Field of the Invention:
The present invention relates to an improved process for the preparation of deferasirox as well as a process for its purification. Deferasirox is chemically known as 4-[3,5-bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl]benzoic acid and represented by the following structural formula-1. It also relates to novel amine salts of deferasiox compound of general formula-8 and the process for their preparation.

Deferasirox is an iron chelating compound and is used in the treatment of patients suffering from chronic iron overload due to blood transfusion of greater than twenty units. Deferasirox is commercially available under the brand name of EXJADE and supplied as a dispersible tablet with different strengths.
Background of the Invention:
Deferasirox, its pharmaceutically acceptable salts and process for their preparation were disclosed in US 6465504. The disclosed process involves the reaction of salicylamide and salicyloyl chloride at 170°C followed by recrystallisation from ethanol provides the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one as a solid, which on reaction with 4-hydrozinobenzoic acid at reflux temperature in ethanol provides deferasirox. In the above process, reactions are carried out at very high temperature and the final product is contaminated with the impurities, but no purification method is given.
The said patent discloses the process for the preparation of deferasirox in an example-5 using ethanol and isolated a crystalline deferasirox showing melting point of 264-265°C. We prepared the deferasirox as per this process and characterized the obtained crystalline solid by PXRD and the corresponding 2 theta values are 5.27, 6.64,

10.08, 10.62, 13.24, 14.15, 15.33, 16.65, 17.32, 20.37, 23.16, 25.68, 26.2, 28.3 ± 0.2 degrees 2 theta.
European Journal of Inorganic Chemistry 2004, 4177-4192 disclosed a process for the preparation of deferasirox. The disclosed process involves the condensation of salicylic acid, salicylamide and pyridine in xylene in the presence of thionyl chloride at reflux temperature, followed by recrystallisation from 2-methoxyethanol to provide2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one as solid, which further reacts with 4-hydrazino benzoic acid in presence of triethylamine in ethanol at reflux temperature to provide deferasirox, which is allowed to be exposed to air to form deferasirox monohydrate. As per disclosed process, the intermediate compound 2-(2-hydroxyphenyl)-benz[e][l,3] oxazin-4-one is not stable when exposed to moisture, would lead to the formation of bis(salicyl)imide as a impurity. Hence the isolation of the said intermediate will lead to the formation of unwanted impurity. Hence there is a need in the art for a process which avoids the formation of bis(salicyl)imide impurity.
Helvetica Chimica Acta Vol.55, 1 (1972), 152-153, 1566-1594 disclosed a process for the preparation of 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one. The disclosed process involves the addition of thionyl chloride in molar ratio 1.9 in a single lot over (with respect to salicylic acid) to reaction mixture containing salicylic acid, salicylamide and pyridine in xylene at reflux temperature, followed by crystallization form methanol to provide 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one. When 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one prepared as per the above process, was utilized for the preparation of deferasirox, some unknown impurity peak in HPLC at the RRT of around 2.1 was observed. As this impurity could not be completely removed by conventional purification methods, it was decided to control the formation of the said impurity by varying the process parameters.
When deferasirox was treated with an amine in a suitable solvent it yielded amine sah of high purity. The novel amine salts of deferasirox were found to be very useful for the preparation of highly pure deferasirox.
The present invention provides an improved process for the preparation of deferasirox which avoids all the above mentioned prior art problems.

Brief Description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of deferasirox compound of formula-1, which comprises of the following steps,
a) Reacting the salicylic acid compound of formula-2 with salicylamide compound of formula-3 in presence of thionyl chloride and a base in a suitable solvent at refiux temperature, followed by crystallization firom a suitable solvent to provide the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4, wherein thionyl chloride is added in two lots,
b) reacting the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of fonnula-4 with 4-hydrazinobenzoic acid compound of formula-5 in a suitable solvent at reflux temperature to provide the deferasirox compound of formula-1,
c) purifying the compound of formula-1 to provide the pure deferasirox.
The second aspect of the present invention is to provide one-pot process for the preparation of deferasirox compound of formula-1, which comprises of reacting the salicylic acid compound of formula-2 with salicylamide compound of formula-3 in presence of a base and thionyl chloride in a suitable solvent at reflux temperature to provide the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4, which on in-situ reaction with 4-hydrazinobenzoic acid compound of formula-5 in a suitable solvent at reflux temperature provides the deferasirox compound of formula-1.
The third aspect of the present invention is to provide a process for the purification of deferasirox compound of formula-1, which comprises of the following steps,
a) Treating the deferasirox with a suitable aqueous base in the presence or absence of a solvent and stirring the reaction mixture to provide solution,
b) filtering the solution, and optionally extracting the filtrate with a suitable water immiscible solvent to remove the impurities,
c) treating the filtrate with hydrose,
d) treating the reaction mixture with suitable acid and filtering the solid formed,
e) suspending the wet solid in a suitable solvent and heating the suspension to reflux,

