Field of the invention:
The present invention provides an improved process for the preparation of N-(3-chloro-4-fiuorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine represented by the following structural formula-1 and its pharmaceutically acceptable salts.
Formula-1
Background of the invention:
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine, commonly known as Gefitinib is a well-known inhibitor of epidemial growth factor receptor (EGFR) used to treat certain lung, breast and other cancers.
Gefitinib, its pharmaceutically acceptable salts and process for their preparation is first disclosed in US5770599A (herein after referred as '599' patent). This patent discloses two processes for the preparation of Gefitinib, one in example-1 and the other in example-10. The process disclosed in example-1 involves the selective demethylation of 6,7-dimethoxy quinazolin-4(3H)-one with methanesulfonic acid and L-methionine to provide corresponding 6-hydroxy derivative. Protection of the hydroxy moiety with acetyl group followed by chlorination with thionyl chloride provides 4-chloro-7-methoxyquinazolin-6-yl acétate, which is then reacted with 3-chloro-4-fluoroaniline. Deprotection of obtained intermedíate followed by etherification with 4-(3-chloropropyl)morpholine provides crude Gefitinib, which is purified by column chromatography and finally recrystallized from toluene to get required product in 50% yield. The process disclosed in example-1 is schematically represented in scheme-A.

Scheme-A:
Gefítinib
The above process suffers from several disadvantages. The selective demethylation using
methionine and methanesulfonic acid results in isomeric impurities and has to be purified or else the impurity carnes over to subsequent steps in the preparation of Gefítinib making it more difficult to isolate the required product in puré form.
The process also involves steps like protection and deprotection of 6-hydroxy group during the synthesis of Gefitinib which leads to more number of steps and making the process lengthy and time consuming.
One of the main drawbacks of the above process is formation of impurities during the introduction of morpholinopropyl side chain. During this stage, the main impurity that may form is N-alkyl impurity of the following formula.
N-alkyl impurity Removal of such impurities from Gefitinib requires extensive purification like column chromatography which is lengthy, cumbersome process and henee not viable on commercial scale for bulk production.

The process disclosed in example-10 of '599' patent is schematically represented as follows.
Scheme-B:
The extreme low yields in the above process are due to the formation of dimer impurity which is a result of condensation of two molecules of quinazoline compound at both the bromine atoms of 1,3-dibromopropane. Such extreme low yields highly impact the cost of the production.
The above process involves column purification at every step which is not advisable on industrial scale. In this process also there is a chance for the formation of the above said N-alkyl impurity.
Keeping in view of all the above difficulties, there is a significant need in the art to develop an improved and industrially advantageous process for the preparation of Gefitinib, which overcomes all the problems associated with the prior-art.
The present inventors tried different processes for the preparation of Gefitinib and found the process disclosed in the present invention as advantageous over prior-art processes in terms of yield and quality of the product with reduced time cycle.

Brief description of the invention:
The first aspect of the present invention is to provide a process for the preparation of puré Gefitinib compound of formula-1, comprising of;

a) Reacting the ethyl 3,4-dihydroxybenzoate compound of formula-2 with a suitable methylating agent in presence of a suitable base in a suitable solvent to provide ethyl 3,4-dimethoxybenzoate compound of formula-4,

b) treating the compound of formula-4 with nitric acid or nitration mixture (HNO3+H2SO4) in a suitable solvent to provide ethyl 4,5-dimethoxy-2-nitrobenzoate compound of formula-5,

c) treating the compound of formula-5 with a suitable base in a suitable solvent to provide 5-hydroxy-4-methoxy-2-nitrobenzoic acid compound of formula-6 which on in-situ reaction with methanolic HC1 provide methyl 5-hydroxy-4-methoxy-2-nitrobenzoate of formula-7,

d) reacting the compound of formula-7 with l-bromo-3-chloropropane in presence of a suitable base in a suitable solvent to provide mixture of methyl 5-(3-chloropropoxy)-4-methoxy nitrobenzoate/methyl 5-(3-bromopropoxy)-4-methoxy-2-nitrobenzoate which on in-situ reacting with morpholine in presence of suitable base and suitable catalyst in suitable solvent to provide methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate of formula-8,

e) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to provide methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate of formula-9,

f) reacting the compound of formula-9 with a suitable cyclization agent in a suitable solvent to provide 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one of formula-10,

g) treating the compound of formula-10 with a suitable chlorinating agent in presence of a suitable base in a suitable solvent to provide 4-(3-(4-chloro-7-methoxyquinazolin-6-yloxy) propyl)morpholine hydrochloride compound of formula-1 la which on in-situ reacting with 3-chloro-4-fluoroaniline compound of formula-12 in a suitable solvent to provide Gefitinib dihydrochloride salt compound of formula-la,

h) neutralizing the compound of formula-la with a suitable base in a suitable solvent to provide Gefitinib of compound of formula-1,

i) recrystallizing the compound of formula-1 from a suitable solvent or mixture of solvents to provide puré compound of formula-1.

