FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION / COMPLETE SPECIFICATION (See section 10 and rule 13)

1. TITLE OF THE INVENTION
IMPROVED PROCESS FOR PREPARATION OF GEFITINIB
2. APPLICANTS)
(a) NAME : CADILA PHARMACEUTICALS LIMITED
(b) NATIONALITY : An INDIAN Company
(c) ADDRESS : "Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat, Ahmedabad - 382210,
Gujarat, India
3. PREAMBLE TO TH E DESCRITION
PROVISIONAL SPECIFICATION
The following specification describes the invention.
COMPLETE SPECIFICATION
^Fhe-foHowing specification partieulariy-describes the invention-and-the-marmer in which it'faio be performed

4. DESCRIPTION


(Description starts from next page)


FIELD OF THE INVENTION:
The present invention relates to preparation of N-(3-chloro-4-fluoro-phenyl)-7-methoxy- 6-(3-morphoIi'n-4-yIpropoxy) quinazoIin-4-amine BACKGROUND OF THE INVENTION:
Gefitinib 2D1839(WO 96/33980) having tyrosine kinase inhibitor activity, is useful for treatment of neoplastic diseases like small solid lung Cancer etc. The anti-tumor activity of the gefitinib has provoked interest in its potential for clinical application in the treatment of variety of tumors especially non-small cell lung cancer and hematological malignancies. Receptor tyrosine kinases are important in the transmission of biochemical signals which initiate cell replication.
Chemically Gefitinib is N-(3-chloro-4-fluoro-phenyl)-7-methoxy- 6-(3-morpholin-4-ylpropoxy) quinazolin-4-amine, has chemical abstract registry no. [184475-35-2], and has structural formula as shown below.

Gefitinib
Gefitinib is disclosed in International publication WO9633980; and US patent no. 5770599. International publication WO 96/33980 and its equivalent US 5770599 disclose a process for the preparation of Gefitinib depicted in scheme-1 as follows.
The process involves steps of selective demethylation, acetyl protection, and preparation of chloroimine from cyclic amide, condensation with 3-chloro 4-fluoro aniline followed by de-protection and O-alkylation with N-morpholino propyl chloride.
Further, preparation of 6,7-dimethoxy quinazoline involves 8 steps and during our laboratory experiment we found that selective 0-demeth.ylation at 6th position using L-methionine and methane sulphonic acid leads to formation cjf impurities which are difficult to separate and by crystallization results in low yield.


US5770599 describes [Example -1, column lines 23-25] preparation of chloroimine from cyclic amide (15 gm) using thionyl chloride (225 ml) in DMF; the reaction leads to unwanted demethylation at 71 position which generates new reactive impurity. Use of 14.33 times vol. of thionyl chloride per wt of cyclic amide is commercially not viable.
Condensation of N-morpholine propyl chloride at final step using DMF and potassium carbonate leads to the formation of O, N- bis alkylated impurity of formula B, removal of which requires column chromatography, making commercial manufacture unsuitable on industrial scale.


International publication WO 2004/024703 Al discloses a process for the preparation
4
of geiitinib comprising , reacting isovanillin with hydroxyl amine and formic acid to give isovanilonitrile, O-AIkylating isovanilonitrile with N-morpholinepropyl chloride, followed by nitration, reduction, hydrolysis of nitrile group using tert-amyl alcohol/KOH, to cyclic amide, which undergoes cyclization using formic acid, followed by its conversion to cyclic imino chloride and reacting, with 3-chloro 4-fIuoro aniline to give Gefitinib. [Scheme-2] Scheme-2

The instant process is a linear synthesis wherein overall yield is poor. Cyclisation using formic acid at higher temperature is not viable as process.
International publication WO 2005/070909 Al discloses a process for the preparation of Gefitinib from isovanillin comprising the steps:
O-alkylation of isovanillin with N-morpholine propyl chloride followed by nitration, oxime formation, dehydration to give nitrile, conversion of nitrile to give an amide ,

reduction of nitro group to amino group using Palladium-on-carbon, cyclization of amino amide using formic acid to give cyclic amide, chlorination , followed by coupling with 3-Chloro-4-fluoroaniline to give Gefitinib.[Scheme-3]
Alternatively nitro-cyano ether compound can be converted directly to amino amide intermediate using hydrazine hydrate in presence of Raney Ni in methanol. Scheme-3


The oxime formation leads to E, Z isomers, which lead to incomplete conversion due to different reactivity of isomers. The instant process involves the use of Pd/C has been used for hydrogenation which is fire hazardous, also recovery and reprocessing of palladium is cumbersome and a lengthy process. Preparation of Quinazoline ring using formic acid at higher temperature is not a viable process on commercial scale.
International publication WO 2004/024703 describes preparation of Gefitinib as per scheme-4 as shown below.

