FORM 2
THE PATENTS ACT  1970
[39 of 1970]
&
THE PATENTS RULES  2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF PURE DEFERASIROX ”

IND-SWIFT LABORATORIES LIMITED 
S.C.O. No. 850  SHIVALIK ENCLAVE 
NAC  MANIMAJRA 
CHANDIGARH-160 101
(AN INDIAN ORGANIZATION)

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a process for preparation of pure 4-[3 5-bis(2-hydroxyphenyl)-1H-1 2 4-triazol-1-yl]benzoic acid  normally known as deferasirox. The present invention particularly relates to a novel process for purification of deferasirox.

BACKGROUND OF THE INVENTION
Deferasirox of formula 1 is chemically named as 4-[3 5-bis(2-hydroxyphenyl)-1H-1 2 4-triazol-1-yl]benzoic acid.

Formula I

Deferasirox is an iron chelating agent and it is indicated for the treatment of the chronic iron overload due to blood transfusion. Patient with chronic anaemia such as thalassemia or sickle cell anemia often require regular blood cell transfusion. Repeated transfusions result in toxic  fatal  accumulation of iron as insoluble ferritin in various tissues of the body. Iron overload if not treated can cause severe damage to organs such as the liver  the heart and the endocrine organs and can lead to death. Iron chelators can excrete the iron deposited in the organs and therefore lower the iron-related morbidity and mortality. Deferasirox was approved by United States food and drug administration (USFDA) in november 2005. Deferasirox is sold by Novartis under the brand name EXJADE.

Deferasirox and its pharmaceutically acceptable salts are first disclosed in US patent 6 465 504. Several synthetic routes have been disclosed for preparation of deferasirox.
According to one synthetic process  deferasirox is prepared by ring rearrangement reaction of 1 2 4-dithiazolidine compound with a substituted hydrazine compound in a polar solvent or solvent mixture at ambient temperature or elevated temperature. However  experimental details are not provided for this synthetic process.
According to another synthetic process  deferasirox is prepared by reaction of salicyloyl chloride with salicylamide at 170°C followed by crystallization from ethanol to provide slight yellow crystals of 2-(2-hydroxyphenyl)benz[e][1 3]oxazin-4-one as a solid  which on reaction with 4-hydrazinobenzoic acid in ethanol at reflux provides deferasirox. The crystals of deferasirox precipitates on cooling are washed with ethanol. The process is as shown in following scheme:

According to one another synthetic process  deferasirox is prepared by reaction of diacylamine compound with substituted hydrazine in presence of polar  protic solvents under weak acid catalysis  preferably in aqueous acetic acid at elevated temperature. However  experimental details are not provided for this synthetic process.
This patent does not disclose any purification step and is silent about purity and impurities. In our hands by repeating the above process  final product is found to be contaminated with ethyl ester impurity of following formula in about up to 0.5%.

There could be possibility of formation of above impurity namely deferasirox ethyl ester in preparation of deferasirox  because process involves reaction in final step in ethanolic solvent.

International patent publication WO2009/094956 discloses a process for preparation of deferasirox by reaction of 2-(2-hydroxyphenyl)benz[e][1 3]oxazin-4-one with 4-hydrazinobenzoic in an organic acid or in a mixture of organic acid and organic solvent at boiling temperature. Patent application disclosed a purification process  wherein charcoalization is done in methanol. Still during this purification  there are chances of formation of methyl ester impurity.

International patent publication WO2011/021218 discloses a process for preparation of deferasirox by reaction of salicylic acid with salicylamide in presence of base  solvent and thionyl chloride at reflux temperature to provide 2-(2-hydroxyphenyl)benz[e][1 3]oxazin-4-one  which on reaction with 4-hydrazinobenzoic in alcoholic solvent at reflux temperature to provide deferasirox. Further deferasirox is purified to reduce HBA content and residue on ignition to achieve desire purity. Patent has not provided any method to remove alkyl ester impurity.