The second aspect of the present invention is to provide a process for the preparation of methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of formula-9, comprising of;

a) reacting the methyl 5-hydroxy-4-methoxy-2-nitrobenzoate compound of formula-7 with l-bromo-3-chloropropane in presence of a suitable base in a suitable solvent to provide mixture of methyl 5-(3-chloropropoxy)-4-methoxy-2-mtrobenzoate/methyl 5-(3-bromo propoxy)-4-methoxy-2-nitrobenzoate which on in-situ reacting with morpholine in presence of a suitable base and suitable catalyst in a suitable solvent to provide methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8,

b) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to provide methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate of formula-9.
The third aspect of the present invention is to provide a process for the preparation of methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8, comprising of reacting the methyl 5-hydroxy-4-methoxy-2-nitrobenzoate compound of formula-7 with l-bromo-3-chloropropane in presence of a suitable base in a suitable solvent to provide mixture of methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate/methyl 5-(3-bromopropoxy)-4-methoxy-2-nitrobenzoate which on in-situ reacting with morpholine in presence of a suitable base and suitable catalyst in a suitable solvent to provide methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8.
The fourth aspect of the present invention is to provide a process for the preparation of methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of formula-9, comprising of reducing the methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8 with a suitable reducing agent in a suitable solvent to provide methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of formula-9.
The fifth aspect of the present invention is to provide a process for the preparation of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine dihydrochloride compound of formula-la, comprising of treating the 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one compound of formula-10 with a suitable chlorinating agent in presence of a suitable base in a suitable solvent to provide 4-(3-(4-chloro-7-methoxyquinazolin-6-yloxy)propyl)morpholine hydrochloride compound of formula-lla which on in-situ reacting with 3-chloro-4-fluoroaniline compound of formula-12 in a suitable solvent to provide N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine dihydrochloride compound of formula-la.
The sixth aspect of the present invention is to provide a process for the purification of Gefitinib compound of formula-1.

Detailed description of the invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane, cycloheptane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, di-tert-butyl ether, dimethoxy methane, 1,2-dimethoxy ethane, diglyme, 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran and the like; "ester solvents" such as methyl acétate, ethyl acétate, n-propyl acétate, isopropyl acétate, n-butyl acétate, iso-butyl acétate, tert-butyl acétate, diethyl carbonate and the like; "polar-aprotic solvents" such as dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), hexamethylphosphoramide (HMPA) and the like; "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile and like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbón tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol, 2-pentanol, ethylene glycol, diethylene glycol, propylene glycol, 2-ethyl hexanol, benzyl alcohol and the like; "polar solvents" such as water; acetic acid or mixtures thereof.
The term "suitable base" used in the present invention refers to inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium 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 and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA) and the like; "alkali metal phosphates" such as disodium hydrogen phosphate, dipotassiumhydrogen phosphate; and "organic bases" selected from but not limited to methyl amine, ethylamine, dimethylamine, diethylamine, triethylamine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole or mixtures thereof.

The first aspect of the present invention is to provide a process for the preparation of puré Gefitinib compound of formula-1, comprising of;

a) Reacting the ethyl 3,4-dihydroxybenzoate compound of formula-2
Formula-2 with a suitable methylating agent in presence of a suitable base in a suitable solvent to provide ethyl 3,4-dimethoxybenzoate compound of formula-4,

Formula-4

b) treating the compound of formula-4 with nitric acid or nitration mixture in a suitable solvent
to provide ethyl 4,5-dimethoxy-2-nitrobenzoate compound of formula-5,

Formula-5

c) treating the compound of formula-5 with a suitable base in a suitable solvent to provide 5-
hydroxy-4-methoxy-2-nitrobenzoic acid compound of formula-6

Formula-6 which on in-situ reaction with methanolic HC1 provide methyl 5-hydroxy-4-methoxy-2-nitrobenzoate compound of formula-7,
Formula-7

d) reacting the compound of formula-7 with l-bromo-3-chloropropane in presence of a suitable base in a suitable solvent to provide mixture of methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate/methyl 5-(3-bromopropoxy)-4-methoxy-2-nitrobenzoate which on in-situ reacting with morpholine in presence of suitable base and suitable catalyst in suitable solvent to provide methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate of formula-8,
Formula-8

e) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to
provide methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate of formula-9,

Formula-9
f) reacting the compound of formula-9 with a suitable cyclization agent in a suitable solvent to
provide 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one of formula-10,

Formula-10
g) treating the compound of formula-10 with a suitable chlorinating agent in presence of a suitable base in a suitable solvent to provide 4-(3-(4-chloro-7-methoxyquinazolin-6-yloxy)propyl)morpholine hydrochloride compound of formula-11a

Formula-11a
which on in-situ reacting with 3-chloro-4-fluoroaniline compound of formula-12
Formula-12
in a suitable solvent to provide Gefitinib dihydrochloride salt compound of formula-la,

Formula-1a
h) neutralizing the compound of formula-la with a suitable base in a suitable solvent to provide
Gefitinib of compound of formula-1, i) recrystallizing the compound of formula-1 from a suitable solvent or mixture of solvents to provide puré compound of formula-1. Wherein,
In step-a) the suitable methylating agent is selected from dimethyl sulfate, methyl iodide and the like; the suitable base is selected from organic and inorganic bases, preferably alkali metal carbonates; and the suitable solvent is selected from ester solvents, ether solvents, alcohol solvents, ketone solvents, polar solvents, polar-aprotic solvents, nitrile solvents, chloro solvents, hydrocarbon solvents or their mixtures;

