FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of pure 4-(3,5-bis(2-hydroxyphenyI)-lH-l,2,4-triazol-1-yI)benzoic acid (hereafter referred to as the compound (I)) commonly known as deferasirox, and its crystallization method.
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context, and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.
Deferasirox (the Compound (I)), is an iron chelator and the drug is marketed under the tradename "EXJADE" in the form of tablets for oral suspension.
Exjade is an iron chelator indicated for the treatment of chronic iron overload due to blood transfusions in patients 2 years of age and older. This indication is based on reduction in serum ferritin and liver iron concentration (L1C). Also, Exjade is indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia (NTDT) syndromes and with a liver iron (Fe) concentration (LIC) of at least 5 mg Fe per gram of dry weight (mg Fe/g dw) and a serum ferreting greater than 300 mcg/L. This indication is based on achievement of an LIC less than 5 mg Fe/g dw.
Deferasirox has the chemical name 4-(3,5-bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl)benzoic acid, and is structurally represented as follows;

Deferasirox being an important iron chelating agent; a number of processes for its preparation as well as for its purification and crystallization are known in the art.
US Patent No. 6,465,504 describes a process for the synthesis of Deferasirox 4-[3,5-Bis(2-hydroxyphenyl)-[l,2,4]triazol-l-yl]benzoic acid (I) consisting of reacting 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one with 4-hydrazinobenzoic acid under reflux condition for 2 h in 75 ml of ethanol. The crystals precipitating on cooling are washed with ethanol. The process however results in providing the product deferasirox with high quantity of impurities.
US Patent No. 9,018,389 disclosed preparation of deferasirox which comprises reacting 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one with 4-hydrazinebenzoic acid in the presence of dehydrating agent such as potassium hydrogen sulphate, sodium hydrogen sulphate and the like or mixture thereof in suitable solvent and optionally in the presence of water. The patent US'389 further disclosed a purification process for obtaining highly pure deferasirox comprising the steps of suspending deferasirox in a solvent selected from the group consisting of polar organic solvent and treating with 30% H2O2 and water; to get pure deferasirox substantially free of hydrazine impurity.
US Published Patent Application US 2011/0171138 disclosed preparation of deferasirox comprising reaction of 2-(2-Hydroxyphenyl)-4/-l,3-benzoxazin-4-one with 4-hydrazinobenzoic acid; the patent application further disclosed a process for purification of deferasirox comprising, the steps of adding aqueous alkali metal hydroxide solution to a suspension of crude deferasirox in water; heating the reaction mixture and admixing the solution with a co-solvent and precipitating pure deferasirox substantially free of hydrazine impurity by adjusting the pH between 1-3 with an acid.
Published PCT application WO 2014/136062 provides a method for obtaining pure deferasirox consisting of reacting 2-(2-Hydroxyphenyl)benz[e]oxazin-4-one sodium salt with 4-hydrozenobenzoic acid in isopropanol; acidified to pH 4 using hydrochloric acid to obtain crude

deferasirox. The said product was further purified using solvent mixtures such as isopropanol/ethyl acetate or isopropanol/ methyl tert-butyl ether (MTBE) to obtain product with purity 99.4%.
US Published Patent Application 2008/0262060 disclosed purification and crystallization of Deferasirox; comprising of treating deferasirox with base such as sodium hydroxide in water at pH greater than 10 and further adjusting pH of the solution to about 6 with diluted aqueous HC1.
In addition to the afore discussed patent documents, there are a number of patent documents such as US 2005/0235428, US 8,129,421, US 2011/0097413, US 8,907,083; and published PCT application WO 2009/016359, WO 2011/21218, WO 2012/131017 that describes process for the preparation of pure deferasirox, its salts and crystallization methods.
It is evident from the discussion of the processes for the purification of Deferasirox that the reported processes involve treatment of the crude compound with reagents such as H2O2, it is practically not convenient to store high quantities of H2O2 at any storage space, also it has been found to at times exhibit explosive behavior if not handled critically during work up procedure. Similarly other purification methods involve treatment of crude Deferasirox with base to form a salt and again converting to free base which involves multiple additional process steps.
Apart from the above processes, some of the other reported processes involve solvent-anti solvent treatment and precipitation methods which renders the process costlier and hence, is not an industrially feasible process.
In view of these drawbacks, there is a need to develop an industrially viable commercial process for the crystallization and purification to obtain pure deferasirox; more particularly substantially free of hydrazine impurity; which is simple, efficient and cost-effective process and provides the desired compounds in improved yield and purity.
Inventors of the present invention have developed an improved process that addresses the problems associated with the processes reported in the prior art. The process of the present