f) cooling the reaction mixture, filtering the solid precipitated, washing with a suitable solvent and drying to get the pure compound of formula-1.
The fourth aspect of the present invention is to provide a process for the purification of deferasirox compound of formula-1, which comprises of treating the deferasirox with a suitable aqueous base in the presence or absence of a solvent, and stirring the reaction mixture to provide solution. Filtering the solution, optionally extracting the filtrate with a suitable water immiscible solvent to remove the impurities. Treating the filtrate with hydrose, filtering it and treating it with a suitable acid. Filtering the precipitated solid to get pure deferasirox.
The fifth aspect of the present invention is to provide a process for the purification of deferasirox compound of formula-1, which comprises of suspending the deferasirox in a suitable solvent, heating the suspension to reflux and stirring it for certain period of time. Cooling the reaction mixture, filtering the solid precipitated, washing the solid with a suitable solvent and drying to get the pure compound of formula-1.
The sixth aspect of the present invention is to provide a process for the purification of deferasirox compound of formula-1, which comprises of treating deferasirox in a suitable polar aprotic solvent, followed by precipitating it by adding an anti solvent to provide pure deferasirox.
The seventh aspect of the present invention provides novel amine salts of deferasirox compounds of formula-8. The novel amine salts of deferasirox are usefiil for the preparation of highly pure deferasirox.
The eighth aspect of the present invention is to provide a process for the preparation of amine salts of deferasirox compound of formula-8, which comprises of the following steps; a) Treating the crude deferasirox with an amine NR1R2R3 of formula-7 in a suitable
solvent selected from ester solvents and/or hydrocarbon solvents and/or ketone
solvents, preferably ester solvents.

b) stirring the reaction mixture for sufficient period of time for the formation of amine salt of deferasirox,
c) separating the solid by filtration and washing with suitable ester solvent,
d) optionally purifying the deferasirox amine salt compound of formula-8 using ester solvents or hydrocarbon solvents or ketone solvents or alcohol solvents or their mixtures thereof,
e) drying the solid to get the amine sah of deferasirox.
Advantages of the present invention:
• Provides an improved process which avoids the formation of impurity observed at 2.1 RRT in the final API.
• Provides one pot synthesis of deferasirox without isolating the intermediate compound 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one, there by avoiding the formation bis(salicyl)imide impurity.
• Provides an process which avoids the formation of uncyclized compound of formula-6, in the intermediate compound 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one.
• Provides novel amine salts of deferasirox.
• Provides a process for the purification of deferasirox which is eco-fi:iendly and commercially viable process
Brief Description of the Drawings:
Figure-1: Illustrates the powder X-ray diffraction pattern of crystalline deferasirox
prepared as per the prior art process
Figure-2: Illustrates the DSC of crystalline deferasirox
Figure-3: Illustrates the IR spectrum of crystalline deferasirox
Detailed Description of the Invention:
Unless otherwise indicated, this disclosure uses definitions provided below. As used herein, the term "alkyl" refers to straight chain or branched hydrocarbon groups, generally having specified number of carbon atoms. A "C1.12 alkyl" refers to alkyl group having 1 to 12 carbon atoms. Examples of alkyl groups include, without limitation.

methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-l-yl, 3-methylbut-2-yl,2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl and the like.
As used herein, the term "cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon rings, generally having a specified number of carbon atoms that comprise the ring i.e C3.7 cycloalkyl refers to a cycloalkyl group having 3,4,5,6and 7 carbon atoms as ring members. Examples of monocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of bicyclic cycloalkyl groups include without limitation, bicyclo[1.1.0]butyl, bicyclo[l.l.l]pentyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl, and the like.
As used herein, the term "aryl-Ci-e alkyl" refers to an aryl group attached to the substrate through an alkyl group containing one to six carbon atoms. The term "aryl" refers to monovalent or divalent aromatic groups respectively including 5 and 6 membered monocyclic aromatic groups that contain zero to four heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of monocyclic aryl groups include, without limitation, phenyl, pyrrolyl, pyranyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyradazinyl, pyrimidinyl, and the like. The aryl groups also include bicyclic groups, tricyclic groups etc including fused 5 and 6 membered rings described above. Examples of multicyclic aryl groups include, without limitation, naphthyl, biphenyl, anthracenyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, indolizinyl and the like. The aryl groups may be attached to the substrate at any ring atom, unless such attachment would violate valence requirements. Aryl groups may include one or more non hydrogen substituents unless such substitution would violate valence requirements. Useful substituents include, without limitation alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, halo, hydroxy, mercapto, nitro, amino, alkyl amino and the like.

