Title of Invention


Abstract The present invention provides a process for synthesizing 4-(3-chloro 4 -fluoro phenylamino)- 7 -methoxy-6 -[ 3-( 4-morpholinyl) propoxy ] quinazoline (gefitnib) having the formula comprising reacting 3-hydroxy-4-methoxy benzaldehyde with substituted morphilino propyl moiety to obtain 4-methoxy-3-[3-( 4- morpholinyl)propoxy]-benzaldehyde .This is converted to give 4- methoxy3-[3-( 4-morpholinyl)propoxy]benzonitrile. On furthur nitration we obtain 4-methoxy-5-[3-( 4-morpholinyl)ropoxy]-2-nitrobenzonitrile which on nitro reduction we get 2-amino-4,5-bis(2-methoxyethoxy)benzonitrile. Coupling of this compound with N"-(3-chloro-4-flurophenyl)N,N-dimethyl formamidine to give gefitnib
[See Section 10]
A process for the synthesis of 4-(3-chloro-4-fluorophenyIamino)-7-methoxy-6-
(3-(4-morpholinyl) propoxyj-quihazolinc
VITTAL MALLYA SCIENTIFIC RESEARCH FOUNDATION, an Indian organization of P.B. No. 406, K.R. Road, Bangalore - 560 004, Karnataka, India
The following specification describes and ascertains the nature of this invention and the manner in which it is to be performed:

The present invention relates to a novel process for the synthesis of 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morphoIinyl) propoxy]-quinazoline having the formula (1).

It is a low molecular weight, orally active, selective epidermal growth factor receptor- tyrosine kinase inhibitor (EGFR-TKI). It exhibits significant anti-tumor activity in a broad range of solid human tumor xenografts in vivo. Clinical toxicology studies have demonstrated good oral bio-availability and was well tolerated in long term oral administration.
Description of the Prior Art
Three methods for preparation of the compound of formula I are already described in published patents viz., US 5770599; PCT/IN2004/000223 (WO 2005/070909); PCT/GB2004/003720 (WO 2005/023783).
The conventional process for the synthesis of 4-(3-chloro-4-fluorophenylamino)-7-methoxy~6-[3-(4-morpholinyl) propoxy]-quinazoline described in US Patent No. 5770599 which comprises reacting 4-(3-chloro-4-fluoroanilino)6-hydroxy-7-methoxyquinazoline with 3-morpholin propyl chloride under basic conditions using potassium carbonate in solvent like dimethyl formamide. The steps of the process given in US Patent 5,770,599 are:

In above known method, the yield is low and is about 50%. Further, preparation of 4-(3-chloro-4-fluoroanilino)-6-hydroxy-7-methoxy quinazoline involves making of 6-hydroxy~7-methoxy-3,4-dihydroquinazoline-4-one by selective demethylation of 6,7-dimethoxy-3,4-dihydro quinazoline-4-one using methane sulphonic acid and L-methionine. In this process a large excess of methanesulphonic acid has been used (about 1:11 molar ratio of substrate v/s methanesulphonic acid) in conjunction with methionine which acts as a nucleophile. Then protection and deprotection of 6-hydroxy group has been done which requires a large excess of acetic anhydride (about 1:14 molar ratio of substrate v/s acetic anhydride) while coupling with 3-chloro-4-fiuoroaniline.
Yields in demethylation step of 6,7-dimethoxy-3,4-dihydro quinazoline-4-one are about 47%. Apart from yield loss methanesulphonic acid is very corrosive. Acetylation of 6-hydroxy-7-methoxy-3, 4-dihydroquinazoline-4-one also ended in lower yields of about 75% of 6-acetoxy-7-methoxy-3, 4-dihydroquinazoline-4-one. Thus yield losses, together with excess usage of reagents and large number of reaction steps

