WO2010076810A2

WO2010076810A2 - A process for the preparation of gefitinib

Info

Publication number: WO2010076810A2
Application number: PCT/IN2009/000746
Authority: WO
Inventors: Ashvin Kumar Aggarwal; Anshul Kumar Jain; Venkateswaran Srinivasan Chidambaram; Lalit Wadhwa
Original assignee: Ind-Swift Laboratories Limited
Priority date: 2008-12-30
Filing date: 2009-12-29
Publication date: 2010-07-08
Also published as: WO2010076810A3

Abstract

The present invention provides an improved, industrial advantageous process for the preparation of gefitinib of formula (I), and its pharmaceutically acceptable salts thereof in high yield and purity.

Description

A Process For The Preparation Of Gefitinib

FIELD OF THE INVENTION

The present invention relates to an industrially advantageous process for the preparation of gefitinib of formula I,

Formula I and pharmaceutically acceptable salts thereof, an anilinoquiriazoline which is useful in the treatment of certain type of lung cancer. BACKGROUND OF THE INVENTION

Gefitinib of formula I, is an anilinoquinazoline which is useful in the treatment of certain type of lung cancer (non-small cell lung cancer) that does not respond to chemotherapy and is chemically known as N- (3-chloro-4-fluorophenyl)-[7-methoxy-6-(3-(4-morpholinyl)propoxy)-4-quinazolinamine.

Formula I

It is the first selective inhibitor of epidermal growth factor receptor's (EGFR) tyrosine kinase domain. Gefitinib and pharmaceutically acceptable salts thereof were first reported in EP 0823900 Bl. The process disclosed for the preparation of gefitinib involves the selective demethylation of quinazoline derivative, 6,7-dimethoxy-3H-quinazolin-4-one, using methanesulfonic acid and L-methionine to form corresponding 6-hydroxyl derivative. Protection of the hydroxyl moiety by acetylation of the 6-hydroxyl derivative, followed by reaction with thionyl chloride to form the corresponding chloro derivative, which is then condensed with chlorofluoroaniline. Hydrolysis of the resulting intermediate is followed by etherification with 3-morpholinopropyl chloride to give gefitinib, which is further purified by column chromatography.

Above process suffers from several disadvantages as it involves the use of large amount of methane sulfonic acid and- L-methionine for demethylation which results in the formation of isomeric impurities. Main drawback of the above process is formation of impurities during the introduction of morpholinopropyl side chain, during this stage main impurity that may form is N-alkylated impurity of following formula,

Removal of such impurities requires extensive purification like column chromatography, being lengthy and cumbersome not viable for the bulk production. Chinese patent CN l 733738 discloses a process for the preparation of gefitinib by the nitration of the 3,4- dimethoxy benzoic acid with red fuming nitric acid followed by simultaneous demethylation and reduction with potassium hydroxide and sodium hydrosulfite to form 2-amino-4-methoxy-5- hydroxybenκoic acid intermediate. This intermediate is then cyclised using formamide or formamidine salts thereof, chlorinated by using thionyl chloride, condensed successively with 3-chloro-4-fluoroaniline in isopropanol and with morpholinopropyl chloride in presence of potassium carbonate and dimethyl formamide to give gefitinib in 48 % yield. Such a low yield of the final compound is not desirable on the commercial scale. _& hydroxy-4-methoxy benzonitrile which involves its condensation with morpholinopropyl chloride followed by nitration, reduction with sodium dithionite to amino compound, hydrolysis of nitrile to amide, cyclization in the presence of formamide to obtain quinazolihe, chlorination with phosphorous oxychloride and finally condensation with chloro-fluoro aniline to give gefitinib. The process involves multiple steps and hence is time consuming.

PCT publication, WO 2005/023783 discloses a process for the manufacture of gefitinib starting from 2- amino-4-methoxy-5-(3-moφholinopropoxy)benzonitrile. The process involves a rearrangement of 3-(3- chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholine propoxy)3,4-dihydroqunazoline-4-imine. The process is not feasible industrially, as the basic raw material is not readily available on a commercial scale. A further draw back of the process lies in the isomerization of the 4-imine compound, which requires anhydrous conditions at high temperature for a longer duration of 96 hours. PCT publication WO 2005/070909 discloses a process for the preparation of the gefitinib by the reaction of iso-vanillin with morpholinopropyl halide to give an 4-methoxy-3-(3-morpholin-4-yl-propoxy)- benzaldehyde, intermediate which undergoes nitration, reaction with hydroxylamine, dehydration to form cyano intermediate, hydrolysis and cyclisation to form quinazolinone intermediate. The keto functionality of the quinazolinone intermediate, is converted to a good leaving group and then condensed with 3- chloro-4-fluoroaniline to form gefitinib. The main drawbaclct5f the process lies in the use of large amount of acetic anhydride for the conversion of oxime to nitrile functionality in the molecule at high temperature.

A recently published PCT application WO 2008/125867 discloses two processes for the preparation of gefitinib. In one of the processes, gefitinib is prepared by the nitration of iso-vanillin followed by condensation with dihalopropane in presence of base to give an intermediate, 3-(3-halo-propoxy)-4- methoxy-6-nitro-benzaldehyde. Above intermediate undergoes oxidation, reduction, cyclisation with formamide, chlorination and then condensation with morpholine to give 4-chloro-7-methoxy-6-(3- morpholin-4-yl-propoxy)-quinazoline. This intermediate finally condensed with 3-chloro-4-fluoro aniline to give gefitinib.