The first aspect of the present invention provides an improved process for the preparation of deferasirox compound of formula-1, which comprises of the following steps, a) Reacting the salicylic acid compound of formula-2
OH Formula-2
with salicylamide compound of formula-3,

O Formula-3
in presence of a suitable base in a suitable solvent in presence of thionyl chloride at
reflux temperature, characterized in that the thionyl chloride is used in the mole ratio
of 1.7-1.9 and is added in two lots at reflux temperature, wherein the second lot is
added after maintaining the reaction mixture for some time after the addition of first
lot of thionyl chloride, followed by crystallization from a suitable alcoholic to provide
the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4,
OH O
Formula-4
b) reacting the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4
with 4-hydrazinobenzoic acid compound of formula-5,
H00C-^~/-H-NH2 Formula-5 in a suitable solvent to provide the deferasirox compound of formula-1,
c) purifying the compound of formula-1 by treating it with a base and optionally
extracting the mixture with a suitable water immiscible solvent, followed by
treatment with an acid to provide pure deferasirox.

The second aspect of the present invention provides a one-pot process for the preparation of deferasirox compound of formula-1, which comprises of reacting the salicylic acid compound of formula-2
OH Formula-2
with salicylamide compound of formula-3
O Formula-3
in presence of a suitable base in a suitable solvent in presence of thionyl chloride which
is added in two lots at reflux temperature to provide the 2-(2-hydroxyphenyl)-
benz[e][l,3]oxazin-4-one compoimd of formula-4,
OH O -
Formula-4
which on in-situ reaction with 4-hydrazinobenzoic acid compound of formula-5
HOOG—{^ V-N-NH2 Formula-5 in a suitable solvent selected from alcoholic to provide pure deferasirox compound of formula-1.
In first and second aspects of the above invention the base used for the condensation of salicylic acid, compound of formula-2 with salicylamide, compound of formula-3 is selected from pyridine, trimethylamine, triethylamine, and the suitable solvent is selected from toluene, cyclohexane, heptane, chlorobenzene, xylene or a mixture thereof; preferably xylene. The solvent used for crystallization is a suitable alcoholic solvent like methanol, ethanol, isopropanol or a mixture thereof; preferably methanol. The reaction formula-4 with phenylhydrazine is performed in an alcoholic

solvent like methanol, ethanol, isopropanol, butanol or a mixture thereof, at reflux temperature. The water immiscible solvent optionally used is selected from ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, toluene, xylene, cyclohexane, hexane, heptane and the like
In step a) salicylic acid compound of formula-2 condenses with salicylamide compound of formula-3 in presence of thionyl chloride, to provide the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compoimd of formula-4. But along with the compound of formula-4 an uncyclised derivative namely 2-hydroxy-N-(2-hydroxybenzoyl) benzamide compound of formula-6 was also formed.
.OH HO.

0 O Formula-6
If the compound of formula-6 is present in a concentration less than 10% in the
mixture, then it completely reacts with 4-hydrazinobenzoic acid compound of formula-5
to provide deferasirox. But if it is present in a concentration above 10% then it is not
consumed completely, and hence will be present as an impurity in the final API. In the
present invention the formation of the uncyclised derivative 2-hydroxy-N-(2-
hydroxybenzoyl) benzamide compound of formula-6 is well controlled to the level below
10%.
It was observed that some unknown impurity was detected in the final API which showed a peak in HPLC at 2.1 RRT. It was identified that the origin of the impurity is at the initial condensation of salicylamide and salicylic acid in the presence of thionyl chloride.
After conducting various experiments, it was found that a compound of molecular mass of 508 was formed as an impurity in the first step of the condensation reaction which carried forward to the next step and reacts with 4-hydrazinobenzoic acid to provide the compound with the molecular mass value of 774 as an impurity, eluted at the RRT of 2.1 in HPLC of deferasirox. This impurity could not be removed by conventional

purification methods. Hence it was decided to control the formation of the said impurity by varying the process parameters. After extensive research it was found that by adding thionyl chloride (1.9 equivalents) in more than one lot (instead of addition of thionyl chloride in single lot as in prior art) the formation of the impurity at 2.1 RRT was controlled to less than 0.10%.
The PXRD, IR and the DSC of the crystalline deferasirox prepared according the present invention enclosed as figure-1, figure-2 and figure-3 respectively are conforming to the PXRD, IR and the DSC of the prior art crystalline deferasirox.
The third aspect of the present invention provides a process for the purification of deferasirox compound of formula-1, which comprises of the following steps,
a) Treating the deferasirox with a suitable aqueous base in the presence or absence of a solvent and stirring the reaction mixture to provide solution,
b) filtering the solution, and optionally extracting the filtrate with a suitable water immiscible solvent to remove the impurities,
c) treating the filtrate with hydrose,
d) treating the reaction mixture with suitable acid and filtering the solid formed,
e) suspending the wet solid in a suitable solvent and heating the suspension to reflux,
f) cooling the reaction mixture, filtering the solid precipitated, washing with a suitable solvent and drying to get the pure compound of formula-1.
The fourth aspect of the present invention provides a process for the purification of deferasirox compound of formula-1, which comprises of the following steps,
a) Treating the deferasirox with a suitable aqueous base in the presence or absence of a solvent, and stirring the reaction mixture to provide solution,
b) filtering the solution, optionally extracting the filtrate with a suitable water immiscible solvent to remove the impurities,
c) treating the filtrate with hydrose,
d) treating the reaction mixture with suitable acid,
e) filtering the precipitated solid to get pure deferasirox.

