F0RM2
THE PATENTS ACT 1970 (39 of 1970) . &
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1]. TITLE OF THE INVENTION:
"PROCESS FOR THE PREPRATION OF GEFITINIB"
2. APPLICANTS:
(a) NAME: MAC CHEM PRODUCTS INDIA PVT. LTD.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 304, town Centre, Andheri-kurla Road, Andheri (E),
Mumbai-400059, Maharashtra, India.
(a) NAME :SHANGHAI PARLING PHARMATECH CO. LTD.

(b) NATIONALITY. China Company incorporated under the Chinese
Companies Law

(c) ADDRESS: Suite 2, No. 868 Zhenchen Road, Baoshan District, Shanghai,
200 444, China.
3. PREAMBLE TO THE DESCRIPTION
Thc following specification particularly describes the invention and the manner in which it is to be performed.

Technical Field:
The present invention relates to a synthetic process for the preparation of 4-(3- chloro-4- fluoro-phenyI)-7-methoxy-6-(3-morphoIin-propoxy) quinazoIine(Gefitinib).
Background and prior art:
4- (3 - chloro - 4 - fluoro - phenyl) -7 - methoxy - 6 - (3-morpholin - propoxy ) quinazoline (Gefitinib, trade name: Iressa) is known as an selective inhibitor of epidermal growth factor receptor (EGFR) protein-tyrosine kinase, and currently, it is mainly used clinically for the treatment of non-small cell lung cancer.
■ F

Gefitinib
The synthetic route of Gefitinib is mainly reported by K. H. Gibson from Astrazeneca Pharmaceuticals Ltd. (WO9633980, CN96193526) . Its synthetic process is described as follows:

This synthetic route comprises using 6,7-dimethoxy-3.4-dihydroquinazoline-4-one as the raw material which is reacted with methylsulphonic acid and L-methionine for selective demethylation at 6 position to get its 6-hydroxyI derivative, acetylate protected (acetyl a ted to protec the hydroxyl group) and chlorinated, aminated with 3-

chloro-4-fluoro-benzenamine and deprotected, arid then finally reacted with halohydro-3-morpholin-Propane to obtain Gefitinib.
* ■
The drawback of the above process involves using a large amount of non-recycled
reagents methylsulphonic acid and L-methionine for demethylation, which will lead to serious environment pollution and lower yield rate { <50% ) .
The route adopted by Jinbo et al. from China Pharmaceutical University (Journal of
China Pharmaceutical University, 2005, 36, 92-94) is basically just the same as the
above patent described to obtain Gefitinib, which also has the problems like serious
environment pollution and lower yield rate.
• *' \ ■ '

J. P. Gilday and D. Moody from Astrazeneca Pharmaceuticals Ltd. improved the original method and promoted a synthetic route (WO2004024703 ) suitable for industrial production.

This synthetic route comprises using isovaniiline as the raw material, firstly conversion of aldehydic group of isovaniiline into cyario-group and then nitration; reduction step of nitro to amine; hydrolyzation step of cyano-group to amide followed by cyclization reaction and chlorination. and finally reacted to 3-chIoro-4-

fluoro-Benzenamine to obtain Gefitinib.
Although this route has been improved and can carry out on industrial production, it is hard to control the hydrolyzation step of cyano-group, and acid by-product is unavoidable in this hydrolyzation step.
Yuanli etc. from Shenyang Pharmaceutical University (Chinese Journal of Pharmaceutical Chemistry, 2005, 15, 39) use 3-hydroxy-4-methoxybenzoic acid methyl ester as the raw material, which follows the similar synthetic way as J. P. Gilday did, and also has the drawbacks of many unwanted by-products:
Objective of the invention:
The object of the present invention is to provide a synthetic method for Gefitinib by removing the drawbacks of existing prior technologies and improving the yields.

Summary of the invention:
The present invention discloses a new improved synthetic process for the preparation
of Gefitinib involving isovanillin as raw material to synthesize 7-methoxy -6-(3-
morpholin-propoxy) quinazoline-4-one (6).The chlorination of compound (6)
followed by reacting with 3-Chloro-4-fluoroaniline to yield Gefitinib Hydrochloride
which is directly neutralized to remove HC1 and finally obtained as Gefitinib. All the
reactions are carried out under controlled conditions. The method disclosed herein is
simple and suitable for industrial production.

