Field of the Invention:
The present invention relates to a process for the purification of deferasirox. 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.

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 and does not discloses any purification process. Even though the purity of obtained compound is satisfactory, it contaminates with high level of content toxic material like HBA and very poor residue on ignition and also having very poor in color. Hence there is a need in the art for the purification of deferasirox to remove the toxic content and improve the Residue on Ignition as well as color.
The main objective of the present invention is to provide a process for the purification of deferasirox compound of formula-1 which avoids the problems associated with the prior art.

Brief Description of the Invention:
The first 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) Suspending the deferasirox compound of formula-1 in a suitable alcoholic solvent,
b) dissolving the suspension by adding the suitable organic base,
c) stirring the solution,
d) filtering the solution,
e) adding the filtrate to the aqueous acid solution and stirring,
f) filtering the solid and washing with water,
g) slurrying the wet solid in water and then filtering the solid, h) suspending the wet solid in a suitable alcohol solvent,
i) heating the suspension to reflux and stirring,
j) cooling the reaction mixture,
k) filtering the solid and washing with alcohol solvent,
1) drying the solid to get the highly pure deferasirox compound of formula-1.
The second aspect of the present invention is to provide alternate process for the purification of deferasirox compound of formula-1, which comprises of the following steps,
a) dissolving the deferasirox in a suitable ether solvent,
b) filtering the solution through hyfiow,
c) adding the filtrate to aqueous alcohol and stirring,
d) filtering the solid and washing with water,
e) dissolving the wet solid in aqueous base,
f) subjecting reaction mixture to carbon treatment,
g) filtering through reaction mixture through hyfiow and acidifying the filtrate with suitable acid,
h) stirring the reaction mixture,
i) filtering the solid and washing with suitable solvent,
j) drying the solid to get the highly pure deferasirox compound of formula-1.

Detailed Description of the Invention:
Accordingly the present invention provides a process for the purification of deferasirox compound of formula-1 which reduces the toxic HBA content, increase the physical characteristics like colour as well as Residue on Ignition (Rol)

The first 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 compound of formula-1 in a suitable alcoholic solvent selected from methanol, ethanol, isopropanol, butanol or mixtures thereof,
b) dissolving the suspension by adding the suitable organic base selected from triethylamine, triethanolamine, di-n-propylamine diisopropylethylamine, and tributylamine or mixtures thereof,
c) stirring the solution and filtering through filter paper,
d) adding the filtrate to the aqueous acid solution selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid and stirring,
e) filtering the formed solid and washing with water,
f) slurrying the wet solid in water and then filtering the solid,
g) suspending the wet solid in a suitable alcohol solvent selected from methanol, ethanol, isopropanol and butanol or mixtures thereof,
h) heating the suspension to reflux temperature and stirring,
i) cooling the reaction mixture,
j) filtering the solid and washing with suitable alcohol solvent,
k) drying the solid to get the highly pure deferasirox compound of formula-1.
The reported process for the preparation of deferasirox involves the usage of 4-hydrazinobenzoic (HBA), which is toxic material and as per ICH guidelines it should

be controlled to less than 5 ppm in active pharmaceutical ingredients and formulation. Even though the purity of deferasirox by HPLC obtained as per process known in the art is well with in the limits set by ICH, the deferasirox compound containing 4-hydrazinobenzoic acid (HBA) in high ratio of upto 1500ppm, which is very high in comparison with the required limit. Hence it is not acceptable. It is important that API should free of toxic material to possible extent limits set by ICH. Moreover the Residue on Ignition and colour of the material obtained were also poor. When we are trying to reduce the HBA content by conventional purification methods like recrystallisation, slurring, washing or distillation in different solvent do not result in the reduction of HBA content and however results in slight improvement in colour of the material. In order to reduce HBA content and to improve the ROI and colour simultaneously we the present inventors working on the purification of deferasirox through various combination of methods using different solvent, after extensive experimentation, we surprisingly found that recrystallisation followed by acid-base treatment and then slurrying the obtained compound in water yield the good results and reduction of HBA content less than 5 ppm and also improves the colour and residue on ignition to less than 0.1 % w/w.
In a preferred embodiment of the present invention, the purification of deferasirox compound of formula-1, which comprises of the following steps
a) Suspending the deferasirox compound of formula-1 in methanol,
b) adding triethylamine to the suspension and stirring for 15 minutes,
c) filtering the solution through filter paper,
d) adding the filtrate to the aqueous hydrochloric acid solution and stirring the reaction mixture for 30-45 minutes at 25-35°C,
e) filtering the formed solid and washing with water,
f) slurrying the wet solid in water for 20 minutes at 25-35°C and then filtering the solid,
g) suspending the obtained wet solid in methanol,
h) heating the suspension to 60-65°C and stirring the reaction mixture for 30 minutes,
i) cooling the reaction mixture to 25-35°C,
j) filtering the solid and washing with methanol,