The fifth aspect of the present invention provides a process for the purification of deferasirox compound of formula-1, which comprises of the following steps,
a) Suspending the deferasirox in a suitable solvent,
b) heating the suspension to reflux and stirring the reaction mixture for certain period of time,
c) cooling the reaction mixture,
d) filtering, washing the solid with a suitable solvent and drying to get the pure compound of formula-1.
As per any of the third, fourth, and fifth aspects of the present invention, the suitable acid used is selected fi"om a group consisting of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid and the like; and the suitable base used is selected fi-om sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, sodium bicarbonate, potassium bicarbonate and ammonia; and the suitable solvent is selected fi"om water; alcoholic solvents like methanol, ethanol, isopropanol, n-propanol, and butanol and water immiscible solvent is selected from ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, toluene, xylene, cyclohexane, hexane, heptane and the like.
The sixth aspect of the present invention provides a process for the purification of deferasirox compound of formula-1, which comprises of the following steps,
a) Suspending the deferasirox in a suitable polar aprotic solvent and heating it to reflux,
b) cooling the reaction mixture,
c) adding an anti solvent and stirring the reaction mixture,
d) filtering the solid formed, washing the solid with a suitable solvent and drying to get the pure compound of formula-1.
The polar aprotic solvent used in the above aspect is selected fi-om dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, and the like and the anti solvent used is water, ketone solvents like acetone, ethyl methyl ketone, diethyl ketone etc.;

hydrocarbon solvents namely hexane, cyclohexane, n-heptane and the like; ether solvents like diethyl ether, isopropyl ether and the like.
The seventh aspect of the present invention provides novel amine salts of deferasirox compounds of general formula-8.

HOOC
t ^ • NRi N-N R2R3
■^OH HO ^
Formula-8
wherein NR1R2R3 is an amine wherein Ri, R2 and R3 are same or different and are each independently selected fi^om either hydrogen, C1.12 alkyl, C3.7 cycloalkyl, aryl-Ci-e alkyl, aryl and the like. The novel amine salt of the present invention is used to prepare highly pure deferasirox compound of formula-1.
The eighth aspect of the present invention is to provide a process for the preparation of amine salts of deferasirox compound of formula-8, which comprises of the following steps;
a) Treating the crude deferasirox with an amine NR1R2R3 compound of formula-7, wherein Ri, R2 and R3 are same or different and are each independently selected from either hydrogen, C1.12 alkyl, C3-7 cycloalkyl, aryl-Ci.6 alkyl, aryl and the like; in a suitable solvent selected from ester solvents and/or hydrocarbon solvents and/or ketone solvents, preferably ester solvents more preferably ethyl acetate,
b) stirring the reaction mixture for sufficient period of time for the formation of amine salt of deferasirox,
c) separating the solid by filtration and washing with suitable ester solvent,
d) optionally purifying the deferasirox amine sah compound of general formula-8 using ester solvents or hydrocarbon solvents or ketone solvents or alcohol solvents or their mixtures thereof,
e) drying the solid to get the amine salt of deferasirox.

