CLIAMS:Claims:

1) A process for the preparation of highly pure Gefitinib of Formula (I).

(I)
comprising the steps of:
a) reacting 4-methoxy-3- hydroxy benzoic acid, methyl ester of Formula II

(II)
with4-(3-chloropropyl) morpholineof Formula III

(III)
in the presence of alkali metal iodide and a carbonate salt using an organic solvent to yield Methyl 4-methoxy-3-(3-morpholinopropoxy) benzoate of Formula IV

(IV)
b) nitration of Methyl 4-methoxy-3-(3-morpholinopropoxy) benzoate (IV) in presence of nitric acid and organic acid to provide Methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate of Formula (V);

(V)
c) reducing Methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate (V) in presence of alkali metal dithionate to provide Methyl 4-methoxy-5-(3-morpholinopropoxy)-2-aminobenzoate of Formula VI

(VI)
d) cyclizing Methyl 4-methoxy-5-(3-morpholinopropoxy)-2-aminobenzoate(VI) using formamidine acetate in presence of methanol solvent to provide 7-methoxy-6-(3-morpholinopropoxy) quinazolin-4(3H)-one of Formula VII;

(VII)
e) halogenating 7-methoxy-6-(3-morpholinopropoxy) quinazolin-4(3H)-one (VII) using Phosphorous halides to provide 4-chloro-7-methoxy-6-(3-morpholinopropoxy)-3, 4-dihydroquinazoline of Formula VIII;

(VIII)
f) condensing 4-chloro-7-methoxy-6-(3-morpholinopropoxy)-3, 4-dihydroquinazoline (VIII) with 3-chloro-4-fluoroaniline to provide Gefitinib of Formula (I);
g) purifying using toluene or ethyl acetate or methanol.

2) A process for the preparation of Gefitinib according to claim 1, wherein alkali metal iodide used in step a) is selected from potassium iodide, Sodium iodide or Lithium iodide.

3) A process for the preparation of Gefitinib according to claim 1, wherein carbonate salt used in step a) is selected from Potassium carbonate, Sodium carbonate, Lithium carbonate, Cesium carbonate, Magnesium carbonate.

4) A process for the preparation of Gefitinib according to claim 1, wherein organic solvent used in step a) is selected from amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinylacetamide, N-vinyl pyrrolidone, 2- pyrrolidone, dimethyl acetamide.

5) A process for the preparation of Gefitinib according to claim 1, wherein organic acid used in step b) is selected from Formic acid, Acetic acid, Propionic acid, Butyric acid, Valeric acid, Caproic acid, Oxalic acid, Lactic acid, Malic acid, Citric acid, Benzoic acid, Carbonic acid.

6) A process for the preparation of Gefitinib according to claim 1, wherein alkali metal dithionate used in step c)is selected from potassium dithionate, Sodium dithionate, Barium dithionate.

7) A process for the preparation of Gefitinib according to claim 1, wherein Phosphorous halides used in step e)is selected from Phosphorous trihalides such as Phosphorous tri chloride, Phosphorous tribromide, Phosphorous triiodide; Phosphorous pentahalides such as Phosphorous penta chloride, Phosphorous penta bromide, Phosphorous oxyhalides such as Phosphorous oxy trichloride, Phosphorous oxy tribromide.

8) A process for the purification of Gefitinib (I) comprising the steps of
a) stirring Gefitinib in ethyl acetate or methanol solvent ;
b) heat to reflux and stirred for 30 min;
c) optionally adding activated carbon/charcoal and stirred for 30 min at reflux temperature;
d) recovering pure Gefitinib (I) substantially free from process related impurities; and/or
e) optionally, repeating step a) & b) to get desired purity.

9) A process for the preparation of Gefitinib according to claim 8, wherein Gefitinib obtained as per the process is having a purity of greater than 99.9 %.

10) A process for the preparation of Gefitinib according to any of the preceding claims, wherein Gefitinib obtained as per the process disclosed in the specification.

