DESC:Priority
This application claims the benefit to Indian Provisional Application 171/MUM/2014 filed on January 09, 2014 entitled "AN IMPROVED PROCESS FOR THE PREPARATION OF GEFITINIB", which are incorporated herein by reference.
FIELD OF INVENTION:
The present invention relates to an improved process for the synthesis of Gefitinib of formula 1 given below.

BACKGROUND OF THE INVENTION
Gefitinib chemically known as N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy) quinazolin-4-amine have antineoplastic activity. It inhibits the catalytic activity of the epidermal growth factor receptor (EGFR), which may result in inhibition of tyrosine kinase-dependent tumor growth, thereby inhibiting receptor autophosphorylation and resulting in inhibition of signal transduction accordingly is useful in the treatment of various solid tumors, especially non-small cell lung cancer.

Various methods for the preparation of formula 1 already have been reported in literature.
International application number WO2004024703A1 describes the synthesis of Gefitinib by reacting 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile with sodium dithionite in water which gives 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile, resulting benzonitrile was converted into the benzamide and it was condensed with formamide to give quinazolinone, was treated with phosphorus oxychloride to give 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline which was alkylated with 3-chloro-4-fluoroaniline to give Gefitinib.
International application number WO2005023783A1 describes the synthesis of Gefitinib via rearrangement of 3-(3’-chloro-4’-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-imine with use of suitable catalyst furnish Gefitinib. Although the invention is novel but for the rearrangement of 3-(3’-chloro-4’-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-imine required acid catalyst and elevated temperature. The intermediate N-(3-Chloro-4-fluorophenyl) -N’-[2-cyano- 5-methoxy-4-(3-morpholinoprpoxy) phenyl]formamidine have two geometric isomer Z and E, and patent does not disclose the reactivity of Z or E to cyclize into quinazolin-4-imine.
International application number WO2005070909A1 describes the synthesis of Gefitinib comprises etherification of isovanillin with 3-morpholinopropyl halide furnish 4-methoxy-3-[3-(morpholin-4-yl)propoxy]benzaldehyde, followed by nitration, oximation, dehydration, reduction cum hydrolysis furnish 7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4(3H)-one, introduction of a leaving group at C-4 position in resulting quinazolinone and condensed with 3-chloro-4-fluoroaniline to get crude Gefitinib. In this preparation of 2-amino-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzamide from 4-methoxy-5-[3-(morpholin-4-yl)propoxy]-2-nitrobenzamide involved potentially hazardous hydrogenation reaction using Raney nickel and methanol under pressure.
International application number WO2008125867A2 discloses a process for the synthesis of Gefitinib starting from isovanillin as below.

International application number WO2003072108 and WO2006090413 discloses different crystalline Forms of Gefitinib designated as Form 1, 2, 3, 5 and 6. There is a need for processes for the preparation of Gefitinib that are simple, cost effective, and viable on commercial scale and further avoid use of hazardous reagents.

SUMMARY OF THE INVENTION
Aspect of the present invention provides processes for the preparation of pure gefitinib which is free of genotoxic and process related impurities. Each step of the processes disclosed herein are contemplated both in the context of the multistep sequences described, and individually
In an aspect, the present invention provides an improved process for the preparation of gefitinib of formula I comprising the steps of;
a) reacting 4-(3-halopropyl) morpholine of formula-IV(a) or its salts thereof with a compound of formula-IV in presence of a base to obtain a compound of formula-V

Wherein X is any halogen
b) reducing the compound of formula-V in presence of a reducing agent to obtain a compound of formula-VI

c) condensing the compound of formula-VI with formic acid or reactive derivative thereof to obtain a compound of formula-VII in a suitable solvent

d) Converting the compound of formula-VII to a compound of formula-VIII in presence of suitable agent

e) reacting formula-VIII with 3-choloro-4-fluoroaniline to obtain Gefitinib of Formula-I.
In another aspect, present invention provides the novel intermediates compound of formula-V and formula VI, which is key intermediate used for the preparation of Gefitinib

In another aspect of the present invention a novel polymorphic crystalline Form-AL of Gefitinib and its preparation process thereof.
In another aspect of the present invention provide a compound of structure formula I with very high purity, typically in excess of 99.95%. Obtained compound of formula I is -is free from genotoxic impurities.
BRIEF DESCRIPTION OF THE DRAWINGS

Fig 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of the Gefitinib Form AL, prepared according to Example 12.