International patent publication WO2011/070560 discloses a process for preparation of deferasirox by converting salicylic acid to salicyloyl chloride which then reacted with hexamethyldisilazane provides disalicylimide  which on reaction with 4-hydrazinobenzoic acid in presence of ethanol and trifluoroacetic acid at reflux temperature to provide deferasirox. The process is as shown in following scheme:

This method involves use of hexamethyldisilazane and trifluoroacetic acid. Hexamethyldisilazane is a corrosive reagent and has corrosive effect on skin  mucous membranes and eyes. Trifluoroacetic acid has pungent odour  causes severe burns  toxic by ingestion  inhalation and through skin contact  very destructive for mucous membranes and eye contact may cause severe damage  including blindness. Therefore it is not advisable to use hexamethyldisilazane and trifluoroacetic acid for commercial scale process due to their hazardness. Patent application is silent about purity and purification methods.

Purity of an API as well as intermediates is of great importance in the field of pharmaceutical chemistry. It is well documented in the art that direct product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. The impurities that can be present in pharmaceutical compounds are starting materials  by-products of the reaction  products of side reactions  or degradation products. Similarly  synthetic strategy employed for the preparation of deferasirox is complex  therefore may results in the formation of several undesired by products due to competing side reactions. Impurities in deferasirox or any other active pharmaceutical ingredient are undesirable and in extreme cases  might even be harmful to a patient being treated with a dosage form containing the API.

According to ICH guidelines  process impurities should be maintained below set limits by specifying the quality of raw materials  their stoichiometric ratios  controlling process parameters  such as temperature  pressure  time and including purification steps  such as crystallization  distillation and liquid-liquid extraction  in the manufacturing process. Typically  these limits are less than about 0.15 % by weight of each identified impurity. Limits for unidentified and/or uncharacterized impurities are obviously lower  typically less than 0.10 % by weight. Therefore  in the manufacture of a drug substance  the purity of the products  such as deferasirox is required before commercialization. Therefore  pharmaceutical active compounds must be either free from these impurities or contain impurities in acceptable limits. In addition to this  regulatory authorities worldwide require that drug manufacturers should isolate  identify and characterize the impurities in their products.
Therefore there is need in the art for process for purification of deferasirox to remove impurities  in particular ester impurity. Thus  present invention fulfills the need of art and provides a purification process which is very simple  cost-effective  high yielding and easy to implement on industrial scale.

OBJECT OF THE INVENTION
The object of the present invention is to provide a novel process for purification of deferasirox.
Another object of the invention is to provide a novel process for purification of deferasirox for removal of ester impurity.
Furthe another object of the invention is to provide an improved  efficient  safe and convenient process for preparation of deferasirox free from impurities.

SUMMARY OF THE INVENTION
Accordingly  the present invention provides an improved and industrially advantageous process for preparation of highly pure deferasirox of formula I  free from impurities.

Formula I

According to one embodiment  the present invention provides a novel process for purification of deferasirox of formula I  which comprises steps of:
a) suspending crude deferasirox in a mixture of water and water immiscible solvent 
b) treating the suspension with a base selected from quaternary ammonium hydroxides to form a biphasic solution 
c) separating the layers 
d) washing the aqueous layer with water immiscible solvent to remove impurities 
e) optionally filtering the solution 
f) optionally  subjecting the aqueous layer to carbon treatment 
g) acidifying the aqueous layer with suitable acid 
h) filtering to obtain resulting solid compound 
i) suspending resulting solid in water miscible solvent 
j) isolating highly pure deferasirox of formula I.

According to another embodiment  the present invention provides a process for preparation of highly pure deferasirox of formula I  free from impurities  which comprises steps of :
a) reacting salicylic acid of formula ΙΙ


Formula ΙΙ

with a chlorinating agent in presence of a solvent to provide salicyloyl chloride of formula ΙΙΙ

Formula ΙΙΙ

b) reacting salicyloyl chloride of formula ΙΙΙ with salicylamide of formula ΙV

Formula ΙV
in the presence of a base to provide 2-(2-hydroxyphenyl)benz[e] [1 3]oxazin-4-one  compound of formula V 

Formula V

c) reacting compound of formula V with 4-hydrazino benzoic acid of formula VΙ

Formula VΙ
to provide deferasirox of formula I 
d) treating crude deferasirox of formula I with a base in biphasic medium
e)washing the aqueous layer with water immiscible solvent to remove impurities 
f)acidifying the aqueous layer with suitable acid 
g)isolating highly pure deferasirox of formula I.