The amine used for the preparation of the deferasirox amine salt is selected from a group which includes but is not limited to methylamine, ethylamine, n-propylamine, isopropylamine n-butylamine, isobutylamine, tertiary butyl amine, diethyl amine, octylamine, 2-ethylhexylamine, benzylamine, phenethylamine, dibenzylamine, N-methylbenzylamine, N-ethylbenzylamine, dibenzylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethylcycloheptylamine, dicyclohexylamine, pyrrolidine, N-methylpyrrolidine, piperidine, N-methylpiperidine, morpholine and the like
The present invention also provides a process for the preparation of high pure deferasirox compound of formula-1 form the novel amine salts of deferasirox. The process comprises of;
a) suspending deferasirox amine salt in an suitable solvent,
b) treating it with an acid,
c) filtering the solid obtained and washing with an alcoholic solvent and drying it to provide highly pure deferasirox
The acid used for cleaving the amine salt is selected from a group consisting of, but not limited to an inorganic acid like hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; an organic acid like acetic acid, propionic acid, acetic acid and the like. The suitable solvent used is selected from a group consisting of water, alcoholic solvents namely methanol ethanol, n-propanol, isopropanol, n-butanol and the like; chlorinated hydrocarbons like dichloromethane, chloroform etc., ester solvents for example ethyl acetate, isopropyl acetate and the like
The formation of the amine salt deferasirox followed by conversion into deferasirox, not only improved the yield and purity but also the description of the final API to provide highly pure deferasirox.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention
Examples:
Example-1: Preparation of 2-(2-hydroxyphenyl)-benz[e] [l^]oxazin-4-one.
Mixture of salicylic acid (100 grams), salicylamide (89.3 grams), pyridine (15.2 ml) and xylene (600 ml) was heated to reflux temperature. Thionyl chloride (100.5 ml) was added to the above mixture at reflux temperature for 3 hours. Intense evolution of SO2 and hydrochloric acid was observed, the reaction mixture was then stirred for 8 hrs. Xylene was removed from the reaction mixture by distillation under reduced pressure. The resulting residue was suspended in methanol (200 ml) and raised the temperature to 60-65 °C. The reaction mixture was stirred for one hour and cooled to 0-5 °C and further stirred for one hour. The solid obtained was filtered, washed with methanol and dried to get the title compound. Yield: 130 grams
Example-2: Preparation of deferasirox compound of formula-1.
4-hydrazinobenzoic acid (76 grams) was added to the mixture of 2-(2-hydroxyphenyl)-
benz[e][l,3]oxazin-4-one obtained as per example-1 and methanol (2 L) and heated to
60-65°C then stirred for 5 hours at reflux temperature. The reaction mixture was cooled
to 0-5°C stirred for 1.5 hours. The solid formed was filtered, washed with methanol and
then dried to get the title compound.
Yield: 142 grams
Purity by HPLC: 99.44 %; impurity at 2.1 RRT 0.21%.
Example-3: Preparation of 2-(2-hydroxyphenyl)-benzIe] [l,3]oxazin-4-one.
Mixture of salicylic acid (50 grams), salicylamide (44.6 grams), pyridine (7.6 ml) and xylene (300 ml) was heated to reflux temperature. Thionyl chloride (lot one 39.6 ml) was added to the above mixture at reflux temperature for 3 hours. Intense evolution of SO2 and hydrochloric acid was observed, the reaction mixture was then stirred for 6 hrs. Thionyl chloride (lot two 7.9 ml) was added to the above mixture at reflux temperature,

reaction mixture was then stirred further for 2 hrs. Xylene was removed from the reaction mixture by distillation under reduced pressure. The resulting residue was suspended in methanol (100 ml) and raised the temperature to 60-65°C. The reaction mixture was stirred for one hour and cooled to 0-5°C and further stirred for one hour. The solid obtained was filtered, washed with methanol and dried to get the title compound. Yield: 61.7 grams
ExampIe-4: Preparation of deferasirox compound of formula-1.
4-hydrazinobenzoic acid (38 grams) was added to the mixture of 2-(2-hydroxyphenyl)-
benz[e][l,3]oxazin-4-one obtained as per example-3 and methanol (1 L) and heated to
60-65°C then stirred for 5 hours at reflux temperature. The reaction mixture was cooled
to 0-5°C stirred for 1.5 hours. The solid formed was filtered, washed with methanol and
then dried to get the title compoimd.
Yield: 75 grams; Purity by HPLC: 99.77 %; impurity at 2.1 RRT 0.01%.
Particle size distribution:
D(0.1):2.40 ^m; D(0.5):6.28 ^m; D(0.9):12.98 ^m; D(1.00):21.27 ^im.
Example-5: One pot preparation of deferasirox compound of formula-l.
Mixture of salicylic acid (25 grams), salicylamide (22.3 grams), pyridine (3.8 ml) and xylene (150 ml) wad heated to 120-125°C. Thionyl chloride (20 ml) was added to the above mixture at 120-125°C for 3 hours and stirred for 6 hours. Thionyl chloride (4 ml) was added to the reaction mixture for 45 minutes and stirred for 2 hours at 120-125°C. The solvent from the reaction mixture was distilled off under reduced pressure. Methanol (500 L) followed by 4-hydrazinyl benzoic acid (17.9 grams) was added to the obtained residue and then heated to 60-65°C. The reaction mixture was stirred for 5 hours at reflux temperature then cooled to 0-5°C and stirred for 1.5 hours. The solid formed was filtered, washed with methanol and then dried to get the title compound. Yield: 37.5 grams; Purity by HPLC: 99.73 %; impurity at 2.1 RRT 0.03%.
Example-6: Purification of Deferasirox.
To a solution of aqueous sodium hydroxide (10%, 250ml) added of deferasirox (25g). Stirred for fifteen minutes and filtered it. To the clear solution added hydrose