DETAILED DESCRIPTION OF THE INVENTION
All percentages and ratios used herein are expressed by weight of the total composition and all measurements made are at ambient temperature and atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. The present invention can comprise (open ended) the components of the present invention as well as other ingredients or elements described herein.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at the very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material has 99% purity or higher, as determined using methods conventional in the art such as high performance liquid chromatography (HPLC), gas chromatography (GC), or spectroscopic methods. In general, this refers to purity with regard to unwanted residual solvents, reaction by-products, impurities, and unreacted starting materials. In the case of stereoisomers, "pure" also means 99% of one enantiomer or diastereomer, as appropriate. "Substantially pure" refers to the same as "pure," except that the lower limit is about 98% purity or higher and, likewise, "essentially pure" means the same as "pure" except that the lower limit is about 97% purity.
In an aspect, the present invention provides an improved process for the preparation of Gefitinib of formula I comprising the steps of;
a) reacting 4-(3-halopropyl) morpholine of formula-IV(a) or its salts thereof with a compound of formula-IV in presence of a base to obtain a compound of formula-V

Wherein X is any halogen
b) reducing the compound of formula-V in presence of a reducing agent to obtain a compound of formula-VI

c) condensing the compound of formula-VI with formic acid or reactive derivative thereof to obtain a compound of formula-VII in a suitable solvent

d) chlorination of the compound of formula-VII to a compound of formula-VIII in presence of suitable agent

e) reacting formula-VIII with 3-choloro-4-fluoroaniline to obtain Gefitinib of Formula-I.

Step a involves reacting 4-(3-halopropyl) morpholine of formula-IV (a) or its salts thereof with a compound of formula-IV in presence of a base to obtain a compound of formula-V
Suitable base that may be used step a selected from inorganic base such as alkali metal or alkaline earth metal hydroxide, carbonates, bicarbonates, hydride thereof or organic base such as diisopropyl ethylamine, triethylamine, pyridine and the like. Preferably base is selected from sodium carbonate, potassium hydrogen carbonate, sodium bicarbonate, potassium carbonate and the like or the mixtures thereof.
The suitable solvent employed in the reaction includes but not limited to nitriles such as acetonitrile; amide solvents such as dimethylformamide (DMF); ketones such as acetone; ethers such as tetrahydrofuran, dioxane; aprotic solvent such as dimethylsulfoxide; and the like or mixture thereof. Preferably solvent is selected from acetonitrile and DMF.Step (b) involves reducing the compound of formula-V in presence of a reducing agent to obtain a compound of formula-VI
The said reducing agent includes hydrogen in presence of noble metal catalyst with or without support. The noble metal catalyst is selected from but not limited to platinum, nickel, rhodium, platinum dioxide, ruthenium, palladium, with or without support (carbon, clay, silica or alumina) and the like. Preferably, the catalyst is palladium on carbon.
The Suitable solvents used may be used in the step (b) includes alcohols such as methanol, ethanol, isopropanol and preferably methanol.
Step (c) involves condensation the compound of formula-VI with formic acid or reactive derivative thereof to obtain a compound of formula-VII in a suitable solvent
The formic acid reactive derivative includes formamidine acetate, formamide and the like.
Further, in an embodiment the rate of reaction of the above condensation is increased by addition of few drops or few milliliters of organic acid such as carboxylic acid such as acetic acid and the like. More preferably, by addition of acetic acid.
Step (d) involves chlorination of the compound of formula-VII to a compound of formula-VIII in presence of suitable agent
Suitable agent is chlorinating agent includes but not limited to thionyl chloride, phosphorous oxychloride or a mixture of carbon tetrachloride and triphenylphosphine, phosphorous trichloride, phosphorous pentachloride, phosphorous oxychloride, oxalyl chloride, methanesulfonyl chlorides, benzenesulfonyl chloride, p-toluenesulfonyl chloride, and the like. The solvent employed in this reaction include but not limited to halogenated solvents such as dichloromethane, chloroform; aromatic hydrocarbon such as toluene; ether such as tetrahydrofuran, dioxane, nitrile such as acetonitrile; aliphatic hydrocarbon such as cyclohexane; N,N-dimethylformamide and mixture thereof. Preferably, the halogenating agent selected from POCl3 and thionyl chloride.
Further, in an embodiment, the compound of formula VIII can be isolated from the reaction mixture by suitable techniques.
Step (e) involves reacting the reaction of formula VIII with 3-chloro-4-fluoroaniline in the presence of solvent to obtain gef?tinib of formula I.
The said solvent for the reaction include but not limited to alcohol such as methanol, ethanol, isopropanol, ethyl acetate, isoamyl alcohol; ester; water, halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride; ether such as tetrahydrofuran or 1,4-dioxan; aromatic solvent, such as toluene; ketones such as acetone, ethyl methyl ketone; dipolar aprotic solvent such as N,N-dimethylformamide, N.N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide and the like or mixtures thereof.
In another embodiment, in the above step for preparation of Gefitinib of formula I, the reaction mixture is added with an acid such as acetic acid and oxalic acid and their hydrates thereof and the like. Preferably, oxalic acid dihydrate.
The reaction yields the mixture of Gefitinib and its salts such as hydrochloride salt; therefore after the completion of the reaction, reaction mixture can be neutralized using a suitable base. The suitable base employed in the reaction include organic amine base such as triethylamine, morpholine, N-methylmorpholine; alkali or alkaline earth metal carbonate or bicarbonates or its hydroxide such as sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide. More preferably base is selected from potassium or sodium hydroxide.
In an embodiment the preparation of Gefitinib is as shown in below scheme

