TITLE:
Synthesis of quinazolines and its conversion to an anticancer product gefitinib,4-(3-Chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy] quinazoline.
FILED OF INVENTION:
This invention describes a modified and short route of synthesis for quinazolinones of formula Vli as claimed in an additional patent application and its further conversion to an anti-cancer product viz. gefitinib.
BACKGROUND OF THE INVENTION :
The epidermal growth factor (EOF) receptor is known to be over expressed in a large number of human cancer, including mammarian, ovarian, oesophagel, head and neck, colorectal, prostate etc., The activation of the EGF receptor tyrosine has been identified as a key initiating event for ceil proliferation .For these reasons, inhibitors of the EGF receptor tyrosine kinase are potentially useful as chemotherapeutic agent for the treatment for cancer.
4-(3-Chloro-4-fluorophenylamino)"7-methoxy-6-[3-(4-morpholinyl)propoxy] quinazoline, hereirpefter called, gefitinib, is a novel addition to the array of anti tumor agents, especially the epidermal growth factor tyrosine inhibitors, that has shown promising effect in the treatment of a variety of solid tumors, especially non-small cell lung cancer and hematological malignances.

PRIOR ART:
As known in the art, the Indian publications and patents relating to this compound are not found. Some of the United States and European patents have described processes which are not related to the process described herein. Other publications referred herein are also not- related to the novel process developed but are only supportive documents to the present invention.
The synthesis of gefitinib has been described in the patents listed herein, Viz EP 0823900, JP 1999 50 40 33, US 5770599,WO 9633980. The methods described in these patents make use of 6-hydroxy-7-methoxy quinazoline-4-(3H)-one of formula-ll as the crucial intermediate. This product can be obtained by demethyiation of 3H-6.7-dimethoxy quinazoline-4-one of formula-l. The synthesis of gefitinib is described in scheme-l


As per the patent methods, the synthesis starts but utilizing 6,7-dimethoxy quina2olin"4(3H)-one of formula - I. This was demethylated using L-methionine in methane sulphonic acid to give 6-hydroxy-7-methoxy quina2oline-4 (3H)-one of formula - II, which was converted to 6-acetoxy-7-
methoxy quina2olin-4 (3H)-one of fomiula - III. Halo'^nation of formula - III
.. ^
with POCI3 resulted in the formation 4-chloro quinazoline derivative of formula - IV. The product of formula - IV

was reacted with 3-chloro-4-fluoro aniline to yieid the product of formula -V, Viz. 6-acetoxy-4-(3-chloro-4-fi'joro phenyl)"amino-6-hydroxy-7-methoxy quinazoline of formula - VI, which on reaction with 1,3 dibrorho ethane yielded the quinazoline derivative of formula - VII. Reaction of the product of formula - VII with morpholine gave gefitinib of formula - VIII. Another approach was reacting the product of formula - VI, with 4-(3-chloro propyl) morpholine of formula. Reaction of 1 -bromo-3-chloro propane with morpholine gave 4-(3-propyl) morpholine, which was reacted with quinazoline derivative to give gefitinib.
The above described process has a major disadvantage, in the preparation of 6-hydroxy-7-methoxy quinazolin-4(3H)-one, which was achieved by demethylating 6,7-dimethoxy quinazolin-4(3H)-one using L-methionine in methane sulphonic acid. We have tested the same reaction using DL-methionine in the methane sulphonic acid, which is equally effective. This method had to be reconsidered, since methane sulphonic acid is corrisive and highly polluting.
DESCRIPTION OF THE INVENTION : ^^
One of the objective of the present invention was to develop a novel method of synthesizing 6-hydroxy"7-methoxy quinazolin4-(3H)-one. Another objective of the present invention was to convert this intermediate

of formula - H to gefitinib of formula - VIII through a new intermediate. The scheme considered for the synthesis of 6-hydroxy-7-methoxy quinazoim-4(3H) one is given in scheme - II.

