DESC:This application claims the benefit of priority of our Indian patent application numbers IN 201621019498 filed on 07th Jun 2016 which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention provides an improved process for the preparation of Afatinib of Formula-I.

Formula-I
The present invention provides a process for the preparation of Afatinib of Formula-I in substantial pure Form-A.
BACKGROUND OF THE INVENTION:
Afatinib, which is chemically known as N-[4-[(3-Chloro-4-fluorophenyl) amino]-7-[[(3S tetrahydro-3-furanyl] oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide, has the following structural formula:

Afatinib is formulated in the form of its dimaleate salt and marketed under the name GILOTRIF™ (US). GILOTRIF is a kinase inhibitor indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test
Afatinib, its salt, their preparation and solid state forms thereof are described in USRE 43, 431, US 8,426,586 , WO2012/121764 and WO2013/052157
There is always a need for a novel preparation process of drugs with inexpensive, feasible reagents, solvents and intermediates and the process that can afford desired products with good yields and to prepare a substantially pure Form thereof, in the present case substantially pure and stable Form-A.
SUMMARY OF THE INVENTION:
The present invention relates to a process of preparation of Afatinib of formula-I

Formula-I
comprising the steps of;
a. reacting N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine with tetrahydrofuran-3-ol to obtain N-(3-Chloro-4-fluorophenyl)-6-nitro-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin-4-amine of Formula-II

Formula-II
b. converting N-(3-Chloro-4-fluorophenyl)-6-nitro-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin-4-amine of Formula-II in presence of a reagent to afford N-(3-Chloro-4-fluorophenyl)-7-[(3S)-tetrahydrofuran-3-yloxy]quinazoline-4,6-diamine of Formula-III

Formula-III
c. reacting N-(3-Chloro-4-fluorophenyl)-7-[(3S)-tetrahydrofuran-3-yloxy]quinazoline-4,6-diamine with (2E)-4-(Dimethylamino)but-2-enoyl chloride or its salt thereof to afford Afatinib or its salt of Formula-I
d. purifying Afatinib free base
e. converting Afatinib or its salt to Afatinib dimaleate in presence of maleic acid and suitable medium.
The present invention relates to purification of Afatinib base comprises converting afatinib base to salt of afatinib and then converting to purified Afatinib base.
The present invention relates to preparation of 2E-4-(dimethylamino)but-2-enoyl chloride from acid compound of formula with oxalyl chloride in solvent isopropyl acetate and in presence of DMF.
The present invention relates to improved process for preparation of substantially pure Form-A.
The present invention relates highly pure Afatanib or salt thereof substantially free of impurities.
BRIEF DESCRIPTION OF THE DRAWINGS:
Fig I is an illustration of a powder X-ray diffraction (PXRD) pattern of Form-A
Fig II is an illustration of a powder X-ray diffraction (PXRD) pattern following process according to Example-4
Fig III is an illustration of a powder X-ray diffraction (PXRD) pattern following process according to Example-4 and 5
Fig IV is an illustration of a powder X-ray diffraction (PXRD) pattern following process according to Example-5

DETAILED DESCRIPTION OF THE INVENTION:
In one embodiment, the present invention provides a process of preparation of Afatinib of Formula-I

Formula-I
Comprising the steps of;
a. reacting N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine with tetrahydrofuran-3-ol to obtain N-(3-Chloro-4-fluorophenyl)-6-nitro-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin-4-amine of Formula-II

Formula-II
b. converting N-(3-Chloro-4-fluorophenyl)-6-nitro-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin-4-amine of Formula-II in presence of a reagent to afford N-(3-Chloro-4-fluorophenyl)-7-[(3S)-tetrahydrofuran-3-yloxy]quinazoline-4,6-diamine of Formula-III

