.
Yield: 42.5 g.
Example-26: Preparation of the compound of formula-L
A round bottom flask was charged with formula-9 (42 g), THF (210 ml) under nitrogen atmosphere at 30±5°C. Cooled the reaction mass to 15-20°C and charged 1, 1 -carbonyl di imidazole (36 g) followed by dimethyl amino pyridine (1.35 g) and stirred for 5 hr. The reaction mixture was purged with ammonia gas till the pH of the reaction mixture attained ~10 and with continues heating 50-60°C stirred form 12 hr. Cooled the reaction mass to 15-20°C charged with water, dichloromethane and stirred for 30 min. The organic layer separated and dried evaporated to get the crude compound. The obtained compound was stirred in ethanol for 1 hr at 55-65°C, filtered the obtained solid and dried to get the title compound.
Yield: 32 g; chiral purity >99.5 %; R- isomer <0.15 %
Example-27: purification of compound of formula-L
A round bottom flask was charged with formula-I (17 g), ethanol (255 mL) and heated to 75-85° and stirred for 1 hr. Filtered the reaction mixture through hyflow bed and washed with ethanol. The filtrate solution was distilled-off about 20 %, and the resulting solution was stirred for 1 hr at 15-20°C. Filtered the precipitated solid and washed with ethanol and dried to get the title compound.
Yield: 12.6 g; chiral purity >99.8 %; R- isomer <0.1 %