push the manufacturing cost to a higher side. Thus, this known method involves various industrial difficulties.
As per patent process of PCT/IN2004/000223 a method is mentioned wherein 4-chioro-6-(3-morphoIinopropoxy)-7-methoxy-quinazoline is coupled with 3-chIoro-4-fluoroaniline in isopropanol using triethylamine as a base. Preparation of 4-chioro-6-(3-morpholinopropoxy)-7-methoxy quinazoline involves several independent steps starting from isovanillin. Preparation of 2-amino-4-methoxy-5-[3-(morpholinyl) propoxy] benzamide involved potentially hazardous hydrogenation reaction using Raney nickel and methanol under reduced pressure. Then preparation of gefitinib from 7-methoxy-6-(3-morpholinopropoxy)-3, 4-dihydroquinazolin-4-one required first the preparation of 4-chloro-6-(3-morpholinopropoxy)-7-methoxy quinazoline and then coupling with 3-chloro-4-fluoroaniIine which formed two independent steps. Large number of reaction steps together with risky hydrogenation step may cause difficulties in production of gefitinib on industrial scale.
A further route for preparing the compound of formula I is disclosed in
international patent application WO 2005/023783. Here the method involved
is the rearrangement reaction of 3-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-
morpholinopropoxy)-3,4-dihydroquinazoline-4-imine at an elevated
temperature. The intermediate that cyclises to provide this imine is believed
to be N-(3-chloro-4-fluorophenyl)-N'-[2-cyano-5-methoxy-4-(3-
morpholinopropoxy) phenyl] formamidine which in turn was prepared from 2-amino-4-methoxy-(3-morpholinopropoxy) benzonitrile and N, N'-bis-(3-chloro-4-fluorophenyl) formamidine. One of the main disadvantage of this process is the usage of excess of the substrate 3-chloro-4-fluoroaniline which is expensive. Further draw back of the process is in the isomerization of 4-imine compound which takes place at around 110 ° C and a longer reaction period.
Summary of the present Invention

In view of problems as described in above processes, there is provided a process in the present invention a more efficient and convergent process for the synthesis of 4»(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl) propoxy]-quinazoline (scheme-l) having the above formula! by substantially reducing the number of steps and also intermediates that must be isolated. Further the present invention has significant advantage in terms of cost and time. In present invention, processes are provided for the preparation of key intermediates that must be used in the synthesis of compound of formula I.
According to still another objective of this invention there is provided a novel compound of the formula VI which is an intermediate for the preparation of the compound of formula I and a process for its preparation.
The object of the invention is to obviate the disadvantages of the prior art by simplifying the process and have yield higher than 75%. The invention provides a process for the synthesis 4-(3-chloro -4-fluorophenylamino) -7-methoxy -6- [3~(4-morpholinyl) propoxy] quinazoline having the formula I,
a) reacting 3 - hydroxy - 4 - methoxy benzaldehyde with morpholino propyl moiety in presence of base and an inert solvent to obtain 4-methoxy-3-[3-(4-morpholinyI) propoxy] -benzaldehyde having
formula II,

b) converting compound of the formula II into an oxime in presence of a base and an organic solvent and dehydration of the oxime in the presence of a dehydrating agent to obtain 4-methoxy-3-[3-(4-morpholinyl) propoxy] benzonitrile having formula III,

c) nitrating the compound of the formula III in presence of a nitrating agent to obtain 4-methoxy-5-[3-(4-morpholinyl) propoxy]-2-nitro benzonitrile having formula IV.

d) subjecting compound of the formula IV to nitro reduction in the presence of a reducing agent, to get compound having the formula V, and

e) coupling of the compound of formula V with the N'-(3-chloro-4-flurophenyO^N-dimethylformamidine of formula VI to give us compound of formula (I) in the presence of acid catalyst.

The compound of formula VI is obtained by formylation of 3- chloro-4-fluroaniline.
The compound of formula (I) is purified by.recrystallisation from solvents to get the compound of acceptable purity.
The inert solvent in step (a) is an aprotic solvent selected from aliphatic Ketones, substituted amides preferably dimethylformamide.
The morpholino propyl moiety in step (a) is substituted with a chloro, bromo, hydroxy or methoxy group preferably bromo group
The base used in step (a) is alkali or alkaline earth metal carbonate and hydroxide preferably sodium or potassium carbonates.
The solvent used in step (b) is methanol, ethanol or isopropanol preferably methanol or isopropanol.
The base in step (b) is organic base or inorganic base selected from pyridine,4-dimethylaminopyridine, triethyiamine, sodium acetate, ammonium acetate: the base preferably used is pyridine.