Dated this 09th day of April 2015 Signature:
Dr. A.K.CHATURVEDI
,TagSPECI:FIELD OF THE INVENTION

The present invention relates to a process for the preparation of highly pure N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine or Gefitinib of Formula (I).

(I)

The present invention further relates to a process for the purification of N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine or Gefitinib.

BACKGROUND OF THE INVENTION

N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)quinazolin-4-amine or Gefitinib is an anilinoquinazoline, orally available. Gefitinib inhibits the intracellular phosphorylation of numerous tyrosine kinases associated with transmembrane cell surface receptors, including the tyrosine kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is expressed on the cell surface of many normal cells and cancer cells. No clinical studies have been performed that demonstrate a correlation between EGFR receptor expression and response to Gefitinib.

USFDA approved Gefitinib in May 2003 and the approval is withdrawn due to lack of evidence that it extended life. However, Gefitinib is marketed under the brand name Iressa®, as an important chemotherapeutic agent useful for the treatment of certain breast, lung and other cancers. Gefitinib is an EGFR inhibitor, like Erlotinib, which interrupts signaling through the epidermal growth factor receptor (EGFR) in target cells. Therefore, it is only effective in cancers with mutated and overactive EGFR.

Gefitinib is a white colored powder substance with empirical formula C22H24ClFN4O3 and molecular weight of 446.9. Gefitinib a sparingly soluble substance at pH 1, but is practically insoluble above pH 7, with the solubility dropping sharply between pH 4 and pH 6. In non-aqueous solvents, Gefitinib is freely soluble in glacial acetic acid and dimethylsulphoxide, soluble in pyridine, sparingly soluble in tetrahydrofuran, and slightly soluble in methanol, ethanol (99.5%), ethyl acetate, propan-2-ol and acetonitrile.

Gefitinib is generically and specifically disclosed in EP 0 823 900 and its equivalents. EP ‘900 discloses two routes for the preparation of Gefitinib. Each route involves the use of the compound 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline as an intermediate with the formation of the 3-morpholinopropoxy side-chain at the 6-position occurring at the end of the synthesis.

These existing routes are satisfactory for the synthesis of relatively small amounts of the Gefitinib, but they involve linear rather than convergent syntheses, each requiring the multiple uses of chromatographic purification steps and the isolation of a substantial number of intermediates.

As such, the overall yields of these syntheses are not high. There is therefore a need for a more efficient synthesis of the compound of Gefitinib suitable for use to make larger quantities of that compound. The present inventors now developed a new synthesis, which does not involve costly and time-consuming chromatographic purification procedures.

US7705145 discloses a process for Gefitinib starting from 3-hydroxy-4-methoxybenzonitrile. This patent discloses the use of excess of formamide acts as a solvent as well as reactant for cyclization. However, this reactant individually itself is very toxic and better to avoid in large scale synthesis.

CN 101148439 discloses a process for Gefitinib starting from 4-methoxy-3- hydroxy benzoic acid, methyl ester. However, this process involves the use of acetic anhydride in the nitration step. Because of its high reactivity towards water generates high vapors, which are harmful and handling of Acetic anhydride is cumbersome as it is an irritant and combustible liquid. The process disclosed in this patent is as summarized below:

Journal of Chemical Research 2009, 388-390 also discloses similar process for the preparation of Gefitinib starting from 4-methoxy-3-hydroxy-benzoic acid methyl ester. The process disclosed in this Journal is as summarized below:

This Journal process also disclosed the use of acetic anhydride in the nitration step. Because of its high reactivity towards water generates high vapors, which are harmful and handling of Acetic anhydride is cumbersome as it is an irritant and combustible liquid.

Further the use of ethanol in large scale is very expensive. Parallel, the use of ethanol, which is having high boiling point, requires high energy to distill off the solvent and time taking.

The present inventors has repeated the above process and found the following disadvantages:
? In most of the patent literature, toluene and ethanol are used as solvent in coupling stage, which is tedious for the removal.
? Unwanted reactions are observed during the formation of Gefitinib, due to the involvement time lagging process and high boiling solvents.
? Incomplete reactions were observed with excessive impurity formation due to incomplete conversion.