The synthesis of 6-hydroxy-7-methoxy quinazolin-4(3H)-one was started
from 3-hydroxy-4-methoxy benzaldehyde (Iso vanillin) of formula X, which is
quite cheap. The benzylation of iso vanillin yielded the product of formula -
XI. The benzylation was tried in several solvents ranging from acetone,
acetonitrile to more polar solvents like dimethyl formamide, dimethyl
acetamide, N-methyl pyrrolidone etc., It was observed that latter set of
solvents was more suitable that the former set. Among the solvents like di
methyl formamide, di methyl acetamide, and N-methyl pyrrolidone, di methyl

formamide was preferred, since it is cheaper and easier to recover. The bases tried for scavenging acid were sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, etc., The reaction was tried at temperature ranging from 250 C to 1000 C. The most preferred temperature was 30 - 400 C. The reaction went to completion in about 2 to 4 hours. The yield for this stage was nearly quantitative.
The product of formula - XI was nitrated to yield 3-hydroxy-4-methoxy-6-nitro benzaldehyde of fomiuia - XII. The nitrating agents tried were H2SO4 - HNO3 . H2SO4 - ANO3, (A = Na, K ) acetic acid - HNO3 , acetyl nitrite. It \A/as preferable to use sulphuric acid - nitric acid or sodium / potassium nitrate and Sulphuric acid. It was more preferable to use concentrated sulphuric acid and nitric acid as the nitrating agent. The temperature used for the reaction was preferably 5 to 250 C. The temperature used for the reaction was more preferably 10 - 200 C. The nitro derivative was formed in about 90-95 % yield of theory.
The nitro benzaldehyde derivative of formula - XII was converted to the nitrobenzonitrile derivative of formula - XIII. This was achieved by a one-pot method by treatment of the aldehyde derivative with hydroxyl amine in the presence a mixture of heterocyclic amine like pyridine or a or p picolines or a mixture of picolines and acetic anhydride or acetyl chloride. It was preferable to conduct the reaction at 50 - 1000 C. It was more preferable to conduct the reaction at a temperature of 85 - 1000 C. The

conversion at this stage was about 90 %. We wished lo convert the nitro benzo nitrile to amino benzamide of formula - XiV in one-pot so that the economics for the process is better. A suitable condition was by conducting the hydrogenation using Raney Nickel and hydrazine nydrate. The preferable solvents v/ere methanol, ethanol, 1-propanol, 2-propanol etc., The catalyst was used, preferably in about 10 weight percentage of the substrate and hydrazine hydrate was used in about 1 : 2 moles of the substrate. The conversion at this stage was about 90 - 95 % of the theory.
The anthranilamide of formula - XIV was reacted with formic acid to yield 7- methoxy-6-phenyl methoxy quinazolin-4(3H)-one of formula - XV. The reaction was conducted preferably at about 60 - 100° C and the conversion was neariy quantitative. The product of formula - XV on debenzylation will yield the crucial intermediate. Viz. 6-hydroxy-7-methoxy-quinazolin-4(3H)-one of formula - II. This was achieved by two different methods a) debenzylation using Pd / C or b) using trifluoroacetic acid. Both processes were very effective. In the case of Pd / C, the catalyst could be recycled'several times and in the case of trifluoroacetic acid, the excess of the acid could be recovered and reused making the process economical and ecofriendly. The invention describes a novel method of converting iso vanillin of formula - X to 6-hydroxy-7-methoxy quinazolin-4(3H)-one of formula - II and has the following advantages,
— ^ **t.**.s.*^ ^^,mtj.i ^^l^^^^^^r^^

b) economical and eco friendly
c) high yields
d) less cycle time
The product of formula - II was converted to the prduct of formula - VI as given in scheme - I. Herein we looked at the possibility of converting the product of formula - VI to gefitinib through a new intermediate having, some advantages over the process described in the prior art. The reaction studied is given in scheme - Hi.


Hence reaction of 6-Hydroxy quinazoline of formula XVil v/ss tried with 1-Bromc-3-chloro propane in order to prepare the novel intermediate. The reaction was tried under different conditions which are listed below.
a) in DMF using K2CO3 as base at 80 - 1500 C
b) in acetonitrile using K2CO3 as base at reflux
c) in chloro bromo propane using K2CO3 as base and PTC at 80 - 1500 C
Among these conditions, the one using DMF and K2CO3 yielded good results. The reaction in DMF was conducted at a temperature of 80 -1500 C. It was preferable to the conduct the reaction at a temperature of 90 - 110° C. 1-Bromo-3-Chloro propane was used 1 to 3 mole in excess of the substrate. 1-Bromo-3-Chloro propane was preferably 2 to 2.5 mole excess of the substrate and preferably conducted for a period of 4 to 6 hours. The product of formula XVII was converted to product of formula Vila in about 80% yield of theory.