In another process, gefitinib is prepared by the oxidation and esterification of iso-vanillin followed by nitration using a nitrating reagent and reduction to give 2-amino-5-hydroxy-4-methoxy-benzoic acid methyl ester. The intermediate undergoes cyclisation with formic acid or reactive derivative thereof, acetylation, chlorination and condensation with 3-chloro-4-fluoro aniline to give 6-acetoxy-4-(3-chloro-4- fluoroanilino)-7-methoxyquinazoline intermediate. Thereafter, this intermediate is hydrolysed and condensed with 3 -morpholinopropyl chloride to give gefitinib. Protection and deprotection of the process lengthy and hence time consuming.

In the view of the problems associated with the prior art processes, there is an urgent need to develop a process which avoids the use of large amount of acetic anhydride and minimize the formation of isomeric and N-alkylated impurities, to avoid purification using column chromatography. Thus, the present invention provides a process, which is highly efficient, industrially advantageous, and commercially viable avoiding use of toxic intermediates and column chromatography.

OBJECT OF THE INVENTION

The principal object of the present invention is to provide an efficient and industrially advantageous process for the preparation of gefitinib and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide an improved process for the preparation of intermediates useful in the preparation-of gefitinib and pharmaceutically acceptable salts thereof.

SUMMARY OF THE INVENTION

The present invention provides an efficient and industrially advantageous process for the preparation of gefitinib of formula I,

Formula I and pharmaceutically acceptable salts thereof starting from nitro acid compound of formula II.

Formula II

The process comprising the steps of: a) ^"esterifying the nitro acid compound of formula II using suitable esterifying agent to form compound of formula III,

Formula HI wherein R is selected from alkyl, cycloalkyl, aralkyl, aryl b) condensing the compound of formula HI with morpholine compound of formula IV

Formula IV w erein is a gooa eav ng group se ec e rom a ogen suc as c oro, rυrnυ, umu*y .HU» as methoxy; aryloxy such as phenoxy; sulphonyloxy group such as methanesulphonyloxy or toluene-4- sulphonyloxy group or salt thereof in organic solvent, optionally in the presence of suitable base to form compound of formula V,

Formula V wherein R is as defined above c) reducing the compound of formula V in the presence of a suitable reducing agent to form a compound of formula VI,

Formula VI wherein R is as defined above d) optionally, isolating the compound of formula VI; e) cyclizing the compound of formula VI using formic acid or reactive derivative thereof to form quinazolinone compound of formula VII, and

Formula VII f) converting the quinazolinone compound of formula VII to gefϊtinib of formula I and its pharmaceutically acceptable salts thereof..

According to another embodiment, the present invention provide an improved process for the preparation of gefitinib of formula I and its pharmaceutically acceptable salts thereof, comprises the step of: a) esterifying the nitro acid compound of formula II using suitable esterifying agent to form compound of formula III,

Formula III wherein R is as defined above b) condensing the compound of formula III with morpholine compound of formula IV, Formula IV wherein X is as defined above or salt thereof in an organic solvent and optionally, in the presence of suitable base to form compound of formula V;

Formula V wherein R is as defined above c) reducing the compound of formula V in the presence of a suitable reducing agent to form a compound of formula VI;

Formula VI wherein R is as defined above d) optionally, isolating compound of formula VI; e) cyclizing the compound of formula VI using formic acid or reactive derivative thereof to form quinazolinone compound of formula VII,

Formula VII f) activating the quinozplinone compound of formula VII with suitable reagent to form quinazoline compound of formula VIII, and

Formula VIII wherein X is as defined above g) optionally, isolating compound of formula VIII; and h) condensing the quinazoline compound of formula VIII with 3-chloro-4rfluoroaniline in presence of solvent to form gefitinib of formula I and its pharmaceutically acceptable salts thereof. ccor ing to yet ano er em o imen , e presen inven ion provi e a process. iui u c pi ep la ion o compound of formula V, comprises the step of condensing the compound of formula III with morpholine compound of formula IV or salt thereof in organic solvent and optionally, in the presence of base. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. Illustrates the powdered. X-ray diffraction pattern of gefitinib hydrochloride prepared in example 12.

Figure 2. Illustrates the powdered X-ray diffraction pattern of gefitinib prepared in example 12. DETAILED DESCRIPTION OF THE INVENTION The present invention provides an improved, efficient and industrially viable process for the preparation of gefitinib of formula I and its pharmaceutically acceptable salts thereof.

According to one embodiment of the present invention, gefitinib of formula I can be prepared starting from nitro acid compound of formula II.

