DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of earlier Indian provisional patent application IN 201741035782 filed on Oct 09, 2017 which is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION

The present invention provides an improved process for the preparation of a compound of Formula (II), or its salt.
The present invention also provides a process for the preparation of Osimertinib or their pharmaceutically acceptable salts
DESCRIPTION OF RELATED ART
Osimertinib mesylate, N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate salt (AZD9291) having the following structure (Formula I), Osimertinib is a kinase inhibitor indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC).

The present invention provides an improved process for the preparation of a compound of Formula (II), or its salt.

The compound of Formula (II) or its salt, is useful as an intermediate in the preparation of Osimertinib, and in the preparation of pharmaceutically acceptable salts of Osimertinib.
The present invention also provides a process for the preparation of Osimertinib of Formula (I), or their pharmaceutically acceptable salts

WO 2013014448, WO 2016202125, WO2017134051, CN 106366072, Journal of chemical research 2015, VOL. 39, page 318 and Journal of Medicinal Chemistry 2014, Vol 57, Issue 20, Page 8254 discloses process for the preparation of Osimertinib mesylate or its intermediates.
WO 2013014448, WO2016070816, CN 104844580, CN 105348267 discloses process for the preparation of compound of formula (II) by reducing its corresponding nitro compound using various metal catalyst like Iron (Fe), palladium(Pd) or nickel(Ni).
WO2017134051 discloses process for the preparation of compound of formula (II) by reducing its corresponding nitro compound using palladium-on-carbon catalyst or platinum-on-carbon catalyst with an acid.

OBJECT AND SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of a compound Formula (II), or its salt

a) treating a compound of Formula (III) with acetic acid and a solvent
b) optionally isolating compound of Formula (III) acetic acid solvate

c) and reducing in the presence of catalyst.

The present invention provides an improved process for the preparation of a compound Formula (II), or its salt

a) treating a compound of Formula (III) with acid and a solvent,
with proviso that acid is not an acetic acid,
b) optionally isolating compound of Formula (III) acid salt

c) and reducing in the presence of catalyst.

The present invention also provides a process for the preparation of Osimertinib of Formula (I), or their pharmaceutically acceptable salts

a) reacting a compound of Formula (IA) or its salts with base, antioxidant and phase transfer catalyst in a solvent to give Osimertinib of formula I

b) optionally converting to its pharmaceutically acceptable salts

BRIEF DESCRIPTION OF THE DRAWINGS

Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:
Figure 1 shows 1H-NMR spectrum of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine acetic acid solvate.
Figure 2 shows IR spectrum of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine acetic acid solvate.
Figure 3 shows 1H-NMR spectrum of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine TFA salt.
Figure 4 shows a 1H-NMR spectrum of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of a compound Formula (II), or their pharmaceutically acceptable salts thereof.
One aspect of the present invention provides, an improved process for the preparation of a compound Formula (II), or its salt

a) treating a compound of Formula (III) with acetic acid and a solvent
b) optionally isolating compound of Formula (III) acetic acid solvate

c) and reducing in the presence of catalyst.
In one embodiment of the present invention, compound Formula III is treated with an acetic acid and a solvent. Optionally isolate compound of Formula (III) acetic acid solvate. Then Formula (III) acetic acid solvate is reduced in the presence of catalyst to give a compound Formula (II).
Within the context of this embodiment, suitable catalyst may be a metal catalyst. Suitable metal catalyst useful in this step include, but not limited to copper, iron, zinc, tin, ruthenium, palladium, rhodium, iridium, silver, cobalt, nickel, manganese, molybenium, vanadium and rhenium. In some particularly useful embodiments, nickel as a catalyst was found to be effective.
Within the context of this embodiment, the solvent used may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Suitable non-polar solvents useful within this reaction include, but not limited to 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane, and mixtures thereof. Suitable polar aprotic solvents useful within this reaction include, but not limited to 1,2-dimethoxyethane and mixtures thereof. Suitable polar protic solvents useful within this reaction include, but not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, the use of water or isopropyl alcohol as a solvent was found to be particularly effective.
The present invention provides an improved process for the preparation of a compound Formula (II), or its salt

a) treating a compound of Formula (III) with acid and a solvent,
with proviso that acid is not an acetic acid,
b) optionally isolating compound of Formula (III) acid salt, and