DETAIL DESCRIPTION OF THE INVENTION
Accordingly  the present invention provides an improved and industrially advantageous process for preparation of highly pure deferasirox of formula I  free from impurities.

According to one embodiment  the present invention provides a novel process for purification of crude deferasirox of formula I  having purity between 99% to 99.6% (by HPLC). The process comprises suspending crude deferasirox in a mixture of water  water immiscible solvent and treating the suspension with a base to form a biphasic solution. Water immiscible solvent includes but not limited to C3-6 esters such as methyl acetate  ethyl acetate  propyl acetate  isopropyl acetate  butyl acetate; C1-4 halogenated hydrocarbons such as dichloromethane  chloroform  carbon tetrachloride  1 2- dichloroethane; C5-14 aromatic hydrocarbon toluene  xylene  ethyl benzene;C4-14 ethers such as isopropyl ether  methyl tertiary butyl ether  diphenyl ether  and like thereof   preferably solvent used is water and ethyl acetate.

Base can be selected from quaternary ammonium hydroxides such as tetraalkyl ammonium hydroxides  arylalkyl trialkyl ammonium hydroxides. Preferably base used for purification of crude deferasirox is tetrabutyl ammonium hydroxide.. Generally  reaction may be carried out at a temperature of 10 to 40 °C  for few minutes to few hours or till completeion of reaction. Preferably reaction is conducted at a temperature of 20 to 30 °C and it takes 30 to 180 minutes for completeion of reaction.

Thereafter solution can optionally be filtered to remove undissolved suspended particles. Layers are separated and aqueous layer is optionally washed with water immiscible solvent to remove impurities. Solvents used for washing of the aqueous layer to remove the impurities may be selected from water immiscible solvents such as C3-6 esters such as methyl acetate  ethyl acetate  propyl acetate  isopropyl acetate  butyl acetate; C1-4 halogenated hydrocarbons such as dichloromethane  chloroform  carbon tetrachloride  1 2- dichloroethane  C5-14 aromatic hydrocarbon toluene  xylene  ethyl benzene; C4-14 ethers such as isopropyl ether  methyl tertiary butyl ether  diphenyl ether  and like thereof  preferably solvent used for washing of the aqueous layer to remove the impurities is ethyl acetate.

Generally  washing of aqueous layer with water immiscible solvent may be carried at a temperature of 5 to 35 °C  preferably at a temperature of 20 to 30 °C. Aqueous layer may be treated with finely powdered carbon or silica gel to improve colour and purity. The carbon or silica gel treatment can be performed at a temperature of 25°C to reflux temperature of solvent for 30 to 180 minutes. Preferably carbon or silica gel treatment may be done at 30 to 70 °C  more preferably carbon treatment is done at 30 to 40 °C. The carbon or silica gel can be removed from the aqueous layer by suitable techniques such as centrifugation  direct filtration or filtration through hyflo.

Further aqueous layer may be acidified using a suitable acid such as hydrochloric acid  hydrobromic acid  sulphuric acid  nitric acid  phosphoric acid and acetic acid  propionic acid and like at a temperature range 0 to 40 °C  preferably at a temperature range of 10 to 30 °C to precipitate desired compound.

The precipitated solid can be isolated by suitable techniques such as filtration  centrifugation and the like  optionally wet solid can be slurred in water miscible solvent such as methanol  ethanol  propanol  isopropanol  n-butanol  isobutanol  acetone  acetonitrile  tetrahydrofuran at a temperature range of 10 to 40 °C for 30 to 180 minutes   preferably at a temperature range of 20 to 30 °C for 30 minutes to further improve the quality of product.

Crude deferasirox which is purified by present invention has purity more than 99%  preferably more than 99.5%. Crude deferasirox can be prepared by following prior art procedures  in particular deferasirox is prepared by reacting salicylic acid of formula ΙΙ  with a chlorinating reagent in presence of a solvent to provide salicyloyl chloride of formula ΙΙΙ.

Chlorinating reagent may be selected from the thionyl chloride  oxalyl chloride  phosphorous oxychloride  phosphorous trichloride  phosphorous pentachloride  preferably chlorinating reagent used for the reaction is thionyl chloride.