The compound of formula II is esterified using suitable reagents for the esertification to form compound of formula III. Generally, the reaction is carried out by treating the nitro acid compound of formula II with an esterifying agent at a temperature of 0 to 150 ⁰C for few minutes to few hours. Preferably reaction is carried out using an esterifying agent in the presence of an acid. Usually, the reaction mixture is refluxed for 15 to 48 hours, preferably till the completion of the reaction. Completion of the reaction is monitored by suitable chromatographic techniques such as thin- layer chromatography or high performance liquid chromatography. The carboxylic acid group of compound of formula II can be esterified by any method known in art. Generally, the esterifϊcation reaction requires an acid compound and alcoholic depending upon the type of group to be incorporated. Suitable esterifying agent includes alcohol or alcohol with a suitable acid or alcohol saturated with a suitable acid. Alcohols include but not limited to methanol, ethanol, isopropanol, butanol, tertiary butanol, benzyl alcohol and the like. Acid include but not limited to organic acid such as para-toluene sulfonic acid, benzene sulfonic acid and the like or inorganic acid such as hydrochloric acid, sulfuric acid and the like. The esterification can be carried out first by converting the acid compound of formula II to corresponding acid halide using suitable halogenating agent such as thionyl halide, preferably thionyl chloride, followed by conversion to ester compound of formula IH using above mentioned estrifying agent. The reaction can be advantageously carried out in the presence of a catalyst such as triethyl orthoformate; trimethyl orthoformate and the like. After the completion of the reaction, compound of formula III is isolated by suitable techniques like evaporation, distillation, extraction, filtration with solvent and the like. Preferably, the isolation is carried out by the distillation of the solvent followed by extraction of resulting residue with extracting solvent. Extracting solvent include , uuυiυiυuu, cuici isopropyl ether, methyl tert-butyl ether; ketone such as methyl isobutyl ketone; aliphatic or aromatic hydrocarbon such as toluene; or mixture thereof. Thereafter, the compound of formula III is recovered from the solution by conventional techniques such as distillation, evaporation and the like. The compound of formula III, if desired can be purified with a solvent such as aliphatic hydrocarbon such as n-heptane, hexane; cyclic hydrocarbon such as cyclohexane and the like or mixture thereof. Specifically, the compound of formula III is stirred in a suitable solvent at a temperature of -10 to 3O⁰C for 2 hours. Compound of formula III can be recovered from the mixture using methods such as centrifugation, filtration and the like. The compound of formula III is further condensed with morpholine compound of IV, or salt thereof to form compound of formula V.

Generally, the process involves reaction of compound of formula III with compound of formula IV or salt thereof in an organic solvent at a temperature of 0⁰C to reflux temperature of the solvent for few minutes to few hours. Preferably, the reaction mixture is heated to reflux temperature of the solvent for 2-8 hours, more preferably till the completion of the reaction. Completion of the reaction is monitored by suitable chromatographic techniques such as thin- layer chromatography or high performance liquid chromatography. Compound of formula IV employed for the reaction can be used as free base or acid addition salt of compound of formula IV with a suitable acid that can be with organic acid which include but not limited to carboxylic acid such as oxalic acid, citric acid, succinic acid and the like; or inorganic acid which include but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid and the like. Preferably, the compound of formula IV is 4-(3-chloropropyl)morpholine or its hydrochloride salt. The solvent employed in the reaction includes but not limited to nitriles such as acetonitrile; amide solvents such as dimethylformamide; ketones such as acetone; ethers such as tetrahydrofuran, dioxane; aprotic solvent such as dimethylsulfoxide; and the like or mixture thereof. In another preferred embodiment, reaction of compound of formula III with acid addition salts of compound of formula IV can optionally be carried out in the presence of suitable base. Suitable base can be inorganic base such as alkali metal or alkaline earth metal hydroxide, carbonates, bicarbonates, hydride thereof or organic base such as diisopropyl ethylamine, triethylamine, pyridine, DBU(1, 8- diazabicyclo [5.4. 0] undec-7-ene), DABCO (1, 4-diazabicyclo [2.2.2] octane and the like. Preferably base is selected from sodium carbonate, potassium hydrogen carbonate, sodium bicarbonate, potassium carbonate and the like, whenever reaction is carried out using free base of compound of formula IV, then presence of base in the reaction mixture is optional and if the reaction is carried out using acid addition salt of compound of formula IV, then it is require the addition of suitable base to the reaction mixture. er comp e ion or me reac on, ompoun o ormu a can e use as suc u iuimci icuuiuu isolation or can be isolated by suitable techniques like evaporation, extraction, distillation, filtration with solvent and the like. Preferably, the isolation is carried out by the distillation of the solvent followed by extraction of resulting residue with extracting solvent. Extracting solvent include ester such as ethyl acetate; halogenated solvent such as dichloromethane, chloroform; ether such as isopropyl ether, methyl tertiary butyl ether; ketone such as methyl isobutyl ketone; aliphatic or aromatic hydiocarbon such as toluene and the like or mixture thereof. Thereafter, the compound of formula V is recovered from the resulting solution containing compound of formula V by conventional techniques such as distillation, evaporation and the like. The compound of formula V, if desired can be purified with a solvent such as aliphatic hydrocarbon such as n-heptane; cyclic hydrocarbon such as cyclohexane; ether such as isopropyl ether and the like or mixture thereof. Specifically, the compound of formula V is stirred in a suitable solvent at a temperature of 0 to 30 ⁰C for few minutes to few hours, preferably for 1 hour. Compound of formula V can be recovered from the mixture using methods such as centrifugation, filtration and the like. The compound of formula V is then reduced by any method known in the art for the reduction of nitro functionality to give compound of formula VI.