In another aspect, the invention provides a process for preparing Formula-VII comprises reacting 2-amino-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzoate with formic acid or reactive derivative thereof in the presence of solvent as shown in below scheme.

Formula VII
The formic acid reactive derivative includes formamidine acetate, formamide and the like and the solvent is an organic acid such as carboxylic acid such as acetic acid and the like. More preferably, by addition of acetic acid.
In one aspect, the invention provides a process for preparing Gefitinib of Formula-I and its pharmaceutically acceptable salts comprises conversion 4-chloro-7-methoxy-6-[3-(morpholine-4-yl) propoxy] quinazoline to Gefitinib in presence of acetone, water and oxalic acid dihydrate.

In another embodiment, the crude Gefitinib thus obtained according to above embodiments can be purified and recrystallised from suitable solvent(s).
In one embodiment, the suitable solvents include but not limited to toluene, acetonitrile; alcohol such as methanol, ethanol, isopropanol, n-propanol, isoamyl alcohol; ethyl acetate, ethyl methyl ketone or a mixture thereof. Preferably, the mixture of ethyl acetate and n-propanol.
In another embodiment, alternatively, the crude product can be dissolved in aqueous acid, treated with carbon and neutralized with a base to get pure compound of formula-I. The acid used during purification is selected from organic acids such as acetic acid, propionic acid, oxalic acid, succinic acid, toluic acid, mandelic acid, tartaric acid, preferably acetic acid or oxalic acid.
Further, in an embodiment the crude is treated with activated carbon and the like during recrystallization process.
In an embodiment the preparation of Gefitinib is as shown in below scheme