Raw materials required for the synthesis of Gefitinib through this route are not readily available for commercial manufacture.
International publication WO 2005/023783 discloses a process for the preparation of
4-(3,-chloro-4-fluoroanilino,)-6-hydroxy-7-methoxy-quina^oline using Dimroth
rearrangement reaction.

The process comprises rearrangement reaction in the presence of catalyst.
The drawback of this process is that it is suitable for lab scale only, as the reaction is performed at elevated temperature between 100-170 C, which is difficult to perform on commercial scale.

N, N'-bis-(3-chloro-4-fluorophenyl) Formamidine Formula-V Formula V is prepared by using 3-chloro-4-fluro aniline; Triethyl orthoformate and acetic acid in toluene at 80 C for 1.5 hrs, distillation of toluene give the title compound in low yield.

Formula-Ill
Formula III and formula V are heated in toluene in presence of 4-toluene sulphonic acid to get final Gefitinib through the formation of intermediate of formula II and VI, results in low yield.
During the process, amidine is used in excess wherein only half of the quantity is consumed during the reaction, remaining quantity is ieft unused which increases the cost of production on large scale. The raw material for the syntheses requires four additional steps as per scheme described in WO 2005/023783.
There is therefore a need for a more efficient synthesis of the Gefitinib which results in high yield and purity, uses easily available materials, and does not involve use of chromatographic purification of intermediates.
SUMMARY OF THE INVENTION:
The main object of the present invention is to provide an improved process for the preparation of Gefitinib.

I
Yet another object of the invention is to provide an improved process for the preparation of Gefitinib with high yield and purity.
Yet another object of the invention is to provide an improved process for the preparation of Gefitinib, which involves substantial reduction in the number of isolated and stable intermediates in high purity.
Yet another object of the invention is to provide time and cost efficient process for the preparation of Gefitinib.
Yet another object of the invention is to provide an improved process for the preparation of Gefitinib without involving the use of colurrin chromatography at any stage of synthesis.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention is directed to process for the preparation of Gefitinib as per synthetic scheme 5.

Formula II Formula I
In a preferred embodiment of the present invention involves the reaction of Isovanilin with sulphamic acid in presence of sodium chlorite to get Isovanillic acid of formula-IX.
,COOH

In the second step esterification of Isovanillic acid is carried out by using Methanolic HC1 or p-TSA/MeOH or SOCl2/MeOH to get the compound of Formula-VIII. The percentage assay of Methanolic HC1 is ranging from 10 to 20% and temperature of the reaction is preferably about 30-70°C.

Benzylation of ester compound of Formula - VIII is carried out in presence of benzylating agent such as benzyl chloride, benzyl bromide at temperature ranging from 30 to 55° C using dry potassium carbonate and potassium iodide to isolate product of the formula-

In the fourth step, nitration of Formula- VII is done by using a nitration mixture such as acetic acid and cone. Nitric acid to give a compound of formula-VI at temperature ranging from 0 to 40° C using nitric acid (60-90%).
BnCk ^s. ,COOCHa

H3CO ^ ~NOs
Formula-VI In the fifth step, reduction of nitro group of the compound of Formula-VI is carried out using iron metal powder, acetic acid and HCl at temperature ranging from 40 to 70 C.

Cyclisation of compound of Formula-V is carried out using formamidine acetate using alcohol. Preferably C1-C4 alcohol is used as a solvent for cyclisation at a temperature ranging form 50 to 80°C.


Conveniently the chlorination of compound of Formula-IV is carried out using thionyl chloride in the presence of DMF in catalytic amount by using chloroform as a solvent to get compound of formula Ilia which on further condensation with 3-Chloro-4-fluoroaniline in the presence of isopropyl alcohol to give the compound of Formula-Ill without isolation. Temperature of the reaction is ranging from 60 to 90° C.

Formula-IIIa Formula-Ill
In another embodiment Debenzylation of benzyl group in Formula-Ill is carried out using metal catalyst such as 2-10% palladium-on-carbon at 40-50 psi (acetic acid) or CH3SO3H/CHCI3 or FeCh/CFkCh. The hydrogen pressure required can be in the range of 40-50 psi. Debenzylation is optionally carried out in presence of acetic acid.
Alternatively debenzylation is optionally carried out using ferric chloride and in presence of dichloromethane.