invention does not involve use of any hazardous reagents. Moreover, the process does not require additional purification and critical crystallization procedure. Accordingly, the present invention provides a process for the preparation of pure Deferasirox and its salts; which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to an improved process for obtaining pure Deferasirox (I) or its salt containing hydrazine, impurity less than about 0.75 ppm; comprising treating the crude deferasirox with oxone.
In one aspect, the present invention relates to an improved process for obtaining pure Deferasirox (I) or its salt containing hydrazine impurity less than about 0.2 ppm; comprising treating the crude deferasirox with oxone.
In one aspect of the present invention, there is provided an improved process for obtaining pure Deferasirox (I); comprising
(a) suspending deferasirox in a solvent,
(b) adding oxone to the reaction mixture of step (a),
(c) heating the reaction mixture of step (b),
(d) isolating the pure deferasirox.
In one aspect, the present invention relates to an improved process for obtaining pure Deferasirox (I) containing hydrazine impurity less than about 0.75 ppm; comprising treating the crude deferasirox with a ketone solvent.
In one aspect, the present invention relates to an improved process for obtaining pure Deferasirox (I) containing hydrazine impurity less than about 0.2 ppm; comprising treating the crude deferasirox with a ketone solvent.

In one aspect of the present invention, there is provided an improved process for obtaining pure Deferasirox (I); comprising
(i) suspending Deferasirox in a ketone solvent,
(ii) heating the reaction mixture of step (i),
(iii) cooling the reaction mixture of step (ii),
(iv) isolating the pure Deferasirox.
In one aspect, the present invention relates to an improved process for obtaining pure Deferasirox (I) containing hydrazine impurity less than about 0.75 ppm; comprising treating the crude deferasirox with acetone.
In one aspect, the present invention relates to an improved process for obtaining pure Deferasirox (I) containing hydrazine impurity less than about 0.2 ppm; comprising treating the crude deferasirox with acetone.
In one aspect of the present invention, there is provided an improved process for obtaining pure Deferasirox (I) containing hydrazine impurity less than about 0.2 ppm; comprising
(1) suspending Deferasirox in a ketone solvent,
(2) heating the reaction mixture of step (1),
(3) cooling the reaction mixture of step (2),
(4) adding water to the reaction mixture of step (3),
(5) isolating the pure Deferasirox.
In one aspect the present invention provides compound, Deferasirox or its salt containing hydrazine impurity less than about 0.75 ppm.
In one aspect the present invention provides compound, Deferasirox or its salt containing hydrazine impurity less than about 0.2 ppm.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to an improved process for obtaining pure deferasirox (I) or its salt containing hydrazine impurity less than about 0.75 ppm; comprising treating the crude deferasirox with oxone.
For the purpose of instant invention, the term as used herein "pure" deferasirox or its salt, in
which deferasirox has a purity of more than about 99.9% and containing the hydrazine impurity
in an amount of less than about 0.75 ppm (parts per million). Particularly, the deferasirox, as
disclosed herein, contains less than about 0.2 ppm, more specifically less than about 0.05 ppm,
still more specifically less than about 0.02 ppm of hydrazine impurity.
In purview of the present invention, the 'hydrazine impurity' refers to the compound 4-hydrazinobenzoic acid represented by the following formula,
Accordingly, the present invention relates to an improved process for obtaining pure 4-(3,5-bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl)benzoic acid (1); represented by the following formula,
comprising,
(a) suspending deferasirox in a solvent,