Generally, the reduction involve the treatment of compound of formula V with a suitable reducing agent at a temperature of 0 to 150 ⁰C for few minutes to few hours.. Preferably, the reduction is carried out at a temperature ranging from about 25 ⁰C to about reflux temperature of the solvent if used. The compound of formula V is treated with reducing agents till the completion of the reaction. The progress of the reaction is monitored by suitable chromatographic techniques such as thin layer chromatography (TLC), High-pressure liquid chromatography (HPLC). Suitable reducing agent includes hydrogen in presence of noble metal catalyst with or without support. Noble metal catalyst includes but not limited to platinum, nickel, rhodium, platinum dioxide, ruthenium, palladium, with or without support (carbon, clay, silica or alumina) and the like. The source of hydrogen may be hydrogen gas or a hydrogen-donating compound such as ammonium formate or hydrazine hydrate in absence or presence of a hydrogen transfer catalyst. Hydrogen transfer catalyst includes, but not limited to Fe (II) oxide, Zn-C, Pd-C, Pt-C, Raney nickel, graphite, clays and the like. Preferably, the hydrogenation of compound of formula V is carried out using palladium catalyst in an organic solvent at 0 to 150 ⁰C preferably at 25 to 35 ⁰C under pressure of 1 to 12 kg/cm² and preferably at 3 to 4 kg/cm². The organic solvent can be selected from solvent comprises one or more of alcohols and preferably methanol. The reduction can be carried out by refluxing the compound of formula V in solvents (such as alcohol or dioxane) or using ammonium formate and a hydrogenation catalyst in the presence of inert solvent. Hydrogenation catalyst comprises a noble metal catalyst such as , , , , , _v , clay, silica or alumina) and the like. Inert solvent include but not limited to alcohol such as methanol, ethanol, isopropanol and the like or polar aprotic solvent such as nitriles (acetonitrile); amide solvent (dimethyl formamide), dimethyl sulfoxide; ethers (tetrahydrofuran); acid solvent (formic acid, acetic acid) and the like or mixture thereof.

It is optional to isolate compounds of formula VI from the reaction mixture, or after the removal of catalyst the reaction mixture as such can be proceeded for the further cyclisation reaction. However, isolation of the compound of formula VI can be accomplished by the removal of catalyst from the reaction mixture by any suitable techniques like filtration, followed by removal of the solvent. The solvent may be removed by any techniques such as distillation, evaporation and the like; preferably required product i.e. compound of formula VI is isolated by the distillation of the solvent. The compound of formula VI or reaction mixture containing compound of formula VI undergoes cyclisation reaction to form quinazolinone compound of formula VII. Generally, the compound of formula VI is reacted with formic acid or reactive derivative thereof in the presence of solvent at a temperature of 20 to 180⁰C for few minutes to few hours. Preferably, the reaction is carried out at a temperature 65 to 70 ⁰C till the completion of the reaction. Reactive derivative of formic acid include but not limited to formamidine acetate, formamide and the like. Suitable solvent for the reaction includes but not limited to alcohol such as methanol, ethanol, butanol, isopropanol and the like or mixture thereof. The cyclization reaction may conveniently be carried out in the presence of formamidine acetate at the temperature range of 20 to 70⁰C in presence of a alcoholic solvent.

The compound of formula VII thus prepared by the process of present invention can be converted to gefitinib of formula I by any method known in the prior art. Generally, the compound of formula VII is converted to gefitinib through quinazoline intermediate of formula VIII. The reaction involves the treatment of the compound of formula VII with a suitable activating reagent that converts hydroxyl functionality in to a good leaving group in the absence or presence of solvent. Suitable reagent containing good leaving include but not limited to a halogenating agent such as 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 to provide compound of formula VIII. Preferably, thionyl chloride, oxalyl chloride, phosphorous oxychloride or methanesulfonyl chloride is used. The solvent employed in the 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 an e i e or mixture ereo . e reac on s carr e ou a a empera ure ιυ renux icnψcid u e 30 minutes to 4 hours preferably till the completion of the reaction. The progress of the reaction is monitored by suitable chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC). The compound of formula VIII can be isolated from the reaction mixture by suitable techniques or used as such for the further reaction.

The compound of formula VIII can be isolated from the reaction mixture by any convention method. Specifically, after the completion of the reaction mixture was quenched with water or chilled water or using ice followed by neutralization of the reaction mixture by adding a suitable ba'se and layer separation. Base employed here can be organic or inorganic base. Organic base include but not limited to N,N-diisopropyl ethyl amine; and inorganic base include alkali or alkaline metal hydroxide, carbonate, bicarbonate, hydrides or alkoxides thereof such as potassium carbonate and the like or combination thereof. The compound of formula VIII can be recovered from organic layer by the removal of solvent using suitable techniques such as distillation. The compound of formula VIII, if desired can be purified by crystallization in a suitable solvent to enhance the purity of the product or to minimize the presence of undesired impurities. Suitable solvent employed includes alcohol such as isopropanol, isoamyl alcohol and the like or mixture thereof. The compound of formula VIII or the reaction mixture containing the compound of formula VIII is made to react with 3-chloro-4-fluoroaniline in the presence of organic solvent to form gefϊtinib of formula I . Generally, the reaction is carried out in presence of organic solvent at a temperature of 0 ⁰C to reflux temperature of the solvent for few minutes to few hours, preferably the reaction is carried out at the reflux temperature of the solvent till the completion of the reaction. Suitable organic solvent for the reaction include but not limited to alcohol such as methanol, ethanol, isopropanol, ethyl acetate, isoamyl alcohol; ester; halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride; ether such as tetrahydrofuran or 1,4-dioxan; aromatic solvent, such as toluene; dipolar aprotic solvent such as N,N- dimethylformamide, N.N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide and the like or mixture thereof. The reaction yields the mixture of gefitinib and its hydrochloride salt; therefore after the completion of the reaction, reaction mixture can be neutralized using a suitable base. The reaction can be optionally carried out by the addition of base to the reaction mixture. Suitable base employed in the reaction include organic amine base such as pyridine, 2,6-lutidine, collidine, 4- dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7- ene); alkali or alkaline earth metal carbonate or bicarbonates thereof hydroxide such as sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide; alkali metal or alkaline earth metal amide such as sodium amide or sodium bis(trimethylsilyl)amide and the like. The ge i ini o lormula i can e iso a e y any sui a e ec niques or use as bucii JΛJI me iuimd ion o gefitinib pharmaceutically acceptable salts thereof.

