Description:Field of the Invention
The present invention generally relates to the field of process chemistry, and more particularly to an improved process for purification of deferasirox with reduced genotoxic impurities less than 0.5ppm.

Background of the Invention
Deferasirox has been approved to reduce chronic iron overload in patients who are receiving long-term blood transfusions for conditions such as beta-thalassemia and other chronic anemia.

Chemically referred as 4-[3,5-bis (6-oxo-1-cyclohexa-2, 4-dienylidene)-1,2,4-triazolidin-1-yl]benzoic acid, Deferasirox is a first medication approved as an oral iron chelator and structurally represented by Formula (I)

Formula (I)
Due to periodical blood transfusions in the patients with thalassemia and anemia, the excess of iron deposited in body tissues can cause severe damage to organs such as the liver, the heart and the endocrine organs which can lead to death. Iron chelators are small molecules that bind very tightly to iron ions and detoxifies preventing iron mediated injury to the cells. Deferasirox is mainly used to reduce chronic iron overload in patients who are receiving long-term blood transfusions for conditions such as beta-thalassemia and other chronic anemia.

Deferasirox is known to be prepared by process as disclosed involving condensation of salicylamide with salicyloyl chloride by heating at 170°C to yield 2-(2-hydroxy phenyl)-benz[e] [1,3]oxazin-4-one, which is further reacted with 4-hydrazinobenzoic acid in refluxing ethanol to give deferasirox.

There is no process for purification as disclosed in this patent application. The purity of the obtained compound is satisfactory however it contains high level of impurity F. The purity of deferasirox is very important with respect to the impurity F content which is genotoxic, and its limit is 0.5 ppm. The impurity F as shown below.

US2011/0171138 discloses a process for purification of deferasirox, comprising a) providing a solution of crude deferasirox in a solvent selected from the group consisting of an alcohol, a ketone, and mixtures thereof; b) optionally, subjecting the solution obtained to carbon treatment or silica gel treatment; c) partially removing the solvent from the solution; and d) precipitating pure deferasirox substantially free of hydrazine impurity from the solution.

WO2019016637 discloses process for preparation of deferasirox with impurity F less than 0.5 ppm. The process comprises purification of Deferasirox by refluxing in absolute alcohol in presence of sodium methoxide followed by glacial acetic acid addition and then cooled to room temperature. The product was filtered and washed with absolute alcohol to obtain pure Deferasirox. However, in the example part the actual hydrazine content in the isolated Deferasirox is not mentioned.

Thus, to purify and isolate Deferasirox with impurity F less than 0.5 ppm is the major challenge. Various processes involve use of various inorganic oxidizing agents such as sodium peroxymonosulfate (NaHSCF), potassium persulfate (K2S2O4), sodium persulfate (Na2S2O4), ceric ammonium nitrate ((NH4)2Ce(NO3)6), ceric ammonium Sulfate ((NH4)4Ce(SO4)4). These reagents are effective in reducing Impurity F below 0.5 ppm limits, however with these reagents, the deferasirox obtained does not qualify in sulfated ash. Hence additional purifications are needed for qualifying sulfated ash test.

Hence, there remains need for an improved process for purification of deferasirox providing deferasirox with reduced toxic impurities and with high purity substantially free of hydrazine impurity.

Summary of the Invention
The present invention provides a process for preparing pure Deferasirox of Formula (I) having Impurity F less than 0.5 ppm.

The present invention further provides a process for purification of deferasirox of Formula (I)

Formula (I)
by reacting deferasirox with a suitable ketone of formula (II) in a mixture of solvent and acid solution,

wherein R1 = and R2 = C1-C4 alkyl, phenyl, (1-4C) alkyl substituted by phenyl, -COOR3 , C1 and C2 together form (-CH2)n; n = 4 and 5; R3 = C1-C4 alkyl.

Detailed Description of the Invention
The hydrazino impurity F is a genotoxic impurity and it is formed in the synthesis of deferasirox with any of the processes described in the prior art. The present invention provides an improved process for purification of deferasirox for qualifying ICH limit of impurity F. The process is optimized to remove impurity F below 0.5 ppm level.

The present invention provides an process for the purification of deferasirox of Formula (I)

Formula (I)

with high purity and substantially free of hydrazine impurity.