(b) adding oxone to the reaction mixture of step (a),
(c) heating the reaction mixture of step (b),
(d) cooling the reaction mixture of step (c),
(e) isolating the pure deferasirox.
In the context of the present invention, the pure deferasirox obtained by the above process refers to Deferasirox (I) having a purity of more than about 99.9% and containing the hydrazine impurity in an amount of less than about 0.75 ppm (parts per million).
In the context of the present invention, the term "heating" when used in reference to any element; including a process step, e.g. by heating the reaction mixture; it is intended to mean that the temperature of the reaction mixture was increased to a temperature ranging from room temperature till reflux.
In an embodiment, in step (c) the reaction mixture was heated at a temperature ranging from 50 °C to 90 °C.
In an embodiment, the 'solvent' used in the step (a) above is selected from the group consisting of an alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol and hexanol; halogenated solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene and chloroform; ketone such as acetone; an ether solvent such as tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether and 1,4-dioxane; an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); an aromatic solvent such as toluene, xylene and benzene; water or a mixture thereof.
In the context of the present invention, the term "cooling" when used in reference to any element; including a process step e.g. by cooling the reaction mixture; it is intended to mean that the temperature of the reaction mixture was reduced to a temperature ranging from room temperature till 20 °C.

In an embodiment, in step (d) the reaction mixture was cooled to a temperature ranging from 20 °C to 30 °C.
In a specific embodiment, the process for obtaining pure Deferasirox (I) comprises the steps of:
(k) suspending Deferasirox in a solvent;
(1) adding 5% oxone solution to the reaction mixture of step (k);
(m) heating the reaction mixture of step (1) at a temperature of about 75 °C;
(n) cooling the reaction mixture of step (m) at a temperature of about 30 °C;
(o) isolating the pure deferasirox.
The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme (I),
The solvent used in the step (k) of the above process (as depicted in the Scheme (I)) is selected from an alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol and hexanol; halogenated solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene and chloroform; ketone such as acetone; an ether solvent such as tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether and 1,4-dioxane; an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); an aromatic solvent such as toluene, xylene and benzene; water or a mixture thereof.
The term 'temperature of about 75 °C referred to in the step (m) of the above process (as depicted in the Scheme (I)) can range from 60 °C to 80 °C.

The term 'temperature of about 30 °C referred to in the step (n) of the above process (as depicted in the Scheme (I)) can range from 25 °C to 35 °C.
The term 'isolating' referred to in the step (o) corresponds to the steps involving isolating the precipitated product by filtration, washing and drying.
The process of the present invention as illustrated in the above Scheme (I) comprises suspending deferasirox in DMF and stirred at room temperature; adding 5% oxone solution to the same and heating the reaction mixture at a temperature of about 65-75 °C, cooling the reaction mixture to a temperature of about 30 °C and isolating pure Deferasirox (I) by filtration with HPLC purity 99.9%, containing hydrazine impurity less than about 0.75 ppm.
In an embodiment there is provided, deferasirox or its salt containing hydrazine impurity less than about 0.75 ppm.
In an embodiment there is provided, deferasirox or its salt containing hydrazine impurity less than about 0.2 ppm.
Accordingly, the present invention relates to an improved process for obtaining pure deferasirox (I) or its salt containing hydrazine impurity less than about 0.75 ppm; comprising treating the crude deferasirox with a ketone solvent.
In one aspect of the present invention, there is provided an improved process for obtaining pure Deferasirox (I); comprising
(i) suspending deferasirox in a ketone solvent,
(ii) heating the reaction mixture of step (i),
(iii) cooling the reaction mixture of step (ii),
(iv) isolating the pure deferasirox.
In the context of the present invention, the pure deferasirox obtained by the above process wherein the Deferasirox (I) has a purity of more than about 99.9% and containing the hydrazine