Detailed description of the invention:
The present invention provides a synthetic method for Gefitinih, which comprises the following steps:
i) reacting isovanilline with hydroxylamine hydrochloride in a suitable solvent in presence of p-toluenesulfonic acid as catalyst and dehydrating agent to
convert aldehyde group into cyano-group to obtain compound (1)
ii) reacting compound (1) with 3-Morpholino-l- chloroproparie under inorganic or organic base conditions in the presence of a catalyst to obtain compound (2); iii) nitrating compound (2) in mixed acids to obtain compound (3); iv) oxidizing compound (3) to obtain compound (4); v.) reducing compound (4) to obtain compound (5); vi) cyclizing compound (5) to obtain compound (6); vii) chlorinating compound (6) in presence of DMF as catalyst and precipitating
the product using methylene chloride: followed by reacting with 3-chloro - 4-
fluoro aniline to obtain Gefitinib.
In step I, solvent is selected from the group of benzene, methyl benzene. 1,2-dimethylbenzene, N.N-dimety I form amide or dimethyl sulfoxide; and the dehydrating agent is selected from sodium sulfate anhydrous, magnesium sulfate anhydrous, acetic anhydride or thionyl chloride.
In step 2 , solvent is selected from benzene, methylbenzene, 1,2-dimethylbenzene,
N,N-dimetylformamide or dimethyl sulfoxide: inorganic base is selected from the group of sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate; organic base is selected from triethylamine, N.N-diisopropylethylamine, trimethylamine, tripropylamine or tri butyl amine; catalyst is selected from tetrabutyl ammonium iodide, tetrabutyl ammonium bromide or tetrabutylammoniumchloride.

In step 3, mixed acids are selected from acetic acid and nitric acid or sulfuric acid and nitric acid or nitric acid and fuming nitric acid or acetic acid and sulfuric acid with fuming nitric acid, or sulfuric acid and fuming nitric acid; the reaction temperature is 0°C'to70°C.
In step 4, reactant solvent is selected from N.N-dimetylformamide, dimethyl sulfoxide, methyl alcohol, ethyl alcohol or isopropyl alcohol; oxidizing agent is selected from hydrogen peroxide, tert-butyl hydroperoxide, sodium perborate, potassium tetraborate or benzoyl peroxide, and the optimize option is hydrogen, peroxide or sodium perborate.
In step 5, reactant solvent is selected from methvl alcohol, ethyl alcohol, propanol, butanol, and the optimize option is methyl alcohol or ethyl alcohol; catalyst is selected from 2%-20%(weight %)Pd-C, hydrochloric acid or acetic acid; reducing agent is selected from hydrogen, ammonium formate, formamide, formylarriine, iron powder, zinc dust or sodium dithionite.
In step 6 , cyclization agent is selected from formic acid or formamide or combination thereof.
In step 7 , chlorinating agent is selected from the group of thionyi chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachlofide or phosphorus oxychloride; the solvent is selected from the group of methylbenzene, dichloromethane, dimethyl sulfoxide, n-hexane or 1,2-dichloroethane.
The specified synthetic route is as follows:

The synthetic route for Gefitinib
The advantages of this invention are as follows:
I. This invention avoids demethylation, protection and deprotection steps of the process disclosed in WO9633980, thus successfully shorten the synthetic route; II. Oxidation of cyano group into acidamide; then reducing nitro group, can effectively avoid the risk of overhydrolyzation of nitrile group into acid during cyano group hydrolyzation;
III. First oxidizing cyano-group into amides to obtain poor water-soluble solid product to centrifugate, can avoid large amount of solvent used for extraction.
IV. All the reactions are carried out under moderate conditions and are fit for industrial production.
The following examples are to illustrate the invention,'tnot to limit the scope of
invention. Example 1
(j) Synthesis of compound (1)
To a solution of double distilled methylbenzene (5L) in 10L 4-neck flask, isovanilline (1kg). hydroxyzine hydrochloride (500g), p-toluenesulfonic acid (160g, as catalyst) and anhydrous magnesium sulfate (5kg) were added and stirred. The reaction mixture was refluxed for 6 hours, then cooled to room temperature, and filtered. The filter cake was extracted with hot ethyl acetate and undertaken for TLC detection. The combined solution of ethyl acetate was washed with water and brine in succession,