The product, viz 4(3-ch!oro-4-fiuoro phenyl) amino 6(3 chloro propoxy)-?-/ methoxy quinazoline i3(a) hitherto unreported and has been characterized The product of formula Vila was converted to gefitinib by reacting with morpholine. The reaction was tried in different conditions such as
a) in DMF containing K2CO3 and Ki at 80-120*^0
b) in DMF containing 2-3 moles of rnorpholine and KI at 80-1200 C
c) In DMF containing 1 to 1.5 moles of morpholine using Zinc as the acid scavenging agent at 70-1200 C.
The reaction in DMF was conducted using 1.5 to 3 moles of anhydrous K2CO5, catalytic amount of KI and 1 to 2 moles of morpholine. The reaction was conducted preferably at 80-1200 C for 6 to 10 hours. The reaction was more preferably conducted using 2 to 2.2 moles of anhydrous K2CO3 , catalytic amount of KI and 1 to 1.2 moles of morpholine at a temperature of 95 to 1100C for a period of 8 to 9 hours.

j^'^ j^*^
Another method of conducting the reaction was heating the product of formula Vila at 80 to 120°C with 2 to 3 moles of morpholine in DMF
containg catalytic amount of KI at a temperature of 95- 1100 C for 8 to
10 hours.

Yet another method of performing the reaction was heating the product of formula Vila with about 1 to 1.2 moles of morpholine, 1 to 2 mdes of Zinc in DMF at a temperature of 70 to 900 C for about 8 to 10 hours.
The following are the major gains of this invention :
a) a short .economical, eco-friendly and high yielding process for the synthesis of 6-hydroxy-7-methoxy quinazolin-4(3H)-one
b) synthesis of a new intermediate viz 4-(3-ch!oro-4-fluoro phenyl amino-6-(3-chloro propoxy)-7-methoxy quinazoline
c^ conversion of this intermediate to aefitinib in hiah vield and excellent purity.
The following examples illustrate the present invention in more detail, but are not to be construed to limit its scope in any manner.
Example :
The invention is further illustrated by the way of non-limitive examples to explain the nature of the invention, which should not be constructed as limiting the scope of the invention For more complete understandina of the instant invention reference is now made to the following description taken in conjunction with examples.

Exam Die 1 : Preparation of 3-benzyloxy-4-methoxy benzaldehyde (X!)
!n a 500 m! three-necked RB flask filled with a stirrer, condenser fitted with a guard tube and thermometer socket, was charged. 90 gms (C,59 mo!) of iso vanillin, 200 m! DMF and 83 gm (0,65 mo!) of pure benzyi chJorlde and the mixture v/as stirred at about 70^ C for 1 hour. On Gompletlon (TLC), the reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was crystallized from isopropyl alcohol to give 136 gm (95% yield) of the produci having rn.p. 61 -62^C.
Example 2 : Preparation of 5-benzyloxy-4-methoxy-2-nitro-ben2aldehyde(X!i) In g lit three-necked RB flask filled with a stirrer, addition funnel and a thermometer socket was added 200 ml acetic acid. The product !! 96 gms (0.396 mol) obtained in example 1 was added in instalments to the stirred acetic acid. Then the solution was cooled to about 150 C and nitric acid(200 ml 70% HNO3) was added drop wise maintaining the reaction temperature at 15 to 200 C. On completion of addition of nitric acid, the reaction mixture was stirred at 150 C for about 30 minutes. Then ttie reaction mixture was quenched in ice water. The precipitate was filtered, washed free of acid, pressed dry ^ later dried in the oven at 800 C. The product, 108 gm(95%) having rn.p. 133 to 1350 C was obtained.
Example 3 : Preparation of 5-benzy!oxy-4-methoxy 2-nitro benzonitrile (Xlll)

To a 1 lit three-necked R5 flask filled with a stirrer, thermometer socket and 3 condenser carrying a guard tube, was added. The product obtained under example 2 (57.5 gm, 0.2 mole), NH2OH.HGI (146 gm, 0.21 moie), dry pyridine (250 ml) and acetic anhydride (300 ml). The reaction mixture was stirred at 90-950C for 2 hours. Later the reaction mixture was cooled to room temperature and poured into crushed ice 3 Kg . The precipitated solid was filtered, thoroughly washed with water and dried. The product was purified by crystallization from isopropyl alcohol give 40 gms (-85%) of the pure product having m.p. 136-1370 C.
Example 4 : Preparation of 2-amino-5-benzyloxy-4-methoxy-benzamide(XIV) To a 2 lit three-necked RB flask fitted with a stirrer, condenser and an addition funneMOO gm of the product obtained under example 3, 800 ml methanol and 10 gm of Raney Ni were added. A solution of hydrazine hydrate (80%) 150 gm in 200ml methanol was added to the stirred solution in the flask at 50 to 600 C. The hydrazine hydrate solution was added at such a rate that the solution was maintained at 50 to 600 C. After completing the addition, the reaction solution was stirred at 50 to 600 C for about 2 hours. The reaction mixture was cooled to room temperature and filtered. The methanolic solution was concentrated and oi! obtained was triturated with petroleum ether (60 - 800 C) to yield 90 gms (94%) of product having m.p. 159 - 1610 C. Example 5 : Preparation of 5-benrylox7-7-methox7 quinazolin 4(3H)-one(XV)

