TITLE :
Synthesis of 6-hydroxy-7-methoxy quinazoIin-4(3H)-one or quinazoiinones .
FIELD OF THE INVENTION : .
This invention describes a modified and short route of synthesis for quinazolinones of formula - Vll. BACK GROUND OF THE INVENTION :
The epidermal groNArth factor (EGF) receptor is known to be over expressed in a large number of human cancer, including mammarian, ovarian, oesophage!, head and neck, colorectal, prostate etc., The activation of the EGF receptor tyrosine has been identified as a key initiating event for cell 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-fluorophenyl)amino-7"methoxy-6-[3-(4-morpholinyl}propoxy] quinazoline, herein after called, gefftinib, is a novel addition to the array of anti-cancer 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.
It can be noticed that 6-l1fc|roxy-7-methoxy quinazoHn-4(3H)-one of the formula - II is the crucial intermediate. The method given is by demethylation of 6,7-dimethoxy quinazolin 4(3H)-one using L-methionine in

methane sulphonic acid.

The synthesis ofgefitinib has been described in the patents listed herein Viz. EP 0823900, JP 199950 40 33, US 5770599, WO 96 33980 and is given in the scheme - I. The methods described in these patents make use of 6-hydroxy-7-methoxy quinazolin-4(3H)-one of formula - II as the crucial intermediate. This product can be obtained by demethylation of 6,7-dimethoxy quinazolin-4(3H)-one.

PRORART :
As known in the art, the Indian publications and patents relleting to this
X
compound are not found. Some of the United States and European paints have described processes, which are not related to the process dascribc-d herein. Other publications referred herein are also not related to the present process and they only form supportive documents to the present invention.
The synthesis of 6,7-dimethoxy quinazolin-4(3H)-one is described in EP 565226, Journal of Biological Chemistry 1998,273(28), 17742-17748 and synthesis 2004(3)429-435, The scheme-II describes the process followed in the first two references,

As per EP 566226, the synthesis was achieved by reacting anthranilic acid derivative of formula ~ IX with formamide at a temperature of 140-1500 C to give the quinazolinone derivative of formula - I in about 20% yield. As per the method described in Synthesis 2004 (3) 429-435,

the preparation was achieved by heating the formula - IX with formamidine acetate at about
The third method (Journal of Biological Chemistn/ 1998, 273(28) 17742-17748), is described in scheme - HI,

In this procedure, 3,4-dimethoxy-6-nitro benzoic acid of formula -X was reacted with thionyl chloride, followed by ammonium hydroxide to give benzamide derivative of formula - XI, which was reduced with CUSO4-
to give anthranilamide derivative of formula - XII. The anthranilamide derivative on reaction with formic acid yielded the quinazolinone derivative of formula - I.
JMC 1977 20 147-149 described preparation of anthranilamide / derivatives, which could converted into quinazolinone /
IV gives the details of the synthesis of anthranilamide.


As per this procedure (Scheme - IV), benzaldehyde derivatives of / formulae XIII & Xllla v\^re benzylated to give products of formula XIV & XIVa. Nitration of the products of formula XIV & XIVa yielded the nitro benzaldehyde derivatives of formulae XV & XVa. Oxidation of the nitro benzaldehyde derivatives gave nitro benzoic acids of formulae XVI & XVIa. Reaction of the nitro benzoic acid derivatives of formula XVI & XVIa with

tiiiony! chloride followed by ammonia resulted in the fonTiiition of vnto benzamide derivatives of formulae XVII & XVIIa. Reduction of the nitro benzamide derivatives of formulae XVII & XVIIa, with iron acetic acid gave anthranilamides of formulae XVIII & XVIIIa. These compounds are / crucial iiitermediatecs6 for the synthesis of quinazolinones. SHORT COMINGS OF THE PRIOR ART :
The synthesis of 6,7-dimethoxy quinazo!ine-4(3H)-one using t^le reported methods have the following draw backs.
a) reaction of 2-amino-4,5-di methoxy benzoic acid with formamide gives poor yield ^ 20 %.
b) reaction of 2-amino-4,5-di methoxy benzoic acid with formajnideine acetate results in moderate yield ^ 50 %.
c) the synthesis starting from 3,4-di methoxyr6-nitro benzoic acid involves the use of corrosive reagent like thionyl chloride and also uses copper sulphate.

a.) benzylation takes very long time •*- 48 hours S^ yields are poor.
b) nitration methodology also results in poor yields.
c) conversion of nitro benzoic acid derivatives of formulae XVI &


respectively makes use of thiorr/i chloride, which is a
corrosive reagent and is botl;er to be avoided for an eco-
friendly process, d) conversion of nitro benzamides of formulae XVII & XVII a
involve the use of iron and acetic acid. The method is laborious and yieds are moderate.
Apart from this, the synthesis of 6-hydroxy-7-mettioxy quinazolin"4-(3H)-'One of formula - II is described in the patents by demethylation of 6,7-di methoxy quinazolin"4(3H)-one using L-methionine in methane sulphonic acid. Methane sulphonic acid is a corrosive reagent and polluting. The yse of this reagent has to be avoided.