In one aspect of the present invention, a process for preparation of pure deferasirox of Formula (I) is having Impurity-F less than 0.5 ppm comprises the step of reacting crude Deferasirox with a suitable ketone of formula (II) in a mixture of solvent and acid solution

wherein R1 = and R2 = C1-C4 alkyl, phenyl, (1-4C) alkyl substituted by phenyl, -COOR3 , C1 and C2 together form (-CH2)n; n = 4 and 5; R3 = C1-C4 alkyl.

The acid used in the process is selected from the group comprising of hydrochloric acid, sulfuric acid, methane sulfonic acid, p-toluenesulfonic acid, acetic acid, and trifluoacetic acid.

The solvent is selected from the group comprising of methylene chloride, ethyl acetate, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethyl sulfoxide, acetone, methanol, ethanol, 1,4-dioxane, and mixtures thereof.

The reaction is carried out at 60-100°C, preferably at 70-90°C, more preferably at 75-85°C.

In the process, the hydrazino impurity reacts with the ketone and gets converted to aromatic indol in acidic conditions.

Hence, a chemical reaction occurs in the purification step and the impurity F is removed from deferasirox as an indol. However, it does not affect the deferasiorx and the purification is effective to remove impurity efficiently below 0.5 ppm without any yield loss.

Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure.

It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.

Example 1
Preparation of 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl] benzoic acid (Deferasirox)
2-(2-hydroxyphenyl)-4H-1,3-benzoxazin-4-one (100 g) and 4-hydrazino benzoic acid (57.24 g) was charged in ethanol (500 ml). The temperature of the mixture was raised to 75-80°C and stirred for 5-6 hours. The reaction mass was cooled to room temperature, stirred and filtered. The wet cake was washed with ethanol (100 ml). The wet cake obtained is dissolved in isopropyl alcohol (3000 ml) at 80-85°C, filtered hot to remove any insoluble matter and the filtrate concentrated (300 ml). The precipitate obtained was cooled to room temperature, stirred and filtered. The wet cake was suck dried well and dried under vacuum at 50-55°C for 8-10 hours.

Yield: 120 g
Impurity F (4-HBA): 955.4 ppm
HPLC purity: 99.90 %

Example 2
Purification of Deferasirox
Deferasirox isolated in example 1 (100 g) was charged to dimethyl formamide (200 ml) at room temperature and stirred for 30 minutes. After complete dissolution of the solid, methyl ethyl ketone (100 ml) was charged to the solution. Concentrated HCl was charged gradually to the reaction mixture and the temperature was reaised to 75-80°C. The reaction mixture was stirred for 4-5 hours. The mass was cooled gradually to 30-35°C and this mass was charged to water (600 ml). The mixture was stirred for 1-1.5 hours. The mass was filtered and solid was washed with water (100 ml) followed by washing with acetone (50 ml). Deferasirox obtained was suck dried and the wet cake was charged to water (500 ml) at 30-35°C and stirred for 10-15 minutes. The mixture was filtered and the solid was washed with water (100 ml) and suck dried.

The solid obtained was added to chloroform (500 ml) and the mixture was heated to 60-63°C for 1-1.5 hours. The mass was cooled to 50-53°C filtered and washed with hot chloroform (100 ml). The wet cake was dried under vacuum at 75-80°C for 10 hours.

Impurity F: 0.01 ppm
HPLC purity: 99.84%

Example 3
Purification of Deferasirox
Deferasirox isolated in example 1 (100 g) was charged to a mixture of N,N-dimethyl formamide (200 ml), acetone (100 ml) and conc. hydrochloric acid (10 ml). The reaction mixture was heated to 55-60°C and stirred for 4 hours. The reaction mass was cooled to room temperature and quenched in water (600 ml). The precipitate obtained was filtered, washed with water till neutral pH and suck dried. The material was dried under vacuum at 50-55°C for 8-10 hours.