In another aspect, the present invention features a novel polymorph of Gefitinib designated as Form-AI, characterized by an x-ray powder diffraction pattern having peaks expressed as 2? at approximately 6.48, 7.11, 11.3, 12.3, 14.2, 15.9, 16.39, 19.38, 24.04, 24.35, and 26.41.
Yet in another aspect, Form-Al is characterized by an X-ray powder diffraction having peaks expressed as 2? at approximately 6.48, 7.11, 8.35, 9.25, 10.00, 11.27, 12.34, 12.93, 13.91, 14.23, 14.55, 15.34, 15.88, 16.39, 17.73, 18.65, 19.38, 20.22, 20.75, 21.23, 22.39, 22.61, 24.04, 24.35, 25.13, 26.41, 27.31, 28.04, 28.61, 29.78, 30.68, 32.11, 32.98, 34.17, 34.86, 36.11, and 37.74 as shown in fig 1.
In another aspect, present invention provides the novel intermediates compound of formula-V and formula VI.

In one aspect of the invention, formula V is prepared by condensation formula IV with 4-(3-chloropropyl) morpholine in presence of a base and in a suitable medium or solvent.
In another aspect of the invention, the Gefitinib obtained by the process described herein above, free from the below listed Genotoxic impurities.

N-(4-Fluorophenyl)-7-methoxy-6-(3-morpholine-4-yl propoxy) quinazxoline-4-amine

N-(3-Chlorophenyl)-7-methoxy-6-(3-morpholine-4-yl propoxy)quinazxoline-4-amine

N-(3,4-DiChloro)-7-methoxy-6-(3-morpholine-4-yl propoxy)quinazxoline-4-amine

N-(3,4-Difluoro)-7-methoxy-6-(3-morpholine-4-yl propoxy)quinazxoline-4-amine

N-(4-Chloro-3-Fluorophenyl)-7-methoxy-6-(3-morpholine-4-yl propoxy)quinazxoline-4-amine

7-Methoxy-6-(3-mprpholin-4-yl)qunoazolin-4(3H)-one

Methyl 2-amino-4-methoxy-5-[3-(morpholine-4-yl)propyl]benzoate.

4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline.

4-[(3-chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-ol.