In step-b) the suitable solvent is selected from acetic acid, ether solvents, chloro solvents or their mixtures;

In step-c) the suitable base is selected form alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates; the suitable solvent is selected from polar solvents, ether solvents, ester solvents, hydrocarbon solvents, ketone solvents, alcohol solvents, chloro solvents or their mixtures;

In step-d) the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates, organic bases; the suitable solvent is selected from polar-aprotic solvents, polar solvents, ether solvents, ester solvents, hydrocarbon solvents, ketone solvents, alcohol solvents, chloro solvents, nitrile solvents or their mixtures; the suitable catalyst is selected from alkali metal bromides, alkali metal iodides; preferably potassium iodide;

In step-e) the suitable reducing agent is selected from Ni, Raney Ni, Pd/C, Fe, Fe in acidic media like HCl, acetic acid, NH4CI; Sn-HCl, stannous chloride (SnC^), Zn in acidic media like HCl, acetic acid, NH4CI, Zinc dust, sodium borohydride, lithium borohydride, lithium

aluminium hydride, sodium aluminium hydride, diborane, hydrazine hydrate, sodium dithiomte and the like; the suitable solvent is selected from alcohol solvents, ether solvents, ester solvents, hydrocarbon solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents or their mixtures;

In step-f) the suitable cyclization agent is selected from formic acid, formic acid esters, orthoformic acid esters in combination with ammonia or ammonium aliphatic or aromatic carboxylates; formamide optionally in combination with ammonium aliphatic or aromatic carboxylates; the suitable solvent is selected from alcohol solvents, ether solvents, ester solvents, hydrocarbon solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents, nitrile solvents or their mixtures;
In step-g) the suitable chlorinating agent is selected form phosphorous oxychloride, thionyl chloride, phosphorous trichloride and he like; the suitable base is selected from organic bases and the suitable solvent is selected from hydrocarbon solvents, alcohol solvents, ether solvents, ester solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents, nitrile solvents or their mixtures;

In step-h) the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and the suitable solvent is selected from polar solvents, alcohol solvents, hydrocarbon solvents, ether solvents or their mixtures;

In step-i) the suitable solvent is selected from alcohol solvents, chloro solvents or their mixtures.
Apreferred embodiment of the present invention provides a process for the preparation of Gefitinib, comprising of;

a) Reacting ethyl 3,4-dihydroxybenzoate compound of formula-2 with dimethyl sulfate in presence of potassium carbonate in ethyl acétate to provide ethyl 3,4-dimethoxybenzoate compound of formula-4,

b) treating the compound of formula-4 with nitric acid in acetic acid to provide ethyl 4,5-dimethoxy-2-nitrobenzoate compound of formula-5,

c) treating the compound of formula-5 with aqueous potassium hydroxide solution to provide 5-hydroxy-4-methoxy-2-nitrobenzoic acid compound of formula-6 which on in-situ reacting with methanolic HC1 to provide methyl 5-hydroxy-4-methoxy-2-nitrobenzoate of formula-7,

d) reacting the compound of formula-7 with l-bromo-3-chloropropane in presence of potassium carbonate in N,N-dimethyl formamide to provide mixture of methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate/methyl 5-(3-bromopropoxy)-4-methoxy-2-nitrobenzoate which on in-situ reacting with morpholine in presence of potassium carbonate and potassium iodide to provide methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate of
formula-8,

e) reducing the compound of formula-8 using Fe/acetic acid in methanol to provide methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of formula-9,
f) reacting the compound of formula-9 with triethyl orthoformate in presence of ammonium acétate in methanol to provide 7-methoxy-6-(3-morpholino propoxy)quinazolin-4(3H)-one compound of formula-10,

g) treating the compound of formula-10 with phosphorus oxychloride in presence of triethylamine in toluene to provide 4-(3-(4-chloro-7-methoxyquinazolin-6-yloxy)propyl) morpholine hydrochloride compound of formula-lla which on in-situ reaction with 3-chloro-4-fluoroaniline compound of formula-12 in isopropyl alcohol provides N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine dihydrochloride compound of formula-1 a,

h) treating the compound of formula-la with aqueous sodium hydroxide solution in water to provide Gefitinib compound of formula-1, i) recrystallizing the compound of formula-1 from a mixture of dichloromethane/methanol to provide puré Gefitinib, which on further recrystallization from a mixture of methanol/isopropyl alcohol provides highly puré Gefitinib.

The process of the present invention involves less number of steps and doesn't involve any protection and deprotection steps.

The present inventors found that in order to avoid the formation of N-alkyl impurity as observed in prior-art process, it is preferable to introduce the 3-morpholinopropoxy group in earlier steps of the synthetic process.

By adopting the process of the present invention, the present inventors avoided the highly expensive and cumbersome column chromatography technique for the purification of Gefitinib and its intermediares and making the process highly advantageous over prior reported processes.