k) drying the solid at 65-70°C to get the highly pure deferasirox compound of formula-1.
The second aspect of the present invention provides alternate process for the purification of deferasirox compound of formula-1, which comprises of the following steps,
a) dissolving the deferasirox in a suitable ether solvent,
b) filtering the solution through hyflow,
c) adding the filtrate to the aqueous alcohol and stirring,
d) filtering the solid and washing with water,
e) dissolving the wet solid in aqueous base,
f) subjecting reaction mixture to carbon treatment,
g) filtering the reaction mixture through hyflow and acidifying the filtrate with suitable acid,
h) stirring the reaction mixture,
i) filtering the solid and washing with suitable solvent,
j) drying the solid to get the highly pure deferasirox compound of formula-1.
In a preferred embodiment, alternate process for the purification of deferasirox compound of formula-1 comprises of the following steps,
a) dissolving the deferasirox in tetrahydrofuran,
b) filtering the solution through hyflow,
c) the filtrate was added to aqueous methanol and stirring the reaction mixture for 10 minutes,
d) filtering the solid and washing with water,
e) dissolving the wet solid in aqueous sodium hydroxide solution,
f) subjecting the solution to carbon treatment,
g) filtering solution through hyflow and acidifying the filtrate with aqueous hydrochloric acid solution,
h) stirring the reaction mixture for 45 minutes at 25-35°C i) filtering the solid and washing with water,

j) drying the solid to get the highly pure deferasirox compound of formula-1.
The deferasirox obtained after purification process as per the present invention having HBA content less than 5 ppm, preferably less than 2 ppm and more preferably less than 1 ppm. The deferasirox obtained after purification is having residue on ignition less than 0.1% w/w and improvement in colour.
The deferasirox used in the purification process can be prepared as per the process disclosed in US 6465504 and having HBA content in the range of 1500-3000 ppm. The input material can also prepared by any other conventional methods.
4-hydrozino benzoic acid (HBA) content in deferasirox was measured by High performance Liquid Chromatography by using the following conditions; Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector; Column: Symmetry CI8, 250X4.6 mm, 5um; Flow rate: 0.5 ml/min; Wavelength: 316 run; Temperature: 25°C; Runtime:45 minutes; Diluent: methanolic orthophosphoric acid; Elution: gradient and using mixture of buffer and acetonitrile & acetonitrile and water as a mobile phases. Buffer is aqueous potassium dihydrogen orthophosphate.
Related substances of deferasirox were analyzed by HPLC using the following conditions:
Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector; column: Inertsil ODS, 250X4.6 mm, 5um; Flow rate: 1.5 ml/min; Wavelength: 235 nm; Temperature: 25°C; Runtime:55 minutes; Diluent: acetonitrile and methanol; Elution: gradient and using mixture of buffer and acetonitrile & acetonitrile and water as a mobile phases. Buffer is aqueous potassium dihydrogen orthophosphate.

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-l: Purification of Deferasirox.
A suspension of deferasirox (100 grams) and methanol (1.2L ) was stirred for 10 minutes and triethylamine (45 ml) was added to it then stirred for 15 minutes. The obtained solution was filtered through filter paper and washed with methanol. The filtrate was added to aqueous hydrochloric acid solution (125 ml in 375 ml of water) and stirred the reaction mixture for 45 minutes at 25-35°C. The solid was filtered and washed with water. Water (500 ml) was added to the wet solid and stirred for 20 minutes at 25-35°C. Methanol (2 L) was added to the wet solid and heated to 60-65°C then stirred for 30 minutes. The reaction mixture was cooled to 25-35°C and the solid was filtered and washed with methanol. The wet solid was dried at 65-70°C to get pure deferasirox compound of formula-1. Yield: 85 grams HBA content: 1.8 ppm ROI: 0.3 % w/w Purity by HPLC: 99.96%
Example-2 to 4: Purification of Deferasirox.
The deferasirox compound of formula-1 was purified in a similar manner to example-l except that bases like triethanolamine, diisopropylethylamine and di-n-propylamine was used in place of triethyl amine and the corresponding results are tabulated below.


Example-5: Purification of deferasirox compound of formula-l:
Deferasirox (100 gram) was dissolved in terahydrofuran (600 ml) and stirred. The solution was filtered through hyflow and washed with tetrahydrofuran. The filtrate was added slowly to a mixture of methanol (750 ml) and water (750 ml) at 25-35°C then stirred for 30 minutes. The solid obtained was filtered and washed with water. The wet solid was dissolved in aqueous sodium hydroxide solution (40 grams in 1L of water) and subjected to carbon treatment. The solution was filtered through hyflow and the filtrate was acidified with aqueous hydrochloric acid then stirred for 45 minutes at 25-35°C. The solid obtained was filtered, washed with water and dried at 65-70°C to get the high pure title compound. Yield: 84 grams Purity by HPLC: 99.92% HBA content: 1.4 ppm