Solvent used for the reaction can be selected from C1-4 halogenated hydrocarbons such as dichloromethane  chloroform  carbon tetrachloride  1 2-dichloroethane; C1-6 alcohols such as methanol  ethanol  propanol  isopropanol  n-butanol  isobutanol; aliphatic or aromatic hydrocarbons such as pentane  hexane  heptane  cyclopentane  cyclohexane  cycloheptane  toluene  xylene  ethyl benzene; C3-6 esters such as methyl acetate  ethyl acetate  propyl acetate  isopropyl acetate  butyl acetate; C4-8 ethers such as diethyl ether  disopropyl ether  methyl t-butyl ether  1 2-dimethoxy ethane  1 2-diethoxy ethane  tetrahydrofuran  dioxane; C3-6 ketones such as acetone  methyl ethyl ketone  diethyl ketone  methyl isobutyl ketone; amides such as N N-dimethylformamide  N N-dimethylacetamide; alkyl nitrile such as acetonitrile  propionitrile and mixture thereof. Preferably solvent used for the reaction are dichloromethane and N N-dimethylformamide.

Reaction is generally performed at temperature of 5 to 75°C for a few minutes to few hours  Preferably reaction is carried out at a temperature of 50 to 60°C for 60 to 180 minutes or till the completion of the reaction. The reaction completion is monitored by high performance liquid chromatography (HPLC)  thin layer chromatography (TLC) or ultra performance liquid chromatography (UPLC). After the completion of reaction solvents from the reaction mixture were removed by techniques such as distillation  evaporation or the like.

The distillation process can be performed at atmospheric pressure or reduced pressure. Specifically  the distillation process is carried out at a temperature of about 30 to 100 °C  more specifically at about 30 to 90 °C  and most specifically at about 40 to 70°C.

Generally  solvent is removed at a pressure of about 760 mm of Hg or less  more specifically at about 400 mm Hg or less  still more specifically at about 80 mm Hg or less  and most specifically from about 30 to about 80 mm Hg.

Thereafter  salicyloyl chloride of formula ΙΙΙ is reacted with salicylamide of formula ΙV to provide 2-(2-hydroxyphenyl)benz[e][1 3]oxazin-4-one ( compound of formula V). The reaction is generally conducted at a temperature of 100 to 200°C for 30 to 180 minutes  preferably between 130 to 180°C for 60 to 120 minutes or till the completion of reaction. The reaction completion is monitored by high performance liquid chromatography (HPLC)  thin layer chromatography (TLC) or ultra performance liquid chromatography (UPLC). The reaction can be carried out in the presence of a base. Base used for the reaction may be selected from amines like triethyl amine  diisoproylethylamine  N-methyl morpholines  pyridine  N-methyl piperidine  N-methyl pyrrolidine  N N-dimethyl piperazine  DBU.

The reaction can be carried out in the presence or absence of the solvent. The solvent is not critical for the reaction. The solvent used for the reaction may be selected from C5- 10 aliphatic or aromatic hydrocarbons such as n-hexane  n-heptane  cyclohexane  toluene  xylene  ethyl benzene; ethers such as anisole  diphenyl ether and like thereof.

After completion of reaction  the resulting product is isolated from reaction mixture by adding a solvent to purify the compound of formula V by crystallization or slurrying at a temperature of 0 to 120°C. Solvent used for crystallization of compound of formula V may be selected from C1-6 alcohols such as methanol  ethanol  propanol  isopropanol  n-butanol  isobutanol  glycols like monoethylene glycol; C1-4 halogenated hydrocarbons such as dichloromethane  chloroform  carbon tetrachloride  1 2-dichloroethane; C5- 10 aliphatic or aromatic hydrocarbons such as n-hexane  n-heptane  cyclopentane cyclohexane  toluene  xylene  ethyl benzene; C3-6 esters such as methyl acetate  ethyl acetate  propyl acetate  isopropyl acetate  butyl acetate; C3-6 ketones such as acetone  methyl ethyl ketone  diethyl ketone  methyl isobutyl ketone; alkyl nitrile such as acetonitrile  propionitrile; C4-8 ethers such as diethyl ether  disopropyl ether  t-butyl methyl ether  1 2-dimethoxy ethane  1 2-diethoxy ethane  tetrahydrofuran  dioxane and like thereof  Preferably solvent used for crystallization is ethanol.

Further compound of formula V is reacted with 4-hydrazino benzoic acid of formula VI in presence of a solvent to provide crude deferasirox of formula I.

