FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"AN IMPROVED PROCESS FOR PREPARATION OF PURE IRON
CHELATOR"
2. APPLICANT:
(a) NAME: CIPLA LIMITED
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: Mumbai Central, Mumbai - 400 008, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be formed.

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to an improved process for preparation of a pure iron chelator.
BACKGROUND OF THE INVENTION:
Deferasirox is chemically known as 4-[3,5-Bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl]benzoic acid and represented as follows :

US6465504 describes various 3,5-diphenyl-l,2,4-triazoles which are used as an iron chelators in the treatment of iron overload in human or animal body. This patent also describes deferasirox & its preparation.
WO2009094956 describes process for preparation of deferasirox by condensation of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one with 4-hydrazino benzoic acid in presence of organic acid or mixture of organic acid & organic solvent.
WO2009147529 describes process for purifying deferasirox to give highly pure deferasirox or a pharmaceutically acceptable salt thereof substantially free of hydrazine impurity ie. 4-hydrazino benzoic acid which is genotoxic & carcinogenic. This application also describes preparation of deferasirox by condensation of 2-(2-hydroxypheny])benz[e][l,3] oxazin-4-one with 4-hydrazino benzoic acid in inert solvent. The hydrazine impurity has structure as follows :


US6465504 describes preparation of deferasirox from 2-hydroxy-N-(2-
hydroxybenzoyl)benzamide. 2-hydroxy-N-(2-hydroxybenzoyl)benzarnide is prepared by
condensation of salicyloyl chloride and salicylamide. During this reaction, 5-chloro-2-
hydroxy-N-(2-hydroxybenzoyl)benzamide is produced as a side product in addition to 2-
hydroxy-N-(2-hydroxybenzoyl)benzamide. This 5-chloro-2-hydroxy-N-(2-
hydroxybenzoyl)benzamide further results into undesired products. These undesired products cause contamination of the final product.
The undesired impurities reduce the purity of the API in the pharmaceutical product and often decrease the stability and shelf life of the pharmaceutical product.
Hence, there is a need to develop an improved process which provides substantially pure deferasirox or a pharmaceutically acceptable salt thereof which has process impurities and 4-hydrazino benzoic acid impurity below certain levels.
SUMMARY OF THE INVENTION:
According to the first aspect of the present invention, there is provided an improved process for the preparation of substantially pure deferasirox or a pharmaceutically acceptable salt thereof.
The process involves step of reacting 2-hydroxy-N-(2-hydroxybenzoyl)benzamide with inorganic acid salt of 4-hydrazinobenzoic acid in presence of an acid in a suitable solvent.
In another aspect of the present invention, there is provided substantially pure deferasirox or a pharmaceutically acceptable salt thereof which is substantially free of Chloro deferasirox impurity.

In yet another aspect of the present invention, there is provided a crystallization process to obtain deferasirox or a pharmaceutically acceptable salt thereof having particle size D90 less than 50 microns (μ).
DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides a process for preparation of deferasirox which process involves step of reacting 2-hydroxy-N-(2-hydroxybenzoyl)benzamide with inorganic acid salt of 4-hydrazinobenzoic acid in presence of an acid in a suitable solvent.
4-hydrazinobenzoic acid when used as a base in the organic solvents such as alcohols, an ester of deferasirox is formed, which contaminates the final product decreasing its purity. The formation of this ester impurity is decreased to a large extent by the use of water as a solvent in combination with alcohols.
It is also observed that reaction does not proceed to completion with 4-hydrazinobenzoic acid in a mixture of alcohol & water.
Hence, inorganic salt of 4-hydrazinobenzoic acid is used and it is found that the solubility of the said salt is increased considerably in a said mixture of alcohol & water. The increased solubility of inorganic salt of 4-hydrazinobenzoic acid helps to proceed the reaction to completion with maximum yield.
The inorganic acid used for salt formation is selected from hydrochloric acid, sulphuric acid and the like. Preferably, hydrochloric acid salt is used.
The solvents used for the reaction may be selected from water, ethanol, methanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol. 4-hydrazinobenzoic acid hydrochloride easily gets dissolved in these solvents.
Acid used for a reaction is inorganic acid which is selected from hydrochloric acid, sulphuric acid and the like.