The present inventors now developed a process for the preparation of Gefitinib, which is advantageous in all aspects and yields highly pure Gefitinib in good yield on large scale. The process is more convergent than the previous routes and allows a substantial reduction of using toxic and corrosive reagents, which is more commercially feasible.

According to the present invention, Gefitinib is developed with a cost effective process and reducing the time, without using any Chromatographic purification procedures.

In view of the above and to overcome the prior-art problems the present inventors had now developed an improved process for the preparation of Gefitinib, using industrially feasible and viable process, with the use of industrially friendly solvents, which does not include tedious work up and time lagging steps.

OBJECTIVE OF THE INVENTION

The main objective of the invention relates to a process for the preparation of highly pure 4-Quinazolinamine,N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin) propoxy] or Gefitinib (I).

Yet another objective of the invention relates to a process for the purification of 4-Quinazolinamine, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholin)propoxy] or Gefitinib (I).

SUMMARY OF THE INVENTION

The main aspect of the present invention relates to a process for the preparation of highly pure Gefitinib of Formula (I).

(I)
comprising the steps of:
a) reacting 4-methoxy-3- hydroxy benzoic acid, methyl ester of Formula II

(II)
with 4-(3-chloropropyl) morpholineof Formula III

(III)
in the presence of alkali metal iodide and a carbonate salt using an organic solvent to yield Methyl 4-methoxy-3-(3-morpholinopropoxy) benzoate of Formula IV

(IV)
b) nitration of Methyl 4-methoxy-3-(3-morpholinopropoxy) benzoate (IV) in presence of nitric acid and organic acid to provide Methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate of Formula (V);

(V)
c) reducing Methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate (V) in presence of alkali metal dithionate to provide Methyl 4-methoxy-5-(3-morpholinopropoxy)-2-aminobenzoate of Formula VI

(VI)
d) cyclizing Methyl 4-methoxy-5-(3-morpholinopropoxy)-2-aminobenzoate(VI) using formamidine acetate in presence of methanol solvent to provide 7-methoxy-6-(3-morpholinopropoxy) quinazolin-4(3H)-one of Formula VII;

(VII)
e) halogenating 7-methoxy-6-(3-morpholinopropoxy) quinazolin-4(3H)-one (VII) using Phosphorous halides to provide 4-chloro-7-methoxy-6-(3-morpholinopropoxy)-3, 4-dihydroquinazoline of Formula VIII;

(VIII)
f) condensing 4-chloro-7-methoxy-6-(3-morpholinopropoxy)-3, 4-dihydroquinazoline (VIII) with 3-chloro-4-fluoroaniline to provide Gefitinib of Formula (I);
g) purifying using toluene or ethyl acetate or methanol.

In yet another aspect of the invention relates to a process for the purification of Gefitinib (I) comprising the steps of
a) stirring Gefitinib in ethyl acetate or methanol solvent ;
b) heat to reflux and stirred for 30 min;
c) optionally adding activated carbon/charcoal and stirred for 30 min at reflux temperature;
d) recovering pure Gefitinib (I) substantially free from process related impurities; and/or
e) optionally, repeating step a) & b) to get desired purity.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of Gefitinib of Formula (I) comprising reacting 4-methoxy-3- hydroxy benzoic acid, methyl ester(II) with 4-(3-chloropropyl) morpholine(III) in presence of alkali metal iodide selected from potassium iodide, Sodium iodide, Lithium iodide, Cesium iodide, Rubidium iodide; and a carbonate salt selected from potassium carbonate, Sodium carbonate, Lithium carbonate, Cesium carbonate, Magnesium carbonate using an organic solvent is selected from amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinyl acetamide, N-vinyl pyrrolidone, 2- pyrrolidone, dimethyl acetamide; at a temperature ranging from 60-100°C for a period of 2 hrs to 8 hrs. The reaction mixture was allowed to cool at room temperature and cooled water was added slowly under stirring for 1 hr to 2 hr. The precipitated solid was filtered and washed with water; suck dried the material under vacuum and further dried at 55-60 °C for 14-16 hrs under vacuum to obtain Methyl 4-methoxy-3-(3-morpholinopropoxy) benzoate (IV).