Generally reaction is conducted at a temperature of 50°C to reflux temperature of the solvent for 30 to180 minutes  preferably between 70 to 90°C for 60 to 120 minutes or till completion of reaction. Solvent used for the reaction includes  but not limited to water  alcohols  ketones  cyclic ethers  aliphatic ethers  aliphatic or aromatic hydrocarbons  halogenated hydrocarbons  nitriles  esters  polar aprotic solvents and mixture thereof. Preferably solvents used for the reaction may be selected from alcohols such as methanol  ethanol  propanol  isopropanol  n-butanol  isobutanol  tert-butanol  hexanol and mixture thereof. A specific reaction solvent is ethanol. The reaction completion is monitored by high performance liquid chromatography  thin layer chromatography or ultra performance liquid chromatography. The product may be isolated from the reaction mixture by cooling at 0 to 40 °C  preferably from 20 to 40 °C to precipitate the crude deferasirox. The crude deferasirox can be isolate by any standard method known in the art such as filtration  centrifugation or decantation. Typically the product is isolated by filtration.

Deferasirox obtained by following process of the present invention after purification is found to be highly pure in nature more than 99.6%  preferably more than 99.7%  more preferably more than 99.9% and have impurities less than 0.15 %; more preferably less than 0.10 %. As per the recommendation of regulatory authorities  the impurities present in the final API must be identified and characterized. Therefore  final API i.e deferasirox is analyzed for presence of impurities and found to display the presence of following impurities less than 0.10 % by HPLC.

As used herein  the term alkyl refers to straight chain or branched hydrocarbon groups such as but not limited to methyl  ethyl  n-propyl  isopropyl  n-butyl  sec-butyl  iso-butyl  t-butyl  n-pentyl  n-hexyl and like thereof.

As used herein  the term aryl-alkyl refers to aryl group attach to an alkyl group such as but not limited to substituted or unsubstituted phenyl and like thereof.

Major advantages realized in the present invention are that process can be easily and conveniently scaled-up for industrial large scale production. The process is simple  economic  high through output  operationally efficient  environment friendly.

Although the following examples illustrate the present invention in more detail  but the examples are not intended in any way to limit the scope of the present invention. It will thus be readily apparent to the one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus  it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features  modifications and variation of the concepts herein disclosed may be resorted to by those skilled in the art  and that such modifications and variations are considered to be falling within the scope of the invention.

EXAMPLES
Example 1: Preparation of 2-(2-hydroxy phenyl)benz[e] [1  3] oxazin-4-one
To a suspension of salicylic acid (50gm; 0.362mol) in dimethylformamide (0.3gm) and dichloromethane (150ml) was added thionyl chloride (51.5 ml) at 25-30°C. The temperature of the reaction mixture was raised to 55-60°C and stirred for 1hour. The reaction completion was checked by TLC. After completion of reaction  solvents were distilled off at 55-60oC under vacuum. The reaction mixture was cooled to 25-30°C and salicylamide (34.75gm; 0.25mol) was added to the reaction mixture under nitrogen atmosphere. The temperature of reaction mixture was raised to 170°C and stirred for 1hour. The reaction completion was checked by HPLC. After completion of reaction  the reaction mixture was cooled and ethanol (100ml) was added and thereafter reaction mixture was further cooled to 25-30°C and stirred for 30 minutes. The product was filtered  washed with ethanol (400ml) and dried at 45-50°C under vacuum to obtain 67.6gm of the title compound having purity 99.5% by HPLC.

Example 2 : Preparation of deferasirox
4-Hydrazino benzoic acid (70gm; 0.460mol) was added to a mixture of 2-(2-hydroxyphenyl)benz[e][1 3]oxazin-4-one(100gm; 0.418mol) and ethanol (1.5 liter)  at 25-30°C. The reaction mixture was heated to 80-85°C and stirred for 1hour. The reaction completion was checked by HPLC. After completion of reaction  the reaction mixture was cooled to 25-30°C. The solid  thus obtained was filtered  washed with ethanol (300ml) and dried at 45-50°C under vacuum to obtain 125gm of deferasirox having purity 99.5% and ethyl ester impurity 0.42% by HPLC.