(1.25 grams) and stirred for 10-15 min. The pH of this solution is adjusted to 2, using dilute hydrochloric acid with constant stirring. The precipitated solid was filtered and washed with water. Methanol (500 ml) was added to the solid, stirred and the suspension was refluxed for Ihr, cooled to 0-5°C and stirred for Ihr. The precipitated solid is filtered and dried to provide pure deferasirox. Yield: 23grams; Purity by HPLC: 99.79 %.
Example-7: Purification of Deferasirox.
To a solution of aqueous sodium hydroxide (10%, 250ml) added of deferasirox (25g). Stirred for fifteen minutes and filtered it. The filtrate was extracted with dichloromethane, and to the filtrate added hydrose (1.25 grams) and stirred for 10-15 min. The pH of this solution is adjusted to 2, using dilute hydrochloric acid with constant stirring to precipitate a solid. The precipitated solid was filtered, washed with water and dried to provide pure deferasirox. Yield: 21grams; Purity by HPLC: 99.83 %.
Example-7: Purification of Deferasirox.
Deferasirox (25 grams) was suspended in 500 ml of methanol and refluxed for Ihr. The reaction mixture was cooled to 0-5*^ C with stirring. The solid was filtered and dried to get pure deferasirox. Yield: 23 grams; Purity by HPLC: 99.89 %
Example-8: Preparation of deferasirox methylamine amine salt compound of formula-8a.
Added 30 ml of ethyl acetate to the crude deferasirox (3 grams) followed by 40% aqueous methyl amine (0.74ml) at 25-30°C.Stirred the reaction mixture for 2 hours at 25-30°C. Filtered the precipitated solid and washed with ethyl acetate. Dried the material for 5 hours. Added 40 ml of acetone to the above obtained dried material and heated to reflux. Stirred the reaction mixture for 30 minutes and cooled the reaction mixture to 25-35°C.Stirred the reaction mixture for 6 hours at 25-35°C. Filtered the precipitated solid and dried the material at 50-55°C to get the title compound. Yield: 3.1 grams.

Example-7: Preparation of deferasirox isopropyl amine salt compound of formuIa-8b.
Added 100 ml of ethyl acetate to the crude deferasirox (10 grams) followed by isopropyl amine (1.5 ml) at 25-30°C. Stirred the reaction mixture for 2 hours at 25-30°C. Filtered the precipitated solid and washed with ethyl acetate. Added 100 ml of ethyl acetate to the above solid and heated to reflux. Stirred the reaction mixture for 30 minutes and cooled the reaction mixture to 25-35°C. Stirred the reaction mixture for 6 hours at 25-35°C. Filtered the precipitated solid and dried the material at 50-55°C to get the title compound. Yield: 9.4 grams.
Example-8: Preparation of deferasirox n-butyl amine salt compound of formula-8c.
Added 100 ml of ethyl acetate to the crude deferasirox (10 grams) followed by n-butyl amine (2 ml) at 25-30°C.Stirred the reaction mixture for 2 hours at 25-30°C. Filtered the precipitated solid and washed with ethyl acetate. Dried the material for 6 hours. Added 100 ml of ethyl acetate to the above obtained dried material and heated to reflux. Stirred the reaction mixture for 30 minutes and cooled the reaction mixture to 25-35°C.Stirred the reaction mixture for 6 hours at 25-35°C. Filtered the precipitated solid and dried the material at 50-55°C to get the title compound. Yield: 9.8 grams
Example-9: Preparation of deferasirox dicyclohexylamine salt compound of formula-8d.
Added 50 ml of ethyl acetate to the crude deferasirox (5 grams) followed by dicyclohexylamine (2 ml) at 25-30°C.Stirred the reaction mixture for 2 hours at 25-30°C. Filtered the precipitated solid and washed it with ethyl acetate. Dried the solid material for 6 hours. Added 60 ml of toluene to the above obtained dried material and heated to reflux. Stirred the reaction mixture for 30 minutes and cooled the reaction mixture to 25-35°C.Stirred the reaction mixture for 6 hours at 25-35°C. Filtered the precipitated solid and dried the material at 50-55°C to get the title compound. Yield: 4.9 grams