c) reducing in the presence of catalyst.
In another embodiment of the present invention, compound Formula III is treated with an acid and a solvent. Optionally Formula (III) acid salt is isolated and acid salt is reduced in the presence of catalyst to give a compound Formula (II).
Within the context of this embodiment, the acid used in the step (a) may be an organic acid but not acetic acid or an inorganic acid. Suitable organic acids useful in this step include, but not limited to, formic acid, propanoic acid, tartaric acid, oxalic acid, maleic acid, mandellic acid, malonic acid, methane sulphonic acid, p-toluene sulphonic acid, trifluoroacetic acid (TFA), benzene sulfonic acid, and combinations thereof. Suitable inorganic acids useful in this step include, but not limited to hydrochloric acid, hydrobromic acid, hydro iodic acid, sulphuric acid, nitric acid, boric acid, phosphoric acid, chromic acid, and combinations thereof. In some particularly useful embodiments, trifluoroacetic acid (TFA) is used as the acid.
Within the context of this embodiment, suitable catalyst may be a metal catalyst. Suitable metal catalyst useful in this step include, but not limited to copper, iron, zinc, tin, ruthenium, palladium, rhodium, iridium, silver, cobalt, nickel, manganese, molybenium, vanadium and rhenium. In some particularly useful embodiments, nickel as a catalyst was found to be effective.
Within the context of this embodiment, the solvent used may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Suitable non-polar solvents useful within this reaction include, but not limited to 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane, and mixtures thereof. Suitable polar aprotic solvents useful within this reaction include, but not limited to 1,2-dimethoxyethane and mixtures thereof. Suitable polar protic solvents useful within this reaction include, but not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, the use of water or isopropyl alcohol as a solvent was found to be particularly effective.
The present invention also provides a process for the preparation of Osimertinib of Formula (I), or their pharmaceutically acceptable salts

a) reacting a compound of Formula (IA) or its salt with base, antioxidant and phase transfer catalyst in a solvent to give Osimertinib of formula I

a) optionally converting to its pharmaceutically acceptable salts
In another embodiment of the present invention, compound Formula (IA) or its salt is treated with base, antioxidant and phase transfer catalyst in a solvent to give Osimertinib, optionally converting to its pharmaceutically acceptable salts.
The base useful in this embodiment may be an organic base, an inorganic base, or mixtures thereof. Suitable organic bases useful for this reaction include, but not limited to pyridine, trimethylamine, N, N-diisopropylethylamine, and mixtures thereof. Suitable inorganic bases for use in this reaction include, but not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides, and mixtures thereof. Suitable alkaline metal hydroxides for use in this reaction include, but not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof. Suitable alkaline metal bicarbonates useful in this reaction include, but not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Suitable alkaline metal carbonates useful in this reaction include, but not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Suitable alkaline alkoxides useful in this reaction include, but not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. In some particularly useful embodiments, the use of sodium hydroxide as a base was found to be effective. The base useful in this embodiment may be dissolved in water and added to the reaction.
Within the context of this embodiment, suitable phase transfer catalyst may be quaternary ammonium salt or crown ethers include, but not limited to, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutyl ammonium hydrogen sulfate, benzyltrimethylammonium chloride ammonium, benzyl triethyl ammonium chloride, trioctyl methyl ammonium chloride, 18-crown-6 or diphenyl-18-crown-6. In some particularly useful embodiments, tetrabutylammonium bromide as a phase transfer catalyst was found to be effective.
Within the context of this embodiment, suitable antioxidants may be phenolic-based antioxidants useful in this reaction include, but not limited to butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butyl-hydroquinone (TBHQ), 4-hydroxymethyl-2,6-di-tert-butylphenol (HMBP), 2,4,5-trihydroxy-butyrophenone (THBP), propyl gallate (PG), triamyl gallate, gallic acid (GA), a-Tocopherol (vitamin E), tocopherol acetate.
Within the context of this embodiment, the solvent used may be a non-polar solvent, a polar aprotic solvent, a polar protic solvent, or mixtures thereof. Suitable non-polar solvents useful within this reaction include, but not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane, and mixtures thereof. Suitable polar aprotic solvents useful within this reaction include, but not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2-dimethoxyethane and mixtures thereof. Suitable polar protic solvents useful within this reaction include, but not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof. In some particularly useful embodiments, the use of toluene as a solvent was found to be particularly effective.
In some embodiments of the present invention, compound Formula (IA) or its salt is prepared by reacting compound of formula II with 3-chloropropionyl chloride in presence of an acid.
Within the context of this embodiment, the acid used in the step (a) may be an organic acid but not acetic acid or an inorganic acid. Suitable organic acids useful in this step include, but not limited to, formic acid, propanoic acid, tartaric acid, oxalic acid, maleic acid, mandellic acid, malonic acid, methane sulphonic acid, p-toluene sulphonic acid, trifluoroacetic acid, benzene sulfonic acid, and combinations thereof. Suitable inorganic acids useful in this step include, but not limited to hydrochloric acid, hydrobromic acid, hydro iodic acid, sulphuric acid, nitric acid, boric acid, phosphoric acid, chromic acid, and combinations thereof. In some particularly useful embodiments, hydrochloric acid is used as the acid.
In another embodiment of the present invention, Osimertinib may be in one-pot formed from compound of formula (II).
Within the context of this embodiment, Osimertinib free base is converted to its pharmaceutically acceptable salt preferably Mesylate salt by following procedures disclosed in prior art such as WO2013014448.
Within the context of this embodiment, a compound of Formula (III) is prepared from 3-(2-Chloropyrimidin-4-yl)-1-methylindole following procedures disclosed in prior art such as WO2013014448.