Example 3 : Preparation of pure deferasirox
Tetrabutyl ammonium hydroxide (21ml; 20% aqueous sol.; 0.0161mol) was added to a suspension of deferasirox (5gm; ethyl ester impurity 0.42%) in a mixture of water (50ml) and ethyl acetate (40ml) at 25-30°C to form a solution. After dissolution  the reaction mixture was stirred for 1hour. The layers were separated and aqueous layer was washed with ethyl acetate (15ml).The aqueous layer was filtered through hyflo to remove suspended particles. Thereafter aqueous layer was acidified with dilute hydrochloric acid (4.9ml) and stirred for 30 minutes at 25-30oC. The solid  thus obtained  was filtered  washed with water (10ml) and suck dried. The solid was then suspended in ethanol (30ml) and stirred for 30 minutes at 25-30oC. The solid was filtered  wash with ethanol and dried under vacuum at 50-60oC to obtain 3.8.gm of pure deferasirox having purity 99.95% and ethyl ester impurity 0.05 % by HPLC..

Example 4 : Preparation of pure deferasirox
Tetrabutyl ammonium hydroxide (21ml; 20% aqueous sol.; 0.0161mol) was added to a suspension of deferasirox (5gm;ethyl ester impurity 0.42%) in a mixture of water (50ml) and methyl tertiary butyl ether (40ml) at 25-30°C to form a solution. After dissolution  the reaction mixture was stirred for 1hour. The layers were separated and aqueous layer was washed with methyl tertiary butyl ether (15ml). The aqueous layer was filtered through the hyflo to remove suspended particles. Thereafter aqueous layer was acidified with dilute hydrochloric acid (4.9ml) and stirred for 30 minutes at 25-30oC. The solid thus obtained was filtered  washed with water (10ml) and suck dried. The solid was suspended in ethanol (30ml) and stirred for 30 minutes at 25-30oC. The solid was filtered  washed with ethanol and dried under vacuum at 50-60oC to obtain 4.2gm of the pure deferasirox having purity 99.96% and ethyl ester impurity 0.02 % by HPLC.

Example 5 : Preparation of pure deferasirox
Tetrabutyl ammonium hydroxide (21ml; 20% aq sol.; 0.0161mol) was added to a suspension of deferasirox (5gm; ethyl ester impurity 0.42 %) in a mixture of water (50ml) and methyl tertiary butyl ether (40ml) at 25-30°C to form a solution. After dissolution  the reaction mixture was stirred for 1hour. The layers were separated and aqueous layer was washed with methyl tertiary butyl ether (15ml). Activated carbon (0.5gm) was added in the aqueous layer and stirred at 40oC for 1 hour. The aqueous layer was filtered through the hyflo. Thereafter aqueous layer was acidified with dilute hydrochloric acid (4.9ml) and stirred for 30 minutes at 25-30oC. The solid thus obtained was filtered  washed with water (10ml) and suck dried. The solid was suspended in ethanol (30ml) and stirred for 30 minutes at 25-30oC. The solid was filtered  washed with ethanol and dried under vacuum at 50-60oC to obtain 4gm of the pure deferasirox having purity 99.93% and ethyl ester impurity.0.05 % by HPLC.

WE CLAIM
1. The process for the purification of deferasirox of formula I  which comprises steps of:
a).suspending crude deferasirox in a mixture of water  water immiscible solvent 
b).treating the suspension with a base to form a biphasic medium 
c).separating the layers 
d).washing the aqueous layer with water immiscible solvent to remove the impurities 
e).optionally filtering the solution 
f).optionally  subjecting the aqueous layer to carbon treatment 
g).acidifying the aqueous layer with suitable acid 
h).filtering to obtain the solid compound 
i).suspending the solid in water miscible solvent 
j).isolating highly pure deferasirox of formula I.

2. The process according to claim 1  wherein in step a) water immiscible solvent is selected from C3-6 esters such as methyl acetate  ethyl acetate  propyl acetate  isopropyl acetate  butyl acetate; C1-4 halogenated hydrocarbons such as dichloromethane  chloroform  carbon tetrachloride  1 2- dichloroethane; C5-14 aromatic hydrocarbon toluene  xylene  ethyl benzene; C4-14 ethers such as isopropyl ether  methyl tertiary butyl ether  diphenyl ether and like thereof; in step b) base is selected from quaternary ammonium hydroxides such as tetraalkyl ammonium hydroxide  arylalkyl trialkyl ammonium hydroxide.