i ne aenyarating agent used in step (b) is thionyl chloride, phosphorous oxy chloride, acetic anhydride, propionic anhydride; preferably acetic anhydride.
The reaction in step (b) is performed from ambient to reflux temperature
preferably at 110° C.
The process as claimed in claim 1 wherein the nitrating agent used in step (c) is nitric acid.
The reaction in step ( c) is carried out in the temperature range from 25° C to
60° C preferably 40 ° C .
The nitro reduction in step (d) is carried in the presence of the catalyst on an
inert carrier and in an inert solvent or in the presence of an inorganic reducing
The catalyst in step (d) is selected in from palladium .platinum or iron , and the inert carrier used is carbon and the inert solvent is selected from water, or ethanol, or methanol or acetic acid and the inorganic reducing agent used is sodium dithionate at a temperature in the range from 30 to 50 ° C conveniently at 30 ° C .
The formylated reagent used for making compound of formula VI which in turn used in step (e) is N,N-dimethylformamide dimethylacetal in polar aprotic solvent , aromatic solvent , or a dipolar aromatic solvents at a temperature range 30 to 140°C , conveniently at 110°C .
The polar .aprotic solvent used is tetrahydrofuran or 1,4 dioxane.The aromatic solvent used is toluene. The dipolar solvent used is N,N -dimethylformamide.
The acid catalyst in step (e) is trifluroacetic acid or formic acid, preferably acetic acid at temperature range 30 to 140 ° C f conveniently at 130 ° C The process of preperation of 4-(3-chloro-4-flurophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy]-quinazoline is substantially as herein described with reference to the foregoing example.

a) 4-methoxy-3-[3-(4-morpholinyl)-propoxy] benzaldehyde:
A mixture of 3-hydroxy -4- methoxy benzaldehyde (20g), 3-
morpholinopropyl chloride (28g), potassium carbonate (50g) and DMF
(140ml) was stirred and heated to 100°C for 3 hours. The reaction mixture
was cooled and filtered. The filtrate was evaporated and the residue
obtained was dissolved in ethyl acetate (200ml). The ethyl acetate layer was
washed with water, dried over anhydrous sodium sulphate. Evaporation of
ethyl acetate yielded 4-methoxy-3-[3-(4-morpholinyl)-propoxy]
benzaldehyde (34.8 gms,95%) of the formula II.
b) 4-methoxy -3[3-(4-morpholinyl)-propoxy] benzonitrile:
The above 34.8 gms of compound was dissolved in 200 ml methanol, and to this added 34.8 g of hydroxylamine hydrochloride and 35 ml of pyridine. The reaction mixture was heated to reflux for 3 hours and then cooled to 10 °C. The material precipitated mass was filtered and the solid mass obtained was washed with chilled methanol (50ml) and dried at room temperature. To this dried material was added 2 volumes of acetic anhydride and heated to 110°C for 4 hours. Then quenched the reaction mass in water and adjusted the pH to 8.0 with sodium bicarbonate and extracted with methylene dichloride. Washed the methylene dichloride layer with water and dried over calcium chloride. On evaporation of the solvent 4-methoxy -3[3-(4-morphoinyl)-propoxy] benzonitrile (31 gms, 90%) of the formula III.
NMR spectrum (CDCI3): 5 2.05 (m, 2H), 2.53 (m, 6H), 3.72 (m, 4H), 3.91 (s, 3H). 4.10(mf 2H), 6.89 (d, 1H), 7.25 (d, 1H), 7.28 (dd, 1H).
c) 4-Methoxy-5-[3-(4-morpholinyl)-propoxy]- 2-nitro benzonitrile: The above compound (31 gms) of the formula III was dissolved in 30 ml of 70% nitric acid and this was added to 55°C preheated 30 ml of 70% nitric acid slowly over a period of 2 hours under stirring. After completion of the addition, continued stirring at the same temperature for further an hour. Cooled the reaction mixture and quenched in cool water and