The second aspect of the present invention is to provide a process for the preparation of methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of formula-9, comprising of;
a) reacting the methyl 5-hydroxy-4-methoxy-2-nitrobenzoate compound of formula-7 with 1-bromo-3-chloropropane in presence of a suitable base in a suitable solvent to provide mixture of methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate/methyl 5-(3-bromopropoxy)-4-methoxy-2-nitrobenzoate which on in-situ reacting with morpholine in presence of a suitable base and suitable catalyst in a suitable solvent to provide methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8,

b) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to provide methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate of formula-9.
Wherein, in step-a) the suitable base, the suitable solvent and the suitable catalyst are same as defined in step-d) of the first aspect of the present invention;

In step-b) the suitable reducing agent and the suitable solvent are same as defined in step-e) of the first aspect of the present invention.
Apreferred embodiment of the present invention provides a process for the preparation of methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of formula-9, comprising of;

a) reacting the methyl 5-hydroxy-4-methoxy-2-nitrobenzoate compound of formula-7 with l-bromo-3-chloropropane in presence of potassium carbonate in N,N-dimethylformamide to provide mixture of methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate/methyl 5-(3-bromopropoxy)-4-methoxy-2-nitrobenzoate which on in-situ reacting with morpholine in presence of potassium carbonate and potassium iodide to provide methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8,

b) reducing the compound of formula-8 using Fe/acetic acid in methanol to provide methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of formula-9.

The third aspect of the present invention is to provide a process for the preparation of methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8, comprising of reacting the methyl 5-hydroxy-4-methoxy-2-nitrobenzoate compound of formula-7 with l-bromo-3-chloropropane in presence of a suitable base in a suitable solvent to provide mixture of methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate/methyl 5-(3-bromopropoxy)-4-methoxy-2-nitrobenzoate which on in-situ reacting with morpholine in presence of a suitable base and suitable catalyst in a suitable solvent to provide methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8.

Wherein, the suitable base, the suitable solvent and the suitable catalyst are same as defined in
step-d) of the first aspect of the present invention.
Apreferred embodiment of the present invention provides a process for the preparation of methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8, comprising of reacting the methyl 5-hydroxy-4-methoxy-2-nitrobenzoate compound of formula-7 with l-bromo-3-chloropropane in presence of potassium carbonate in N,N-dimethylformamide to provide a mixture of methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate/methyl 5-(3-bromopropoxy)-4-methoxy-2-nitrobenzoate which on in-situ reacting with morpholine in presence of potassium carbonate and potassium iodide to provide methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8.
The fourth aspect of the present invention is to provide a process for the preparation of methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of formula-9, comprising of reducing the methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8 with a suitable reducing agent in a suitable solvent to provide methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of formula-9.
Wherein, the suitable reducing agent and the suitable solvent are same as defined in step-e) of the first aspect of the present invention.
Apreferred embodiment of the present invention provides a process for the preparation of methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of formula-9, comprising of reducing the methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate

compound of formula-8 with Fe/acetic acid in methanol to provide methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of formula-9.

The fifth aspect of the present invention is to provide a process for the preparation of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine dihydrochloride compound of formula-la, comprising of treating the 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one compound of formula-10 with a suitable chlorinating agent in presence of a suitable base in a suitable solvent to provide 4-(3-(4-chloro-7-methoxyquinazolin-6-yloxy)propyl)morpholine hydrochloride compound of formula-lla which on in-situ reacting with 3-chloro-4-fluoroaniline compound of formula-12 in a suitable solvent to provide dihydrochloride compound of formula-1a.
Wherein, the suitable chlorinating agent, the suitable base and the suitable solvent are same as defined
In step-g) of the first aspect of the present invention.
Apreferred embodiment of the present invention provides a process for the preparation of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine dihydrochloride compound of formula-la, comprising of treating the 7-methoxy-6-(3-morphoiinopropoxy)quinazolin-4(3H)-one compound of formula-10 with phosphorus oxychloride in presence of triethylamine in toluene to provide 4-(3-(4-chloro-7-methoxy quinazolin-6-yloxy)propyl) morpholine hydrochloride compound of formula-lla which on in-situ reaction with 3-chloro-4-fiuoroaniline compound of formula-12 in isopropyl alcohol provides N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine dihydrochloride compound of formula-1a.
The sixth aspect of the present invention is to provide a process for the purification of Gefitinib compound of formula-1. The said purification process comprises recrystallizing Gefitinib from a suitable solvent or mixture of solvents.
Wherein, the suitable solvent is selected from alcohol solvents, chloro solvents, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, nitrile solvents, ketone solvents, polar-aprotic solvents or their mixtures.

The purification process of the present invention preferably comprises recrystallization of Gefitinib from alcohol solvents or chloro solvents or mixture of alcohol and chloro solvents.

A preferred embodiment of the present invention provides a process for the purification of Gefitinib comprising recrystallizing it from a mixture of dichloromethane and methanol to provide puré Gefitinib.

Another preferred embodiment of the present invention provides a process for the purification of Gefitinib comprising recrystallizing it from a mixture of isopropyl alcohol and methanol to provide puré Gefitinib.

Gefitinib obtained by the process of the present invention is highly puré and all the impurities are well within the limits and in compliance with ICH.