3. The process according to claim 1  wherein in step d) water immiscible solvent is selected from C3-6 esters such as methyl acetate  ethyl acetate  propyl acetate  isopropyl acetate  butyl acetate; C1-4 halogenated hydrocarbons such as dichloromethane  chloroform  carbon tetrachloride  1 2- dichloroethane; C5-14 aromatic hydrocarbon toluene  xylene  ethyl benzene; C4-14 ethers such as isopropyl ether  methyl tertiary butyl ether  diphenyl ether and like thereof.
4. The process according to claim 1  wherein in step g) acid is selected from hydrochloric acid  hydrobromic acid  sulphuric acid  nitric acid  phosphoric acid and acetic acid  propionic acid and like thereof; in step i) water miscible solvent is selected from such as C1-6 alcohols such as methanol  ethanol  propanol  isopropanol  n-butanol  isobutanol  acetone  acetonitrile  tetrahydrofuran.

5. A process for preparation of highly pure deferasirox of formula I 

Formula Ι
which comprises steps of :
a). reacting salicylic acid of formula ΙΙ

Formula ΙΙ

with a chlorinating reagent in presence of a solvent to provide salicyloyl chloride of formula ΙΙΙ 

Formula ΙΙΙ
b). reacting salicyloyl chloride of formula ΙΙΙ with salicylamide of formula ΙV

Formula ΙV
in presence of a base to provide 2-(2-hydroxyphenyl)benz[e][1 3]oxazin-4-one  compound of formula V 

Formula V

c).reacting compound of formula V with 4-hydrazino benzoic acid of formula VΙ

Formula VΙ
in presence of a solvent to provide deferasirox of formula I.
d). treating crude deferasirox of formula I with a base in biphasic medium
e) washing the aqueous layer with water immiscible solvent to remove impurities 
f) acidifying the aqueous layer with suitable acid 
g).isolating highly pure deferasirox of formula I.

6. The process according to claim 5  wherein in step a) chlorinating reagent is selected from thionyl chloride  oxalyl chloride  phosphorous oxychloride  phosphorous trichloride  phosphorous pentachloride; solvent is selected from water  alcohols  ketones  aliphatic ethers  cyclic ethers; aliphatic or aromatic hydrocarbons  halogenated hydrocarbons  nitriles  esters  polar aprotic solvents and mixture thereof.

7. The process according to claim 5  wherein in step b) base is selected from amines like triethyl amine  diisoproylethylamine  N-methyl morpholines  pyridine  N-methyl piperidine  N-methyl pyrrolidine  N N-dimethyl piperazine  DBU.
8. The process according to claim 5  wherein in step c)solvent is selected from water  alcohols  ketones  aliphatic ethers  cyclic ethers; aliphatic or aromatic hydrocarbons  halogenated hydrocarbons  nitriles esters  polar aprotic solvents and mixture thereof.
9. The process according to claim 5  wherein in step d) base is selected from quaternary ammonium hydroxides such as tetraalkyl ammonium hydroxide  arylalkyl trialkyl ammonium hydroxide.
10. The process according to claim 5  wherein in step e) water immiscible solvent is selected from C3-6 esters such as methyl acetate  ethyl acetate  propyl acetate  isopropyl acetate  butyl acetate; C1-4 halogenated hydrocarbons such as dichloromethane  chloroform  carbon tetrachloride  1 2- dichloroethane; C5-14 aromatic hydrocarbon toluene  xylene  ethyl benzene; C4-14 ethers such as isopropyl ether  methyl tertiary butyl ether  diphenyl ether and like thereof; in step f) acid is selected from hydrochloric acid  hydrobromic acid  sulphuric acid  nitric acid  phosphoric acid and acetic acid  propionic acid and the like.

Dated this 11th day of August  2011

Dr. Asha Aggarwal
HEAD-IPM-Department
Ind-Swift Laboratories Limited

ABSTRACT OF THE INVENTION
The present invention provides an improved  efficient  safe and convenient process for preparation of highly pure deferasirox. The present invention also provides a novel process for purification of deferasirox by using quaternary ammonium hydroxides as a base.