EXAMPLES
Example 1:
Preparation of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyram-iddin-2-amine (Formula IV)
10 gm of 3-(2-Chloropyrimidin-4-yl)-1-methylindole,7.63 gm of 4-Fluoro-2-methoxy-5-Nitro aniline and 7.8 gm of p-Toluene sulfonic acid in isopropyl alcohol were heated 80°C . The reaction the mixture was cooled to 25°C and then added aqueous ammonia solution and filtered off. The wet material was slurried in aqueous methanol and then filtered. The product was dried at 50°C under vacuum for 16 hours to give N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl indol-3-yl)pyrimidin-2-amine. Yield: 15 gm (93%)
Example 2:
Preparation of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine (Formula III)
10 gm of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl indol-3-yl)pyrimidin-2-amine were heated in acetonitrile at 80°C in the presence of 3.33 gm of N,N,N-Trimethylethane1,2 diamine and potassium carbonate. The reaction mixture was cooled to 25°C and then added water and filtered off. The wet material was slurried in water and then filtered. The product was dried at 50°C under vacuum for 16 hours to give N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine. Yield: 10 gm (83%)
Example 3:
Preparation of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-1,2,4-benzenetriamine (Formula II)
10 gm of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine was suspended in water / acetic acid and reduced at 25-35°C in presence of Raney Ni and Hydrogen. To the reaction mixture aqueous NaOH to get precipitation. Dichloromethane was loaded and the pH of aqueous phase was adjusted to about 10 with aqueous NaOH. The phases were separated, then the organic layer was concentrated to residue was purified with methanol. The product was dried at 50°C under vacuum for 12 hours to give N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-1,2,4-benzene triamine. Yield: 7 gm (75%).
Example 4:
Preparation of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine acetic acid solvate
10 gm of example (2) and acetic acid (6.3g) were heated in isopropyl alcohol (100 ml) at 80°C then cooled to room temperature and stirred for 24 hours, filtered off. The product was dried at 50°C under vacuum for 12 hours to give N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzene diamine acetic acid solvate . Yield: 10 gm (89%)
Example 5:
Preparation of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-1,2,4-benzenetriamine (Formula II)
10 gm of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine acetic acid solvate was suspended in water and reduced at 25-35°C in presence of Raney Ni and Hydrogen. The reaction mixture was precipitated with aqueous NaOH. Dichloromethane was added and the pH of aqueous phase was adjusted to about 10 with aqueous NaOH. The phases were separated, then the organic layer was concentrated. The residue was purified with methanol. The product was dried at 50°C under vacuum for 12 hours to give N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-1,2,4-benzenetriamine. Yield: 7 gm (75%).