Claims

We Claims: l.A process for the preparation of compound of formula-8 by the chemical resolution of compound of formula-6.
Figure imgf000025_0001
Comprising of: treating the compound of formula-6 with suitable chiral reagent, solvents to provide compound of formula-8.
2. An improved process for finerenone the compound of formula-I.
Figure imgf000025_0002
Comprising of a)reacting the compound of formula- 1 with compound of formula-2
Figure imgf000025_0003
in presence of suitable solvent and reagents to provide compound of formula-3,
Figure imgf000026_0001
b)reacting the compound of formula-3 with compound of formula-4 with suitable reagent, solvent to provide compound of formula-5
Figure imgf000026_0002
c)reacting the compound of formula-5 with suitable reagent, suitable solvent to provide compound of formula-6, purifying the compound in suitable solvent, d) treating compound of formula-6 with suitable chiral reagent, solvents to provide compound of formula-8,
Figure imgf000026_0003
[8] [9] e)deprotecting of compound of formula-8 with suitable reagent, solvent to provide compound-9, purifying the compound in suitable solvent, f) reacting compound of formula-9 with source of ammonia, suitable reagent, solvent to provide compound of formula-I, g) optionally purifying the compound of formula-I using suitable solvents to provide pure compound of formula-I.
3. A process according to any proceeding claims the suitable solvents as per the above claims wherein in the suitable solvent is selected from hydrocarbon solvents, chloro solvents, ester solvents, ether solvents, nitrile solvents, ketone solvents, polar aportic solvent, alcohol solvents , polor protic solvents, acetic acid, water or any mixture thereof; suitable temperature: 10-150°C;
4. A process according to any proceeding claims the suitable reagents are wherein step-a) suitable reagents are piperidine, morpholine, triethyl amine, diethylamine, acetic acid and mixture thereof; step-b) specifically alcohol solvents; step-c) suitable reagents are triethyl orthoformate, triethyl orthoacetate, chloroethane, bromoethane, iodo ethane; e) suitable reagents are selected form palladium catalyst, palladium hydroxide, ammonium formate, acetic acid, HC1, HBr, trifluoroacetic acid and mixture thereof; f) suitable reagents are selected form carbonyldiimidazole, EDC- HC1, hexamethyl disilazane, ammonia (g), aq. ammonia, ammonium chloride, ammonium carbonate and mixture thereof;
5. A process according to any proceeding claims wherein in the suitable chiral reagents include L-tartaric acid, D-tartaric acid, camphor sulphonic acid, di-para-toluoyl-L-tartaric acid, di-para-toluoyl-D-tartaric acid, dibenzoyl-L-tartaric acid, dibenzoyl-D-tartaric acid, Phenylalanine, Phenylglycine, Phenyl glycinamide, S-(+)mandelicacid, R-(-) mandelic acid, L-malicacid, D-malic acid, D-(+)-maleicacid, (-)- naproxen, (-t-)-naproxen, (IR)-(-) camphor sulfonic acid, (lS)-(+)- camphor sulfonic acid, (lR)-(+)-bromocamphor-10- sulfonic acid, (lS)-(-)-bromo camphor- 10-sulfonic acid, L(-)-pyro glutamic acid, L(+)- pyroglutamic acid, (-)-lacticacid, L-lysine, D-lysine, (2R,3R)-2,3-bis(phenyl sulfonyloxy)succinic acid, (2S,3S)-2,3-bis(phenylsulfonyloxy)succinic acid, benzene sulfonyl derivatives of tartartic acid and mixtures thereof;
6. An improved process for finerneone the compound of formula-I.
Comprising of a)reacting the compound of formula- 1 with compound of formula-2b in presence of acetic acid, piperidine in isopropanol
Figure imgf000028_0001
to provide compound of formula-3b,
Figure imgf000028_0002
b)reacting the compound of formula-3b with compound of formula-4 in ethylene glycol to provide compound of formula-5b, c)reacting the compound of formula-5b with triethylorthoacetate, sulfuric acid in dimethyl formamide to provide compound of formula-6b, purifying in alcohol solvent,
Figure imgf000028_0003
[5b] [6b] d) treating compound of formula-6b with di-p-toluoyl-L-tartaric acid in acetonitrile and water to provide compound of formula-6A, further treating with sodium hydroxide in water to provide compound of formula-8b, e) deprotecting the compound of formula-8b with palladium hydroxide in tetrahydrofuran under hydrogen pressure to provide compound of formula-9,
Figure imgf000029_0001
f) reacting the compound of formula-9 with carbonyl diimidazole, ammonia in tetra hydofuran, to provide compound of formula-I. g) purifying the compound of formula-I in ethanol to provide the compound of formula-I
7. A process for the preparation of compound of formula-8b by the chemical resolution of compound of formula-6b.
Figure imgf000029_0002
Comprising of: a)Treating the compound of formula-6b with di-p-toluoyl-L-tartaric acid in acetonitrile, water provide compound of formula-6A (((S)-4-methylbenzyl 4-(4-cyano-2-methoxy phenyl)-5 -ethoxy-2, 8-dimethyl- 1 ,4-dihydro- 1 ,6-naphthyridine-3 -carboxylate di-p-toluoyl -L-tartaric acid salt), b) treating the compound of formula-6A with sodium hydroxide in water to provide compound of formula-8b (((S)-4-methylbenzyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy- 2, 8-dimethyl- l,4-dihydro-l,6-naphthyridine-3-carboxylate).
8. A process for the preparation of compound of formula-7b by the chemical resolution method of compound of formula-5b.
Figure imgf000030_0001
Comprising of: a)Treating the compound of formula-5b with di-p-toluoyl-L-tartaric acid in acetonitrile , water provide compound of formula-5A(DPTTA salt of compound of formaul-5a). b) treating the compound of formula-5A with sodium hydroxide in water to provide compound of formula-7b.
9. Finerenone according to the preceding claims is having particle size distribution of D90 <300 pm.
10. Finerenone obtained according to the preceding claims is having purity of at least about 95%; preferably of at least about 97%; more preferably of at least about 98%; most preferably of at least about 99.9% as measured by HPLC; Finerenone obtained according to the preceding claims is having R-isomer, N-ethyl impurity, R-isomer of finerenone, des-ethyl impurity, aromatization impurity are less than 0.15% as measured by HPLC.
PCT/IN2023/050906 2022-10-06 2023-10-05 A process for preparation of finerenone and intermediates thereof WO2024075139A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN202241057129 2022-10-06
IN202241057129 2022-10-06
IN202341015807 2023-03-09
IN202341015807 2023-03-09

Publications (1)

Publication Number Publication Date
WO2024075139A1 true WO2024075139A1 (en) 2024-04-11

Family

ID=90607675

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2023/050906 WO2024075139A1 (en) 2022-10-06 2023-10-05 A process for preparation of finerenone and intermediates thereof

Country Status (1)

Country Link
WO (1) WO2024075139A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016016287A1 (en) * 2014-08-01 2016-02-04 Bayer Pharma Aktiengesellschaft Method for the preparation of (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1-6-naphthyridine-3-carbox-amide and the purification thereof for use as an active pharmaceutical ingredient
WO2017032673A1 (en) * 2015-08-21 2017-03-02 Bayer Pharma Aktiengesellschaft Method for the preparation of (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1-6-naphthyridine-3-carboxamide and the purification thereof for use as an active pharmaceutical ingredient
WO2019206909A1 (en) * 2018-04-24 2019-10-31 Bayer Aktiengesellschaft Method for the preparation of (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1-6-naphthyridine-3-carbox-amide by racemate separation by means of diastereomeric tartaric acid esters