Formula-III
c. reacting N-(3-Chloro-4-fluorophenyl)-7-[(3S)-tetrahydrofuran-3-yloxy]quinazoline-4,6-diamine with (2E)-4-(Dimethylamino)but-2-enoyl chloride or its salt thereof to afford Afatinib of Formula-I
d. purifying Afatinib free base, wherein purification comprising converting the crude base in to afatinib diamleate and then converting in to purified afatinib base,
e. converting Afatinib to Afatinib dimaleate in presence of maleic acid and suitable medium.
The step a) is carried out in presence of a suitable base and suitable solvent. The suitable base in step a) is selected from of a group consisting of metal alkoxides, wherein the alkoxides selected from group sodium tert-butoxide, potassium tert-butoxide; silanolate, wherein the silanolate is selected from group consisting of sodium trimethylsilanolate, sodium triphenylsilanolate, potassium trimethylsilanolate and the mixtures thereof.
The suitable solvent in step a) is selected from amide solvents, wherein amide solvents is selected from group consisting of diethylformamide, N,N-dimethylacetamide (DMAc), N,N-diethylacetamide, N,N-dimethylpropionamide, N,N-dimethylbutyramide, N-methylpyrrolidone and N-ethylpyrrolidone and the mixtures thereof.
In preferred embodiment the step a) is carried out in presence of dimethyl acetamide and sodium t-butoxide.
The conversion in the step b) is hydrogenation or reduction reaction.
The reagent in step b) is hydrogenation reagent or reducing reagent.
The hydrogenation step b) is carried out in presence of hydrogenation reagents selected from metal oxides, metals, platinum dioxide, Raney–Nickel, NiCl2.6H20, and mixture thereof.
The reduction step b) is carried out in presence of reducing reagents in step b) during reduction are selected from iron powder, FeCl3 and source of hydrogen selected from hydrazine hydrate, and ammonium formate.
In preferred embodiment the step b) is carried out in presence of FeCl3 and Hydrazine hydrate.
The step c) is carried out in presence of triethyl amine in NMP, and wherein, (2E)-4-(Dimethylamino) but-2-enoyl chloride is prepared from (2E)-4-(Dimethylamino)but-2-enoic acid in presence of oxalyl chloride and catalytic amount of DMF in isopropyl acetate.
The step d) is purifying crude Afatinib free base, wherein purification comprising converting the crude base in to afatinib diamleate and then converting in to purified afatinib base.
Preferably step d) comprises steps of converting afatinib crude base obtained in step c) to Afatinib dimaleate salt using maleic acid and solvents DMF and ethyl acetate, and converting the obtained dimaleate salt to pure afatinib base using acetone and water system and a NH3 treatment.
The step e) comprises converting Afatinib to Afatinib dimaleate in presence of maleic acid in Ethanol (Denatured with Cyclohexane)
In one embodiment, the invention provides process of purification of Afatinib base comprises steps of converting afatinib crude base obtained in step c) to Afatinib dimaleate salt using maleic acid and solvents DMF and ethyl acetate, and converting the obtained dimaleate salt to pure afatinib base.
In one embodiment, the invention relates to an improved process of preparing substantially pure Form-A of Afatinib dimaleate.
In one embodiment, the present invention provides a process of preparation of Afatinib of Formula-I

Formula-I
comprising the steps of;
a. reacting N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine with tetrahydrofuran-3-ol to obtain N-(3-Chloro-4-fluorophenyl)-6-nitro-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin-4-amine of Formula-II

Formula-II
wherein the said reaction is carried out in presence of DMAc and t-BuoNa.
b. converting N-(3-Chloro-4-fluorophenyl)-6-nitro-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin-4-amine of Formula-II in presence of a reagent to afford N-(3-Chloro-4-fluorophenyl)-7-[(3S)-tetrahydrofuran-3-yloxy]quinazoline-4,6-diamine of Formula-III

Formula-III
wherein the reagent FeCl3 and Hydrazine hydrate.
c. reacting N-(3-Chloro-4-fluorophenyl)-7-[(3S)-tetrahydrofuran-3-yloxy]quinazoline-4,6-diamine with (2E)-4-(Dimethylamino)but-2-enoyl chloride or its salt thereof to afford crude Afatinib base of Formula-I
wherein the reaction is carried out in presence of TEA in NMP, and wherein, (2E)-4-(Dimethylamino)but-2-enoyl chloride is prepared from (2E)-4-(Dimethylamino)but-2-enoic acid in presence of oxalyl chloride and catalytic amount of DMF in isopropyl acetate.
d. purifying Afatinib free base, wherein purification comprising converting the crude base in to afatinib diamleate and then converting in to purified afatinib base,
e. converting Afatinib to Afatinib dimaleate in presence of maleic acid and suitable medium.
In one embodiment, the present invention relates to Afatinib dimaleate comprising a compound of formula impurity-A, which is a cyclised impurity.