then dried and concentrated, till product separated out which is washed with petroleum ether (2.5L) and dried with little petroleum ether to obtain dry compound 1 (750g).
(II) Synthesis of compound (2)
Compound(lXlkg), 3-Morpholino-l- chloropropane (2kg), potassium carbonate (3kg), tetrabutyl ammonium iodide (500g) and DMSO (5L) were added to 10L 4-neck flask and refluxed. The reaction was monitored by TLC and after the completion of reaction, the reaction mixture was cooled and poured into ice water (lGL).The reaction mixture extracted with methylene dichloride, which was washed with salt water and dried and concentrated to obtain compound (2) (1.5kg).
(III) Synthesis of compound (3)
A solution of compound (2) (1kg) in acetic acid (5L) was added drop wise into nitric acid (3D , which has been cooled to 0°C. Temperature of the reaction mixture was maintained at about 10°C and the mixture was stirred till reaction gets completed. Mixture was poured into ice water (50 L) and stirred. Large amount of solid was precipitated, which was centrifuged after 30min. The product obtained was further washed, dried and recrystallized by methyl alcohol to obtain compound (3)(lkg).
(IV) Synthesis of compound (4)
To a solution of compound (3) (1kg) and potassium carbonate (2kg) in DMSO (2L) , hydrogen peroxide (1L) was added drop wise. After addition, the reaction mixture was poured into ice water (20 L). A large amount of solid was precipitated, which was then centrifuged and dried to obtain compound (4) (10kg).
(V) Synthesis of compound (5)
To a solution of compound (4)(lkg) in methyl alcohol (8L): ammonium formate (1kg)
and Pd/C (200g) were added. The mixture was then heated to reflux till the reaction completed. The mixture was then cooled to room temperature and filtered. The filtrate

was concentrated and the remainant (compound 5) was used directly without purification.
(VI) Synthesis of compound (6)
A solution of compound (5) (1kg) in formamide (4L) and formic acid (4L) was heated to reflux till clear solution was obtained. It was then cooled to room temperature, centrifuged and washed to obtain compound (6) (800g)..
(VII) Synthesis of Gefitinib
To a solution of thionyl chloride (20L), compound (6) (Ikg)and DMF (50mL, as
catalyst) were added respectively, and refluxed. After the solid dissolved, excess thionyl chloride was removed under vacuum. The mixture was cooled to room temperature and dichloromethane was added to precipitate the chlorinated product. It was further washed with saturated sodium, bicarbonate solution, dried and concentrated. The product obtained used without further purification.
To a solution of the above chlorinated product in DMF, 3-chloro-4-fluoro aniline (500g) was added. The mixture was heated to 100°C. After the reaction completed, the mixture was cooled to 10°C. A large amount of solid precipitated. It was filtered and the cake was washed with ethyl acetate, and dried to obtain product Gefitinib hydrochloride.(lkg). The action spectrum is in consistent with literature data.
Example 2
(I) Synthesis of compound (1)
To a solution of double distilled methylbenzene (5L) in 10L 4-neck flask, isovanillin (lkg), hydroxyamine hydrochloride (500g),p-toluenesulfonic acid (160g, as catalyst) and anhydrous magnesium sulfate (4kg) were added and stirred. The reaction mixture was refluxed for 16 hours, then cooled to room temperature. and filtrated. The filter cake was extracted by hot ethyl acetate and undertaken for TLC detection. The combined solution of ethyl acetate was washed with water and brine in succession,


then dried and concentrated, till product separated out which is. washed with petroleum ether (2.5L) and dried with little petroleum ether to obtain dry compound 1 (800g).
(II) Synthesis of compound (2)
Compound (1) (1kg), 3-morpholino-l-chioropropane (2kg), potassium carbonate (3kg), tetrabutylammonium iodide (l00g) and DMSO (5L) were added to 10L 4-neck flask, and refluxed. . The reaction was monitored by TLC and after the completion of reaction, the reaction mixture was cooled and poured into ice water (l0L).The reaction mixture extracted with methylene dichloride, which was washed with salt water and dried and concentrated to obtain compound (2) (1.45kg).
(]]J) Synthesis of compound (3)
A solution of compound (2) (1kg) in acetic acid (5L) was added drop wise into nitric acid (3D and sulfuric acid (ID which has been cooled to 0 C. The temperature of reaction mixture was maintained at about I0°C and the mixture was stirred till the reaction gets completed. Mixture was poured into ice water (50 L) and stirred. Large amount of solid was precipitated, which was then centrifuged after 30mins. It was further washed and dried and recrystallized by methyl alcohol to obtain compound (3) (1kg).
(IV) Synthesis of compound (4)
To a solution of compound (3) (1kg) and sodium carbonate (500g) in DMSO (2D , hydrogen peroxide (1L) was added drop wise. After addition, the reaction mixture was poured into ice water (20 L). A large amount of solid was precipitated, which was then centrifuged and dried to obtain compound (4) (1 kg).
(V) Synthesis of compound (5)
To a solution of compound (4) (1kg) in ethyl alcohol (8L), ammonium formate (1kg) and Pd/C (200g) were added. The mixture was then heated to reflux till the reaction