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016016287A1 (en) * 2014-08-01 2016-02-04 Bayer Pharma Aktiengesellschaft Method for the preparation of (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1-6-naphthyridine-3-carbox-amide and the purification thereof for use as an active pharmaceutical ingredient
WO2017032673A1 (en) * 2015-08-21 2017-03-02 Bayer Pharma Aktiengesellschaft Method for the preparation of (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1-6-naphthyridine-3-carboxamide and the purification thereof for use as an active pharmaceutical ingredient
WO2019206909A1 (en) * 2018-04-24 2019-10-31 Bayer Aktiengesellschaft Method for the preparation of (4s)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1-6-naphthyridine-3-carbox-amide by racemate separation by means of diastereomeric tartaric acid esters

Similar Documents

Publication Publication Date Title
US9695122B2 (en) Processes for preparing heterocyclic compounds including trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and salts thereof
EP2649060B1 (en) Process for the preparation of benzimidazole derivatives and its salts
US9718779B2 (en) Intermediate and polymorphs of 1-(4-methoxypheny1)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetra hydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide and process thereof
US10544107B2 (en) Process for the preparation of 2-{4-[(5,6-diphenyl pyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide and novel polymorphs thereof
US20160122354A1 (en) PROCESS FOR THE PREPARATION OF (3R,4R)-4-METHYL-3-(METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL-AMINO)-ß-OXO-1-PIPERIDINEPROPANENITRILE AND ITS SALTS
US9273030B2 (en) Process for the preparation of benzimidazole derivatives and salts thereof
US8481729B2 (en) Processes for the preparation of paliperidone
US10913717B2 (en) Solid state forms of N-[2-[(I S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methyl sulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-L H-isoindol-4-yl]acetamide and process for preparation thereof
WO2023131978A1 (en) Improved process for the preparation of upadacitinib
WO2019167085A1 (en) Process for the preparation of (s)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methyl]amino propanamide methanesulfonate
US11279696B2 (en) Processes for the preparation of 7-{4-[4-(1-benzothiophen-4-yl) piperazin-1-yl]butoxy}quinolin-2(1H)-one
US11236050B2 (en) Polymorphs of 4-[3-chloro-4-(n′-cyclopropyl ureido)phenoxy] -7-methoxyquinoline-6-carboxamide, its salts and process for the preparation thereof
US8557991B2 (en) Process for preparing enantiomerically pure indolopyridines
WO2024075139A1 (en) A process for preparation of finerenone and intermediates thereof
US7928232B2 (en) Method for producing asymmetric tetrasubstituted carbon atom-containing compound
WO2016139677A1 (en) Improved process for the preparation of 2-({6-[(3r)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihvdropvrimidin-1(2h)-yl}methyl)benzonitrile and pharmaceutically acceptable salts thereof
WO2019058387A1 (en) An improved process for the preparation of (5α,6α)-17-allyl-6-(2,5,8,11,14,17,20- heptaoxadocosan-22-yloxy)-4,5-epoxymorphinan-3,14-diol and its pharmaceutically acceptable salts
US10556887B2 (en) Processes for the preparation of Veliparib and intermediates thereof
WO2018096550A1 (en) Process for the preparation of methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1h-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate and its polymorphs thereof
WO2007063556A2 (en) An improved and industrial process for the preparation of alfuzosin hydrochloride and its novel polymorphs
US20120259116A1 (en) Novel Process for the Preparation of Paliperidone
WO2002042306A1 (en) Benzimidazole derivatives, preparation and therapeutic use thereof
US11434256B2 (en) Process for the preparation of 3α,7α-dihydroxy-6α-ethyl-5β-cholan-24-oic acid
WO2023017541A1 (en) Improved process for the preparation of 1-((2r,4r)-2-(1h-benzo[d]imidazol-2-yl)-1-methyl piperidin-4-yl)-3-(4-cyanophenyl)urea maleate
Rajan et al. A process for the preparation of 2-[3, 5-dichloro-4-(5-isopropyl-6-oxo-1, 6-dihydropyridazin-3-yloxy) phenyl]-3, 5-dioxo-2, 3, 4, 5-tetrahydro [1, 2, 4] triazine-6-carbonitrile

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23874452

Country of ref document: EP

Kind code of ref document: A1