impurity-A
In an embodiment the present invention relates to Afatinib dimaleate comprising impurity-A less than 0.5% (By HPLC, % Area)
In one more embodiment, the present invention provides novel impurities: Impurity-II, Impurity-V, Impurity-VI, Impurity-VII, Impurity-VIII, Impurity-IX, Impurity-X of Afatinib and its salts thereof.
In one more embodiment, the present invention provides isolated compound of formula Impurity-II, Impurity-V, Impurity-VI, Impurity-VII, Impurity-VIII, Impurity-IX, Impurity-X of Afatinib and its salts thereof.
In one more embodiment, the present invention provides use of isolated compound of formula Impurity-II, Impurity-V, Impurity-VI, Impurity-VII, Impurity-VIII, Impurity-IX, Impurity-X of Afatinib and its salts thereof as reference standard for determining assay of afatinib or its salts thereof.
In an embodiment the present invention relates to Afatinib dimaleate substantially free of following impurities.
Impurity Chemical Name Structure
Impurity-I 1-{4-[(3-Chloro-4-fluorophenyl) amino]-7-[(3S)-tetrahydrofuran-3-
yloxy]quinazolin-6-yl}-5-hydroxypyrrolidin-2-one
(Cyclized Impurity)

Impurity-II N-{4-[(3-Chloro-4-fluorophenyl)amino]-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin- 6-yl}Formamide (Formyl Impurity)

Impurity-III N4-(3-Chloro-4-fluorophenyl)-7-[(3S)-tetrahydrofuran-3-yloxy]quinazoline-4,6-diamine

Impurity-IV (2E)-4-(Dimethylamino)but-2-enoic acid Hydrochloride

Impurity-V (2E)-N-{4-[(3-Chloro-4-fluorophenyl)amino]-7-hydroxyquinazolin-6-yl}-4-
(dimethylamino)but-2-enamide (Hydroxy Impurity)

Impurity-VI (S,E)-N-(4-(3,4-Difluorophenylamino)-7-(tetrahydrofuran-3-yloxy) quinazolin-6-yl)-4-(dimethylamino)but-2-enamide (Difluoro Impurity)

Impurity-VII (S,E)-N-(4-(3,4-Dichlorophenylamino)-7-(tetrahydrofuran-3-yloxy) quinazolin-6-yl)-4-(dimethylamino)but-2-enamide (Dichloro Impurity)

Impurity-VIII (2E)-N-[4-(3-Chloro-4-fluorophenyl) amino]-7-[[(3S)-tetrahydrofuran-3-
yloxy]quinazolin-6-yl]but-2-enamide (Crotonamide Impurity)

Impurity-IX N,N'-bis{4-[(3-chloro-4-fluorophenyl)amino]-7-[(3S)-tetrahydrofuran-3-yloxy]-quinazolin-6-yl}ethanediamide
(Dimer Impurity)

Impurity-X (S)-N1-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl)-N2,N2-dimethyloxalamide
(DMA Impurity)

R-isomer of Afatinib (2E)-N-[4-(3-Chloro-4-fluorophenyl)amino]-7-[[(3R)-tetrahydrofuran-3-yloxy]quinazolin-6-yl]-4-(dimethylamino)but-2-enamide

According to one more embodiment of the invention there is provided a highly pure Afatinib or salt substantially free of impurities.
As used herein, “highly pure Afatinib or salt substantially free of impurities” refers to Afatinib or salt comprising above mentioned impurity or its salt thereof in an amount of less than about 0.15% as measured by HPLC. Specifically, the Vorapaxar sulphate, as disclosed herein, contains less than about 0.10%, more specifically less than about 0.05%, still more specifically less than about 0.02% of impurity, and most specifically is essentially free of impurity.
In one embodiment, the present invention relates to a pharmaceutical composition comprising Afatinib dimaleate prepared according to present invention and pharmaceutically acceptable carriers.
In one embodiment, the present invention provides a process for the preparation of compound of Formula-I as represented schematically in scheme I as shown below.

Scheme-I
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.