Gefitinib obtained by the process of the present invention was analyzed by HPLC under the following conditions;

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector and integrator; Column: Inertsil ODS4, 250><4.6 mm, 5 um or equivalent; Flow rate: 1.2 mL/minute; Wave length: 240 nm; Injection volume: 5 [iL; Column temperature: 35°C; Run time: 38 minutes; Mobile phase-A: Buffer: acetonitrile (95:05 v/v); Mobile phase-B: Acetonitrile: water (90:10 v/v); Buffer: Weigh accurately 1.54 gm of ammonium acétate, transfer into 1000 mi of milli-Q-water, filter through 0.22 um nylon membrane filter paper; Diluent: water:acetonitrile (1:1 v/v); Elution: Gradient.

Gefitinib obtained by the process of 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 milis, roller and hammer milis and jet milis. Milling or micronization may be performed before drying or after the completion of drying of the product.

The present invention is schematically represented as follows.
Gefitinib Formula-1

Examples:
The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and henee should not be construed as limitation to the scope of the invention.
Example-1: Preparation of ethyl 3,4-dimethoxybenzoate (Formula-4)
Potassium carbonate (56.9 gm) was added to a solution of ethyl 3,4-dihydroxybenzoate compound of formula-2 (25 gm) in ethyl acétate (200 mi) at 25-30°C. Dimethyl sulfate (39 mi) was slowly added to the reaction mixture, heated the reaction mixture to 50-5 5°C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 45-50°C, water was added and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to below 20°C and water was added. Raised the temperature of the reaction mixture to 25-30°C, ethyl acétate was added and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water followed by 20% aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 26.7 gm.
ExampIe-2: Preparation of ethyl 4,5-dimethoxy-2-nitrobenzoate (Formula-5)Ethyl 3,4-dimethoxybenzoate compound of formula-4 (110 gm) was dissolved in acetic acid (330 mi) at 25-30°C. This solution was added to pre-cooled nitric acid (198 gm) at 0-5°C and stirred for 15 min at the same temperature. Heated the reaction mixture to 40-45°C and stirred for 2 hrs at the same temperature. Cooled the reaction mixture to 10-15°C, water and dichloromethane were added and stirred the reaction mixture for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with water followed by sodium bicarbonate solution. Distilled off the solvent completely from the organic layer. Pet ether (550 mi) was added to the obtained solid at 25-30°C and stirred for 45 min at the same temperature. Filtered the solid, washed with pet ether and dried to get the title compound.

Example-3: Preparation of methyl 5-hydroxy-4-methoxy-2-nitrobenzoate (Formula-7)
A mixture of ethyl 4,5-dimethoxy-2-nitrobenzoate compound of formula-5 (120 gm) and aq.potassium hydroxide solution (840 mi) was heated to 90-95°C and stirred for 8 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and adjusted the pH of the reaction mixture to 1.0 with hydrochloric acid. Ethyl acétate was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure to get 5-hydroxy-4-methoxy-2-nitrobenzoic acid compound of formula-6. Methanolic HC1 (1200 mi) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 8 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure and co-distilled with methanol. Pet ether (600 mi) was added to the obtained solid at 25-30°C and stirred for 60 min at the same temperature. Filtered the solid,
washed with pet ether and dried to get the title compound. Yield: 85.0 gm.
Example-4: Preparation of methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate (Formula-8)
Potassium carbonate (85.2 gm) was added to a mixture of methyl 5-hydroxy-4-metho'xy-2-nitrobenzoate compound of formula-7 (70 gm) and N,N-dimethylformamide (280 mi) at 25-30°C and stirred for 15 min at the same temperature. l-bromo-3-chloropropane (107.5 gm) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 50-55°C and stirred for 45 min at the same temperature. Water (7 mi) was added to the reaction mixture at 50-55°C and stirred for 3 hrs at the same temperature. Reduced the temperature of the reaction mixture to 35-40°C. Filtered the reaction mixture through hyfiow bed and washed the hyflow bed with ethyl acétate. Both the organic and aqueous layers were separated and the organic layer was washed with 20% aqueous sodium chloride solution. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure. N,N-dimethylformamide (175 mi) was added to the obtained compound and stirred the reaction mixture for 15 min. Potassium carbonate (106.5 gm) was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Morpholine (80.5 gm) and potassium iodide (5.1 gm) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 8 hrs at the same temperature. Cooled the reaction mixture to 5-10°C, water was slowly added and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with water and suck dried. The obtained solid was added to water (280 mi) at 25-30°C and stirred for 45 min at the same temperature. Filtered the solid, washed with water and dried. The obtained solid was added to ethyl acétate (210 mi) at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 1 hr at the same temperature. Slowly cooled the reaction mixture to 10-15°C and stirred for 90 min at the same temperature. Filtered the solid, washed with pre-cooled ethyl acétate and dried to get the title compound. Yield: 91.3 gm.