impurity in an amount of less than about 0.75 ppm (parts per million). Particularly, the deferasirox, as disclosed herein, contains less than about 0.2 ppm, more specifically less than about 0.05 ppm, still more specifically less than about 0.02 ppm of hydrazine impurity.
In an embodiment, the 'ketone' solvent used in the step (i) above is selected from the group consisting acetone, methyl ethyl ketone, methyl isobutyl ketone, diisoproyl ketone, methylisopropyl ketone, methylphenyl ketone, and mixtures thereof.
The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme (II),
The term 'heating' referred to in the step (ii) of the above process (as depicted in the Scheme (II)) corresponds to temperature of about 60 °C.
The term 'cooling' referred to in the step (iii) of the above process (as depicted in the Scheme (II)) corresponds to temperature of about 25 °C to 35 °C.
The term 'isolating' referred to in the step (iv) corresponds to the steps involving isolating the precipitated product by filtration, washing and drying.
In an embodiment there is provided, an improved process for obtaining pure Deferasirox (I) containing hydrazine impurity less than about 0.75 ppm; comprising treating the crude deferasirox with acetone.

The process of the present invention as illustrated in the above Scheme (II) comprises suspending deferasirox in acetone and stirring at room temperature; heating the reaction mixture at a temperature of about 50-60 °C, cooling the reaction mixture to a temperature of about 30 °C and adding water to isolating pure Deferasirox (I) by filtration with HPLC purity 99.9%, containing hydrazine impurity less than about 0.75 ppm.
In general, the product Deferasirox (I) of the present invention is obtained by any of the process reported in the prior art and further purification is as depicted in below scheme (III):
It is evident from the below Table (1), that the pure deferasirox obtained from the instantly disclosed process containing the hydrazine impurity in an amount of less than about 0.75 ppm (parts per million) and the process established the reproducibility of the pure material. Particularly, the deferasirox, as disclosed herein, contains less than about 0.2 ppm, more specifically less than about 0.05 ppm, still more specifically less than about 0.02 ppm of hydrazine impurity.

Consistency of results indicating
hydrazine impurity content in different experiments
Oxone Acetone
treatment treatment

0.12 ppm 0.03 ppm
0.2 ppm 0.02 ppm
0.1 ppm 0.04 ppm
0.19 ppm 0.07 ppm
0.2 ppm 0.09 ppm
Table (1)
Advantageously, the above identified elements of the process of the instant invention effectively contribute to the reduction of overall cost of the process.
In another general aspect, there is provided a pharmaceutical composition comprising of pure Deferasirox (I) or its salt containing hydrazine impurity less than about 0.75 ppm, pharmaceuticaly acceptable carriers and excipients.
The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example-1; Preparation of pure Deferasirox (I).
Charged 1000 mL of methanol in a flask followed by the addition of 100 g of 2-(2-hydroxyphenyl) benz [e] [1,3] oxazin-4-one and 63.56 g of 4-Hydrazino benzoic acid. The reaction mixture was heated to a temperature of about 60-65 °C for 6 h. The reaction mixture was cooled to 25-30 °C and stirred for 45 minutes. The solid was filtered and washed with methanol. The obtained solid was suspended in 5000 mL of DMF and was stirred at 25-30 °C. To the stirring solution was added 5% oxone (5 g into 15 mL water) and was stirred for 4 h at 25-30 °C. The reaction mixture was heated to the temperature up to 65-75 °C for 60 min. The reaction mixture was cooled to the temperature of 45-50 °C and the precipitated pure Deferasirox