OBJECT OF THE INVENTION :
"^ ^
The above mentioned shortcomings have given scope for the present invention and the Invention has addressed them successfully by adopting a novel process = One of the objects of the present invention was to develop a modified method of synthesizing of 6,7-di methoxy quinazolin-4(3H)-one. Another objective of the invention was to develop a method of synthesizing 6,7-dimethoxy quinazorm-4(3H)-one by an economically viable and eco friendly process and converting it to the crucial intermediate 6-hydroxy-7-methoxy quinazolin-4(3H)-one, by an economical and eco-friendly process.

The above objectives and other advantages vviil be clear form the following description of the preferred embodin^ent.
The route of synthesis conceived in this invention is given in Schem - V. Herein anthranilamide derivative XV!!! is utilized as the key intermediate, which has been synthesized by a short route.



solvents. The solvents tried were toluene in presence of a PTC, acetone or acetonitrile v/ith or without a PTC and dimethyl formamide. The reacticn was tried at a temperature range of 25 - 90 0 C, Even though the reaction proceeded well in most of these solvents under different conditions the observation was that an aprotic dipolar solvent like acetonitrile or DMF was preferable . It was more preferable to use DMF as the solvent. The reaction was conducted at a temperature of 25 - 900 C for a duration of 1 - 4 hours. It was more preferable to conduct the reaction at a temperature of 25-350 C for a duration of 1 -2 hours. Nitration was attempted wth an array of nitrating reagents to convert formula XIV to formula XV. The reagents tried were a) mixture of Sulphuric acid and 70/98% b) Nitric acid, sulphuricacid and KNO3 / NaNOs, c) 70% or 98%HN03 in a solvent like dichloromethane or dichloro ethane and d) nitric acid in acetic acid. It was preferable to use 70 / 98% HNO3 In acetic acid. It was more preferable to use 70% HNO3 in acetic acid. It was preferable to conduct the reaction at a temperature of 0 to 400 C. It was more preferable to conduct the reaction at a temperature of 10 - 200 C. It was preferred to convert the nitrobenzaldehyde of formula XV to anthranilamide of formula XVIII.
The nitro benzaldehyde derivative of formula XV was treated with 1 to 2 equivalent of hydroxylamine hydrochloride or 0.5 to 1 equivalent of hydroxylamine sulphate in pyridine or a-picoline or |3-picoline or y-picoline or a mixtures of picolines containing acetic anhydride at a temperature of 25 to 1000 C in order to convert it to the benzonitrile of formula XIX.

The conversion of nitro benzaldehyde derivative of forir.ula XV to the nitro benzonitrile derivative of formula XIX has TO go through the corresponding oxime. It was felt, that it will be better to convert tho aldehyde derivative to the nitrile derivative in one-pot rather than isolate the Oxime and then convert to the nitrile. This was achieved in excellent yield, nearly quantitative, by treating the aldehyde with hydroxy! amine in pyridine or picoline containing a dehydrating agent like acetic aiihydride The aldehyde derivative of formula XV was treated with 1 to 2 equivalent of hydroxylamine hydrochloride or 0.5 to 1 equivalent of hydroxylamine sulphate in pyridine or picoline containing acetic anhydride at a temperature of 25 to 1000 C in order to convert it to the benzonitrile of formula XIX. The yield in the conversion of the benzaldehyde derivative to the nitrile was nearly quantitative. There are a few methods, which can effect the conversion 2-nitro benzonitrile to the corresponding anthranilamide mostly by step wise process. But we thought of utilizing a reductive method under basic conditions in the presence of water so as to achieve the reductive hydrolysis in one-pot. Hence the reaction was tried under catalytic transfer hydrogenation conditions. The catalysts used were Raney Ni, Pd/C, Rh/C, and Zn. The hydrogen donor was hydrazine hydrate, which created a basic condition as well as provided water. The reaction was conducted in methanol medium at a temperature of 25 - 600 C. The catalyst was 5 to 10 weight% of the substrate. The mole ratio of the substrate to hydrazine hydrate 1 : 4 to 5. The reaction was preferably

-.-.n --
conducted at a temperature of 40 - 500 C. The conversion was effected to almost quantitative extent. This product was converted to the product of formula VI by heating with formic acid. The debsnzyiation of the product formula Vf was carried out either by hydrogen and Pd/G or trifluoroacetic acid= The catalytic debenzylation was conducted in DMF using 5% Pd/C at 1 atm. hydrogen pressure. The debenzylation was also carried out using trifluoro acetic acid at a temperature of 30 - 700 C. Trifluoroacetic acid was used 2 - 3 volume of the weight of the substrate. Excess tiifluoroacetic acid could be distilled off and reused. This makes the process economical and eco-friendly. Advantages of the present invention :
a) short and elegant
b) economical and eco friendly
c) high yields
d) less cycle time
The following illustrate the present invention in more detail, but are not to be misconstrued to limit its scope in any manner. Example 1 : Preparation of 3-benzyloxy-4-methoxy benzaldehyde (XIV)