Example-5: Preparation of methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate (Formula-9)
A mixture of methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8 (85 gm), methanol (510 mi), acetic acid (85 mi) and Iron powder (53.5 gm) was heated to 55-60°C and stirred for 6 hrs at the same temperature. Cooled the reaction mixture to 0-5°C. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with methanol. Distilled off the solvent completely from the fíltrate under reduced pressure. Cooled the reaction mixture to 25-30°C and water was added. Adjusted the pH of the reaction mixture to 7.5 using 10% sodium carbonate solution. Cooled the reaction mixture to 5-10°C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with water and suck dried the material. The obtained solid was added to a 2:8 mixture of methanol and dichloromethane (850 mi) at 25-30°C and stirred for 45 min at the same temperature. Filtered the reaction mixture through hyflow bed and 10% sodium chloride solution was added to the fíltrate. Both the organic and aqueous layers were separated, distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with pet ether. To the obtained solid, pet ether (425 mi) was added at 25-3 0°C and stirred for 90 min at the same temperature. Filtered the solid, washed with pet ether and dried to get the title compound. Yield: 65.0 gm.

Example-6: Preparation of 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one (Formula-10)
Triethylorthoformate (82.2 gm) and ammonium acétate (42.7 gm) were added to a mixture of methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of formula-9 (60 gm) and methanol (180 mi) at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 8 hrs at the same temperature. Reduced the temperature of the reaction mixture to 45-50°C, methanol was added to it and stirred for 30 min at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 90 min at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound. Yield: 55.6 gm.
Example-7: Preparatíon of 7-methoxy-6-(3-morpholino propoxy)quinazolin-4(3H)-one compound of formula-10

A mixture of methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of formula-9 (5 gm) and formamide (25 mi) was heated to 150-160°C and stirred for 8 hrs at the same temperature. Distilled off the reaction mixture completely under reduced pressure. Acetonitrile (25 mi) was added to the obtained reaction mixture at 65-70°C and stirred for 30 min at the same temperature. Cooled the reaction mixture to 0-5°C, diisopropyl ether (25 mi) was added to it and stirred for 30 min at the same temperature. Filtered the solid, washed with diisopropyl ether and dried to get the title compound. Yield: 2.6 gm.

Example-8: Preparatíon of Gefitinib dihydrochloride (Formula-la)

Triethylamine (21.5 gm) and phosphorous oxychloride (43.2 gm) were added to a pre-cooled mixture of 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one compound of formula-10 (45 gm) and toluene (225 mi) at 0-5°C and stirred for 15 min at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 60 min at the same temperature. Cooled the reaction mixture to 40-45°C and a solution of 3-chloro-4-fiuoroaniline compound of formula-12 (26.6 gm) in isopropyl alcohol (45 mi) was slowly added to it. Heated the reaction mixture to 70-75°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and suck dried the compound. The obtained compound was added to methanol (450 mi), heated the reaction mixture to 55-60°C and stirred for 3 hrs at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 90 min at the same temperature. Filtered the solid, washed with methanol and suck dried. The obtained compound was added to methanol (315 mi) at 25-3 0°C and stirred for 2 hrs at the same temperature. Filtered the solid, washed with methanol and dried to get the title compound. Yield: 73.25 gm.

Example-9: Preparatíon of Gefitinib (Formula-1)

Gefitinib dihydrochloride (55 gm) was added to water (550 mi) at 25-30°C and stirred for 20 min at the same temperature. Heated the reaction mixture to 55-60°C, carbón (11 gm) was added to the solution and stirred for 2 hrs at the same temperature. Filtered the reaction mixture through hyflow bed and adjusted the pH of the reaction mixture to 10.0 using 3% sodium hydroxide solution at 55-60°C. Cooled the reaction mixture to 25-30°C and stirred for 90 min at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 47.3 gm.

Example-10: Purification of Gefitinib (Formula-l)

Gefitinib (40 gm) was added to dichloromethane (200 mi) at 25-30°C and stirred for 15 min at the same temperature. Methanol (200 mi) was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Carbón (8 gm) was added to the obtained solution, heated the reaction mixture to reflux temperature and stirred for 90 min at the same temperature. Filtered the reaction mixture through hyflow bed, distilled off the solvent completely from the fíltrate under reduced pressure and co-distilled with methanol. To the obtained compound, methanol (80 mi) was added and stirred the reaction mixture for 15 min at the same temperature. Isopropyl alcohol (200 mi) was added to the obtained solid, heated the reaction mixture to 55-60°C and stirred for 90 min at the same temperature. Slowly cooled the reaction mixture to 0-5 °C and stirred for 2 hrs at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol and dried to get the puré title compound. Yield: 30.2 gm; M.R: 193-197°C; Purity by HPLC: 99.9%; Keto impurity: 0.004%; Chloro impurity: Not detected; N-oxide impurity: 0.03%; Amine impurity: Not detected.