ExampIe-lO: Preparation of deferasirox from its methylamine amine salt.
Deferasirox methyl amine (2.0 grams) was taken in methanol (20ml) and added water (40ml) and stirred for 15 minutes. The pH of the solution was adjusted to around 2 using dilute hydrochloric acid and stirred the solution for 30 minutes. Filtered the precipitated solid washed with methanol and dried to provide pure deferasirox. Yield: 1.6 grams; HPLC Purity: 99.90 %
Example-11: Purification of Deferasirox.
Deferasirox (5 grams) was suspended in 15 ml of dimethyl formamide and stirred for ten minutes at 25-35°C.Water (20ml) was added to the solution and stirred for one hour. The solid precipitated was filtered and dried to get pure deferasirox. Yield: 4.3 grams; HPLC Purity: 99.62 %
Experimental Conditions:
XRD analysis of deferasirox was carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min. FT-IR spectrum of deferasirox was recorded on Thermo model Nicolet-380 as KBr pellet. The thermal analysis of deferasirox was carried out on Waters DSC Q-10 model differential scanning calorimeter.
The related substances of deferasirox was measured using HPLC with the following chromatographic conditions; Apparatus: A liquid chromatograph is equipped with UV-detector; Column: Inertsil ODS-4 250 X 4.6 mm, 5^m or equivalent; Flow Rate: 1.0 ml'min; Wavelength: 235 nm; Column temperature: 25°C; Injection volume: 10 \i\; Run time: 55 minutes; Diluent: Acetonitrile: Methanol (50: 50 v/v); Elution: Gradient; and using aqueous acetonitrile and aqueous acetonitrile with aqueous potassium dihydrogen ortho phosphate as mobile phases.
Analysis of particle size distribution of deferasirox using the following conditions:
Instrument model: Malvern Mastersizer 2000; Technique used: dry method; Material RI: 1.5 ; Dispersant RI: 1.0; Despersant: Light liquid paraffin; Sensitivity : Normal.

We Claim:
1. An improved process for the preparation of deferasirox compound of formula-1 which comprises of the following steps,

in presence of a suitable base selected from pyridine, trimethylamine, triethylamine, in a suitable solvent selected from toluene, cyclohexane, heptane, chlorobenzene, xylene or a mixture thereof, in presence of thionyl chloride at reflux temperature, followed by crystallization from a suitable alcoholic solvents like methanol, ethanol, isopropanol a mixture thereof, characterized in that the thionyl chloride is used in the mole ratio of 1.7-1.9 and is added in two lots at reflux temperature, wherein the second lot is added after maintaining the reaction mixture for some time after the addition of first lot of thionyl chloride, to provide the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4.


in a suitable solvent selected from alcoholic solvents like methanol, ethanol, isopropanol, butanol or mixtures thereof at reflux temperature to provide the deferasirox compound of formula-1, c) purifying the compound of formula-1 by treating it with a base and optionally extracting the mixture with a suitable water immiscible solvent, followed by treatment with an acid to provide the pure deferasirox

in presence of a pyridine in xylene in presence of thionyl chloride at reflux temperature, followed by crystallization from a methanol, to provide the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4, characterized in that the thionyl chloride is used in the mole ratio of 1.7-1.9 and is added in two lots at reflux temperature, wherein the second lot is added after maintaining the reaction mixture for some time after the addition of first lot of thionyl chloride,

b) reacting the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4 with 4-hydrazinobenzoic acid compound of formula-5


in methanol at 60-65° C to for 3-5 hours to provide the deferasirox compound of formula-1, c) optionally purifying the compound of formula-1 by treating it with aqueous sodium hydroxide, followed by hydrose and subsequently with an acid to provide the pure deferasirox.
3. One-pot process for the preparation of deferasirox compound of formula-1, which comprises of reacting the salicylic acid compound of formula-2

in presence of a suitable base selected from pyridine, trimethylamine, triethylamine, in a suitable solvent selected from toluene, cyclohexane, heptane, chlorobenzene, xyleneor a mixture thereof, in presence of thionyl chloride which is added in two lots at reflux temperature to provide the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4,


in a suitable solvent selected from alcoholic solvents like methanol, ethanol, isopropanol, butanol or a mixture thereof, at reflux temperature to provide deferasirox compound of formula-1.
4. A process of claim 1 to 3, wherein deferasirox compoimd of formula-1, having a
purity greater than 99% by HPLC, having the impurity at 2,1 RRT in a concentration
less than 0.10%.
5. A process of claim 1 to 4, wherein 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one
compound of formula-4 containing the uncyclised derivative 2-hydroxy-N-(2-
hydroxybenzoyl) benzamide compound of formula-6, in a concentration below 10%
and the unknown impurity with molecular mass of 508, in a concentration less than
0.15%.

wherein NR1R2R3 is an amine wherein Ri, R2 and R3 are same or different and are each independently selected from either hydrogen, C1.12 alkyl, C3.7 cycloalkyl, aryl-C1.6 alkyl, aryl and the like.
7. The deferasirox amine salts compound of general formula-8, wherein NR1R2R3 is an amine and is selected from a group which includes but is not limited to methylamine, ethylamine, n-propylamine, isopropylamine n-butylamine, isobutylamine, tertiary butyl amine, diethyl amine, octylamine, 2-ethylhexylamine, benzylamine.