Though inorganic acid is added to adjust the pH of the reaction mass in the range of 1-3, it is also found that such acid acts as a catalyst which facilitates the completion of the reaction.
Typically after the addition of both the reactants namely inorganic acid salt of 4-hydrazino benzoic acid and 2-hydroxy-N-(2-hydroxybenzoyl)benzamide and after adjusting the pH of the mixture, the reaction mass is heated to reflux temperature till the reaction is complete. The product obtained is isolated by routine procedures.
US6465504 describes preparation of deferasirox from 2-hydroxy-N-(2-
hydroxybenzoyl)benzamide. 2-hydroxy-N-(2-hydroxybenzoyl)benzamide is prepared by
condensation of salicyloyl chloride and salicylamide. During this reaction, 5-chloro-2-
hydroxy-N-(2-hydroxybenzoyl)benzamide is produced as a side product in addition to 2-
hydroxy-N-(2-hydroxybenzoyl)benzamide. This 5-chloro-2-hydroxy-N-(2-
hydroxybenzoyl)benzamide further results into 5-chloro deferasirox (Chloro impurity). This chloro impurity causes contamination of the final product. The chloro impurity has structure as follows :

Another process related impurity is hydrazine impurity, 4-hydrazino benzoic acid.
These impurities are removed by purification of deferasirox which forms another aspect of the invention.
According to this aspect of the invention, there is provided a process for purification of deferasirox to get substantially pure deferasirox having purity of at least 99.5%.

The process comprises:
1) preparing a solution of deferasirox in a suitable solvent,
2) adding the slurry of Raney nickel to the solution of deferasirox,
3) isolating deferasirox from the solution.
Preparing a solution can include dissolving deferasirox in a solvent described above for the reaction or obtaining a solution comprising deferasirox from previous synthetic step. The slurry of the Raney nickel is prepared in the same solvent as used to prepare the solution of deferasirox.
After addition of Raney nickel the reaction mixture is heated at a temperature below reflux temperature of the solvent used. Further, Raney nickel is removed by filtration and then using ethylenediamine tetraacetic acid disodium salt (EDTA), if required, to remove traces of Raney nickel left.
Deferasirox left in a filtrate after removal of Raney nickel is precipitated by adding inorganic acid preferably hydrochloric acid.
The so obtained deferasirox is further crystallized using a solvent which may be selected from methanol, acetone, toluene or mixture thereof. Deferasirox may further be converted into suitable pharmaceutically acceptable salt.
The crystallization process to prepare deferasirox or a pharmaceutically acceptable salt thereof having particle size D90 less than 50 microns (μ) comprises following steps : i) adding deferasirox to a suitable solvent, ii) heating to dissolve deferasirox in a above solvent, iii) cooling the solution to 30-40°C and filtering to remove insoluble matter, iv) precipitating the pure product by adding the above filtrate to a suitable anti-solvent, v) optionally, washing the product obtained in above step followed by drying and vi) optionally converting deferasirox into its pharmaceutically acceptable salt by known methods.

Suitable solvent may be selected from methanol, acetone, toluene or mixture thereof. Suitable anti-solvent may be selected from water, heptane or mixture thereof.
The crystallization process according to the invention involves addition of the filtrate to the anti-solvent. The addition of filtrate to the anti-solvent provides deferasirox with particle size D90 less than 50 microns (μ).
Usually to get reduced particle size, the product obtained is milled. Milling reduces the yield and also increases the manufacturing time and as well as the cost. Thus, the additional step of further processing such as milling to reduce the particle size is avoided in the process of present invention.
In another aspect of the present invention, there is provided substantially pure deferasirox or a pharmaceutically acceptable salt thereof.
"substantially pure deferasirox or a pharmaceutically acceptable salt thereof means deferasirox or a pharmaceutically acceptable salt thereof having purity of about 99% to about 99.9%. Further, "substantially pure deferasirox or a pharmaceutically acceptable salt thereof also means deferasirox or a pharmaceutically acceptable salt thereof having chloro impurity in an amount not more than 0.05% & hydrazine impurity not more than 5 ppm.
Also substantially pure deferasirox or a pharmaceutically acceptable salt thereof which is substantially free of Chloro deferasirox impurity means deferasirox or a pharmaceutically acceptable salt thereof having chloro impurity in an amount not more than 0.05%.
The details of the invention are given in the examples which are provided below for illustration only and therefore these examples should not be construed to limit the scope of the invention.
Example 1
Preparation of Deferasirox