We Claim:
1. A process for the purification of deferasirox compound of formula-1, which comprises of the following steps,
a) Suspending the deferasirox compound of formula-1 in a suitable alcoholic solvent selected from methanol, ethanol, isopropanol, butanol or mixtures thereof,
b) dissolving the suspension by adding the suitable organic base selected from triethylamine, triethanolamine, di-n-propylamine diisopropylethylamine, tributylamine or mixtures thereof,
c) stirring the solution and filtering through filter paper,
d) adding the filtrate to the aqueous acid solution selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid or mixtures thereof and stirring,
e) filtering the formed solid and washing with water,
f) slurrying the wet solid in water and then filtering the solid,
g) suspending the wet solid in a suitable alcohol solvent selected from methanol, ethanol, isopropanol and butanol,
h) heating the suspension to reflux temperature and stirring,
i) cooling the reaction mixture,
j) filtering the solid and washing with suitable alcohol solvent,
k) drying the solid to get the highly pure deferasirox compound of formula-1.
2. A process for the purification of deferasirox compound of formula-1, which comprises of the following steps,
a) Suspending the deferasirox compound of formula-1 in methanol,
b) adding triethylamine to the suspension and stirring for 15 minutes,
c) filtering the solution through filter paper,
d) adding the filtrate to the aqueous hydrochloric acid solution and stirring the reaction mixture for 30-45 minutes at 25-35°C,
e) filtering the formed solid and washing with water,
f) slurrying the wet solid in water for 20 minutes at 25-35°C and then filtering the solid,

g) suspending the obtained wet solid in methanol,
h) heating the suspension to 60-65°C and stirring the reaction mixture for 30
minutes, i) cooling the reaction mixture to 25-35°C, j) filtering the solid and washing with methanol, k) drying the solid to get the highly pure deferasirox compound of formula-1.
3. A process for the purification of deferasirox compound of formula-1, which
comprises of the following steps,
a) Dissolving the deferasirox in a suitable ether solvent,
b) filtering the solution through hyflow,
c) adding the filtrate to aqueous alcohol and stirring,
d) filtering the solid and washing with water,
e) dissolving the wet solid in aqueous base,
f) subjecting the reaction mixture to carbon treatment,
g) filtering reaction mixture through hyflow and acidifying the filtrate with suitable acid,
h) stirring the reaction mixture,
i) filtering the solid and washing with suitable solvent,
j) drying the solid to get the highly pure deferasirox compound of formula-1.
4. A process for the purification of deferasirox compound of formula-1, which
comprises of the following steps,
a) Dissolving the deferasirox in tetrahydrofuran,
b) filtering the solution through hyflow,
c) adding the filtrate to aqueous methanol and stirring the reaction mixture for 10 minutes,
d) filtering the solid and washing with water,
e) dissolving the wet solid in aqueous sodium hydroxide solution,
f) subjecting the solution to carbon treatment,

g) filtering through hyflow and acidifying the filtrate with aqueous hydrochloric acid
solution, h) stirring the reaction mixture for 45 minutes at 25-35°C, i) filtering the solid and washing with water, j) drying the solid to get the highly pure deferasirox compound of formula-1.
5. A process according to any of the preceding claims, wherein purified deferasirox is having HBA content less than 5 ppm.
6. A process according to any of the preceding claims, wherein purified deferasirox is having HBA content less than 2 ppm.
7. A process according to any of the preceding claims, wherein purified deferasirox is having purity greater than 99.99% by HPLC.
8. Deferasirox having HBA content less than 5 ppm prepared as per the process claimed in claim 1 to 4.
9. A process for the reduction of HBA content in deferasirox compound of formula-1 comprises of the following steps,

a) Suspending the deferasirox compound of formula-1 in a suitable alcoholic solvent selected from methanol, ethanol, isopropanol, butanol or mixtures thereof,
b) dissolving the suspension by adding the suitable organic base selected from triethylamine, triethanolamine, di-n-propylamine diisopropylethylamine, tributylamine or mixtures thereof,
c) stirring the solution and filtering through filter paper,
d) adding the filtrate to the aqueous acid solution selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid or mixtures thereof and stirring,
e) filtering the formed solid and washing with water,
f) slurrying the wet solid in water and then filtering the solid,

g) drying the solid to get the deferasirox compound of formula-1 with reduced level of HBA content.
10. A process for the reduction of deferasirox compound of formula-1 comprises of the following steps,
a) Suspending the deferasirox in a suitable alcohol solvent selected from methanol,
ethanol, isopropanol and butanol or mixtures thereof,
b) heating the suspension to reflux temperature and stirring,
c) cooling the reaction mixture,
d) filtering the solid and washing with suitable alcohol solvent,
e) drying the solid to get the deferasirox compound of formula-1 with reduced level of HBA content.