phenethylamine, dibenzylamine, N-methylbenzylamine, N-ethylbenzylamine,
dibenzylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine,
N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethylcycloheptylamine,
dicyclohexylamine, pyrrolidine, N-methyipyrrolidine, N-methylpiperidine,
piperidine, morpholine and the like.
8. A process for the preparation of deferasirox amine salts, compounds of general formula-8
wherein NR1R2R3 is an amine wherein Ri, R2 and R3 are same or different and are each independently selected from either hydrogen, C1.12 alkyl, C3.7 cycloalkyl, aryl-Ci^ alkyl, aryl and the like: which comprises of the following steps;
a) Treating the crude deferasirox with an amine NR1R2R3 compound of formula-7,
wherein Ri, R2 and R3 are same or different and are each independently selected
from either hydrogen, C1.12 alkyl, C3.7 cycloalkyl, aryl-Ci.6 alkyl, aryl and the
like; in a suitable solvent selected from ester solvents and/or hydrocarbon solvents
and/or ketone solvents,
b) stirring the reaction mixture for sufficient period of time for the formation of
amine sah of deferasirox,
c) separating the solid by filtration and washing with suitable solvent,
d) optionally purifying the deferasirox amine salt compound of formula-8 using
ester solvents or hydrocarbon solvents or ketone solvents or alcohol solvents or
their mixtures thereof,
e) drying the solid to get the amine salt of deferasirox.

9. A process for preparation of methylamine salt of deferasirox compound of
formula-8a, comprising of;
a) Treating the crude deferasirox with an methylamine in ethyl acetate,
b) stirring the reaction mixture for 2 hours at 25-35°C,
c) separating the solid by filtration and washing with ethyl acetate,
d) purifying the solid using ethyl acetate,
e) drying the solid formed to provide deferasirox methyl amine salt.

10. The use of deferasirox amine salts compound of general formula-8 for the preparation of pure deferasirox.
11. A process for the preparation of pure deferasirox from deferasirox amine salt which comprises of;

a) suspending deferasirox amine salt in an suitable solvent selected from a group consisting of water, alcoholic solvents namely methanol ethanol, n-propanol, isopropanol, n-butanol and the like; chlorinated hydrocarbons like dichloromethane, chloroform etc., ester solvents for example ethyl acetate, isopropyl acetate and the like
b) treating it with an acid selected from an inorganic acid like hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; an organic acid like acetic acid, propionic acid, acetic acid and the like,
c) filtering the solid obtained and washing with suitable solvent selected from methanol, ethanol, isopropanol, n-propanol, butanol and the like, and drying it to provide highly pure deferasirox
12. A process for the purification of deferasirox compound of formula-1, which
comprises of the following steps,
a) Treating the deferasirox with a suitable aqueous base like sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, sodium bicarbonate, potassium bicarbonate and ammonia, in absence or presence of a solvent, which is selected from

alcoholic solvents like methanol, ethanol, isopropanol, n-propanol and butanol and stirring the reaction mixture to provide solution,
b) filtering the solution, and optionally extracting the filtrate with a suitable water immiscible solvent selected from ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, toluene, xylene, cyclohexane, hexane, heptane and the like, to remove the impurities,
c) treating the filtrate with hydrose,
d) filtering and treating the reaction mixture with suitable acid selected fi"om a group consisting of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid,
e) suspending the wet solid in a suitable water miscible solvent selected from alcoholic solvents like methanol, ethanol, isopropanol, n-propanol, butanol and heating the suspension to reflux,
f) cooling the reaction mixture and filtering the precipitated solid to get pure deferasirox,
13. A process for the purification of deferasirox compoimd of formula-1, which
comprises of the following steps,
a) Suspending the deferasirox in a suitable alcoholic solvents like methanol, ethanol, isopropanol, n-propanol, butanol or mixtures thereof,
b) heating the suspension to reflux and stirring the reaction mixture for certain period of time,
c) cooling the reaction mixture,
d) filtering, washing the solid with a suitable solvent and drying to get the pure compound of formula-1.
14. A process for the purification of deferasirox compound of formula-1, which
comprises of the following steps,
a) Suspending the deferasirox in a suitable polar aprotic solvent like dimethyl formamide, dimethylacetamide or dimethylsulfoxide and heating it to reflux,
b) cooling the reaction mixture.

c) adding an anti solvent and stirring the reaction mixture,
d) filtering the solid formed, washing the solid with a suitable solvent and drying to
get the pure compound of formula-1.
15. Deferasirox compound of formula-1 having D90 is in the range of 2-100 |jm and mean particle size in the range of 2-40 \im.