Formula-1

We Claim:

1. A process for the preparation of puré Gefítinib compound of formula-1, comprising of;
a) Reacting the ethyl 3,4-dihydroxybenzoate compound of formula-2
Formula-2 with a suitable methylating agent in presence of a suitable base in a suitable solvent to provide ethyl 3,4-dimethoxybenzoate compound of formula-4,
Formula-4

b) treating the compound of formula-4 with nitric acid or nitration mixture in a suitable
solvent to provide ethyl 4,5-dimethoxy-2-nitrobenzoate compound of formula-5,
Formula-5

c) treating the compound of formula-5 with a suitable base in a suitable solvent to provide
5-hydroxy-4-methoxy-2-nitrobenzoic acid compound of formula-6
Formula-6 which on in-situ reaction with methanolic HC1 to provide methyl 5-hydroxy-4-methoxy-2-nitrobenzoate compound of formula-7,

d) reacting the compound of formula-7 with l-bromo-3-chloropropane in presence of a
suitable base in a suitable solvent to provide mixture of methyl 5-(3-chloropropoxy)-4-
methoxy-2-nitrobenzoate/methyl 5-(3 -bromopropoxy)-4-methoxy-2-nitrobenzoate which
on in-situ reacting with morpholine in presence of a suitable base and suitable catalyst in
a suitable solvent to provide methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitro
benzoate compound of formula-8,

Formula-8
e) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent
to provide methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of
formula-9,

Formula-9

f) reacting the compound of formula-9 with a suitable cyclization agent in a suitable solvent
to provide 7-methoxy-6-(3-morpholinopropoxy)quinazolin-4(3H)-one of formula-10,

Formula-10

g) treating the compound of formula-10 with a suitable chlorinating agent in presence of a
suitable base in a suitable solvent to provide 4-(3-(4-chloro-7-methoxyquinazolin-6-yl
oxy)propyl)morpholine hydrochloride compound of formula-11a

Formula-11a
which on in-situ reaction with 3-chloro-4-fluoroaniline compound of formula-12
H2N' ^ XI Formula-12 in a suitable solvent to provide Gefitinib dihydrochloride salt compound of formula-la,
HN' ^ XI

YY^N
.2HC1 ^XJ^^J
Formula-la
h) neutralizing the compound of formula-la with a suitable base in a suitable solvent to
provide Gefitinib of compound of formula-1,

i) recrystallizing the compound of formula-1 from a suitable solvent or mixture of solvents to provide puré compound of formula-1.

2. A process according to claim 1, wherein;
in step-a) the suitable methylating agent is selected from dimethyl sulfate, methyl iodide and the like; the suitable base is selected from organic and inorganic bases, preferably alkali metal carbonates; and the suitable solvent is selected from ester solvents, ether solvents, alcohol solvents, ketone solvents, polar solvents, polar-aprotic solvents, nitrile solvents, chloro solvents, hydrocarbon solvents or their mixtures;
In step-b) the suitable solvent is selected from acetic acid, ether solvents, chloro solvents or their mixtures;
In step-c) the suitable base is selected form alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates; the suitable solvent is selected from polar solvents, ether solvents, ester solvents, hydrocarbon solvents, ketone solvents, alcohol solvents, chloro solvents or their mixtures;
In step-d) the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates, organic bases; the suitable solvent is selected from polar-aprotic solvents, polar solvents, ether solvents, ester solvents, hydrocarbon solvents, ketone solvents, alcohol solvents, chloro solvents, nitrile solvents or their mixtures; the suitable catalyst is selected from alkali metal bromides, alkali metal iodides; preferably potassium iodide;

In step-e) the suitable reducing agent is selected from Ni, Raney Ni, Pd/C, Fe, Fe in acidic media like HCl, acetic acid, NH4CI; Sn-HCl, stannous chloride (SnC^), Zn in acidic media like HCl, acetic acid, NH4C1, Zinc dust, sodium borohydride, lithium borohydride, lithium aluminium hydride, sodium aluminium hydride, diborane, hydrazine hydrate, sodium dithionite and the like; the suitable solvent is selected from alcohol solvents, ether solvents, ester solvents, hydrocarbon solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents or their mixtures;

In step-f) the suitable cyclization agent is selected from formic acid, formic acid esters, orthoformic acid esters in combination with ammonia or ammonium aliphatic or aromatic carboxylates; formamide optionally in combination with ammonium aliphatic or aromatic carboxylates; the suitable solvent is selected from alcohol solvents, ether solvents, ester solvents, hydrocarbon solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents, nitrile solvents or their mixtures;

In step-g) the suitable chlorinating agent is selected form phosphorous oxychloride, thionyl chloride, phosphorous trichloride and the like; the suitable base is selected from organic bases and the suitable solvent is selected from hydrocarbon solvents, alcohol solvents, ether solvents, ester solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents, nitrile solvents or their mixtures;

In step-h) the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates and the suitable solvent is selected from polar solvents, alcohol solvents, hydrocarbon solvents, ether solvents or their mixtures;