300.0 ml purified water was charged in a cleaned round bottom flask followed by addition of 44.0 g of 4-hydrazino benzoic acid hydrochloride under stirring. The pH of the reaction mass was adjusted to 2.0 ± 0.2 with concentrated hydrochloric acid. 40.0 g of 2-hydroxy-N-(2-hydroxybenzoyl)benzamide was charged into the same flask followed by addition of about 340.0 ml isopropyl alcohol to it. The reaction mass was heated to reflux and stirred at reflux temperature for 40 hours. The completion of reaction was checked by TLC. After completion of reaction, the reaction mass was cooled to 25 - 30°C and stirred for 2 hours. The reaction mass was filtered and washed with 30.0 ml of isopropyl alcohol followed by 150.0 ml of purified water. The product obtained was suck dried. Wet weight = 40.00 g. HPLC purity = 98.00% Chloro impurity = 0.18%
Example 2
Purification of Deferasirox using Raney Nickel
About 500.0 ml of water was charged in a cleaned round bottom flask followed by 8.0 g of sodium hydroxide flakes and the mixture was stirred for 10 minutes. Deferasirox obtained in example 1 was charged to the same flask and the reaction mass was stirred to dissolve Deferasirox. About 10.0 ml of water was taken in a beaker and 5.0 g Raney Nickel was added to it to make a slurry. This slurry was added to the reaction mass and stirred for 15 minutes. The reaction mass was heated to 65 - 70°C for 12 hours and then cooled to 45 - 50°C and 1.0 g hyflo was charged into it. About 250.0 ml water was added to the reaction mass, filtered over hyflo and washed the hyflo bed with 25.0 ml of water. The clear filtrate was collected in another clean round bottom flask. 1.5 g of Disodium Edetate was charged to the filtrate and stirred for 15 minutes. The pH of the reaction mass was adjusted to 2.00 - 3.00 with concentrated hydrochloric acid and the reaction mass was heated to 60 - 65°C for 3 hours. The reaction mass was cooled to 35 - 40°C and stirred for 1 hour. The reaction mixture was filtered, washed with 200.0 ml of water and suck dried.
Wet wt. = About 70.0 g. HPLC purity = 99.93% Chloro impurity = Not detected.

Example 2
Crystallization of Deferasirox
8.0 g Deferasirox was charged in 240 ml acetone and heated to reflux for 30 minutes. The reaction mixture was cooled to 35-38°C and filtered through hyflo. In another flask 240 ml purified water was charged followed by addition of the clear filtrate to it at 25-27°C and stirred to precipitate the product. The precipitated deferasirox was filtered and washed with acetone: methanol (1:1) mixture (2 volumes) and suck dried. Finally deferasirox was dried in vacuum oven at 55-60°C. Yield : 7 g.
Particle size : D90 = 15.2μ D50 = 6.77 μ HPLC purity = 99.97%

We claim:
1. A process for preparing substantially pure deferasirox or a pharmaceutically acceptable salt thereof which process comprises reacting 2-hydroxy-N-(2-hydroxybenzoyl)benzamide with inorganic acid salt of 4-hydrazinobenzoic acid in presence of an acid in a suitable solvent.
2. The process according to claim 1 wherein solvent used for the reaction is selected from ethanol, methanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and water.
3. The process according to claim 1 wherein inorganic acid salt of 4-hydrazinobenzoic acid is selected from hydrochloric acid and sulphuric acid.
4. The process according to claim 1 wherein the acid used in the reaction is inorganic acid which is selected from hydrochloric acid and sulphuric acid.
5. Deferasirox or a pharmaceutically acceptable salt thereof having chloro impurity not more than 0.05%.

6. A process for purification of deferasirox having purity of at least 99.5% which
process comprises:
1) preparing a solution of deferasirox in a suitable solvent
2) adding the slurry of Raney nickel to the solution of deferasirox,
3) isolating deferasirox from the solution.
7. The process according to claim 6 wherein the solvent used for preparation of
solution of deferasirox is selected from ethanol, methanol, n-propanol,
isopropanol, n-butanol, isobutanol, tert-butanol and water.

8. The process according to claim 6 wherein after addition of Raney nickel slurry to the deferasirox solution the reaction mass is heated below reflux temperature of the solvent.
9. The process according to claim 6 wherein the solvent used for preparation of slurry of Raney Nickel is selected from ethanol, methanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol and water.
10. A process to obtain deferasirox or a pharmaceutically acceptable salt thereof having particle size D90 less than 50 microns (u) which process comprises :
i) adding deferasirox to a suitable solvent, ii) heating to dissolve deferasirox in a above solvent, iii) cooling the solution to 35-40°C and filtering to remove insoluble matter, iv) precipitating by adding the above filtrate to a suitable anti-solvent, v) optionally, washing the solid obtained in above step and drying and vi) optionally converting deferasirox into its pharmaceutically acceptable salt by known methods.
11. The process according to claim 10 wherein the solvent used in step i) is selected from methanol, acetone, toluene or mixture thereof.
12. The process according to claim 10 wherein the anti-solvent used in step iv) is selected from water, heptane or mixture thereof.
13. Deferasirox having purity of at least 99.5% prepared by the process according to claim 6.