completed. The mixture was then cooled to room temperature and filtrated. The filtrate was concentrated and the remainant (compound 5) was used directly without purification.
(VI) Synthesis of compound (6)
A solution of compound (5) (1kg) in formamide (4L) and formic acid (4L) was heated to reflux till the raw materials disappeared. It was cooled to.room temperature, centrifuged and washed to obtain compound (6) (800g).
(VII) Synthesis of Gefitinib
To a solution of thionyl chloride (15L), compound (6) (1kg) and DMF (100mL: as catalyst) were added respectively, and then heated to reflux. After the solid dissolves, excess thionyl chloride was removed under vacuum. The mixture was cooled to room temperature and dichloromethane was added to precipitate the chlorinated product. Wash with saturated sodium bicarbonate solution, dried, concentrated. Obtained product used without further purification.
To a solution of the above chlorinated product in DMF. 3-chloro-4-fluoro aniline (500g) was added. The mixture was heated to 100°C. After the reaction finished, the mixture was cooled to 10°C. A large amount of solid precipitated. It was filtered and the cake was washed with ethyl acetate, and dried to obtain product Gefitinib hydrochloride (1kg). The action spectrum is in consistent with literature data.
Example 3
(I) Synthesis of compound (I)

To a solution of double distilled methylbenzene (5L) in-1OL 4-neck flask, isovanillin (lkg), hydroxyamine hydrochloride (500g),p-toluenesulfonic acid (160g, as catalyst) and magnesium sulfate anhydrous (5kg) were added and stirred. The reaction mixture was refluxed for 10 hours, then cooled to room temperature, and filtered. The filter cake was extracted with hot ethyl acetate and undertaken for TLC detection. The


combined solution of ethyl acetate was washed with water and brine in succession, then dried and concentrated, till product separated out which is washed with petroleum ether (2.5L) and dried with little petroleum ether to obtain dry compound 1 (780g).
(II) Synthesis of compound (2)
Compound (]) (1kg), 3-morpholino-l-chloropropane (3kg), potassium carbonate (2kg), tetrabutyl ammonium bromide (250g) and DMSO (5L) were added to 10L 4-neck flask and refluxed. The reaction was monitored by TLC and after the completion of reaction, the reaction mixture was cooled and poured into ice water(10L).The reaction mixture was extracted with methylene dichloride, which, was washed with salt water and dried and concentrated to obtain compound (2) (1. 55kg).
(III) Synthesis of compound (3)
A solution of compound (2) (1kg) in acetic acid (5L) was added dropwise into nitric acid (3L) and sulfuric acid (ID which has been cooled to 0°C. Temperature of the "reaction mixture was maintained at about 30°C and the mixture was stirred till the reaction gets complete. Pour the mixture into ice water (50 L) and stir. Large amount of solid was precipitated, which was then centrifuged after 30mins, washed and dried and recrystallized by methyl alcohol to obtain compound (3) (1kg).
(IV) Synthesis of compound (4)
To a solution of compound (3) (1kg) and Potassium carbonate (200g) in DMSO
(2L) , hydrogen peroxide (1.5L) was added drop wise. After addition, the reaction mixture was poured into ice water (20 L). A large amount of solid was precipitated, which was then centrifuged and dried to obtain compound (4) (1kg).
(V) Synthesis of compound (5)
To a solution of compound (4) (1kg) in methyl alcohol (8L). ammonium formate (1kg)
and Pd/C(100g) were added. The mixture was heated to reflux till the reaction
completed. The mixture was then cooled into room temperature and filtered. The