Impurity F (4-HBA): 0.211 ppm
HPLC purity: 99.44%

Example 4
Purification of 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl] benzoic acid (Deferasirox) for Impurity F (4-Hydrazino benzoic acid)

Deferasirox isolated in example 1 (100 g) was charged to a mixture of N,N-dimethyl formamide (200 ml), cyclohexanone (100 ml) and conc. hydrochloric acid (10 ml). The reaction mixture was heated to 75-80°C and stirred for 4 hours. The reaction mass was cooled to room temperature and quenched in water (600 ml). The precipitate obtained was filtered, washed with water till neutral pH and suck dried. The wet cake was charged in chloroform (500 ml) and heated to 55-60°C. The reaction mixture was stirred for 1 hour and filtered hot. The wet cake obtained was charged in a mixture of Isopropyl alcohol (3000 ml) and water (500 ml), treated with activated carbon at 80-85°C and filtered hot through hyflo bed. The filtrate was distilled, and the mass was cooled gradually to 30±5°C. The mass was stirred, filtered and suck dried well. The material was dried under vacuum at 50-55°C for 8-10 hours

Impurity F (4-HBA): 0.04 ppm

Example 5
Purification of Deferasirox
Deferasirox isolated in example 1 (100 g) was charged to a mixture of N,N-dimethyl formamide (200 ml), cyclohexanone (100 ml) and conc. sulfuric acid (10 ml). The reaction mixture was heated to 75-80°C and stirred for 4 hours. The reaction mass was cooled to room temperature and quenched in water (600 ml). The precipitate obtained was filtered, washed with water till neutral pH and suck dried. The wet cake was charged in chloroform (500 ml) and heated to 55-60°C. The reaction mixture was stirred for 1 hour and filtered hot. The wet cake obtained was charged in a mixture of Isopropyl alcohol (3000 ml) and water (500 ml), treated with activated carbon at 80-85°C and filtered hot through hyflo bed. The filtrate was distilled, and the mass was cooled gradually to 30±5°C. The mass was stirred, filtered and suck dried well. The material was dried under vacuum at 50-55°C for 8-10 hours

Impurity F (4-HBA): 0.14 ppm

Example 6
Purification of Deferasirox
Deferasirox obtained in example 1 (100 g) was charged to a mixture of N,N-dimethyl formamide (200 ml), methyl isobutyl ketone (100 ml) and conc. sulfuric acid (10 ml). The reaction mixture was heated to 75-80°C and stirred for 4 hours. The reaction mass was cooled to room temperature and quenched in water (600 ml). The precipitate obtained was filtered, washed with water till neutral pH and suck dried. The material was dried under vacuum at 50-55°C for 8-10 hours.

Impurity F (4-HBA): 0.24 ppm

Example 7
Purification of 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl] benzoic acid (Deferasirox) for Impurity F (4-hydrazino benzoic acid)
Deferasirox obtained in example 1 (100 g) was charged to a mixture of N,N-dimethyl formamide (200 ml), methyl ethyl ketone (100 ml) and conc. sulfuric acid (10 ml). The reaction mixture was heated to 75-80°C and stirred for 4 hours. The reaction mass was cooled to room temperature and quenched in water (600 ml). The precipitate obtained was filtered, washed with water till neutral pH and suck dried. The material was dried under vacuum at 50-55°C for 8-10 hours.

Impurity F (4-HBA): 0.26 ppm
HPLC purity: 98.98%

The foregoing description of specific embodiment of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in the light of the above teaching.
, Claims:1. A process for the purification of deferasirox of formula (I),

Formula (I)
comprising the steps of
reacting crude deferasirox with a suitable ketone of formula (II) in a mixture of solvent and acid solution

isolating deferasirox having impurity F less than 0.5 ppm.
2. The process as claimed in claim 1, wherein the ketone of formula (II) is selected from the group comprising of acetone, methyl ethyl ketone, methyl isopropyl ketone, cyclohexanone, and cyclopentanone.
3. The process as claimed in claim 1, wherein the acid is selected from the group comprising of hydrochloric acid, sulfuric acid, polyphosphoric acid, p-toluenesulfonic acid, boron trifluoride, zinc chloride, iron chloride and aluminum chloride.
4. The process as claimed in claim 1, wherein the solvent is selected from the group comprising of methylene chloride, tetrahydrofuran, ethyl acetate, acetonitrile, N,N-dimethylformamide, N,N-dimethyl sulfoxide, acetone, methanol, ethanol, 1,4-dioxane, and mixtures thereof.
5. The process as claimed in claim 1, where the reaction is carried out at 60 to 120°C.