3-Chloro-4-fluoroaniline used as a raw material for the gefitinib. 3-Chloro-4-fluoroaniline, commercially available, is sometimes found to be contaminated with 3,4-dichloroaniline. The presence of 3,4- dichloroaniline in 3-chloro-4-fluoroaniline result in the formation of 3,4-dichloro gefitinib analogue of following formula,

Above impurity may form along with the final API i.e. gefitinib during the condensation of compound of formula VIII with 3-chloro-4-fluoroaniline contaminated with 3,4-dichloroaniline. Formation of this impurity is confirmed by mass analysis showing [M+ 1 ] peak at 463.

It is further observed that during the force degradation studies, gefitinib on treatment with hydrogen . peroxide give gefitinib N-oxide compound of following formula,

formation of which is confirmed by mass analysis showing [M+ 1] peak at 463. Gefitinib of formula I can optionally be purified by acid base treatment to give highly purified gefitinib. Generally, process involves the dissolution of gefitinib in aqueous acid, optional treatment with carbon followed by neutralization with a base to get pure compound of formula- 1. The acid used during purification is selected from organic acids which include carboxylic acid such as acetic acid, propionic acid, oxalic acid, succinic acid, toluic acid, mandelic acid, tartaric acid, preferably acetic acid or oxalic acid; mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, preferably hydrochloric acid or sulfuric acid. The base used during purification is selected from organic base such as ammonia, triethylamine, ethylamine, propylamine, preferably ammonia; the inorganic base such as sodium or potassium hydroxide, carbonate, bicarbonate, preferably sodium or potassium hydroxide. Gefitinib of formula I, if desired, may be converted into pharmaceutically,acceptable salts thereof by any known method for the salt formation. A suitable pharmaceutically-acceptable salt of a quinazoline e . . , , - υi a iiuuw imc uc i.e. gefitinib which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifϊuoroacetic, citric or maleic acid. The starting material nitro acid of-formula II can be prepared by the method known in the art.

Specifically, nitro acid of formula II can be prepared by the nitration of 3-hydroxy-4-methoxy-benzoic acid. The nitration of the 3-hydroxy-4-methoxy-benzoic acid can be carried out by reacting with a suitable nitrifying agent at a temperature of about 0 to 60 ⁰C for 2 hours, preferably till the completion of the reaction. The completion of the reaction is monitored by suitable techniques such as high-pressure liquid chromatography or thin layer chromatography. Nitrifying agent includes but not limited to fuming nitric acid_* mixture of nitric acid with another acid such as acetic acid or sulfuric acid and the like. After the completion of the reaction, the reaction mass may be quenched with a suitable quenching agent and isolated with suitable techniques such as filtration and the like. Quenching agent includes, but not limited to ice, water and the like. After the completion of the reaction, the isolated product can be purified by suitable techniques such as crystallization, washing or slurry wash and the like.

Alternatively, nitro acid of formula II can be prepared starting from veratric acid i.e. 4,5- dimethoxybenzoic acid. The reaction involves the nitration of the 4,5-dimethoxybenzoic acid followed by demethylation to give nitro acid of formula II. The nitration of the 4,5_^dimethoxybenzoic acid can be carried out by reacting 4,5-dimethoxybenzoic acid with a suitable nitrifying agent as described above to give desired nitrated product. The crude product can be optionally purified by a solvent or used as such for the demethylation reaction. Suitable solvent for washing and purification include water, hydrocarbon solvent such as toluene; ethers such as isopropyl ether; aliphatic or aromatic hydrocarbon such as n- hexane and the like or mixture thereof. It is found that during the nitration of 4,5-dimethoxybenzoic acid; reaction yields decarboxylated product along with desired product. The decarboxylated product i.e. 3,4-dimethoxybenzene may be formed up to 20% during the reaction as a by product. The decarboxylated product may be removed from the desired product by the treatment of the reaction mixture with a suitable base followed by filtration of the reaction mixture. The undissolved decarboxylated product is removed by filtration. Suitable base is selected from alkali or alkaline metal hydroxide thereof such as potassium hydroxide and the like. The treatment of reaction mixture with a suitable base removes the decarboxylated product as well as performs demethylation of the resulting product i.e. 4,5-dimethoxy-2-nitrobenzioc acid to give nitro acid compound of formula II. enera y, e nitrate pro uc o e a ove reac on, , - me oxy- -n πκ)ci ziυ , d nι, rur r converted to nitro acid compound of formula II. 4,5-Dimethoxy-2-nitrobenzioc acid or the reaction mixture containing 4,5-dimthoxy-2-nitrobenzioc acid is reacted with a suitable base at a temperature of 25 ⁰C to reflux temperature. The reaction is generally carried out for few minutes to few hours. Preferably, the reaction mixture is heated at reflux temperature for 0.5 to 30 hours. The base employed in the reaction can be organic or inorganic base and can be used as such or their aqueous solution. Organic base include amines such as triethylamine, tripropylamine, tributylamine; pyridines such as pyridine, picoline and the like. Inorganic base include but not limited to alkali metal or alkaline metal hydroxide, alkoxide, carbonates, bicarbonates, hydride thereof such as sodium carbonate, potassium carbonate, sodium methoxide, sodium bicarbonate, potassium bicarbonate, potassium methoxide, sodium ethoxide, sodium t-butoxide, sodium hydroxide or potassium hydroxide and the like. It is advantageous to carry out reaction in the presence of solvent such as water, alcohol, ketone, sulfones, amides, nitriles, ether, aromatic hydrocarbon, or mixture thereof. Thereafter, reaction mixture can be acidified with a suitable acid. Acid can be organic or inorganic acid. Organic acid include carboxylic acid such as acetic acid and the like. Inorganic acid include hydrochloric acid, sulfuric acid and the like. After the completion of the reaction, the isolated product can be purified by suitable techniques such as crystallization, extraction with a solvent, washing or slurry wash and the like.