Examples:
Example-1: N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine
To a stirred solution of 7-Fluoro-6-nitro quinazolin-4(3H)-one in Acetonitrile were added phosporous oxychloride followed by triethylamine under controlled addition. The reaction mixture was heated till the disappearance of starting material. A solution of 3-Chloro-4-fluoroaniline in 1,4-Dioxane was added to the above reaction mixture and allowed it to stir till the completion of the reaction. Water was added slowly to the reaction mass and separated solid was filtered and washed with water. The obtained solid was stirred with dilute aqueous Sodium hydroxide. Solid was filtered and washed with water, and purified to get N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine.
Example-2: N-(3-Chloro-4-fluorophenyl)-6-nitro-7-[(3S)-tetrahydrofuran-3-yloxy] quin azolin-4-amine
N,N-dimethyl acetamide (500 ml), (3S)-Tetrahydrofuran-3-ol (47.10 gm) and N-(3-Chloro-4-fluorophenyl)-6-nitro-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin-4-amine (100.0 gm) at 25-35oC were charged in to the reaction flask, reaction mixture was cooled to 10-20oC. sodium tert-butoxide (99.90 gm) was charged in three equal lots after every 15 minutes at 10-25oC into above reaction mixture. Temperature of reaction mixture was raised up to 20-30oC and the reaction mixture was stirred at 20-35oC for 2h. Check the completion of reaction by HPLC (Every 1.0 h). If the reaction does not complete in prescribed time, the reaction mixture maintained at temperature 20-30oC until it complies. The reaction mixture was cooled to 5-15oC. process water (1500 ml) was added slowly in to reaction mixture at 5-20oC. Meanwhile a solution of Conc. HCl (70 ml) in process water (500 ml) was prepared at 25-35oC. This solution was added in to reaction mixture at 5-20oC. pH should be acidic on pH paper. The reaction mixture was stirred at 5-20oC for 1h. The temperature of reaction mixture was raised up to 20-30oC. The reaction mixture was stirred at 20-30oC for 1hrs. The solid material was filtered at 20-30oC. The wet cake was washed with process water (4x100 ml) and suck dried for 45min. The wet cake was uploaded. process water (500 ml) was charged at 25-35oC in to a reaction flask and the above obtained wet cake was charged at 25-35oC and stirred at 25-35oC for 2h. The solid material was filtered at 25-35oC. Wet cake was washed with process water (4x100 ml) ) and suck dried for 45min and to obtain wet cake. Ethyl acetate (700 ml) was charged at 25-35oC in to a reaction flask and then added above obtianed wet cake at 25-35oC. the reaction mixture was heated to 55-60oC for 1h and Cooled the reaction mixture at 25-30oC, and then stirred at same temperature for 2 hrs. Stirred the reaction mixture at 25-30oC for 2h. The solid material was filtered at 25-30oC. Washed the wet cake with Ethyl acetate (2x50 ml) ) and suck dried for 45min. The obtained wet cake was dried at 55-60ºC in air tray drier for 8-10 hrs.
Example-3:N-(3-Chloro-4-fluorophenyl)-7-[(3S)-tetrahydrofuran-3-yloxy]quinazol ine-4,6-diamine
IPA (600 ml), N-(3-Chloro-4-fluorophenyl)-6-nitro-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin-4-amine at 25-30oC was charged in to reaction vessel and stirred for 5 min at 25-30oC. Meanwhile a solution of Anhydrous FeCl3 (1.0 gm) in IPA (50 ml) was prepared at 25-30oC and this solution was added in to the above prepared reaction mixture at 25-30oC and stirred the reaction mixture at 25-30oC for 5 min. Prepare a slurry of activated Charcoal (10.0 gm) in IPA (50 ml) at 25-30oC in a separate flask and add this solution into above reaction mixture. The mixture was heated upto 75-80oC. Followed by addition of Hydrazine hydrate (80% solution in water) (53.32 gm) into reaction mixture at 75-80 oC and the reaction mixture was maintained at 75-80 oC for 3-4 h. Check the completion of reaction by HPLC (every 1 hr). If the reaction does not complete in prescribed time, the reaction mixture maintained at temperature 75-80oC until it complies. The reaction mixture was cooled at 40-50oC and then filtered the reaction mixture at 40-50oC through hyflow bed and washed with IPA (200 ml). DM water (1800 ml) was charged into another reactor at 25-30oC. Slowly added filtrate ml reaction mixture into DM water reaction flask at 25-40oC. The reaction mixture was stirred for 2h±10 min at 25-40oC. The solid material filtered at 25-35oC. Wet cake was washed with process water at 25-35oC. Charge the material obtained in to a reaction vessel containing Ethanol (Denatured with cyclohexane)(250 ml), the reaction mixture is heated to 67±3oC and stir for 1h±10 min. Cooled to 25 ±5oC for 1 hr and was stirred at 25±5oC for 2h±10 min, solid material was filtered. Obtained wet material is added in to a reaction vessel with water (450 ml) and stirred at 25±5oC for 2h±10 min and washed with water and filtered and dried.
Example-4: (S,E)-N-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy) quinazolin-6-yl)-4-(dimethylamino)but-2-enamide (Afatinib)