In one embodiment, the present inventors surprisingly found that use of an alkali metal iodide in combination with an organic solvent enhances the rate of conversion of reactant, which leads to the formation of higher yields compare to the prior-art process. Further, the use of alkali metal iodide, which enhances the rate of conversion, also avoids the formation of side products and impurities yields in highly pure material, which is more advantageous compare to prior art processes.

Nitration of Methyl 4-methoxy-3-(3-morpholinopropoxy) benzoate (IV) in presence of nitric acidand organic acid selected from Formic acid, Acetic acid, Propionic acid, Butyric acid, Valeric acid, Caproic acid, Oxalic acid, Lactic acid, Malic acid, Citric acid, Benzoic acid, Carbonic acid at a temperature ranging from 0-10°C for 2 hours to 5 hours. The reaction mixture was cooled was cooled to 0-5 °C and DM water was added. pH was adjusted to 8-9 by using aqueous NaOH solution and stirred for 30 min to 1 hr. The precipitated solid was filtered and washed with DM water. Suck dried the material and further dried at a temperature ranging from 40-60 °C for a period of 10 hours to 16 hours under vacuum to obtain highly pure to provide Methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate of Formula (V);

The present inventors found that the use of an organic acid in nitration steps leads to formation of highly pure material and commercially viable compare to the process as disclosed in the prior art, where nitration is carried using inorganic acid like sulfuric acid. Further, handling of sulfuric acid is cumbersome, when compare to the handling of organic acid.

The present inventors developed nitration process, which does not involve the use of acetic anhydride, avoids the formation of highly reacted process related impurities. The prior art processes involves the use of acetic anhydride, which is high reactivity towards water and generates high vapors, which are harmful and handling of Acetic anhydride is cumbersome as it is an irritant and combustible liquid.

Reducing Methyl 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzoate (V) in presence of alkali metal dithionate selected from potassium dithionate, Sodium dithionate, Barium dithionate at a temperature ranging from 50-60°C for a period of 2 hrs to 4 hrs. The temperature was raised to 70-75 °C and then added Con. HCl slowly for a period of 45 min to 1hr. The reaction mixture was cooled to 10-15 °C and pH was adjusted to 8-9 by using NaOH solution. The reaction mixture was stirred at 10-15 °C for 30 min to 1hr and the precipitated solid was filtered. The wet cake was washed with DM water and suck dried. Dried the material under vacuum to provide Methyl 4-methoxy-5-(3-morpholinopropoxy)-2-aminobenzoate (VI).

Cyclizing Methyl 4-methoxy-5-(3-morpholinopropoxy)-2-aminobenzoate(VI) using formamidine acetate in presence of methanol solvent at a temperature ranging from 60-65 °C for a period of 20 hrs to 26 hrs. The reaction mixture was cooled to 0-5 °C and maintained for 1 hrs at 0-5 °C the precipitated solid was filtered, washed with chilled methanol and suck dried the material. The solid was slurred over DM Water at 25-30°C for 2 hrs to 3 hrs. The solid was dried at 60-65 °C for 5-6 hrs under vacuum to provide 7-methoxy-6-(3-morpholinopropoxy) quinazolin-4(3H)-one of Formula VII;