100 gms of the product obtained in example 4 and 500 m! form?c scid were taken in a 1 lit three-necked RB Hask, fitted with a stirrer, condcriser and a thermometer socket. The mixture was stirred under reflux for abofjt 2 hours. Excess of formic acid was distilled off, the residue was cooled to room temperature and then stirred with ice water (500ml). The precipitate was filtered, wastied with water and dried to give 80 gm(93%) of the quinazolinone derivative having m.p. 287^C .
Example 6 : Preparation of 6-hydroxy-7-methoxy-quinazoline"4(3H)-one (il) 100 gm of the 6-benzy!oxy quinazolinone derivative obtained in example 5 and 200 m! tri fluoroacetic acid were taken in a 500 ml three-necked RB flask and the mixture was stirred under reflux for 2 hours. The excess tri fiuoro acetic acid was distilled off, the residue was cooled and then stirred with diethyl ether. The precipitate was filtered, washed with ether and dried to give 6-hydroxy-7-methoxy quinazin-4(3H)-one , 65 gm (95%) m.p.>300^C
Example 7 : Preparation of 6-hydroxy-7-methoxy quinazolin-4(3H)-one(ll) 100 gms of the S-benzyloxy quinazolinone derivative was dissolved in 400 m! of DMF and charged into a hydrogenation kettle. 5 gms of 5%Pd/G was made into a slurry using DMF (20ml) and transferred into the hydrogenator. The product was subjected to hydrogenation using 1 atm hydrogen. As soon as hydrogen taken up had ceased, the reaction was stopped and the solution was filtered. The filtrate was concentrated under

vacuum and the residue was stirred with dieUtyi e^er. The precipitate was filtered with ether, dried to give 64 grn (94 %) of product having m.p. >300^C.

sn 93 g (0.3 mol) of the 6-hydroxy quinazoline derivative of formula XVll, gm (0.6 mol) 1-bromo-3-chloro propane 83 gm (0,6 mol) of anhydrous
Example 8 : Preparation of 4-(3-chloro-4-fluoro phenyl} aminO"6-(3-chloro propoxy)-7-methoxy quinazo!in-4(3H) one (Vlia) 4-(3-ch!orc-4-fluoro phenyl) amino-S-hydroxy-T-methoxy quinazoline was prepared as per described in Pat us 5770599 (Scheme -!V) In a 2 It three-necked RB flask fitted with a stirrer, condenser fitted with a guard tube and a thermometer socket was taken 93 g (0.3 mol) of the 6-hydroxy quinazoline derivative of formula XVll, 75
K2CO3 and 1 It of DMF. The reaction mixture was stirred at 110 - 115"^ C for 8 to 10 hours. Later the reaction mixture was cooied to about 40^ C and filtered. The filtrate was subjected to reduced pressure distillation. The residue v/as triturated in diisopropylether to give 85gms of the product having m.p.>280°C .
H NMR: 2.8 (M,2H),3.S (t,2H), 4.i (s,5H), 4.5 (t,2H), 7.6 (s,1H), 7.8 (t.iH), 8.0 (m,2H) 8.5 (M,1h), 8.9 {s,1H), 10.0 (s,1H).
Example for preferred embodiment :
Preparation of 4-(3-ch!oro-4-fluoro pheny!) amino-7-m8thoxy-6[3-(4-morpho!iny!)
propoxy] quinaxo!ine(V!!!)

VICLIIWU /~\ .
11.9 gms (0.03 mole) of 4-(3-ch!oro-4-fluoro ph8ny!)amJno-6-(3 chioropropoxvO?-methoxy quinazoline, 3.6 gms (0.045 m) morpholine, 8.28 gms (0.06 m) K2CO3 , 0.5 gms Kl and 100 m! DMF were charged into a 250 ml three-necked RB flask. The reaction mixture was stirred at 100 to 105° C for 10 hours. The completion of the reaction was monitored by TLC. On completion, the solution was cooled to about 40° C and filtered. The filtrate was concenfated under reduced pressure. The residue was crystallized from toluene to give 10.7 gms (80%) of the product having the following