N-(3-Chloro-4-Fluorophenyl)-7-methoxy-6-(3-morpholine-N-Oxide-4-yl propoxy)quinazxoline-4-amine
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: Preparation of 4, 5-dimethoxy-2-nitrobenzoic acid
3, 4-Dimethoxybenzoic acid (100.0 g) was added to pre cooled concentrated nitric acid (550 mL) and the reaction mass were stirred for 2 hours at 0-5°C. After completion of reaction, water was added (550 mL) at 0-5°C. After stirring the reaction mixture for 2 hours at 0-5°C, filtered the precipitated solid, washed with water and purified in acetone (500 mL) to obtain 50.0 g of 4,5-dimethoxy-2-nitrobenzoic acid.
Example-2: Preparation of 5-hydroxy-4-methoxy-2-nitrobenzoic acid
Stage-I (100.0 g) compound was added to aqueous potassium hydroxide solution (10 % w/v, 550 mL) and refluxed for 20 hours. After completion of reaction, reaction mixture cooled to 0°C and adjusted pH 3-5 with conc. hydrochloric acid solution. The precipitated solid was filtered, washed with water and dried at 50°C to obtain 85.0 g of 5-hydroxy-4-methoxy-2-nitrobenzoic acid.
Example-3: Preparation of 3-morpholinopropyl-5-(3-morpholinopropoxy)-4-methoxy-2-nitrobenzoate
A mixture of Stage-II (60.0 g), DMF (420 mL), Sodium carbonate (89.4 g) and 4-(3-chloropropyl) morpholine (101.2 g) were heated to 75- 80°C for 7 hours. After completion of reaction; reaction mixture cooled to 25°C. Reaction mixture diluted with water (500 mL) and extracted with ethyl acetate (500 mL). The layers were separated and organic layer was washed with water and distilled to obtain 107 g of 3-morpholinopropyl-5-(3-morpholinopropoxy)-4-methoxy-2-nitrobenzoate.
Example-4: Preparation of 3-morpholinopropyl-5-(3-morpholinopropoxy)-2-amino-4-methoxybenzoate
Stage-III (90.0 g) was hydrogenated using 10% palladium on carbon (9.0 g) in methanol (900 mL) at 3-4 Kg/cm¬2 at ambient temperature for 5 hours. After completion of reaction, the catalyst was removed by hyflo filtration. The filtrate was distilled off completely to obtain 65.0 g of 3-morpholinopropyl-5-(3-morpholinopropoxy)-2-amino-4-methoxybenzoate.
Example-5: Preparation of 6-(3-morpholinopropoxy)-7-methoxyquinazoline-4(3H)-one
Stage-IV (50.0 g) was added to formamidine acetate (21.5 g) in methanol (400 mL) and refluxed for 10 hours. After completion of reaction, the reaction mass was cooled to room temperature and stirred for 6 hours. The precipitated solid was filtered, washed with methanol and dried to obtain 25.0 g of 6-(3-morpholinopropoxy)-7-methoxyquinazoline-4(3H)-one.
Example-6: Preparation of 6-(3-morpholinopropoxy)-4-chloro-7-methoxyquinazoline
A mixture of Stage-V (10.0 g) and thionyl chloride (40 mL) were refluxed for 4 hours. The reaction mixture was distilled under reduced pressure to remove excess thionyl chloride. To the resulting residue added water (30 mL), basified with aq. sodium carbonate solution (10 %, 20 mL) and extracted the reaction mass with MDC (50 mL). The layers were separated and distilled off MDC to obtain 6-(3-morpholinopropoxy)-4-chloro-7-methoxyquinazoline which was further purified with isopropyl alcohol.
Example-7: Preparation of Gefitinib hydrochloride
A mixture of 6-(3-morpholinopropoxy)-4-chloro-7-methoxyquinazoline (15.0 g), water (75.00 mL), IPA (75.00 mL) and 3-chloro-4-fluoroaniline (7.12 g) was stirred for 15 mins. Charged slowly 35%Con.HCl (4.64g) for 10 min at25±5°C. Maintained reaction at 40-45°C for 3-4 hrs. Cooled it to room temperature and filtered the product. Washed the wet cake with IPA (30 mL). Dried it.
Example-8: Preparation of Gefitinib
Gefitinib hydrochloride is dissolved in MDC (100.00 mL). Aq.Ammonia (20.00mL) was added for 10min at 25±5°C and raised the temperature to 40-45°C for 30 min. Maintained 240-300min at 40-45°C. Cooled reaction mass to 25±5°C for 30 min. maintained for 60-90min at25±5°C The product was filtered. The wet cake was washed with MDC (10 mL). Suck dry the product for 30 minutes. Charged wet material into RBF at 25±5°C. Charged Ethylacetate (80 mL) and Isopropyl alcohol (80 mL) at 25±5°C.Heated the reaction mixture to 75-80°C. Stirred for 2 hours at 75-80°C. Cooled the reaction mixture to 25±5°C. Filtered the precipitated product. The wet material was washed with ethylacetate. Dried the product.
Example-9: Preparation of Methyl 4-methoxy-5-[3-(morpholine-4-yl) propyl]-2-nitrobenzoate:
Potassium carbonate (121.67 g) was added to stirred slurry of Methyl-5-hydroxy-4-methoxy-2-nitrobenzoate (100 g) and 4-(3-chloropropyl) morpholine hydrochloride (96.84 g) in acetonitrile (1000 ml) and resultant mixture was heated to 80±3°C for 6-7 hrs. After completion of reaction Acetonitrile was removed and process water (1000 ml) was added. Wet cake of residual mass was obtained by filtration under vacuum. Again process water was added into it and the reaction mixture was adjusting PH at 6.5 to 7.0 using 3-5.5% aqueous HCl solution. Then the reaction mixture was filtered and wet cake was dried at 50-55°C. There was thus obtain methyl 4-methoxy-5-[3-(morpholine-4-yl) propyl]-2-nitrobenzoate suitable for use in the next stage.
Example-10: Preparation of 7-methoxy-6-[3-(morpholine-4-yl) propoxy] quinazoline-4(3H)-one:
The slurry of Methyl 4-methoxy-5-[3-(morpholine-4-yl) propyl]-2-nitrobenzoate (100 g) in methanol (800ml) was charged into Hydrogenator. Into this slurry 10% Pd/C (10.0 g) was added and reaction mixture was subjected to hydrogenation under H2 gas. The resultant mixture was filtered through Hyflo bed and washed it with methanol. Methanol (400 ml) was distilled off atmospherically below 70 °C. Into the reaction mixture, formamidine acetate (88.14 g) and acetic acid (60 ml) are added and stir the reaction mixture for 12hrs at 65±3°C. Adjusted the pH by adding ammonia solution. The resultant mixture was cooled, and filtered the resulting mass and there was thus obtain 7-methoxy-6-[3-(morpholine-4-yl) propoxy] quinazoline-4(3H)-one suitable for use in the next stage.
Example-11: Preparation of 4-chloro-7-methoxy-6-[3-(morpholine-4-yl) propoxy] quinazoline:
The slurry of 7-methoxy-6-[3-(morpholine-4-yl) propoxy] quinazoline-4(3H)-one (100 g) was prepared in dichloromethane (500 mL), acetonitrile (500 mL) and DMF (20 mL) at 25±5°C. cool the reaction mixture to 3±2°C Stirred the reaction mass at 25±5°C for 10 min, into the resulting reaction mixture POCl3 (120 g) was added slowly and maintained the reaction mixture at 43±2°C and stir for 3 hr. the resulting reaction mixture was cooled to 0-5 °C for 30 min and add 20 % Na2CO3 solution at below 20°C. Then reaction mixture is added with MDC (500ml) and water (500ml). Separating organic layer from water, MDC (300ml) is added at 22±3°C, stirring and separating the lower organic layer (containing product) from aqueous layer at 22±3°C. 10 % brine solution (500 mL) was added into the combined organic layer. Allowing the layers to settle for 15±5 minutes at 22±3°C. Separating the lower organic layer (containing product) from aqueous layer at 22±3°C. Adding Neutral carbon PF SPL511 (5.0 g) into the organic layer. Filtering and drying to 4-chloro-7-methoxy-6-[3-(morpholine-4-yl) propoxy] quinazoline) obtain suitable for use in the next stage.
Example-12: Preparation of Gefitinib (crude) Form AL:
4-Chloro-7-methoxy-6-[3-(morpholine-4-yl) propoxy] quinazoline (100 g) was charged in acetone (700 ml) at 25±5°C. 3-Chloro-4-fluoroaniline (47.40 g) was added into the above slurry at 25±5°C and stirred for few minutes and then process water (700 ml) was added to the reaction mixture. Then oxalic acid dihydrate (37.31 g) was added at RT and stirred for few minutes monitoring reaction until completion. Adjusting the pH by 10% aqueous sodium hydroxide (200 ml) and washing with water to get Gefitinib Form AI
Example-13: Purification of N-(3-Chloro-4-Fluorophenyl)-7-methoxy-6-(3-morpholine-4-yl propoxy) quinazxoline-4-amine (Gefitinib):
Ethyl acetate (1000 mL) was charged into 250.00 mL 4-neck R.B.F at 25±5°C into this N-(3-Chloro-4-Fluorophenyl)-7-methoxy-6-(3-morpholine-4-yl propoxy) quinazxoline-4-amine (100g). Stirred the reaction mixture for 10 min. Then the reaction mixture was heated and maintained the temperature of 75-77°C for 1hrs. Cooled the reaction mixture and filtered the product and again washed it with ethylacetate (100 mL) and dried the wet cake and then add n-propanal (1500 ml) and heated to 85°C and activated carbon (Eno PC carbon) is added and reaction mixture is stirred and finally washing ethyl acetate to get pure N-(3-Chloro-4-Fluorophenyl)-7-methoxy-6-(3-morpholine-4-yl propoxy) quinazxoline-4-amine (Gefitinib- Form-I)
,CLAIMS:1. A process for the preparation of Gefitinib of Formula-I, and pharmaceutically acceptable salts thereof comprising the steps of;

