WO2011021218A2

WO2011021218A2 - Process for the preparation of 4-[3,5-bis(2-hydroxyphenyl)-1h-1,2,4-triazol-1-yl]-benzoic acid and its amine salts

Info

Publication number: WO2011021218A2
Application number: PCT/IN2010/000533
Authority: WO
Inventors: Manne Satyanarayana Reddy; Sajja Eswaraiah; Ghojala Venkat Reddy; Govindan Shanmugam
Original assignee: Msn Laboratories Limited
Priority date: 2009-08-12
Filing date: 2010-08-11
Publication date: 2011-02-24
Also published as: WO2011021218A3

Abstract

An improved process for preparing 4-[3, 5-bis (2-hydroxyphenyl)-l, 2, 4-tπazol-l -yl] benzoic acid of formula-1 and a process for its purification are provided The preparation process comprises reacting salicylic acid with salicylamide in the presence of a suitable base, in a suitable solvent and in the presence of thionyl chloride at reflux temperature, then reacting 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin^-one with 4-hydrazinobenzoic acid in a suitable alcoholic solvent at reflux temperature to provide deferasirox.

Description

Process for the preparation of 4-f3,5-Bis(2-hydroxyphenyl)-lH-l,2,4- triazol-1-yll-benzoic acid and its amine salts

Related Application:

This application claims the benefit of priority of our Indian patent application numbers 1909/CHE/2009 filed on 12/08/2009 and 316/CHE/2010 filed on 9/2/2010 which is incorporated herein by reference.

Field of the Invention:

The present invention relates to an improved process for the preparation of 4-[3,5-bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl]benzoic acid as well as a process for its purification, i 4-[3,5-bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl]benzoic acid is commonly known as Deferasirox and is represented by the following structural formula-1. The present invention also relates to novel amine salts of 4-[3,5-bis(2- hydroxyphenyl)-lH-l,2,4-triazol-l-yl]benzoic acid compound of general formula-8 and the process for their preparation.

Formula-1 Formula-8

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-hydrazinobenzoic acid at reflux temperature in ethanol provides deferasirox. This patent 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 to improve the Residue on Ignition as well as color.

The said patent discloses the process for the preparation of deferasirox in an example-5 using ethanol and isolated a crystalline deferasirox showing melting point of 264-265°C. We prepared the deferasirox as per this process and characterized the obtained crystalline solid by PXRD and the corresponding 2 theta values are 5.27, 6.64, 10.08, 10.62, 13.24, 14.15, 15.33, 16.65, 17.32, 20.37, 23.16, 25.68, 26.2, 28.3 ± 0.2 degrees 2 theta. European Journal of Inorganic Chemistry 2004, 4177-4192 disclosed a process for the preparation of deferasirox. The disclosed process involves the condensation of salicylic acid, salicylamide and pyridine in xylene in the presence of thionyl chloride at reflux temperature, followed by recrystallisation from 2-methoxyethanol to provide 2-(2- hydroxyphenyl)-benz[e][l,3]oxazin-4-one as solid, which further reacts with 4-hydrazino benzoic acid in presence of triethylamine in ethanol at reflux temperature to provide deferasirox, which is allowed to be exposed to air to form deferasirox monohydrate. As per the disclosed process, the intermediate compound 2-(2-hydroxyphenyl)-benz[e][l,3] oxazin-4-one is not stable when exposed to moisture, would lead to the formation of bis(salicyl)imide as a impurity. Hence the isolation of the said intermediate will lead to the formation of unwanted impurity. Hence there is a need in the art for a process which avoids the formation of bis(salicyl)imide impurity.

Helvetica Chimica Acta Vol.55, 1 (1972), 152-153, 1566-1594 disclosed a process for the preparation of 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one. The disclosed process involves the addition of thionyl chloride in molar ratio 1.9 in a single lot over (with respect to salicylic acid) to reaction mixture containing salicylic acid, salicylamide and pyridine in xylene at reflux temperature, followed by crystallization of the obtained compound from methanol to provide 2-(2-hydroxyphenyl)-benz[e][l,3] oxazin-4-one. When 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one prepared as per the above process, was utilized for the preparation of deferasirox, some unknown impurity peak in HPLC at the RRT of around 2.1 was observed. As this impurity could not be completely removed by conventional purification methods, its formation should be controlled by varying the process parameters.

The present invention provides an improved process for the preparation of deferasirox which avoids all the above mentioned prior art problems and process for the purification of deferasirox to overcome the prior art deficiencies like toxic content, Residue on Ignition and color.

Brief Description of the Invention:

The first aspect of the present invention is to provide an improved process for the preparation of deferasirox compound of formula- 1, which comprises of the following steps,

a) Reacting the salicylic acid compound of formula-2 with salicylamide compound of formula-3 in presence of thionyl chloride and a base in a suitable solvent at reflux temperature, followed by crystallization of the obtained compound from a suitable solvent to provide the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4, wherein thionyl chloride is added in two lots,

b) reacting the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4 with 4-hydrazinobenzoic acid compound of formula-5 in a suitable solvent at reflux temperature to provide the deferasirox compound of formula- 1,

c) purifying the compound of formula- 1 to provide the pure deferasirox.

The second aspect of the present invention is to provide one-pot process for the preparation of deferasirox compound of formula- 1, which comprises of reacting the salicylic acid compound of formula-2 with salicylamide compound of formula-3 in presence of a base and thionyl chloride in a suitable solvent at reflux temperature to provide the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4, which on in-situ reaction with 4-hydrazinobenzoic acid compound of formula-5 in a suitable solvent at reflux temperature provides the deferasirox compound of formula- 1. The third 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) Treating the deferasirox with a suitable aqueous base in the presence or absence of a solvent and stirring the reaction mixture to provide solution ,

b) filtering the solution, and optionally extracting the filtrate with a suitable water immiscible solvent to remove the impurities,

c) treating the filtrate with hydrose,

d) treating the reaction mixture with a suitable acid and filtering the solid formed, e) suspending the wet solid in a suitable solvent and heating the suspension to reflux, f) cooling the reaction mixture, filtering the solid precipitated, washing with a suitable solvent and drying to get the pure compound of formula- 1.

The fourth aspect of the present invention is to provide a process for the purification of deferasirox compound of formula- 1, which comprises of treating the deferasirox with a suitable aqueous base in the presence or absence of a solvent, and stirring the reaction mixture to provide solution. Filtering the solution, optionally extracting the filtrate with a suitable water immiscible solvent to remove the impurities.

Treating the filtrate with hydrose, filtering it and treating it with a suitable acid. Filtering the precipitated solid to get pure deferasirox compound of formula- 1,

The fifth aspect of the present invention is to provide a process for the purification of deferasirox compound of formula- 1, which comprises of suspending the deferasirox in a suitable solvent, heating the suspension to reflux and stirring it for certain period of time. Cooling the reaction mixture, filtering the solid precipitated, washing the solid with a suitable solvent and drying to get the pure compound of formula- 1.

The sixth aspect of the present invention is to provide a process for the purification of deferasirox compound of formula- 1, which comprises of treating deferasirox in a suitable polar aprotic solvent, followed by precipitating it by adding an anti solvent to provide pure deferasirox. The seventh aspect of the present invention is to provide novel amine salts of deferasirox compounds of general formula-8. The novel amine salts of deferasirox are useful for the preparation of highly pure deferasirox. The eighth aspect of the present invention is to provide a process for the preparation of amine salts of deferasirox compound of general formula-8, which comprises of the following steps;

a) Treating the crude deferasirox with an amine NRjR₂R₃ compounds of general formula-7 in a suitable solvent selected from ester solvents and/or hydrocarbon solvents and/or ketone solvents, preferably ester solvents,

b) stirring the reaction mixture for sufficient period of time for the formation of amine salt of deferasirox,

c) separating the solid by filtration and washing with suitable ester solvent,

d) optionally purifying the deferasirox amine salt compounds of general formula-8 using ester solvents or hydrocarbon solvents or ketone solvents or alcohol solvents or their mixtures thereof,

e) drying the solid to get the pure amine salt of deferasirox.

The ninth 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 alcoholic solvent,

i) heating the suspension to reflux temperature 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 tenth 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 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 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.

Advantages of the present invention:

• Provides an improved process which avoids the formation of impurity observed at 2.1 RRT in the final API.

• Provides one pot synthesis of deferasirox without isolating the intermediate compound 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one, there by avoiding the formation bis(salicyl)imide impurity.

• Provides a process which avoids the formation of uncyclized compound of formula-6, in the intermediate compound 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one.

• Provides novel amine salts of deferasirox and its use in the preparation of pure deferasirox.

• Provides a process for the purification of deferasirox which is eco-friendly and commercially viable process

• Provides a purification process for deferasirox which reduces the toxic HBA content, increase the physical characteristics like colour as well as Residue on Ignition (RoI).

• Provides highly pure deferasirox through novel amine salts. Brief Description of the Drawings:

Figure- 1: Illustrates the powder X-ray diffraction pattern of crystalline deferasirox prepared as per the prior art process

Figure-2: Illustrates the DSC of crystalline deferasirox

Figure-3: Illustrates the IR spectrum of crystalline deferasirox

Detailed Description of the Invention:

Unless otherwise indicated, this disclosure uses definitions provided below. As used herein, the term "alkyl" refers to straight chain or branched hydrocarbon groups, generally having specified number of carbon atoms. A "Ci_-I2 alkyl" refers to alkyl group having 1 to 12 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pent-1-yl, pent- 2-yl, pent-3-yl, 3-methylbut-l-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-

1-yl, n-hexyl and the like.

As used herein, the term "cycloalkyl" refers to saturated monocyclic and bicyclic hydrocarbon rings, generally having a specified number of carbon atoms that comprise the ring i.e C_3-7 cycloalkyl refers to a cycloalkyl group having 3,4,5,6and 7 carbon atoms as ring members. Examples of monocyclic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of bicyclic cycloalkyl groups include without limitation, bicyclo[ 1.1.0] butyl, bicyclo[l.l.l]pentyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl, and the like.

As used herein, the term "aryl-Ci_-6 alkyl" refers to an aryl group attached to the substrate through an alkyl group containing one to six carbon atoms. The term "aryl" refers to monovalent or divalent aromatic groups respectively including 5 and 6 membered monocyclic aromatic groups that contain zero to four heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of monocyclic aryl groups include, without limitation, phenyl, pyrrolyl, pyranyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyradazinyl, pyrimidinyl, and the like. The aryl groups also include bicyclic groups, tricyclic groups etc including fused 5 and 6 membered rings described above. Examples of multicyclic aryl groups include, without limitation, naphthyl, biphenyl, anthracenyl, pyrenyl, carbazolyl, benzoxazolyl, benzodioxazolyl, benzothiazolyl, benzoimidazolyl, benzothiophenyl, quinolinyl, isoquinolinyl. indolyl, benzofuranyl, purinyl, indolizinyl and the like. The aryl groups may be attached to the substrate at any ring atom, unless such attachment would violate valence requirements. Aryl groups may include one or more non hydrogen substituents unless such substitution would violate valence requirements. Useful substituents include, without limitation alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, halo, hydroxy, mercapto, nitro, amino, alkyl amino and the like. The first aspect of the present invention provides an improved process for the preparation of deferasirox compound of formula- 1, which comprises of the following steps,

a) Reacting the salicylic acid compound of formula-2

with salicylamide compound of formula-3,

Formula-3

in presence of a suitable base in a suitable solvent in presence of thionyl chloride at reflux temperature, characterized in that the thionyl chloride is used in the mole ratio of 1.7-1.9 and is added in two lots at reflux temperature, wherein the second lot is added after maintaining the reaction mixture for some time after the addition of first lot of thionyl chloride, followed by crystallization from a suitable alcoholic solvent to provide the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4,

b) reacting the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4 with 4-hydrazinobenzoic acid compound of formula-5,

Formula-5

in a suitable solvent to provide the deferasirox compound of formula- 1 ,

c) purifying the compound of formula- 1 by treating it with a base and optionally extracting the mixture with a suitable water immiscible solvent, followed by treatment with an acid to provide pure deferasirox. The second aspect of the present invention provides a one-pot process for the preparation of deferasirox compound of formula- 1, which comprises of reacting the salicylic acid compound of formula-2 with salicylamide compound of formula-3 in presence of a suitable base in a suitable solvent in presence of thionyl chloride which is added in two lots at reflux temperature to provide the 2-(2-hydroxyphenyl)- benz[e][l,3]oxazin-4-one compound of formula-4, which on in-situ reaction with 4-hydrazinobenzoic acid compound of formula-5 in a suitable solvent selected from alcoholic solvent provides pure deferasirox compound of formula- 1.

According to the first and second aspects of the present invention, the base used for the condensation of salicylic acid compound of formula-2 with salicylamide compound of formula-3 is selected from pyridine, trimethylamine, triethylamine, and the suitable solvent is selected from toluene, cyclohexane, heptane, chlorobenzene, xylene or a mixture thereof; preferably xylene. The solvent used for crystallization is alcoholic solvent selected from methanol, ethanol, isopropanol or a mixture thereof; preferably methanol. The reaction of compound of formula-4 with phenylhydrazine is performed in an alcoholic solvent like methanol, ethanol, isopropanol, butanol or a mixture thereof, at reflux temperature. The water immiscible solvent optionally used is selected from ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, toluene, xylene, cyclohexane, hexane, heptane and the like. In step a) salicylic acid compound of formula-2 condenses with salicylamide compound of formula-3 in presence of thionyl chloride, to provide the 2-(2- hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4. But along with this compound of formula-4 an uncyclised derivative namely 2-hydroxy-N-(2- hydroxybenzoyl) benzamide compound of formula-6 was also formed.

Formula-6

If the compound of formula-6 is present in a concentration less than 10% in the mixture, then it completely reacts with 4-hydrazinobenzoic acid compound of formula-5 to provide deferasirox. But if it is present in a concentration above 10% then it is not consumed completely, and hence will be present as an impurity in the final API. In the present invention the formation of the uncyclised derivative 2-hydroxy-N-(2- hydroxybenzoyl) benzamide compound of formula-6 is well controlled to the level below

10%.

It was observed that some unknown impurity was detected in the final API which showed a peak in HPLC at 2. IRRT. It was identified that the origin of the impurity is at the initial condensation of salicylamide and salicylic acid in the presence of thionyl chloride.

After conducting various experiments, it was found that a compound of molecular mass of 508 was formed as an impurity in the first step of the condensation reaction which carried forward to the next step and reacts with 4-hydrazinobenzoic acid to provide the compound with the molecular mass value of 774 as an impurity, eluted at the RRT of 2.1 in HPLC of deferasirox. This impurity could not be removed by conventional purification methods. Hence it was necessary to control the formation of the said impurity by varying the process parameters. After extensive research it was found that by adding thionyl chloride (1.9 equivalents) in more than one lot (instead of addition of thionyl chloride in single lot as in prior art) the formation of the impurity at 2.1 RRT was controlled to less than 0.10%. The third aspect of the present invention provides a process for the purification of deferasirox compound of formula- 1, which comprises of the following steps,

c) treating the filtrate with hydrose,

d) treating the reaction mixture with suitable acid and filtering the solid formed, e) suspending the wet solid in a suitable solvent and heating the suspension to reflux, f) cooling the reaction mixture, filtering the solid precipitated, washing with a suitable solvent and drying to get the pure compound of formula- 1.

The fourth aspect of the present invention provides a process for the purification of deferasirox compound of formula- 1, which comprises of the following steps, a) Treating the deferasirox with a suitable aqueous base in the presence or absencejpf a solvent, and stirring the reaction mixture to provide solution,

b) filtering the solution, optionally extracting the filtrate with a suitable water immiscible solvent to remove the impurities,

c) treating the filtrate with hydrose,

d) treating the reaction mixture with suitable acid,

e) filtering the precipitated solid to get pure deferasirox.

The fifth 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 in a suitable solvent,

b) heating the suspension to reflux and stirring the reaction mixture for certain period of time,

c) cooling the reaction mixture,

d) filtering, washing the solid with a suitable solvent and drying to get the pure compound of formula- 1.

As per any of the third, fourth and fifth aspects of the present invention, the suitable acid used is selected from a group consisting of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid and the like; and the suitable base used is selected from sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, sodium bicarbonate, potassium bicarbonate and ammonia; and the suitable solvent is selected from water; alcoholic solvents like methanol, ethanol, isopropanol, n-propanol, and butanol; and water immiscible solvent used is selected from ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, toluene, xylene, cyclohexane, hexane, heptane and the like.

The sixth 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 in a suitable polar aprotic solvent and heating it to reflux, b) cooling the reaction mixture,

c) adding an anti solvent and stirring the reaction mixture,

d) filtering the solid formed, washing the solid with a suitable solvent and dried to get the pure compound of formula- 1.

The polar aprotic solvent used in the above aspect is selected from dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide and the like; and the anti solvent used is selected from water, ketone solvents like acetone, ethyl methyl ketone, diethyl ketone etc.; hydrocarbon solvents such as hexane, cyclohexane, n-heptane and the like; ether solvents like diethyl ether, isopropyl ether and the like; or their mixtures thereof. The seventh aspect of the present invention provides novel amine salts of deferasirox compounds of general formula-8.

Formula-8 wherein NRiR₂R₃ is an amine and Ri₁ R₂ and R₃ are same or different and are each independently selected from either hydrogen, Ci_-I2 alkyl, C_3-7 cycloalkyl, aryl-C]_-6 alkyl, aryl and the like. The novel amine salt of the present invention is used to prepare highly pure deferasirox compound of formula- 1.

-5

The eighth aspect of the present invention provides a process for the preparation of amine salts of deferasirox compound of general formula-8, which comprises of the following steps;

a) Treating the crude deferasirox with an amine compounds of general formula- 7> 10 NRiR₂R₃ - Formula-7

wherein Ri, R₂ and R₃ are same or different and are each independently selected from either hydrogen, C_M2 alkyl, C_3-7 cycloalkyl, aryl-Ci_-6 alkyl, aryl and the like; in a suitable solvent selected from ester solvents and/or hydrocarbon solvents and/or ketone solvents, preferably ester solvents & more preferably ethyl acetate,

5 b) stirring the reaction mixture for sufficient period of time for the formation of amine salt of deferasirox,

c) separating the solid by filtration and washing with suitable ester solvent,

j

d) optionally purifying the deferasirox amine salt compound of general formula-8 using ester solvents or hydrocarbon solvents or ketone solvents or alcohol solvents or their 0 mixtures thereof,

e) drying the solid to get the pure amine salt of deferasirox.

The amine used for the preparation of the deferasirox amine salt is selected from a group which includes but is not limited to methylamine, ethylamine, n-propylamine, 5 isopropylamine nf-butylamine, isobutylamine, tertiary butyl amine, diethyl amine, octylamine, 2-ethylhexylamine, benzylamine, phenethylamine, dibenzylamine, N-methylbenzylamine, N-ethylbenzylamine, dibenzylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethylcycloheptylamine, dicyclohexylamine, pyrrolidine, N-methylpyrrolidine, 0 piperidine, N-methylpiperidine , morpholine and the like. The present invention also provides a process for the preparation of highly pure deferasirox compound of formula- 1 from the novel amine salts of deferasirox. The process comprises of;

a) suspending deferasirox amine salt in an suitable solvent,

b) treating it with a suitable acid,

c) filtering the solid obtained and washing with an alcoholic solvent and drying it to provide highly pure deferasirox

The acid used for cleaving the amine salt is selected from a group consisting of, but not limited to an inorganic acid like hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; an organic acid like acetic acid, propionic acid and the like. The suitable solvent used is selected from a group consisting of water, alcoholic solvents namely methanol ethanol, n-propanol, isopropanol, n-butanol and the like; chlorinated hydrocarbons like dichloromethane, chloroform etc., ester solvents for example ethyl acetate, isopropyl acetate and the like; or their mixtures thereof.

The formation of the amine salt of deferasirox followed by conversion it into deferasirox, not only improved the yield and purity but also the description of the final

API to provide highly pure deferasirox.

The ninth 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 acid (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 solvents, 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 65-7O⁰C to get the highly pure deferasirox compound of formula- 1.

The tenth ^;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 the 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.

The PXRD, DSC thermo gram and the IR spectrum of the crystalline deferasirox are prepared according to the present invention enclosed as figure- 1, figure-2 and figure-3 respectively are conforming to the PXRD, DSC thermo gram and the IR spectrum of the prior art crystalline deferasirox.

2-hydroxy benzamide, 2-hydroxybenzoic acid, 2-hydroxy-N-(2 -hydroxy benzoyl) benzamide, 2-(2-hydroxyphenyl)-4H-benzo[e][l,3]oxazin-4-one and 4-hydrazino benozoic acid are the known possible impurities formed in the preparation deferasirox. In addition to that there is a chance for the formation of one more impurity namely ester impurity in the preparation of deferasirox. In general the process for the preparation of deferasirox involves the reactions carried out at high temperature in alcohol solvent and hence there is a chance for the formation of corresponding ester impurities by reacting it with acid functionality. In order to ensure the highest purity of the deferasirox it is necessary to know the characterization of the impurities formed. Hence there is a need in the art to prepare and characterize the alkyl ester of deferasirox and also need to ensure that the deferasirox that the level of said impurity well with in the limit set by ICH. The present invention provides alkyl ester of deferasirox represented by the following general formula-9

Formula-9

Wherein R is C_1-4 alkyl.

Specifically the present invention provides th methyl 4-(3,5-bis(2-hydroxyphenyl) -lH-l,2,4-triazol-l-yl)benzoate (methyl ester of deferasirox) represented by the following structural formula-9a

Formula-9a

The methyl ester of deferasirox of the present invention is characterized by ¹H NMR (300 MHz) δ(ppm): 11.28 (b, IH), 9.57 (b, IH), 8.25-8.22 (d, 2H), 8.15-8.12 (dd, IH), 7.62- 7.51 (d, 2H), 7.41-7.32 (m, 2H), 7.16-7.02 (m, 3H), 6.93-6.90 (dd, IH), 6.68-6.63 (t, IH), 3.99 (s, 3H) ; Mass spectra m/z =388 (M+H)⁺.

Further the present invention provides a process for the preparation of alkyl ester of deferasirox compound of formula-9, which comprises of reacting the deferasirox compound of formula- 1 with suitable alcohols like methanol, ethanol, isopropyl, butanol in presence of a suitable acid selected from hydrochloric acid or sulphuric acid at reflux temperature of the alcohol used to provide the corresponding alkyl ester of deferasirox.

As used herein the present invention, the term highly pure/high pure refers to the purity of the compound more than 99.50% by HPLC, preferably more than 99.85% by HPLC. 4-hydrazino 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 C 18, 250X4.6 mm, 5μm; Flow rate: 0.5 ml/min; Wavelength: 316 nm; Temperature: 25⁰C; 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, 5μm; 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.

XRD analysis of deferasirox was carried out using SIEMEN S/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.045°/min. FT-IR spectrum of deferasirox was recorded on Thermo model Nicolet- 380 as KBr pellet. The thermal analysis of deferasirox was carried out on Waters DSC Q-IO model differential scanning calorimeter. The ¹H NMR data of alkyl ester of deferasirox was recorded on Bruker 300MHz spectrometer.

Deferasirox prepared by the present invention can be further micronized or milled to get the desired particle size. Analysis of particle size distribution of deferasirox was carried out using Malvern Mastersizer 2000 with the following conditions Technique used: dry method; Material RI: 1.5 ; Dispersant RI : 1.0; Despersant : Light liquid paraffin; Sensitivity : Normal.

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-1: Preparation of 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one.

Mixture of salicylic acid (100 grams), salicylamide (89.3 grams), pyridine (15.2 ml) and xylene (600 ml) was heated to reflux temperature. Thionyl chloride (100.5 ml) was added to the above mixture at reflux temperature for 3 hours. Intense evolution of SO₂ and hydrochloric acid was observed, the reaction mixture was then stirred for 8 hrs. Xylene was removed from the reaction mixture by distillation under reduced pressure. The resulting residue was suspended in methanol (200 ml) and raised the temperature to 60-65°C. The reaction mixture was stirred for one hour at 60-65°C and cooled to 0-5°C and further stirred' for one hour. The solid obtained was filtered, washed with methanol and dried to get the title compound.