(TLC), the reaction mixture was cooled to room temperature, filtered and
the filtrate was concentrated under reduced pressure. The residue was
Grystallized from isopropy! alcoho! to give 136 gm. (95% yield) of the
product having m.p. 61 -620 C=
Example 2 : Preparation of 5"benzYloxv-4-methoxv-2-nitro- benzaldehvde
(XV)
In a lit three-necked RB flask filled with a stirrer, addition funnel and a thermometer socket was added 200 ml acetic acid. The product !! 95 gms (0.396 mo!) obtained in example I was added in installments 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 15*^ C for about 30 minutes. Then the reaction mixture was quenched in ice water. The precipitate was filtered, washed free of acid, pressed dry and later dried in the oven at 800 C. The product, 108 gm(95%) having m.p. 133 to 1350C was obtained.
Example 3 : Preparation of 5-benzyloxy-4-methoxy 2-nitro benzonitrile (XIX) To a 1 lit three-necked RB flask filled with a stirrer, thermometer socket and a condenser carrying a guard tube, was added. The product obtained under example 2 (57=5 nm,0.2 mole), NH2OH.HCI (146 gm, 0.21 mole), dry pyridine (250 ml) and acetic anhydride (300 ml). The reaction mixture was stirred at 90 - 950 C 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 (-35%) of the pure product having m.p. 136-1370C.
Example 4 : Preparation of 2"amiino-5-benzyloxy-4-methoxy-benzamide{XVIil) To a 2 lit three-necked RB flask fitted with a stirrer, condenser and an addition funnel 100 gm of the product obtained under example 3, 800 m! methanol and 10 gm of Raney Ni were added. A solution of hydrazine hvdrate (80%) 150 cm in 200ml methanol was added to the stin-ed solution in the flask at 50 to 600 C. The hydrazine hydrate solution was added at
A.
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 oil obtained was triturated with petroleum ether (60 - 800 C) to yield 90 gms (94%) of product having m.p. 159 — 1610 C.

and a thermometer socket. The mixtur^ was stirred under reflux for about 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

vv
as filtered, washed with water and dried to give 8C gm(93%) of the quinazolinone derivative having m.p. 287^C .
Example 6 : Preparation of 6-hydroxy-7-methox7'quinazo!ine'4(3H)-one (!1)
Method - A
100 gm of the S-benzyloxy quinazolinone derivative obtained in example 5 and 200 ml trifluoro acetic acid were taken in a 500 mi three-necked RB flask and the mixture was stirred under reflux for 2 hours. The excess trifluoro acetic acid was distilled off, the residue was cooled and then stin'ed 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
IVI ethod - B
100 gms of the 6-benzy!oxy quinazolinone derivative was dissolved in 400 ml of DMF and charged into a hydrogenation kettle. 5 gms of 6%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 diethyl etg«r. The precipitate was filtered with ether, dried to give 64 gm (94 %) of product having m.p. >3000C.

We claim.

1. Synthesis of 6-hydroxy-7-methox>' quinazoiine 4(3H)-one, wherein the
quinazolinone derivative of formula V!! Is prepared by,
a. converting iso vanillin {4-hydroxy, 3-methoy benzaldehyde) of
formula - I to a product of formula - II.
b. Nitrating the product of formula - II, to get a product of
formula - II.
c. Converting the roduct of formula - III in one-pot to 4-methoxy-
2-nitro-5-phenyl methoxy benzonitrile of formula - IV
d. Which is again converted by a one-pot method to the
anthranilamide of formula -V
e. Which on further reaction with formic acid and de-protection
with trifluoro acetic acid or Pd/C and hydrogen yields the
quinazolinone derivatives of formula - VII.
2. A claim, as claimed in claim in 2a, where in the benzylation is preferably carried out, using benzyl halide and potassium carbonate in a solvent like DMF or acetone or acetonitrile.
3. A claim, as claimed in claim 2b, where in the nitration is achieved using concentrated nitric acid in acetic acid or acetyl nitrile or alkali nitrate and concentrated sulphuric acid.
4. A claim, as claimed in claim 2c, wherein the one-pot conversion of benzaldehyde derivative of formula - III to the benzonitrile of formula

V
- !V is achieved using a combination of a heterocyclic amine like pyridine or picoline, a salt of hydroxyiamine and dehydrating agent like acetic anhydride or acetyl chloride.
A claim, as claimed in claim 2d, wherein a one-pot reduction of nitro group and hydration of cyano group is achieved by using Raney Nickel and hydrazine hydrate in an alcoholic solvent like methanol, ethanol. Isopropanol at a temperature of 25 - 1000C to get anthranilamide of formula - V
A claim, as claimed in claim 2e, wherein the preparation of quinazolinone derivative of formula - VII is achieved by reaction the product of formula - V with formic acid at a temperature of 20 -800 C and subsequently debenzylating the product of formula - Vl using trifluoro acetic acid or Pd/C and hydrogen.