a) reacting 4-(3-halopropyl) morpholine of formula-IV(a) or its salts thereof with a compound of formula-IV in presence of a base to obtain a compound of formula-V;
wherein X of formula IV (a) is any halogen
b) reducing the compound of formula-V in presence of a reducing agent to obtain a compound of formula-VI;

c) condensing the compound of formula-VI with formic acid or reactive derivative thereof to obtain a compound of formula-VII in a suitable solvent, wherein the reactive derivative is formamide or formamidine acetate and in presence of acetic acid

d) Converting the compound of formula-VII to Gefitinib of formula I or its pharmaceutically acceptable salts thereof.
2. The process as claimed in claim 1, wherein in step a) the base is selected from alkali metal, alkaline earth metal hydroxide, carbonates, bicarbonates and hydride.
3. The process as claimed in claim 1, wherein in step b) the reducing agent is selected from platinum, nickel, rhodium, platinum dioxide, ruthenium and palladium, optionally supported on a support, wherein said support is carbon.
4. A compound of formula-V, used as an intermediate in the preparation of Gefitinib of formula-I

5. A compound of formula-VI, used as an intermediate in the preparation of Gefitinib of formula-I

6. A process for preparation of Gefitinib of formula-I comprises
a) converting the compound of formula-VII to a compound of formula-VIII in presence of a thionyl chloride, phosphorus oxychloride, phosphorus trichloride, oxalyl chloride, or phosphorus pentachloride or the mixture thereof

b) reacting Formula-VIII with 3-chloro-4-fluoroaniline in presence of a acetone, water and oxalic acid or its dihydrate to obtain the Gefitinib of formula-I.
7. A crystalline Gefitinib Form-AL, characterized by an X-ray powder diffraction pattern comprising peaks expressed as at 6.48, 7.11, 11.3, 12.3, 14.2, 15.9, 16.39, 19.38, 24.04, 24.35 and 26.4 +0.2 deg. 2 theta.
8. The crystalline Form-AL according to claim-7 further comprises peaks at 8.35, 9.25, 10.00, 12.93, 13.91, 14.55, 15.34, 17.73, 18.65, 20.22, 20.75, 21.23, 22.39, 22.61, 24.04, 25.13, 27.31, 28.04, 28.61, 29.78, 30.68, 32.11, 32.98, 34.17, 34.86, 36.11 and 37.74+0.2 deg. 2 theta
9. The process as claimed in preceding claims, the Gefitinib obtained is converted to Form 1 of Gefitinib in n-propanol, ethyl acetate or mixtures thereof.

10. A process for preparation of Gefitinib of formula-1 comprises
a) reacting 5-hydroxy-4-methoxy-2-nitrobenzoate with 4-(3-chloropropyl) morpholium chloride to give Methyl 4-methoxy-5-[3-(morpholin-4-yl)propoxyl]-2-nitrobenzoate in presence of potassium carbonate
b) reduction of Methyl 4-methoxy-5-[3-(morpholin-4-yl)propoxyl]-2-nitrobenzoate to 2-amino-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzoate in presence of 10% Pd/C and methanol solvent
c) reacting 2-amino-4-methoxy-5-[3-(morpholin-4-yl)propoxy]benzoate with formamidine acetate to obtain 7-methoxy-6-[3-(morphlin-4-yl)propoxy]quinazolin-4(3H)-one in presence of and acetic acid
d) converting 7-methoxy-6-[3-(morphlin-4-yl)propoxy]quinazolin-4(3H)-one to 4-chloro-7-methoxy-6-[3-(morpholine-4-yl) propoxy] quinazoline presence of phosphorous oxychloride and Dichloromethane, DMF, Acetone
e) converting 4-chloro-7-methoxy-6-[3-(morpholine-4-yl) propoxy] quinazoline to Gefitinib in presence of acetone, water and oxalic acid dihydrate
f) converting obtained Gefitinib to crystalline Form-I in presence of n-propanol and ethyl acetate.