filtrate was concentrated and the remainant (compound V) was used directly without
purification.
(VI) Synthesis of compound (6)
A solution of compound (5) (1kg) in formamide (5L) and formic acid (2L) was heated to reflux till clear solution was obtained. It was then cooled to room temperature, centrifuged and washed to obtain compound VI (780g).
(VII) Synthesis of Gefitinib
To a solution of thionyl chloride (25L), compound (6)(1 kg).and DMF (l00mL, as catalyst)was added respectively, and then heated to reflux. After the solid dissolves, excess thionyl chloride was removed under vacuum. The mixture was cooled to room temperature and dichloromethane was added to precipitate the chlorinated product.. It was further washed with saturated sodium bicarbonate solution, dried, concentrated. Obtained product used without further purification.
To a solution of the above chlorinated product in DMF, 3-chloro-4-fluoro aniline ' (450g) was added. The mixture was heated to 120°C. A large amount of solid precipitated. It was filtered and filter cake was washed with ethyl acetate, and dried to obtain product Gefitinib hydrochloride (1.1kg).The action spectrum is in consistent with literature data.
We claim,
1. A synthetic method for preparing Gefitinib comprising


dehydrating agent to convert ' aldehyde group into cyano-group to
obtain compound (1) ii) reacting compound (1) with 3-Morpholino-l-chloropropane under
inorganic or organic base conditions in the presence of a catalyst to
obtain compound (2); iii) nitrating compound (2) in mixed acids to obtain compound (3); iv) oxidizing compound (3) to obtain compound (4); v) reducing compound (4) to obtain compound (5): vi) cyciizing compound (5) to obtain compound (6); and vii) chlorinating compound (6) in presence of DMF and precipitating the
product using methylene chloride; followed by reacting with 3-chloro-
4-fluoro-aniline to obtain Gefitinib.
The method as claimed in claim I, wherein step (i), the solvent is selected from the group comprising of benzene, methylbenzene, 1.2-dimethylbenzene, N,N-dimetylformamide or dimethyl sulfoxide; and the dehydrating agents is selected from sodium sulfate anhydrous, magnesium sulfate anhydrous, acetic anhydride or thionyl chloride.
The method as claimed in claim 1, wherein step (ji)? the solvent is selected from the group comprising of benzene, methylbenzene, 1,2-dimethylbenzene, N,N-dimetylformamide or dimethyl sulfoxide; inorganic base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate; organic base is selected from triethylamine, N,N-diisopropylethylamine, trimethylamine, tripropylamine or tributylamine: and catalyst is selected from the group of tetrabutyl ammonium iodide, tetrabutyl ammonium bromide or tetrabutylammoniumchloride.


4. The method as claimed in claim 1, wherein step (iii), the mixed acids are selected from the group comprising of acetic acid and nitric acid; sulfuric acid


and nitric acid, nitric acid and fuming nitric acid, acetic acid and sulfuric acid with fuming nitric acid, or sulfuric acid and fuming nitric acid: wherein the reaction is carried out at a temperature ranging 0°C to 70°C.
5. The method as claimed in claim L, wherein step (iv), the solvent is selected from N,N-dimetylformamide, dimethyl sulfoxide, methyl alcohol, ethyl alcohol or isopropyi alcohol; oxidation agent is selected from the group of hydrogen peroxide, tert-butyl hydroperoxide, sodium perborate, potassium tetraborate or benzoyl peroxide.
6. The method as claimed in claim 5, wherein the oxidation agent is hydrogen peroxide or sodium perborate.
7. The method as claimed in claim 1, wherein step (v), the solvent is selected from the group of methyl alcohol, ethyl alcohol, propanol or butanol; catalyst
is selected from the group of 2 % -20 % (weight percentage) Pd-C,
hydrochloric acid or acetic acid; and the reduction agent is selected from hydrogen, ammonium formate, formamide, formylamine, iron powder, zinc dust or sodium dithionite.
8. The method as claimed in claim 7, wherein solvent is methyl alcohol or ethyl alcohol.
9. The method as claimed in claim 1, wherein step (vi), the cyclization agent is selected from formic acid or formamide or combination thereof.
10: The method as claimed in claim 1, wherein step (vii) , the chlorination agent

is selected from the group of thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphor,us-pentachbride or phosphorus oxychloride; solvent is


selected from methylbenzene, dichloromethane, dimethyl sulfoxide, n-hexane
or 1,2-dichIoroethane.
11. The synthetic method for preparation of Gefitinib as substantially described herein with reference to the description and foregoing examples 1 to 3.


Dated this 4th day of August 2008
Jain, Mohan Babulal FerMac Chem Products Pvt. Ltd.

Zhan Huaxing
For Shahhai Parling Pharmatech Co. Ltd.