was isolated by filtration. (132 g, yield: 85%, HPLC purity: 99.9%, hydrazine impurity content: 0.12 ppm)
ExampIe-2: Preparation of pure Deferasirox (I).
Charged 250 mL of DMF in a flask followed by the addition of 100 g of 2-(2-hydroxyphenyl) benz [e] [1,3] oxazin-4-one and 66.74 g of 4-Hydrazino benzoic acid. The reaction mixture was heated to a temperature of about 40-50 °C for 1 h and to the reaction mixture was added 300 mL acetone. The reaction mixture was heated to temperature of about 50-60 °C for 2 h. The reaction mass was cooled to 25-35 °C; to the same was added 500 mL of water was added and the solid was filtered. The solid was suspended in 300 mL of acetone and heated to 50-60°C for 1 h. The reaction mixture was further cooled to 25-35 °C, filtered and washed with 100 mL acetone to provide pure deferasirox (I), (yield: 85%, HPLC purity: 99.9%, hydrazine impurity content: 0.07 ppm)
Example-3: Purification of Deferasirox (I):
Charged 200 mL of DMF and 200 mL of acetone in a flask followed by the addition of 100 g of Deferasirox (with hydrazine impurity content: 0.5 ppm) and stirred for 10-15 min. To the reaction mixture was added 5 g of charcoal and was stirred at 25-35 °C temperature for 10-15 min. The reaction mixture was heated at 40 to 50 °C for 60 min and subsequently cooled to 25-35 °C and filtered through celite. To the filtrate was added 500 mL of water and stirred at 25-35 °C for 2 hr. The desired solid was isolated by filtration (HPLC purity: 99.95%, hydrazine impurity content: 0.02 ppm)
Example-4: Purification of Deferasirox (I):
Charged 40 mL of DMF and 40 mL of acetone in a flask followed by the addition of 20 g of Deferasirox (containing hydrazine impurity) and stirred for 10-15 min. To the reaction mixture was added 1 g of charcoal and was stirred at 25-35 °C temperature for 10-15 min. The reaction mixture was heated at 40 to 50 °C for 60 min and subsequently cooled to 25-35 °C and filtered through celite. To the filtrate was added 500 mL of water and stirred at 25-35 °C for 2 hr. The obtained solid was suspended in 280 mL of Acetone and 20 mL of water, and the mixture was heated at 50-60 °C temperature for 60 min. The reaction mass was distilled out

atmospherically at 60-65°C till 4-5 vol and the reaction mixture was further cooled to 25-35 °C. The desired solid was isolated by filtration (Yield: 80%, HPLC purity: 99.9%, hydrazine impurity content: 0.44 ppm).

We claim
1. A process for obtaining pure Deferasirox (I) or its salt containing hydrazine impurity less than about 0.75 ppm; comprising treating the crude deferasirox with oxone.
2. A process for obtaining pure Deferasirox (I) or its salt containing hydrazine impurity less than about 0.75 ppm; comprising the steps of:
a. suspending deferasirox in a solvent,
b. adding oxone to the reaction mixture of step (a),
c. heating the reaction mixture of step (b),
d. cooling the reaction mixture of step (c),
e. isolating the pure deferasirox.
3. The process according to claim 2, wherein the solvent at step (a) is selected from alcoholic solvent, halogenated solvent, cyclic solvent, protic solvent, aromatic solvent, ketone, ester, hydrocarbon, nitrile, amide, amine, ether, water or a mixture thereof.
4. A process for obtaining pure Deferasirox (1) or its salt containing hydrazine impurity less than about 0.75 ppm; comprising treating the crude deferasirox with a ketone solvent.
5. A process for obtaining pure Deferasirox (I) or its salt containing hydrazine impurity less than about 0.75 ppm; comprising the steps of:
(i) suspending Deferasirox in a ketone solvent, (ii) heating the reaction mixture of step (i), (iii) cooling the reaction mixture of step (ii), (iv) isolating the pure Deferasirox.
6. The process according to the claim 2 or 5, wherein the heating temperature of is ranging from 60 °C to 80 °C.
7. The process according to the claim 2 or 5, wherein the cooling temperature of is ranging

from 25 °C to 35 °C.
8. Deferasirox or its salt containing hydrazine impurity less than about 0.75 ppm.
9. A pharmaceutical composition comprising of pure Deferasirox (I) or its salt containing hydrazine impurity less than about 0.75 ppm, pharmaceuticaly acceptable carriers and excipients.