adjusted the pH to 8.0. The precipitate obtained was filtered and washed with ice cold water and dried the material at 50°C to get 27 gms yellow solid 4-Methoxy-5-[3-(4-morphoiinyl)-propoxy]- 2-nitro benzonitrile (75%) of the formula IV.
NMR spectrum (DMSO-d6): 5 2.18 (m, 2H), 3.26 (m, 4H), 3.53 (m, 4H), 3.99 (s, 3H), 4.04 (m, 2H), 4.29 (m, 2H), 7.73 (s, 1H), 7.91 (s, 1H). d) Synthesis of 2-amino-4-methoxy-5-(3-morpholinopropoxy) benzonitrile: To 4-methoxy-5-[3-(4-morpholinyl) propoxy]-2-nitro benzonitrile (10 g) was added acetic acid (75ml) and water(75ml), stirred the reaction mass for about 10 min, added Iron powder (7g) in portions over a period of 2hrs, Stirred the reaction mixture for about Vi hr at room temperature adjusted PH of the reaction mass to 8 using ammonia solution, extracted the material into ethylacetate, the organic layer was dried over sodium sulfate and concentrated to get product(6g)
1HNMR (CDCI3): 5 2.01 (m, 2H), 2.51 (m. 6H), 3.72 (t, 4H), 3.84 (s, 3H), 3.97 (t, 2H), 4.14 (brs, 2H), 6.23 (s, 1H), 6.85 (s, 1H).
(e) Synthesis of N'-(3-chloro-4-fluorophenyl) N,N-dimethyl formamidine.
To 3-chloro-4-flouro aniline (10g, 0.0687moles) was added Toluene (40ml), N,N-dimethylformamide dimethyl acetal (18.3ml, 0.1374moles) and acetic acid (0.5ml), heated the reaction mixture to 110°C and stirred for about 2hrs, distilled off toluene to yield dark brown liquid (11g)
1HNMR (CDCI3): 5 3.0 (s, 6H), 6.75 (m, 1H) 6.94 (m, 1H), 6.98 (m, 1H), 7.45 (s, 1H).
(f) Synthesis of Gefitinib:
To 2-amino-4-methoxy-5-(3-morpholinopropoxy) benzonitrile (5g, 0.0172moles) was added toluene (30ml), N'-(3-chloro-4-fluorophenyl) N, N-dimethyl formamidine (3.44g, 0.0172moles) and acetic acid (0.5ml) refluxed the reaction mixture for about 4hrs cooled the reaction mass to room temperature, toluene layer was separated washed with water and chilled toluene layer to yield crude gefitinib and which was further recrystallized from

methano! to get pure off-white crystalline compound(3g) having the mp
UV, IR, NMR spectral data together with elemental analysis is in complete
agreement with those of standard substance of Gefitinib


in our copending application 1227/CHE/2005 we have described the process for preparing 4-(3-chloro-4-flurophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline which is different from the process described and claimed in the instant applications


903-che-2006 complete specification as granted.pdf




903-che-2006-complete description .pdf

903-che-2006-correspondance -po.pdf


903-che-2006-form 1.pdf

903-che-2006-form 13.pdf

903-che-2006-form 26.pdf

903-che-2006-form 9.pdf


Patent Number 236843
Indian Patent Application Number 903/CHE/2006
PG Journal Number 49/2009
Publication Date 04-Dec-2009
Grant Date 25-Nov-2009
Date of Filing 25-May-2006
Name of Patentee Vittal Mallya Scientific Research Foundation
Applicant Address P.B. No. 406, K.R.Road, Bangalore 560 004,
# Inventor's Name Inventor's Address
1 Venkateshappa Chandregowda P.B. No. 406, K.R.Road, Bangalore 560 004,
2 Gudapati Venkateswara Rao P.B. No. 406, K.R.Road, Bangalore 560 004
3 Anil Kumar Kush P.B. No. 406, K.R.Road, Bangalore 560 004,
4 Goukanapalli Chandrasekara Reddy P.B. No. 406, K.R.Road, Bangalore 560 004,
PCT International Classification Number A61K31/517, C07D239/72
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA