Claims:1. A process for preparing Deferasirox of Formula (I)

comprising:
(a) reacting a compound of Formula (II)

with a compound of Formula (III),

in presence of a reducing agent and a solvent to obtain crude Deferasirox; and
(b) purifying crude Deferasirox by oxidizing with an oxidizing agent in a solvent to obtain Deferasirox of Formula (I).

2. The process as claimed in claim 1, further comprising reacting Deferasirox obtained in step (a) with hydrazine hydrate in presence of a solvent.

3. The process as claimed in claim 1, further comprising treating Deferasirox obtained in step (a) with charcoal and a solvent.

4. The process as claimed in claim 1, 2 and 3, wherein the solvent is selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and iso-butanol and the like.

5. The process as claimed in claim 1, wherein the compound of Formula (II) is (2-hydroxyphenyl)-1,3-benzoxazin-4-one and the compound of Formula (III) is 4-hydrazinobenzoic acid.

6. The process as claimed in claim 1, wherein the reducing agent selected is Tin (II) chloride dihydrate.

7. The process as claimed in claim 1, wherein the volume of Tin (II) chloride dihydrate is 0.001V to 0.015V, and more preferably 0.003 V.

8. The process as claimed in claim 1, wherein the oxidizing agent is selected from the group comprising of ammonium persulfate ((NH4)2S2O8), sodium peroxymonosulfate (NaHSO5), potassium persulfate (K2S2O8), sodium persulfate: (Na2S2O8), ceric ammonium nitrate ((NH4)2Ce(NO3)6), ceric ammonium Sulfate ((NH4)4Ce(SO4)4), periodic acid (H5IO6), and iodic acid (HIO3).

9. The process as claimed in claim 1, wherein the solvent in step (b) is selected from group comprising of alcoholic solvents, chlorinated solvents and mixture thereof.

10. The process as claimed in claim 1 and 9, wherein the alcoholic solvent is selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol and the like and chlorinated solvent is selected from the group comprising of methylene dichloride, chloroform.
, Description:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
[See Section 10, Rule 13]

“IMPROVED PROCESS FOR PREPARATION OF DEFERASIROX”

AARTI INDUSTRIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ADDRESS, 71, UDYOG KSHETRA, 2ND FLOOR, MULUND GOREGAON LINK ROAD, MULUND (W) MUMBAI, 400080, MAHARASHTRA, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

Field of the Invention
The present invention relates to an improved process for preparation of Deferasirox with reduced genotoxic impurities less than 0.5 ppm and with improved physical characteristics like colour.

Background of the invention
Deferasirox, chemically known as 4-[3,5-bis(6-oxo-1-cyclohexa-2,4-dienylidene)-1,2,4-triazolidin-1-yl]benzoic acid and is structurally represented as Formula (I) below:

Deferasirox is a first medication approved as an oral iron chelator. 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-hydroxyphenyl)-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 toxic material like 4-hydrazinobenzoic acid such as Impurity-F as shown below and also very poor in colour.

The major disadvantage of the process as disclosed is that, in the preparation of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one at high temperature and without solvent, the reaction results in formation of large amount of impurities. The reaction proceeds without solvent, hence another drawback of the reaction observed is sublimation of salicylamide along with hydrolysis of salicylamide. Hence more number of moles of salicylamide are required for reaction completion. Thus the reaction is difficult to handle during large scale production.
Another known patent application discloses a process for purification of Deferasirox, wherein the method involves reacting Deferasirox with 30% hydrogen peroxide in a polar solvent and isolating pure Deferasirox. However in the examples, purity or actual content of hydrazine impurity is not mentioned. The inventors of present invention found that with 30% hydrogen peroxide, hydrazine impurities found in the pure Deferasirox such as Impurity-I (4-[2-(4-carboxyphenyl)iminohydrazino]benzoic acid) as shown below.

Thus there is a need of an improved process for synthesis and purification of Deferasirox providing Deferasirox with reduced toxic impurities and with high purity substantially free of hydrazine impurity and with improved physical characteristics like colour.

Summary of the invention
In one aspect, the present invention relates to a process for preparing pure Deferasirox of Formula (I) having Impurity-F less than 0.5 ppm.
In an embodiment, a process for preparation of Deferasirox of Formula (I)

comprises:
(a) reacting a compound of Formula (II)

with a compound of Formula (III),

in presence of a reducing agent to obtain crude Deferasirox; and
(b) purifying crude Deferasirox by oxidizing with an oxidizing agent in a solvent to obtain Deferasirox of Formula (I).

In this embodiment, Deferasirox obtained in step (a) is further optionally reacting with hydrazine hydrate in presence of a solvent or Deferasirox obtained in step (a) is further optionally reacted with charcoal and a solvent. The Deferasirox obtained in step (a) is dissolved in solvent selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and iso-butanol and the like. The compound of Formula (II) is (2-hydroxyphenyl)-1,3-benzoxazin-4-one and the compound of Formula (III) is 4-hydrazinobenzoic acid. The reducing agent selected is Tin (II) chloride dihydrate. The volume of Tin (II) chloride dihydrate is 0.001V to 0.015V, and more preferably 0.003 V. The oxidizing agent is selected from the group comprising of sodium peroxymonosulfate (NaHSO5), potassium persulfate (K2S2O8), sodium persulfate (Na2S2O8), ammonium persulfate ((NH4)2S2O8), ceric ammonium nitrate ((NH4)2Ce(NO3)6), ceric ammonium Sulfate ((NH4)4Ce(SO4)4), periodic acid (H5IO6), and iodic acid (HIO3). The solvent is selected from group comprising of alcoholic solvents, chlorinated solvents and mixture thereof. The alcoholic solvent is selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol and the like and chlorinated solvent is selected from the group comprising of methylene dichloride, chloroform and the like.

Description of the invention
The present invention provides a improved process for preparation and purification of Deferasirox of Formula (I) with reduced toxic impurities and with high purity substantially free of hydrazine impurity and with improved physical characteristics like colour.
In one aspect, a process for preparation of pure Deferasirox of Formula (I) having Impurity-F less than 0.5 ppm has been provided.

In a preferred embodiment, the process for preparation of pure Deferasirox of Formula (I) is provided.

The process for preparation of pure Deferasirox of Formula (I) comprising the steps of:
(a) reacting a compound of Formula (II)

with a compound of Formula (III),

in presence of a reducing agent to obtain crude Deferasirox; and
(b) purifying crude Deferasirox by oxidizing with an oxidizing agent in a solvent to obtain pure Deferasirox of Formula (I).

In this embodiment, the compound of Formula (II) is (2-hydroxyphenyl)-1,3-benzoxazin-4-one and the compound of Formula (III) is 4-hydrazinobenzoic acid. The reducing agent selected is Tin (II) chloride dihydrate. Tin (II) chloride dihydrate can be used in amount of 0.001V to 0.015V, preferably 0.002 to 0.01V, and more preferably 0.003 V. Step (a) can be carried out in presence of a solvent selected from the group comprising of C1-C4 aliphatic alcohol, especially selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol and the like. Step (a) can be carried out at a temperature of 50°C to 100°C, preferably at 60°C to 90°C, and more preferably at 75°C to 80°C. The oxidizing agent used in the process of the present invention can be selected from the group comprising of ammonium persulfate ((NH4)2S2O8), sodium peroxymonosulfate (NaHSO5), potassium persulfate (K2S2O8), sodium persulfate: (Na2S2O8), ammonium persulfate, ceric ammonium nitrate ((NH4)2Ce(NO3)6), ceric ammonium Sulfate ((NH4)4Ce(SO4)4), periodic acid (H5IO6), iodic acid (HIO3), and potassium peroxymonosulfate (Oxone; KHSO5). The solvent can be selected from group comprising of alcoholic solvent, chlorinated solvents and mixture thereof. The alcoholic solvent can be selected from the group comprising C1-C4 aliphatic alcohols especially selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol and the like and chlorinated solvent can be selected from the group comprising of methylene dichloride, chloroform and the like. Step (b) can be carried out at a temperature of 5°C to 60°C, preferably at 10°C to 40°C.

In another embodiment, the process for preparation of crude Deferasirox is provided.
The process comprising the steps of:
(a) reacting a compound of Formula (II)

with a compound of Formula (III),

in presence of a reducing agent to obtain crude Deferasirox; and
(b) further optionally reacting the crude Deferasirox with hydrazine hydrate in presence of a solvent.
In this embodiment, the compound of Formula (II) is (2-hydroxyphenyl)-1,3-benzoxazin-4-one and the compound of Formula (III) is 4-hydrazinobenzoic acid. The reducing agent selected is Tin (II) chloride dihydrate. Tin (II) chloride dihydrate can be used in amount of 0.001V to 0.015V, preferably 0.002 to 0.01V, and more preferably 0.003 V. Step (a) can be carried out in presence of a solvent selected from the group comprising of C1-C4 aliphatic alcohol, especially selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol and the like. Step (a) can be carried out at a temperature of 50°C to 100°C, preferably at 60°C to 90°C, and more preferably at 75°C to 80°C. If the Deferasirox obtained in step (a) has brown color, then step (b) can be optionally carried out. In step (b), Deferasirox obtained can be dissolved in an alcoholic solvent selected from the group comprising of C1-C4 aliphatic alcohol, especially selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and iso-butanol at 50°C to 100°C, and preferably at 60°C to 90°C to obtain a solution. The solution obtained can be treated with hydrazine hydrate at reflux. Deferasirox with improved color is obtained in step (b). The significance of step (b) is to improve the color of Deferasirox. The color of the Deferasirox improves from brown to white or almost white.

In yet another embodiment, the process for preparation of crude Deferasirox is provided.

The process comprising the steps of:
(a) reacting a compound of Formula (II)

with a compound of Formula (III),

in presence of a reducing agent to obtain crude Deferasirox; and
(b) further optionally reacting the crude Deferasirox with charcoal and a solvent.
In this embodiment, the compound of Formula (II) is (2-hydroxyphenyl)-1,3-benzoxazin-4-one and the compound of Formula (III) is 4-hydrazinobenzoic acid. The reducing agent selected is Tin (II) chloride dihydrate. Tin (II) chloride dihydrate can be used in amount of 0.001V to 0.015V, preferably 0.002 to 0.01V, and more preferably 0.003 V. Step (a) can be carried out in presence of a solvent selected from the group comprising of C1-C4 aliphatic alcohol, especially selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol and the like. Step (a) can be carried out at a temperature of 50°C to 100°C, preferably at 60°C to 90°C, and more preferably at 75°C to 80°C. If the Deferasirox obtained in step (a) has brown color, then step (b) can be optionally carried out. In step (b), Deferasirox obtained can be dissolved in an alcoholic solvent selected from the group comprising of C1-C4 aliphatic alcohol, especially selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and iso-butanol at 50°C to 100°C, and preferably at 60°C to 90°C to obtain a solution. The solution can be treated with charcoal with stirring at reflux. Deferasirox with improved color is obtained in step (b). The significance of step (b) is to improve the color of Deferasirox. The color of the Deferasirox improves from brown to white or almost white.

In a further embodiment, the process for purification of crude Deferasirox having Impurity-F less than 0.5 ppm

is provided. The process comprising:
(i) oxidizing crude Deferasirox with an oxidizing agent in a solvent to obtain pure Deferasirox.
In this embodiment, the oxidizing agent used in the process of the present invention can be selected from the group comprising of ammonium persulfate ((NH4)2S2O8), sodium peroxymonosulfate (NaHSO5), potassium persulfate (K2S2O8), sodium persulfate: (Na2S2O8), ceric ammonium nitrate ((NH4)2Ce(NO3)6), ceric ammonium Sulfate ((NH4)4Ce(SO4)4), periodic acid (H5IO6), iodic acid (HIO3), and potassium peroxymonosulfate (Oxone; KHSO5). The solvent can be selected from group comprising of alcoholic solvent, chlorinated solvents and mixture thereof. The alcoholic solvent can be selected from the group comprising C1-C4 aliphatic alcohols especially selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol and the like and chlorinated solvent can be selected from the group comprising of methylene dichloride, chloroform, and the like. Step (i) can be carried out at a temperature of 5°C to 60°C, preferably at 10°C to 40°C.

In the context of the present invention, the process of the present invention is an improved process for synthesis and purification of Deferasirox. The present invention provides Deferasirox with reduced genotoxic impurities especially 4-hydrazinobenzoic acid impurity (Impurity-F) below 0.5 ppm limit and with improved physical characteristics like colour. The process of present invention provides Deferasirox with improved characteristics like colour. In the present invention if the Deferasirox obtained in step (a) has brown color, then optionally Deferasirox is reacted with hydrazine hydrate or optionally Deferasirox is given charcoal. Thus significance of this optional step is to improve the color of Deferasirox. In the context of present invention, the color of Deferasirox improves from brown to white or almost white. The process of the present invention results in high yield of the pure Deferasirox with maximum purity. The process of the present invention is an eco-friendly and a cost-effective process. 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.
EXAMPLES
Examples and implementations are provided herein below for the illustration of the invention. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.
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 2-(2-hydroxyphenyl)-4H-1,3-benzoxazin-4-one (Compound of Formula (I))
Under inert atmosphere, salicylic acid (100 g) was charged to toluene (500 ml)/Dimethyl fomamide (1 ml) was charged to the mixture at room temperature. The mixture was heated to 70-75°C for 3-4 hours. Thionyl chloride (103.4 g) was added slowly, to the reaction mixture at 70-75°C over the period of 1-2 hours. Salicylamide (139 gm) was added to the reaction mass, the temperature was further raised to 115-120°C and maintained for 1-2 hours. Toluene was distilled out completely. The temperature was raised to 168-173°C. O-xylene was (20 ml) was charged and mass was stirred for 7-8 hours. O-xylene was distilled out completely and the mass was cooled to 75-80°C. Isopropanl (IPA) (500 ml) was charged and the mass was cooled to room temperature. The mass was filtered and washed with IPA (100 ml). The compound was suck dried and dried under vacuum at 50-55°C for 8-10 hours. The obtained yield was 68% with HPLC purity: 98%.

Example 2
Preparation of 4-Hydrazino Benzoic acid (Compound of Formula (II))
pH of 4-hydrazinobenzoic acid hydrochloride (100 g) was adjusted to 8.5-9 using 10% NaOH solution at room temperature. The mixture was stirred for 1-1.5 hours. The pH was adjusted to 3.8-4.2 by adding 10% aq. HCl. The mass was stirred for 1-1.5 hours and filtered. Wet cake was washed with water (200 ml). The compound was suck dried well for 30-45 minutes. The dried material was charged to IPA (500 ml) at 15-20 minutes. The solution was stirred and filtered. The cake was washed with IPA (100 ml) and suck dried well. The material was dried well under vacuum at 50-55°C for 8-10 hours. The obtained yield was 93%, HPLC purity: 99.8%.

Example 3
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). Stannous chloride dihydrate (57.24 g) was added to the mixture. The temperature of the mixture was raised to 75-80°C and stirred for 5-6 hours. The mass was cooled to 30-35°C, stirred and filtered. The wet cake was washed with ethanol. The precipitate was suck dried well and dried under vacuum at 50-55°C for 8-10 hours. The obtained yield was 85%, HPLC purity: 99.8%; Impurity F: 1000 ppm.

Example 4
Preparation of Deferasirox (hydrazine treatment)
Deferasirox obtained in example 3 (100 g) is charged to methanol (4 L) and heated to 65-70°C. Hydrazine hydrate (1.34 gm) and the mass was stirred for 45 minutes at 65-70°C. The mass was filtered through hyflo and hyflo was washed with methanol (100 ml). The filtrate was concentrated till 3 vol remains in the flask. The mass was cooled to RT and filtered. The wet cake obtained was charged to water (1 L) and stirred at 30-35°C. The pH was adjusted to 2 using conc. HCl and the mass was stirred. The mass was filtered and the wet cake was charged to water (1L) and the pH was adjusted to pH 7.0 using Liq. NH3. The mass was stirred and filtered. The wet cake obtained was suck dried and further dried under vacuum at 75-80°C for 8-10 hours. The color improvement was observed from brown to tan yellow.

Example 5
Preparation of Deferasirox (Charcoal treatment)
Deferasirox from example 3 (100 g) was charged to isopropyl alcohol (3.5 L) and the reaction mixture was heated to 80-85°C and stirred for 1 hour. Suspension prepared by suspending Charcoal (10 g) in isopropyl alcohol (100 ml) was charged to the reaction mass. The mixture was again stirred for 1-1.5 hours. The mass was cooled to 65-70°C and filtered through hyflo bed.The hyflo bed was washed with hot isopropyl alcohol. The filtrate was distilled and the mass was cooled gradually to 30-35°C. The mass was stirred, filtered and suck dried well. The material was dried under vacuum at 50-55°C for 8-10 hours. The obtained yield was 85%; HPLC purity: 99.9%; Impurity F: 100 ppm. The color was improved from brown to tan yellow.

Example 6
Purification of 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl] benzoic acid (Deferasirox)
Deferasirox (100 g) was charged to the mixture of Methanol (1750 ml) and MDC (1750 ml). The mixture was heated and stirred for 1 hour at 35-40°C. The solution of ammonium persulfate was prepared by dissolving ammonium persulfate (0.3 g) in water (3 ml). Ammonium persulfate (2 ml) was charged to the mass and stirred for 1 hour. Ammonium persulfate solution (1 ml) was added to the mass and the mass was stirred for 1 hour. IPA (10 ml) was charged and stirring continued for 2 hours. The mass was filtered and precipitate was washed with mixture of methanol (50 ml) and MDC (50 ml). The filtrate was collected and the solvent was distilled out under vacuum. The residue obtained was filtered and washed with mixture of methanol (50 ml) and MDC (50 ml). The precipitate was suck dried well. The dry compound was charged to IPA (3 L) and temperature was raised to 80-85°C and the mass was stirred for 30 to 40 minutes. Charcoal (10 g) was added to the reaction mass and stirred for 1 hour at 80-85°C. The mass was cooled to 60-65°C and filtered through hyflo and washed with hot IPA (100 ml). The filtrate was collected and distilled out under vacuum. The mass was cooled to 30-35°C, stirred and filtered and the precipitate was washed with IPA (100 ml). The compound was suck dried and further dried under vacuum in tray drier at 55-60°C to yield pure Deferasirox (70 g, 70% yield); HPLC purity: 99.9%; Impurity F: 0.3 ppm.
The foregoing description of specific embodiments 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 light of the above teaching.
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.