The intermediates of the present invention can be isolated or used as such in the next step. Isolation and purification of final compound or its pharmaceutically acceptable salts thereof and intermediates described here in the present invention can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, derivatisation, slurry wash, salt preparation or combination of these procedures. However, other equivalent procedures such as acid-base treatment could, of course, also be used. The solvent used for the purification purpose include, but not limited to alcohols, ethers, aliphatic or aromatic hydrocarbon, esters, ethers, nitriles or mixture thereof.

The major advantage lies in the present invention is introduction of the morpholine propyl chain at early stage which avoids the formation of N-alkylated impurity and hence no extensive or column purification is required. Although, the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of the invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples. Example 1: Preparation of 5-hydroxy-4-methoxy-2-nitrobenzoic acid Step I: preparation of 4,5-dimethoxy-2-nitrobenzoic acid

3,4-Dimethoxybenzoic acid (50.0 g) was added to pre cooled concentrated nitric acid (275 ml) and stirred the reaction mass for 60 minutes. After completion of reaction (monitored by TLC), the reaction mass was quenched with ice water. The precipitated solid was filtered, washed with water and purified with toluene to obtain 43.0 g of the title compound. Step II: preparation of 5-hydroxy-4-methoxy-2-nitrobenzoic acid 4,5-Dimethoxy-2-nitrobenzoic acid (50.0 g) was added to aqueous potassium hydroxide solution (10%, 275 ml) and refluxed for 20 hours. After completion of reaction, the reaction mass was cooled to 5 ⁰C and acidified with concentrated hydrochloric acid. The precipitated solid was filtered, washed with water and dried to obtain 46 g of title compound.

Example 2: Preparation of S-hydroxy-^-methoxy-I-nitrobenzoic acid 3,4-Dimethoxybenzoic acid (10Og) was added slowly to a cooled solution of concentrated _^nitric acid (550ml). After completion of reaction, the reaction mass was quenched with ice water. The precipitated solid was filtered, washed with water. The resulting solid was added to 30% aqueous potassium hydroxide (720ml), stirred and filtered, to remove 3,4-dimethoxynitrobenzene decarboxylated byproduct. The filtered mass was refluxed for 15 hours. After completion of reaction, the reaction mass was cooled to 25-30⁰C, acidified with concentrated hydrochloric acid (400 ml) and extracted with ethyl acetate (2000 ml). The solvent was distilled off under reduced pressure. The resulting mass was diluted with cyclohexane (300ml) and'precipitated soΗϊ was filtered, washed with cyclohexane (50ml) and dried to give 86g (73%) of the title compound. Example 3: Preparation of 5-hydroxy-4-methoxy-2-nitrobenzoic acid methyl ester A solution of 5-hydroxy-4-methoxy-2-nitrobenzoic acid (50g) in methanolic hydrochloride (500 ml) was refluxed for 15 hours. After completion of reaction, the solvent was distilled under reduced pressure to give a residue, which was diluted with water and extracted with ethyl acetate. The layers were separated and organic layer was washed with water and distilled to obtain 30 g of title compound. Example 4: Preparation of 5-hydroxy-4-methoxy-2-nitrobenzoic acid ethyl ester A mixture of 5-hydroxy-4-methoxy-2-nitrobenzoic acid (83g), sulfuric acid (83g), triethyl orthoformate (166ml) and ethanol (1245ml) was refluxed for 40 hours. After completion of reaction, the solvent was distilled under reduced pressure. The resulting residue was extracted with toluene. The organic layer was washed with water, dried and distilled. Cyclohexane (300ml) was added to the resulting residue and , , g vc oυ ₁ title compound having purity 99.74% by HPLC.

Example 5: Preparation of 5-hydroxy-4-methoxy-2-nitrobenzoic acid ethyl ester A mixture of 5-hydroxy-4-methoxy-2-nitrobenzoic acid (1Og), sulfuric acid (5g) and ethanol (100ml) was refluxed for 40 hours. After completion of reaction, the solvent was distilled under reduced pressure. The resulting residue was extracted with toluene (200 ml). The organic layer was washed with water, dried and distilled. Cyclohexane (30ml) was added to the resulting residue and stirred. The reaction mixture was filtered, washed with cyclohexane and dried to give I Og (88.5%) of the title compound having purity 99.77% by HPLC. Example 6; Preparation of 4-methoxy-5-(3-morpholin-4-ylpropoxy)-2-nitro benzoic acid methyl ester

To a mixture of 5-hydroxy-4-methoxy-2-nitrobenzoic acid methyl ester (10 g) and anhydrous potassium carbonate (18.2 g) in acetonitrile (100 ml), 4-(3-chloropropyl)-morpholine hydrochloride (10 g) was added and refluxed for 2.5 hours. After completion of reaction, the solvent was distilled under reduced pressure to give residue which was diluted with water and extracted with ethyl acetate. The organic layer was distilled under vacuum and dried to obtain 14 g of the title compound.