Example 6:
Preparation of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-1,2,4-benzenetriamine HCl salt
10 gm of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-1,2,4-benzenetriamine was dissolved in aqueous Hydrochloric acid. Cool the solution to 10-15°C. 3-chloropropionyl chloride was added dropwise under inert atmosphere. aqueous Hydrochloric acid was added to the reaction mixture and filtered off and washed with acetonitrile. The product was dried at 50°C under vacuum for 16 hours to give N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-1,2,4-benzenetriamine HCl salt. Yield: 12 gm (93%).
Example 7:
Preparation of Osimertinib free base (Formula I)
10 gm of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-1,2,4-benzenetriamine HCl salt were heated in aqueous NaOH and Toluene at 60-65°C in the presence of phase transfer catalyst and Butylated hydroxytoluene (BHT). The reaction mixture was separated and organic phase was washed with water. Extract the organic layer with aqueous Hydrochloric acid solution. The aqueous layer was heated to 60-65°C and cooled to 25°C and filtered off. The wet material was slurred with aqueous NaOH and Toluene solution. The product was dried at 50°C under vacuum for 16 hours to give Osimertinib free base. Yield: 12 gm (75%).
Example 8:
Purification of Osimertinib free base (Formula I)
5gm of Osimertinib free base in Methanol (15ml) and acetonitrile (35 ml) mixture were heated to 55-60°C. Cool the reaction mixture to 20-25°C. The product was stirred for 60 min at 20-25° and filtered off. The product was dried at 55°C under vacuum for 16 hours to give pure Osimertinib free base. Yield: 4.15 gm (83%).
Example 9:
Purification of Osimertinib free base (Formula I)
5gm of Osimertinib free base in acetonitrile (40 ml) mixture were stirred at ambient temperature for 6 hrs. Cool the reaction mixture to 20-25°C. The product was stirred for 60 min at 20-25° and filtered off. The product was dried at 55°C under vacuum for 16 hours to give pure Osimertinib free base. Yield: 4 gm (80%).
Example 10:
Preparation of Osimertinib mesylate Form B
20 gm of Osimertinib was added to ethanol (60ml) and Ethyl acetate (40ml) and stirred at 70°C. Methane sulfonic acid (3.9g) as a solution in Ethyl acetate (20ml) was added to the above reaction mixture and stirred for 1.5 hrs. The resulting solid was collected by filtration and dried at 60°C under vacuum to give Osimertinib mesylate salt form-B.
Example 11:
Preparation of Osimertinib mesylate Form A
Prepare the solution of methane sulfonic acid (1.92g) in acetonitrile (20ml). Osimertinib (5g) in Acetonitrile (100ml) was added to the above solution and at 25-30°C and stirred for 1 hr. Solid was collected by filtration and dried at 60°C under vacuum to give Osimertinib mesylate salt form-B.
Example 12:
Preparation of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine trifluoroacetic acid Salt.
10 gm of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine and trifluoroacetic acid (7.2g) in isopropyl alcohol (100 ml) were heated at 80°C. Cool the reaction mixture to room temperature and stirred for 12 hours, filtered and dried to give N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine trifluoroacetic acid salt. Yield: 10 gm (80%).
Example 13:
Preparation of N1-[2-(dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-1,2,4-benzenetriamine (Formula II)
10 gm of N1-[2-(dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-2-nitro-1,4-benzenediamine trifluoroacetic acid salt was suspended in water. The reaction mixture is reduced at 25-35°C in presence of Raney Ni and hydrogen. aqueous NaOH was added to the reaction mixture and product was precipitated. Dichloromethane was added and the pH of aqueous phase was adjusted to bout 12 with aqueous NaOH. The phases were separated, then the organic layer was concentrated to residue was purified with methanol. The product was dried to give N1-[2-(dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-1,2,4-benzenetriamine. Yield: 7 gm (75%).
Example 14:
Preparation of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-1,2,4-benzenetriamine free base
100 gm of N1-[2-(Dimethylamino)ethyl]-5-methoxy-N1-methyl-N4-[4-(1-methyl-1H-indol-3-yl)-2-pyrimidinyl]-1,2,4-benzenetriamine was dissolved in aqueous Hydrochloric acid (7.37 g Conc.HCl in 1000 ml) under Nitrogen atmosphere. Cool the solution to 10-15°C. 3-chloropropionyl chloride (39.9 g) was added dropwise under inert atmosphere, stirred the reaction mass for 2-3 hours then aqueous Hydrochloric acid (100 ml Conc.HCl in 250 ml) was added to the reaction mixture then stirred for 1 hour and filtered off and washed with acetonitrile. The wet product was suspended water (1000 ml), Toluene (800ml) and acetonitrile (100 ml) and reaction mass pH is adjusted to 12.0 using 25% aqueous Sodium hydroxide solution (~100 ml) then stirred for 30 min, separated the organic layer, then to the organic layer added Butylated hydroxytoluene (2.0g) and aqueous sodium hydroxide solution (31.43 gm of sodium hydroxide in 400 ml Water). Heated the reaction mass to 60-65°C and stirred at 60-65°C for 12 hours, after completion of reaction separated the layers then wash the organic layer with water (1000 ml). Cool the organic layer then add heptane (400 ml) slowly and cooled to 0-10°C and filtered off. The product was dried at 50°C under vacuum for 10 hours and the crude was suspended in Acetonitrile (600ml) then heated to 50-60°C then stirred for 45 min and cooled to 25-30°C then stirred at 25-30°C for 8 hours and filtered off. The wet product was dried at 50°C under vacuums to give Osimertinib free base. Yield: 80 gm (71%).