Isopropyl acetate (1000 ml), (2E)-4-(dimethylamino)but-2-enoic acid (87.85 gm) and N,N-Dimethylformamide (DMF) (1 ml) was charged in to reaction flask at 25-35oC. The reaction mixture was cooled to 10-15oC. Oxalyl chloride (74.54 gm, 49.7 ml) was added into reaction mixture at 10-20oC, the temperature was raised up to 20-25oC. The reaction mixture was stirred for 5h at 20oC and cooled to 0-5oC. Triethylamine (26.94 gm, 37.11 ml) was added slowly into reaction mixture at 0-10oC. Meanwhile prepare a solution of N-(3-Chloro-4-fluorophenyl)-7-[(3S)-tetrahydrofuran-3-yloxy] quinazoline-4,6-diamine (100 gm) into NMP (500ml) at 25-30oC. (slight warm if require ). The above solution was slowly added into reaction mixture at 5-20oC within 25-35 min. The reaction mixture was stirred for 30 min at 5-20oC. Check the completion of reaction by HPLC. (Every 30 min). If the reaction does not complete in prescribed time, maintain the reaction mixture at temperature above 0-10oC until it complie¬s. DM water (1000 ml) was added into reaction mixture at 0-10oC, and stirred the reaction mixture at 5-20oC. Allowed it to settle for 5-10 minutes, separated the layer at 10-20oC. Product is in Aq. layer. The reaction mixture was cooled to 10-20oC. pH of reaction mixture was adjusted to 8-10 with 25% NaOH solution (250 ml) at 10-20oC. (Exothermicity observed). The reaction mixture was stirred for 6 hr. at 10-20oC. The solid material was filtered at 10-20oC and wet cake was washed with water (2x100 ml) and suck dried. The wet cake was uploaded (performed XPRD analysis and XPRD as shown in fig-II). The obtained wet cake was added into acetone solution at 25-30oC. The reaction mixture was heated to 50-55oC. Process water (500 ml) was charged into reaction mixture at 50-55 oC. The reaction mixture was stirred at 50-55oC for 1h. The reaction mixture was cooled at 25-35oC. The reaction mixture was stirred at 25-35oC for 2h. The solid material was filtered at 25-35oC. Wet cake was washed with water (3x50 ml) and suck dried. The obtained wet cake was dried at 55-60ºC in air tray drier for 8-10 h till constant weight. (Performed XPRD analysis and XPRD as shown in fig-III) Assay 98.0 to 102.0 (%w/w)(On anhydrous basis)
Example-5: Purification of Afatinib base
N,N-Dimethylformamide (300 ml) and Afatinib base (100 gm) were charged at 25-35oC in to reaction flask. The reaction mixture was heated at 50-55oC to obtained clear solution. Maleic acid (50.13 gm) was charged at 50-55oC. The reaction mixture was stirred for 2h at 50-55oC. The reaction mixture was cooled to 25-35oC. Ethyl acetate (900 ml) was charged at 25-35oC. The reaction mixture was stirred for 2 hrs at 25-35oC. The obtained solid material was filtered at 25-35oC. The wet cake was washed with Ethyl acetate (3 x 100ml) and suck dried. The wet cake was uploaded and charged with N,N-Dimethylformamide (300 ml) at 25-35 oC.
The above obtained wet cake was charged into DMF solution at 25-30oC. the reaction mixture was heated at 50-55oC and stirred for 1h at 50-55oC. The reaction mixture was cooled to 25-35oC. Ethyl acetate (900 ml) was charged at 25-35oC. The reaction mixture was stirred for 2 hr. at 25-35oC. The solid material was filtered at 25-35oC. wet cake was washed with Ethyl acetate (3 x 100ml) and suck dried. Followed by drying at 55-60ºC in tray drier under vacuum for 5-8 hrs (performed XPRD analysis of obtained dimaleate salt and XPRD as shown in fig-IV) Acetone (500 ml) was charged at 45-55oC. The dried material was charged into acetone at 25-35oC. The process water (500 ml) was charged into reaction mixture at 25-35o C. the reaction mixture was stirred at 25-35 oC for 10-15 min to obtain clear solution. Liq. Ammonia (50 ml) was slowly into reaction mixture at 25-35oC. Check pH on pH paper, it should be basic (8-10). The reaction mixture was stirred at 25-35oC for 2h. the solid material was filtered at 25-35oC. wet cake was washed with water (2x100 ml) and suck dried. the wet cake was unload and dried at 55-60ºC in air tray drier for 8-10 hrs till constant weight. (performed XPRD analysis and XPRD as shown in fig-III).
Example-6: Preparation of Afatinib dimaleate Form-A
Ethanol (Denatured with Cyclohexane) (1300 ml) and Afatinib base (100 gm) obtained from above step was charged in to reaction flask at 25-35oC. The reaction mixture was heated at 50±5oC to obtain clear solution. The reaction mixture was filtered at 50±5oC and washed with Ethanol (Denatured with Cyclohexane) (100 ml). Filtrate ml from above step was charged into another reaction vessel and heated the reaction mixture at 55±5oC. Meanwhile a solution of maleic acid (48.92 gm) into Ethanol (Denatured with Cyclohexane) (600 ml) was prepared at 25-35oC. Prepared maleic acid solution charged into the reaction mixture containing Afatinib base at 55±5oC and stirred the reaction mixture for 1h at 55±5oC. The reaction mixture was cooled to 20oC. The reaction mixture was stirred for 2 to 3 hr. at 20oC. Filter the solid material at 20±5oC. Washed the wet cake with Ethanol (Denatured with Cyclohexane) (3x100 ml) and suck dry it. The wet cake was uploaded and dried at 50-55ºC in tray drier under vacuum for 5-6 hrs. Obtained Afatinib dimaleate Form-A is characterized by XPRD and XPRD obtained as in fig I.
,CLAIMS:1. A process for preparing of Afatinib of Formula-I