Example 7: Preparation of 4-methoxy-5-(3-morpholin-4-ylpropoxy)-2-nitro benzoic acid ethyl ester To a mixture of 5-hydroxy-4-methoxy-2-nitrobenzoic acid ethyl ester (55g) and anhydrous potassium carbonate (94.4g) in dioxane (275ml), 4-(3-chloropropyl)-morpholine hydrochloride (78.5g) was added and refluxed for 7 hours. After completion of reaction, the solvent was distilled under reduced pressure. The resulting residue was extracted with ethyl acetate (770 ml). The organic layer was distilled under vacuum. Cyclohexane (200 ml) and isopropyl ether (100 ml) was added to the resulting residue and stirred. The resulting product was filtered, washed with cyclohexane and dried to give 82g (98%) of the title compound having purity 97.5% by HPLC. Example 8: Preparation of 4-methoxy-5-(3-morpholin-4-ylpropoxy)-2-nitro benzoic acid ethyl ester To mixture of 5-hydroxy-4-methoxy-2-nitrobenzoic acid ethyl ester (20Og) and anhydrous potassium carbonate (458g) in acetonitrile (3000ml), 4-(3-chloropropyl)-morpholine hydrochloride (249g) was added and refluxed for 4-6 hours. After completion of reaction, the solvent was distilled under reduced pressure. The resulting residue was extracted with ethyl acetate (6000 ml). The organic layer was distilled under vacuum. Cyclohexane (800 ml) was added to the resulting residue and stirred. The resulting product was filtered, washed with cyclohexane (200 ml) and dried to give 290g (95%) of the title compound having purity 98.9% by HPLC. xamp e : prepara ion o -me oxy- - -morp o in- -v propoxy - -quinazoHπ-t-oπe

Step I: preparation of 2-amino-4-methoxy-5-(3-morpholin-4-ylpropoxy) benzoic acid methyl ester

4-Methoxy-5-(3-moφholin-4-ylpropoxy)-2-nitrobenzoic acid methyl ester (5 g) was hydrogenated using 10% palladium on carbon (0.5 g) in methanol (50 ml) at 3-4 kg/cm² at ambient temperature for 5 hours. After completion of reaction, the catalyst was removed by filtration. The filtrate was distilled off completely to obtain 4.2 g of the title compound.

Step II: preparation of 7-methoxy-6-(3-morpholin-4-ylpropoxy)-3//-quinazolin-4-one 2-Amino-4-methoxy-5-(3-moφholin-4-yfpropoxy)benzoic acid methyl ester (4 g) was added to formamidine acetate (1.34 g) in methanol (32 ml) and heated at 50-60 ⁰C for 6 hours. After completion of reaction, the reaction mass was cooled to room temperature and stirred for 3 hours. The resulting solid was filtered, washed with methanol and dried to obtain 3.5 g of the title compound. Example 10: Preparation of 7-methoxy-6-(3-morpholin-4-ylpropoxy)-3/f-quinazolin-4-one 4-Methoxy-5-(3-moφholin-4-ylpropoxy)-2-nitrobenzoic acid ethyl ester (50g) was hydrogenated using 10% palladium on carbon (50% wet, 5g) in methanol (250ml) at^" 3.0-3.5 kg/cm² for 3 hours. After completion of reaction, catalyst was removed by filtration. Formamidine acetate (22g) in methanol was added to resulting filtrate and refluxed for 6 hours. After completion of reaction, the reaction mass was cooled to room temperature, stirred for 2 hours. The resulting product was filtered, washed with methanol (50 ml) and dried to βive 33g (73%) of the title compound. Example 11: Preparation of gefitinib A mixture of 7-methox^ -6-(3-moφholin-4-ylpropoxy)-3H-quinazolin-4-one (3.5 g) and thionyl chloride (10.5 ml) was refluxeύ lor 4 hours. The reaction mass was distilled under reduced pressure to remove excess of thionyl chloride. To the resulting reaction mass, isoamyl alcoho' (^"i2.5 ml) was added, followed by addition of 3-chloro-4-fluoro-aniline (1.82 g) and refluxed for 6 houis. Thereafter, reaction mixture was cooled to room temperature, filtered, and distilled to obtain title compound which was further purified with methanol.

Example 12: Preparation of gefitinib

Step I: Preparation of 4-chIord-7-methoxy-6-(3-morpholin-4-yl-propoxy)quinazoline

Method A: 7-Methoxy-6-(3-moφholin-4-ylpropoxy)-3H-quinazolin-4-one (12g) was refluxed with thionyl chloride (36ml) in acetonitrile (180ml) and N,N-dimethylformamide (2ml) for 12-15 hours. After completion of reaction, thionyl chloride was distilled out completely under reduced pressure. The resulting reaction mass was diluted with water and extracted with ethyl acetate (180 ml) after neutralizing the reaction mass with potassium carbonate. The organic layer was washed with brine and distilled. The resulting compound was crystallized from isopropanol (36 ml) to give 8g (63%) of the title compound. e -Metnoxy- - -moφ o n- -y propoxy - -qu na_Zo n- -one i w u w phosphorous oxychloride (13.5ml) in a mixture of dichloromethane (150ml), acetonitrile (15ml) and N₁N- dimethylformamide (15ml) for 6 hours. After completion of reaction, the reaction mass was quenched in ice (20Og) and the pΗ of the resulting reaction mass was adjusted to neutral with potassium carbonate. The layers were separated. The separated organic layer was washed with water and distilled. The resulting compound was crystallized from isopropanol (75 ml) to give 13.5g (85%) of the title compound having purity 99.79% by ΗPLC Step II: Preparation of gefitinib A mixture of 4-Chloro-7-methoxy-6-(3-morpholin-4-yl-propoxy)quinazoline (12g) and 3-chloro-4- fluoroaniline (8.8g) in isoamyl alcohol (180ml) were refluxed for 10 hours. After completion of reaction, the reaction mass was cooled to room temperature, filtered and washed to give a solid product which was purified with isoamyl alcohol (72 ml) to give gefitinib hydrochloride having XRD as shown in figure 1. The solid thus obtained was basified with 10% aqueous potassium carbonate (10ml) and filtered to give product, which was purified from ethyl acetate (60ml) to give 14g (89%) of the title compound having purity 99.21%, gefitinib N-oxide impurity 0.06% and 3,4-dichloro analogue impurity not detected by ΗPLC, melting point: 192-195°C and display the XRD spectrum as shown in figure 2.