Condensation of 3-morpholinopropyl halide with the compound of Formula-II can be done in the presence of a suitable base.
The base used for the coupling is selected from carbonates such as anhydrous
Na2C03, K2C03, Li2C03 ,Cs2C03, BaC03)CaC03 and bicarbonates such as,
NaHC03,KHC03; preferred base being anhydrous potassium carbonate.

The solvent used for the reaction is selected but not limited to, ethers such as THF, MTBE, di-n-propyl ether, dibutyl ether; nitriles such as acetonitrile, propionitrile; ketonic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone; polar aprotic solvents such as DMF, DMA, NMP, 1,3- dimethyl imidazolidin 2-one; DMSO; aromatic hydrocarbons such as benzene, toluene xylene,cyclohexane. Further, a combination / mixture of any of the abovementioned solvents can be used. The preferable being acetonitrile.
The reaction is carried out at 0 to 150°C, preferably at 55 to 100°C. Phase transfer catalyst used for the reaction is selected from: (a) Quaternary ammonium salts such as N(RiR2R3R4)X wherein Ri,R2,R3, and R4 is C| to C|3 affcyf or arantyj" group, cycfoafityi', aryf? or heterocyciyi, X being a monovalent anion; include but not restricted to such as aliquat-336,cetyl trimethyl ammonium bromide, cetyl pyridinium bromide, tetra n-butyl ammonium chloride, tetramethyl ammonium chloride, tetraethyl amm0nium chloride, benzyltributyl ammonium bromide, benzyl triethyl ammoniurn bromide, hexadecyl trimethyl ammonium chloride. .The preferred catalyst is trityhylbenzyl ammonium chloride or tetrabutyl ammoniun bromide, tetrabutyl ammoniu.n iodide or tetrabutylammonium hydrogen sulfate; the more preferred catalyst being tetrabutyl ammoniun bromide. The use of inorganic salts facilitate halogen exchange catalysis during O-alkylation, such as Nal, KI, to improve the reaction rate or yield.


The present invention is illustrated using following non-1 inciting examples. Example-1
A mixture of Isovanillin (50g) and DM water (1250ml) was stirred and cooled to 5-10°C for 30 minutes. Then sulphamic acid (47.9g) is addecj into the reaction mass and stirred well for 10-15 minutes. Sodium chlorite (47.59g) is separately dissolved in (250ml) DM water and added dropwise. The mixture was filtered and dried. The crude compound was purified by acid-base purification. There was thus obtained isovanillic acid of Formula-IX (41.9 g, 83%), Purity 97-99%. Examnlc-2a
A mixture of Isovanillic acid (40 g) and methan^iic HC1 (400ml) was stirred and heated to 50-55° C for 4 hours. The methanolic HC1 was removed by distillation and the residue was diluted with 100 ml water. The aqueous mixture was extracted with ethyl acetate (200ml). The combined organic layers were washed with water concentrated completely to ££t_the compound of Formula-VIII (3Z.2&. 88.22°/^ Purity 9#_£9%, Example-2b
Alternatively a mixture of Isovanillic acid (40 g) and p-TSA/ HC1 (400ml) was stirred and heated to 50-55° C for 6-7 hours. The p-TSA/HCI was removed by distillation and the residue was diluted with 100 ml water. The aqueous mixture was extracted with ethyl acetate (200ml). The combined organic layers were washed with water concentrated completely to get the compound of Formula-VIII (37.6 g, 86.5%), Purity <)8-99%. Example-3a
A mixture of methyl 3-Hydroxy-4-methoxy benzc>ate (40 g), acetone (600ml), dry K2C03 (60.65g), KI (9.12g) were stirred at room temperatiare for 10-15 minutes. The benzyl chloride (36.5g), was added. The resultant mixture was headed to reflux for 12-15 hours. The solid was collected by filtration, washed with acetone. The filtrate was evaporated and isolated in hexane to give compound of Formula-VII (54.6^ 91.33%), Purity 98-99%. Examnle-3b
Alternatively a mixture of methyl 3-Hydroxy-4-rr)ethoxy benzoate (40 g), acetone (600ml), dry K2C03 (60.65g), KI (9.I2g) were stirred at 25-30°C for 10-15 minutes. The benzyl bromide (36.5g) was added dropwise. The resultant mixture was heated to reflux for 15-18 hours. The solid was filtered and washed twice w;m acetone. The filtrate was evaporated and isolated in hexane to give compound of Formuja-VII (50.2g, 84%), Purity 98-99%.