In step-i) the suitable solvent is selected from alcohol solvents, chloro solvents or their mixtures.
3. A process for the preparation of puré Gefitinib compound of formula-1, comprising of;

a) Reacting ethyl 3,4-dihydroxybenzoate compound of formula-2 with dimethyl sulfate in presence of potassium carbonate in ethyl acétate to provide ethyl 3,4-dimethoxybenzoate compound of formula-4,

b) treating the compound of formula-4 with nitric acid in acetic acid to provide ethyl 4,5-dimethoxy-2-nitrobenzoate compound of formula-5,

c) treating the compound of formula-5 with aqueous potassium hydroxide solution to provide 5-hydroxy-4-methoxy-2-nitrobenzoic acid compound of formula-6 which on in-situ reacting with methanolic HC1 to provide methyl 5-hydroxy-4-methoxy-2-nitrobenzoate compound of formula-7,

d) reacting the compound of formula-7 with l-bromo-3-chloropropane in presence of potassium carbonate in N,N-dimethyl formamide to provide mixture of methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate/methyl 5-(3-bromopropoxy)-4-methoxy-2-nitrobenzoate which on in-situ reacting with morpholine in presence of potassium carbonate and potassium iodide to provide methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8,

e) reducing the compound of formula-8 using Fe/acetic acid in methanol to provide methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzoate compound of formula-9,

f) reacting the compound of formula-9 with triethylorthoformate in presence of ammonium acétate in methanol to provide 7-methoxy-6-(3-morpholino propoxy)quinazolin-4(3H)-one compound of formula-10,

g) treating the compound of formula-10 with phosphorus oxychloride in presence of triethylamine in toluene to provide 4-(3-(4-chloro-7-methoxyquinazolin-6-yloxy)propyl) morpholine hydrochloride compound of formula-lla which on in-situ reaction with 3-chloro-4-fluoroaniline compound of formula-12 in isopropyl alcohol provides N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine dihydrochloride compound of formula-la,

h) treating the compound of formula-la with aqueous sodium hydroxide solution in water to
provide Gefitinib compound of formula-1, i) recrystallizing the compound of formula-1 from a mixture of dichloromethane/methanol to provide puré compound of formula-1 which on further recrystallization from a mixture of methanol/isopropyl alcohol provides highly puré Gefitinib.

4. A process for the preparation of methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy) benzoate compound of formula-9, comprising of;

a) reacting the methyl 5-hydroxy-4-methoxy-2-nitrobenzoate compound of formula-7 with l-bromo-3-chloropropane in presence of a suitable base in a suitable solvent to provide mixture of methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate/methyl 5-(3-bromopropoxy)-4-methoxy-2-nitrobenzoate which on in-situ reacting with morpholine in presence of a suitable base and suitable catalyst in a suitable solvent to provide methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8, b) reducing the compound of formula-8 with a suitable reducing agent in a suitable solvent to provide compound of formula-9.

5. A process according to claim 4, wherein,
in step-a) the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, alkali metal bicarbonates, organic bases; the suitable solvent is selected from polar-aprotic solvents, polar solvents, ether solvents, ester solvents, hydrocarbon solvents, ketone solvents, alcohol solvents, chloro solvents, nitrile solvents or their mixtures; the suitable catalyst is selected from alkali metal bromides, alkali metal iodides; preferably potassium iodide;

in step-b) the suitable reducing agent is selected from Fe in acidic media like HC1, acetic acid, NH4CI; the suitable solvent is selected from alcohol solvents, ether solvents, ester solvents, hydrocarbon solvents, ketone solvents, chloro solvents, polar solvents, polar-aprotic solvents or their mixtures.

6. A process for the preparation of methyl 4-methoxy-5-(3-morpholinopropoxy)-2-
nitrobenzoate compound of formula-8, comprising of reacting the methyl 5-hydroxy-4-
methoxy-2-nitrobenzoate compound of formula-7 with l-bromo-3-chloropropane in presence
of a suitable base in a suitable solvent to provide mixture of methyl 5-(3-chloropropoxy)-4-
methoxy-2-nitrobenzoate/methyl 5-(3-bromopropoxy)-4-methoxy-2-nitrobenzoate which on
in-situ reacting with morpholine in presence of a suitable base and suitable catalyst in a
suitable solvent to provide compound of formula-8, wherein the suitable base is selected
from inorganic or organic bases; the suitable solvent is selected from polar-aprotic solvents,
polar solvents, ether solvents, ester solvents, hydrocarbon solvents, ketone solvents, alcohol
solvents, chloro solvents, nitrile solvents or their mixtures; the suitable catalyst is selected
from alkali metal bromides, alkali metal iodides; preferably potassium iodide.

7. A process for the preparation of methyl 2-amino-4-methoxy-5-(3-morpholinopropoxy) benzoate compound of formula-9, comprising of reducing the methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate compound of formula-8 with Fe in acidic media like HC1, acetic acid, NH4CI in a suitable solvent to provide compound of formula-9.

8. A process for the preparation of Gefitinib dihydrochloride compound of formula-la, comprising of treating the compound of formula-10 with a suitable chlorinating agent in presence of a suitable base in a suitable solvent to provide 4-(3-(4-chloro-7-methoxy quinazolin-6-yloxy)propyl)morpholine hydrochloride compound of formula-lla which on in-situ reacting with 3-chloro-4-fluoroaniline compound of formula-12 in a suitable solvent to provide Gefitinib dihydrochloride compound of formula-la.

9. A process for the purification of Gefitinib, comprising of recrystallizing Gefitinib from a solvent mixture comprising chloro solvent and alcohol solvent, preferably from a mixture of dichloromethane and methanol to provide puré Gefitinib.

10. A process for the purification of Gefitinib, comprising of recrystallizing Gefitinib from a suitable alcohol solvent or mixture of alcohol solvents, preferably from a mixture of isopropyl alcohol and methanol to provide puré Gefitinib.