,CLAIMS:We claim:
1. A process for the preparation of a compound Formula (II), or its salt

comprising steps of:
a) treating a compound of Formula (III) with acetic acid and a solvent
b) optionally isolating compound of Formula (III) acetic acid solvate

c) and reducing in the presence of catalyst to produce compound of formula (II).

2. The process according to claim 1, wherein solvent used in the step (a) selected from 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2-dimethoxyethane water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof.
3. The process according to claim 1, wherein catalyst used in the step (c) is a metal catalyst selected from copper, iron, zinc, tin, ruthenium, palladium, rhodium, iridium, silver, cobalt, nickel, manganese, molybenium, vanadium and rhenium.
4. A process for the preparation of a compound Formula (II), or its salt

comprising steps of:
a) treating a compound of Formula (III) with acid and a solvent, with proviso that acid is not an acetic acid,
b) optionally isolating compound of Formula (III) acid salt

c) and reducing in the presence of catalyst to produce compound of formula (II).

5. The process according to claim 4, wherein acid used in the step (a) is an organic acid but not acetic acid, selected from formic acid, propanoic acid, tartaric acid, oxalic acid, maleic acid, mandellic acid, malonic acid, methane sulphonic acid, p-toluene sulphonic acid, trifluoroacetic acid (TFA), benzene sulfonic acid, and combinations thereof or an inorganic acid selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, boric acid, phosphoric acid, chromic acid, and combinations thereof.
6. The process according to claim 4, wherein solvent used in the step (a) selected from 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2-dimethoxyethane water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof.
7. The process according to claim 4, wherein catalyst is used in the step (c) is a metal catalyst selected from copper, iron, zinc, tin, ruthenium, palladium, rhodium, iridium, silver, cobalt, nickel, manganese, molybenium, vanadium and rhenium.
8. A process for the preparation of Osimertinib of Formula (I), or their pharmaceutically acceptable salts

comprising steps of:
a) reacting a compound of Formula (IA) or its salts with base, antioxidant and phase transfer catalyst in a solvent to give Osimertinib of formula I

b) optionally converting to its pharmaceutically acceptable salts.

9. The process according to claim 8, wherein base used in the step (a) is an organic base selected from pyridine, trimethylamine, N, N-diisopropylethylamine, and mixtures thereof.; an inorganic base selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof.
10. The process according to claim 8, wherein solvent used in the step (a) is selected from the group consisting of 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2-dimethoxyethane, water, methanol, ethanol, isopropyl alcohol, n-butanol, and mixtures thereof.
11. The process according to claim 8, wherein phase transfer catalyst used in the step (a) is a quaternary ammonium salt or crown ethers selected from tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammoniumiodide, tetrabutyl ammonium hydrogen sulfate, benzyltrimethylammonium chloride ammonium, benzyl triethyl ammonium chloride, trioctyl methyl ammonium chloride, diphenyl-18-crown-6, 18-crown-6.
12. The process according to claim 8, wherein antioxidants used in the step (a) is phenolic-based antioxidants selected from hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butyl-hydroquinone (TBHQ), 4-hydroxymethyl-2,6-di-tert-butylphenol (HMBP), 2,4,5-trihydroxy-butyrophenone (THBP), propyl gallate (PG), triamyl gallate, gallic acid (GA), a-Tocopherol (vitamin E), tocopherol acetate.