Example-4
A mixture of methyl 4-methoxy-3-benzyloxy-benzoate (50g) and acetic acid were stirred and cooled to 0-10°C. Then conc.HNCh (75ml) was added. On complete addition stirring maintained for about 12-15 hrs at temperature ranging 25-40 C. Quench the residue in chilled DM water (1L). The resultant solid was collected by filtration, washed with water and dried to give compound of Formula-VI (54.5g, 93.5%), Purity 90-95%. Example-5
A mixture of Iron powder (26. Ig), acetic acid (270ml) was stirred and heated at 50-60 C for 30minutes. Then methyl 4-methoxy-3-benzyloxy-6-nitro benzoate (45 g) is added in portion wise. Reaction was maintained at same temperature for 5-6 hours. The mixture was hot filtered and filtrate was evaporated and the residue was extracted with ethyl acetate 2x300ml. The combined organic layers were washed with water and concentrated completely to get the compound of Formula-V (34.2 g, 87.1%), Purity 94-96%. Example-6
A mixture of methyl 5-benzyloxy-4-methoxy-2-amino benzoate (45g), Formamidine acetate (30g) and methanol (360ml) were stirred and heated to approximately 15-18 hours to complete the reaction. The reaction mixture was cooled to ambient temperature and the solid was collected by filtration, washed with methanol and dried. There was thus obtained compound of Formula-IV (35.6 g, 91 %), Purity 98-99%. Example-7
A mixture of 6-benzyloxy-7-methoxyquinazolin-4(3.r7) one (40 g), chloroform (200ml) and DMF (3.6ml) is taken in RBF and thionyl chloride is added drop wise to the reaction mass. The reaction was maintained at about 60-65°C for 12 hours. The solvent was removed by distillation and strip off with chloroform. 3-chloro-4-fluoroaniline (36.3g) is dissolved in methanol (480ml) and was added to the reaction mass with stirring at 25-30°C. the reaction is heated to 60-65 C for an hour and allowed to cool at 0-5 C for a period of 1 hour. The solid got separate out and was collected by filtration, and washed with chilled IPA to give dried compound of formula-Ill (53.7g, 93 %), Purity 98-99%. Example-8
A mixture of 4-(3-chloro-4-flurophenylamino) 6~benzyloxy-7-methoxy quinazolin (40g), Palladium-on-carbon 4.0gm in 800ml methanol at 20psi pressure for 30 min. reaction progress is monitor on TLC. On completion of reaction the reaction mass is filtered over celite bed and washed with 50ml methanol twice. The methanol is distilled to get compound formula -II. (24g, 80 %) Purity 80-85%.

Examp1e-9a
A mixture of 4-(3-chIoro-4-flurophenyIamino) 6-benzoyIoxy -7-methoxy quinazolin (5g), methane sulphonic acid (7 ml) in 40mL chloroform, reflux for 3 hour. The dichloromethane is.distilled from reaction mixture and 30 mL water is added. pH is adjusted to 6.5 to 7.0 using aq. Sodium carbonate. Stir the reaction mixture for two hours at room temperature and filter and wash with water to get compound formula -II. (3.5g, 93 %) Purity 97-98%. Example-9b
A mixture of 4-(3-chloro-4-flurophenylamino) 6-benzoyloxy -7-methoxy quinazolin (5g), dichloromethane IOOmL and ferric chloride 9.4g. is refluxed for 1 hours. The reaction mixture is filtered and washed with 20 mL dichloromethane. Dichloromethane is distilled to give compound formula -II. (3.4g, 90.6 %) Purity 98-99%.
A mixture of 4-(3-chloro-4-flurophenylamino)-6-hydroxy-7-methoxy quinazolin (5g), acetonitrile 50mL and KI 0.2g, potassium carbonate 2.4 gm and TBAB 0.4 gm and N(3-chloropropyl)morphoIine 2.8g charged and refluxed for 6-8 hours. The reaction mixture is filter and acetonitrile is distilled. Crude material is purified using Methanol to give pure Gefitinib.
Date: 18-Jun-2009
For, CADILA PHARMACEUTICALS LIMITED.
Dr. Bakulesh Mafatlal Khamar Executive Director - Research