Halogenating7-methoxy-6-(3-morpholinopropoxy) quinazolin-4(3H)-one (VII) using Phosphorous halides selected from Phosphorous trihalides such as Phosphorous tri chloride, Phosphorous tribromide, Phosphorous triiodide; Phosphorous pentahalides such as Phosphorous penta chloride, Phosphorous penta bromide, Phosphorous oxyhalides such as Phosphorous oxy trichloride, Phosphorous oxy tribromide; at a temperature ranging from 90 to 120°C for a period of 3 hours to 6 hours. The reaction mixture was cooled to 60 °C and distilled off the solvents under vacuum. To the reaction mixture Toluene was added and distilled out the solvents and repeat the process to obtain residue. The obtained residue was cooled to 10-15 °C and methylene dichloride was added. The reaction mixture was further cooled to 0-5 °C and then DM water was added. Stirred the reaction mixture for 20 min to 30 min. The organic layer was separated and discarded. The aqueous layer was cooled to 10-15 °C and pH was adjusted to 8-9 with sodium carbonate solution. The reaction mixture was allowed to room temperature and stirred for 2 hrs to 4 hrs. The precipitated solid was filtered and washed with DM water and suck dried the material. The solid was slurred with n-Heptane and dried at 50-55 °C for 4 hrs to 6 hrs. To the obtained solid ethyl aceate was added and heated to reflux for 30 min to 1 hr to get clear solution and added activated carbon and continued heating for another 30 min. The reaction mixture was filtered through celite. The filtrate was concentrated and n-heptane wasadded to obtain solid. The solid was dried at 50-55°C for 6 hrsto 8 hrs to provide 4-chloro-7-methoxy-6-(3-morpholinopropoxy)-3, 4-dihydroquinazoline VIII;

The present inventors found that the use of phosphorous halides in the halogenating step yields in a highly pure halogenated material. As the thionyl chloride is more active and efficient, results in highly halogenated materials as process related impurities.

Condensing 4-chloro-7-methoxy-6-(3-morpholinopropoxy)-3, 4-dihydroquinazoline (VIII) with 3-chloro-4-fluoroanilinein presence of methanol solvent at a temperature ranging from 40 to 60°C for a period of 10hrs to12 hrs. The reaction mixture was cooled to room temperature and pH was adjusted to 8-9 using aqueous ammonia solution. The reaction mixture was stirred at room temperature for 2 hrs to 4 hrs. The precipitated solid was filtered and washed with chilled methanol. Suck dried the material and dried at 60-65 °C for 12 hrs to 15 hrs under vacuum to provide Gefitinib.

The present inventors found that the use of ethanol in large scale is very expensive. Parallel, the use of ethanol, which is having high boiling point, requires high energy to distill off the solvent and time taking.

In another embodiment of the present invention relates to a process for the purification of Gefitinib comprises stirring Gefitinib in a polar selected from ketone solvents such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone (MIBK); amide solvents such as formamide, dimethyl formamide, N-methyl-2-pyrrolidone, N-methyl formamide, N-vinylacetamide, N-vinyl pyrrolidone, 2- pyrrolidone, dimethyl acetamide; alcohols, such as methanol, ethanol, isopropanol; ethers such as tetrahydrofuran, dioxane; esters such ethylacetate; water or mixtures thereof; or mixture of polar and hydrocarbon solvent selected from toluene, xylene, cyclohexane, hexane; halogenated hydrocarbons such as methylene dichloride, ethylene chloride, chloroform; or mixtures thereof at reflux temperature ranging from 40-120°C. Distill off the solvent and recovering substantially pure Gefitinib (I) free from process related impurities. If the desired purity is not achieved repeat these steps to get the desired purity

In another embodiment of the present invention relates to a process for the purification of Gefitinib comprising the steps of
a) stirring Gefitinib in ethyl acetate or methanol solvent ;
b) heat to reflux and stirred for 30 min;
c) optionally adding activated carbon/charcoal and stirred for 30 min at reflux temperature;
d) recovering pure Gefitinib (I) substantially free from process related impurities; and/or
e) optionally, repeating step a) & b) to get desired purity.

Distill off the solvent and recovering substantially pure Gefitinib (I) free from process related impurities. If the desired purity is not achieved repeat these steps to get the desired purity. Gefitinib obtained after this purification is highly pure and having a purity of greater than 99.9 %. The obtained Gefitinib as per the present invention is not only highly pure and also meet the requirements of all ICH guidelines.

Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed at a temperature ranging from 50-65°C for a time ranging from 12 to 16 hours depending upon the physical attributes of the end product obtained i.e. Pure Gefitinib. Gefitinib (I) obtained according to the present invention is highly pure having purity exceeding 99.9%.

Achieving highly pure material was one of the aims of the present invention, as most of the prior disclosed processes resulted in lower purity materials possessing often impurities difficult to remove or involving many purifications. While working on ways to find out to get highly pure material having purity greater than 99.9%, inventors of the present application observed that all the steps of the preparing Gefitinib according to the present invention are desirable, however they should not be construed to limit the scope of the invention

The process related impurities that appear in the impurity profile of the Gefitinib may be substantially removed by the process of the present invention resulting in the formation of highly pure material, which is having a purity of greater than99.9%. The process of the present invention is as summarized below:

In another embodiment, the Gefitinib obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.

The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

Pharmaceutically acceptable excipients used in the compositions comprising Gefitinib obtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Pharmaceutically acceptable excipients used in the compositions derived from Gefitinib of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES

Example-1
Process for preparation of methyl 3-(3-morpholinopropoxy)-4-methoxybenzoate
Methyl 3-hydroxy-4-methoxybenzoate (100 gm, 0.54 mol), K2CO3 (160.0 gm, 1.15 mol), KI (100.0 gm, 0.60 mol) and 4-(3-chloropropyl)morpholine (135 ml, 0.89 mol) were charged into a reaction flask containing DMF (400 ml). The reaction mixture was heated to 90-100 °C and maintained for 6 hrs under stirring. The reaction mixture was allowed to cool at room temperature and pre cooled water was added slowly under stirring for 1 hr. The precipitated solid was filtered and washed with water;suck dried the material under vacuum for 1 hr and further dried at 55-60 °C for 14-16 hrs under vacuum to obtain the title compound.
Yield: 132gm

Example-2
Process for preparation of methyl 5-(3-morpholinopropoxy)-4-methoxy-2-nitrobenzoate
Methyl 3-(3-morpholinopropoxy)-4-methoxybenzoate (90.0 gm, 0.291 mol) was charged in to a reaction flask containing acetic acid (90 ml) and cooled to 0-5 °C. To the reaction mixture nitric acid (180 ml, 70% nitric acid) was added drop wise for a period of 45-60 min. The reaction mixture was stirred at room temperature for 3-4 hrs. The reaction mixture was cooled to 0-5 °C and DM water (900 ml) was added, pH was adjusted to 8-8.5 using aqueous NaOH solution (40 %) and stirred for 30 min. The precipitated solid was filtered and washed with DM water (100 ml). Suck dried the material and further dried at 50-55 °C for 12-14 hrs under vacuum to obtain the title compound.
Yield: 102gm

Example-3
Process for preparation of methyl 5-(3-morpholinopropoxy)-2-amino-4-methoxy benzoate
Sodium dithionite (240.0 gm, 1.164 mol) was charged in to a reaction flask containing Methyl 5-(3-morpholinopropoxy)-4-methoxy-2-nitrobenzoate (120.0 gm, 0.338 mol) and DM water (2040 ml). The reaction mixture was heated to 50-55 °C and stirred for 2 hrs. The temperature was raised to 70-75 °C and Con. HCl(240 ml) was slowly added for 45 min. The reaction mixture was cooled to 10-15 °C and pH was adjusted to 8-9 by using 50% NaOH solution. The reaction mixture was stirred for 30 min at 10-15 °C and the precipitated solid was filtered. The wet cake was washed with DM water (250 ml) and suck dried the material. The solid was further dried at 50-55 °C for 20-24 hrs under vacuum to obtain the title compound.
Yield: 108.0 gm