Claims

1). A process for the preparation of gefitinib of formula I,

Formula I and pharmaceutically acceptable salts thereof, comprising the steps of: ity esterifying the nitro acid compound of formula II,

Formula II using suitable esterifying agent to -form -Ά Gømpound of formula III,

Formula III wherein R is selected from alkyl, cycloalkyl, aralkyl, aryl b) condensing the compound of formula III with morpholine compound of formula IV or salt thereof

Formula IV wherein X is a good leaving group selected from halogen such as chloro, bromo; alkoxy such as methoxy; aryloxy such as phenoxy; sulphonyloxy group such as methanesulphonyloxy or toluene-4-sulphonyloxy group in an organic solvent and optionally in the presence of base to form a compound of formula V,

Formula VI wherein R^'is as defined above op iona y, isolating compoun o ormu a ; e) cyclizing compound of formula VI using formic acid or reactive derivative thereof to form quinazolinone compound of formula VII; and

Formula VII f) converting the quinazolinone compound of formula VII to gefitinib and its pharmaceutically acceptable salts thereof. 2). The process according to claim 1, wherein in step a) esterifying agent includes alcohol or alcohol with a suitable acid or alcohol saturated with a suitable acid.

3). The process according to claim 2, wherein alcohol includes methanol, ethanol, isopropanol, butanol and the like.

4). The process according to claim 2, wherein acid includes organic acid such as para-toluene sulfonic acid, benzene sulfonic^* acid; or inorganic acid such as hydrochloric acid, sulfuric acid and the like. 5). The process according to claim 1, wherein in step b) solvent includes nitriles such as acetonitrile; amide solvents such as dimethylformamide; ketones such as acetone; ethers such as tetrahydrofuran, dioxane; aprotic solvent such as dimethylsulfoxide; and the like or mixture thereof.

6). The process according to claim 1, wherein in step b) suitable base is inorganic base such as alkali metal or alkaline earth metal hydroxide, carbonates, bicarbonates, hydride thereof such as sodium carbonate, potassium hydrogen carbonate, sodium bicarbonate, potassium carbonate and the like; or organic base such as diisopropylethylamine, triethylamine, pyridine, DBU (1,8-diazabicyclo [5.4. 0] undec-7-ene), DABCO (1, 4-diazabicyclo [2.2. 2] octane and the like or combination thereof.

7). The process according to claim 1, wherein in step c) a reducing agent is selected from Noble metal catalyst such as platinum, nickel, rhodium, platinum dioxide, ruthenium, palladium, with or without support (carbon, clay, silica or alumina); source of hydrogen includes hydrogen gas or a hydrogen donating compound such as ammonium formate or hydrazine hydrate in absence or presence of a hydrogen transfer catalyst selected from Fe (II) oxide, Zn-C, Pd-C, Pt-C, Raney nickel, graphite, clays and the like; hydrogenation catalyst and the like. 8). The process according to claim 1, wherein in step e) a reactive derivative of formic acid is formamidine acetate, formamide and the like.

9). The process according to claim 1, wherein in step f) conversion of quinazolinone compound of formula VII to gefitinib and its pharmaceutically acceptable salts thereof, comprises the step of: a) activating the quinozolinone compound of formula VII with a suitable" feagenf quinazoline compound of formula VIII, and

Formula VIII wherein X is as defined above b) optionally, isolating the compound of formula VIII; and c) condensing compound of formula VIII with 3-chloro-4-fluoroaniline in presence of solvent to form gefitinib of formula I.

10). The process according to claim 9, wherein in step a) suitable reagent is selected from halogenating agent such as 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, sulfur oxychloride, and the like;

11). The process according to claim 9, wherein in step c) solvent is selected from alcohol such as methanol, ethanol, isopropanol, ethyl acetate, isoamyl alcohol; ester; halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride; ether such as tetrahydrofuran or 1,4-dioxan; aromatic solvent, such as toluene; dipolar aprotic solvent such as N,N-dimethylformamide, N₁N- dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulphoxide and the like or mixture thereof 12). A process for the preparation of compound of formula V, comprises the step of condensing the compound of formula III with morpholine compound of formula IV or salt thereof in an organic solvent and optionally in the presence of base.

13). The process according to claim 12, wherein in solvent includes nitriles such as acetonitrile; amide solvents such as dimethylformamide; ketones such as acetone; ethers such as tetrahydrofuran, dioxane; aprotic solvent such as dimethylsulfoxide; and the like or mixture thereof. 14). The process according to claim 12, wherein suitable base is inorganic base or organic base. 15). The process according to claim 14, inorganic base is selected from such as alkali metal or alkaline earth- metal hydroxide, carbonates, bicarbonates, hydride thereof such as sodium carbonate, potassium hydrogen carbonate, sodium bicarbonate, potassium carbonate and the like; or organic base is selected from diisopropyl ethylamine, triethylamine, pyridine, DBU-(1, 8-diazabicyclo [5.4.0] undec-7-ene), DABCO (1, 4-diazabicyclo [2.2.2] octane and the like or combination thereof.