Formula-I
comprising the steps of
a. reacting N-(3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine with tetrahydrofuran-3-ol to obtain N-(3-Chloro-4-fluorophenyl)-6-nitro-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin-4-amine of Formula-II

Formula-II
wherein the reaction is carried out in presence of DMAc and t-BuoNa.
b. converting N-(3-Chloro-4-fluorophenyl)-6-nitro-7-[(3S)-tetrahydrofuran-3-yloxy]quinazolin-4-amine of Formula-II in presence of a reagent to afford N-(3-Chloro-4-fluorophenyl)-7-[(3S)-tetrahydrofuran-3-yloxy]quinazoline-4,6-diamine of Formula-III

Formula-III
wherein the reagent FeCl3 and Hydrazine hydrate.
c. reacting N-(3-Chloro-4-fluorophenyl)-7-[(3S)-tetrahydrofuran-3-yloxy]quinazoline-4,6-diamine with (2E)-4-(Dimethylamino)but-2-enoyl chloride or its salt thereof to afford crude Afatinib base of Formula-I
wherein the reaction is carried out in presence of triethyl amine in NMP
d. purifying Afatinib free base, wherein purification comprising converting the crude Afatinib base in to afatinib dimaleate and then converting in to purified afatinib base
e. converting Afatinib to Afatinib dimaleate in presence of maleic acid and suitable solvent.
2. The process according to claim 1, wherein step a) is carried out in presence of dimethyl acetamide and sodium t- butoxide.
3. The process according to claim 1, wherein (2E)-4-(Dimethylamino)but-2-enoyl chloride is prepared by reacting (2E)-4-(Dimethylamino)but-2-enoic acid with oxalyl chloride and catalytic amount of DMF in isopropyl actate.
4. The process according to claim 1, wherein step d) comprises steps of converting Afatinib crude base obtained in step c) to Afatinib dimaleate salt using maleic acid and solvents DMF and ethyl acetate, and converting the obtained dimaleate salt to pure Afatinib base using acetone and water system.
5. The process according to claim 1, wherein step e comprises converting Afatinib to Afatinib dimaleate in presence of maleic acid in Ethanol.
6. The process according to claim 4, further comprises adding liquid Ammonia during the step of coverting afatinib dimaleate to afatinib base to adjust pH.
7. The process according to claim 1, wherein Afatinib dimaleate obtained in step e is Form-A.
8. Isolated impurities of Afatinib or its salt thereof of following structures

Impurity-II Impurity-IX

Impurity-X
9. Highly pure Afatinib or salt thereof substantially free of impurities: Impurity-I, Impurity-II, Impurity-III, Impurity-IV, Impurity-V, Impurity-VI, Impurity-VII, Impurity-VIII, Impurity-IX, Impurity-X and R-isomer of Afatinib.
10. Highly pure Afatinib or salt thereof substantially free of impurities according to claim 9, wherein Impurity-II, Impurity-III, Impurity-IV, Impurity-V, Impurity-VI, Impurity-VII, Impurity-VIII, Impurity-IX, Impurity-X and R-isomer of Afatinib are less than 0.15% (by HPLC) and Impurity-I is less than 0.5% (by HPLC)