Method B :
11.9 gms (0.03 moi) of 4-(3'Ch!oro-4-f!uoro phenyl) amino-6-(3'Ch!oro propoxy)-7-methoxy quinazoline, 7.8 gm (0.09 rrio!) of morpholine, 0.5 gm of K! and 80 ml DMF were taken in a 250 ml three-necked RB flask and stirred at 100 to 110'^C for about 10 hours. The progress of the reaction was monitored by TLC. On completion, the solution was cooled, filtered and DMF was distilled under reduced pressure. The residue was taken in water and extracted with methylene cloride. The methylene chloride extract was concentrated and the residue was crystallized from toluene togivelOgms ( 70% ) of the product having the characteristics similar to the one obtained A .
11.9 gms of (0,03 mo!) 4-(3-chloro-4-f!uoro phenyl) 3mino-6~(3-
ml PiMF \A/oro pharnoH infn Q 9^0 ml thrckO-nor'U'pH PP flacl( Tho mivtiiro
was stirred at 75 - SO*"^ C for 6 -hours. On completion, the solution was

filtered and the filtrate was concentrated under reduced pressure. The residue was freated with water and the pH was adjusted to 9-10. The product was extracted with methylene chloride. The methylene chloride extract was concentrated and the residue was crystallized from toluene to give 11.5 gm ( ~ 86 %) of the product having the characteristics similar to the one obtained under examole A .

1.
T
an anti-cancer product, namehy, gefitiriib of formiila Vii! by
a) benzylating isovanillin of formula - X to give 4-benzy!Qxy-5-methoxy benzaJdehyde of formula - XI,
b) nitrating the product of formula - XI to yield 4-benzyloxy-5-methoxy-2-nitro benzaldehyde of formula - Xll,
c) converting the nitro benzaldehyde of formula - Xil to nitro benzo nitrile of formula - Xill,
d) subjecting the nitro benzonitrile of formula - Xlll to reductive hydrolysis to get anthranilamide derivative of formula - X!V,
e) which is condensed with formic acid to get quinazolinone derivative of formula - XV,
f) followed by debenzylation of the product of formula - XIV to yield the crucial intermediate for gefitinib viz. 6-hydroxy-7-methoxy quinazolin-3(4H)-one of formula - II,
g) which in turn is converted into 4-(3-chloro-4-fluoro phenyl) amino-6-hydroxy-7-methoxy quinazoline as given in scheme -I, and this intermediate is dreacted with 1-bromo-3-chIoro propane to yield hitherto unreported intermediate. 4-(3-chloro=4-fluoro phenyl)amino-6'(3-chloro propyloxy)»7-methoxy quinazoline of formula - Vila,

h) Which was further reacted with morpholine to give gefitinib in excellent yieid and high purity.
2. A claim, as claimed in claim 1 a, where in the benzylation is carried
using benzyl chloride in dimethyl formamide in the presence of

3. A claim, as claimed in claim 1b, wherein the nitration is carried out using H2SO4 / HNO3, H2SO4 / MNO3, where M is Na or K, AcOH / HNO3, or ACONO2.
4. A claim, as claimed in claim 1c, wherein the nitro benzaldehyde derivative of formula XII is converted to nitro benzonitrile derivative of formula by reaction with hydroxyl amine hydrochloride or sulphate in the presence of a mixture of pyridine or a - picoline, or p -picoline or a mixture of picoline and acetic anhydride or acetyl chloride.
5. A claim, as claimed in claim Id, wherein the reductive hydrolysis IS carried out using Raney Nickel and hydrazine hydrate in mettianol or ethanoi or propanol or iso propanol at 50 -
6. A claim, as ciaimed in claim 1c, wherein the anthranilamide of formula XIV is converted to quinazoline of formula XV by reacting
7.
I

Pd/C and hydroger^ in DMF at 25 - or using trifiuoro acetic
acid at 50 -
8, A claim, as clainied in claim 1 g, where in the 4-(3-chloro-4-fiUoro
phenvi)amino-6-hydroxy-7-m8thoxy quinazoline formed by literature
method is reacted with l-bromo-S-chloro propane in DMF and K2GO3
to give hitherto unreported compound of formula Vila Viz. 4-(3-
chloro-4-fluoro phenyl)-amino-7-methoxy-6-(3-chloro propyloxy)
quinazoiine in 85 - 95 % yield.
9. A claim, as claimed in claim 1 h, wherein 4-{3-chloro-4-fiuoro
phenyl)aminO"7-methoxy-6-(3-chloro propyloxy) quinazoline is converted
to gefitinib in excellent yield and high purity by reacting with
morpholine.