Example-4
Process for preparation of 6-(3-morpholinopropoxy)-7-methoxyquinazolin-4(3H)-one
5-(3-morpholinopropoxy)-2-amino-4-methoxybenzoate (100.0 gm, 0.282 mol) and formamidine acetate (200.0 gm, 1.92 mol) was charged in to reaction flask containing methanol (1 lt) and heated the reaction mixture to 60-65 °C. The reaction mixture was stirred for 24 hrs. The reaction mixture was cooled to 0-5° C and maintained for 1hrs at 0-5 °C the precipitated solid was filtered. Wash the material with chilled methanol and suck dried the material. The solid obtained was slurred in DM Water (500 ml) and stirred at 25-30°C for 2 hrs. The solid material was dried at 60-65 °C for 5-6 hrs under vacuum to obtain the title product.
Yield: 98.4gm

Example-5
Process for preparation of 6-(3-morpholinopropoxy)-4-chloro-7-methoxyquinazoline
N,N-diethylaniline (90.0 ml, 0.56 mol) was charged in to a reaction flask containing 6-(3-morpholinopropoxy)-7-methoxyquinazolin-4(3H)-one (90.0 gm, 0.027 mol) and Phosphorus oxychloride (540 ml). The reaction mixture was heated to 100-105 °C and stirred for 4-5 hours. The reaction mixture was cooled to 60 °C and solvents were distilled out under vacuum. To the obtained material Toluene (500 ml) was added and distilled off the solvents. Repeat this process one more time to obtain pure residue. The residue was cooled to 10-15 °C and dichloromethane (900 ml) was added. The contents were cooled to 0-5 °C. DM water (900 ml) was added and the contents were stirred for 20 min. The organic layer was separated and discarded. The aqueous layer was cooled to 10-15 °C and pH was adjusted to 8-9 with 20% sodium carbonate solution. The reaction mixture was cooled to 25-30°C and stirred for 2 hrs. The precipitated solid was filtered and washed with DM water (500 ml) and suck dried the material. The solid was slurred with n-Heptane (50 ml) and dried at 50-55 °C for 4 hrs. To the obtained solid ethyl aceate (900 ml) was added and heated to 75-80 °C. The reaction mixture was stirred for 30 min to get clear solution. To the obtained clear solution activated carbon was added and continued stirring for another 30 min. The reaction mixture was filtered through celite bed. The filtrate was concentrated and added n-heptane (360 ml) to obtain solid. The solid was dried at 50-55 °C for 6 hrs to obtain the title product.
Yield: 42.0 gm

Example-6
Process for preparation of Gefitinib:
6-(3-morpholinopropoxy)-4-chloro-7-methoxyquinazoline (73.0 gm, 0.216 mol) and 3-chloro-4-fluoroaniline (68.0 gm, 0.467 mol) were charged into a reaction flask containing methanol (1460 ml) and heated to 60-65 °C. The reaction mixture was stirred for 10-12 hrs. Cooled the reaction mixture to 25-30°C and pH was adjusted to 8-9 using 25% aqueous ammonia solution. The reaction mixture was stirred at room temperature for 2 hrs. The precipitated solid was filtered and washed with chilled methanol and suck dried the material. The material was dried at 60-65 °C for 12 hrs under vacuum to obtain title product.

Yield: 85.0 gm
Chromatographic Purity (By HPLC): 99.48%

Example-7
Purification of Gefitinib:
Gefitinib (83.0 gm) was charged in to a reaction flask containing Methanol (2.3 lit) and heated to 60-65 °C for 30 min. The reaction mixture was allowed at room temperature and stirred for 30 min to get solid. The precipitated solid was filtered to obtain pure Gefitinib.
Yield: 65.0 gm
Chromatographic Purity (By HPLC): 99.96%

Example-8
Purification of Gefitinib:
Gefitinib (60.0 gm) was charged in to a reaction flask containing Ethyl acetate (3.8 lit) and heated to 75-80 °C for 30 min. 6.0 gm of Activated charcoal was added and stirred for 75-80 °C for 30 min. The reaction mixture was filtered through Hyflow bed and the filtrate concentrated under vacuum to obtain pure Gefitinib.
Yield: 56.0 gm
Chromatographic Purity (By HPLC): 99.99%

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the description and examples are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.