Yield: 130 grams

ExampIe-2: Preparation of deferasirox compound of formula-1.

4-hydrazinobenzoic acid (76 grams) was added to the mixture of 2-(2-hydroxyphenyl)- benz[e][l,3]oxazin-4-one obtained as per example-1 and methanol (2 L) and heated to

60-65°C then stirred for 5 hours at reflux temperature. The reaction mixture was cooled to 0-5°C stirred for 1.5 hours. The solid formed was filtered, washed with methanol and then dried to get the title compound.

Yield: 142 grams

Purity by HPLC: 99.44 %; impurity at 2.1 RRT: 0.21%.

Example-3: Preparation of 2-(2-hydroxyphenyl)-benz[e] [l,3]oxazin-4-one.

Mixture of salicylic acid (50 grams), salicylamide (44.6 grams), pyridine (7.6 ml) and xylene (300 ml) was heated to reflux temperature. Thionyl chloride (lot one 39.6 ml) was added to the above mixture at reflux temperature for 3 hours. Intense evolution of SO₂ and hydrochloric acid was observed, the reaction mixture was then stirred for 6 hrs. Thionyl chloride (lot two 7.9 ml) was added to the above mixture at reflux temperature, reaction mixture was then stirred further for 2 hrs. Xylene was removed from the reaction mixture by distillation under reduced pressure. The resulting residue was suspended in methanol (100 ml) and raised the temperature to 60-65⁰C. The reaction mixture was stirred for one hour and cooled to 0-5°C and further stirred for one hour. The solid obtained was filtered, washed with methanol and dried to get the title compound.

Yield: 61.7 grams

Exaniple-4: Preparation of deferasirox compound of formula-1.

4-hydrazinobenzoic acid (38 grams) was added to the mixture of 2-(2-hydroxyphenyl)- benz[e][l,3]oxazin-4-one obtained as per example-3 and methanol (1 L) and heated to 60-65°C then stirred for 5 hours at reflux temperature. The reaction mixture was cooled to 0-5 °C stirred for 1.5 hours. The solid formed was filtered, washed with methanol and then dried to get the title compound.

Yield: 75 grams; Purity by HPLC: 99.77 %; impurity at 2.1 RRT : 0.01%.

Particle size distribution: D(0.1):2.40 μm; D(0.5):6.28 μm; D(0.9): 12.98 μm; D(1.00): 21.27 μm.

Example-5: One pot preparation of deferasirox compound of formula-1.

Mixture of salicylic acid (25 grams), salicylamide (22.3 grams), pyridine (3.8 ml) and xylene (150 ml) was heated to 120-125°C. Thionyl chloride (20 ml) was added to the above mixture at 120-125⁰C for 3 hours and stirred for 6 hours. Thionyl chloride (4 ml) was added to the reaction mixture for 45 minutes and stirred for 2 hours at 120-125°C. The solvent from the reaction mixture was distilled off under reduced pressure. Methanol (500 L) followed by 4-hydrazinyl benzoic acid (17.9 grams) was added to the obtained residue and then heated to 60-65⁰C. The reaction mixture was stirred for 5 hours at reflux temperature then cooled to 0-5 °C and stirred for 1.5 hours. The solid formed was filtered, washed with methanol and then dried to get the title compound.

Yield: 37.5 grams;' Purity by HPLC: 99.73 %; impurity at 2.1 RRT: 0.03%.

Example-6: Purification of Deferasirox.

To a solution of aqueous sodium hydroxide (10%, 250ml) added of deferasirox (25g). Stirred for fifteen minutes and filtered it. To the clear solution added hydrose (1.25 grams) and stirred for 10-15 min. The pH of this solution is adjusted to 2, using dilute hydrochloric acid with constant stirring. The precipitated solid was filtered and washed with water. Methanol (500 ml) was added to the solid, stirred and the suspension was refluxed for lhr, cooled to 0-5 C and stirred for lhr. The precipitated solid is filtered and dried to provide pure deferasirox.

Yield: 23 grams;

Purity by HPLC: 99.79 %.

Example-7: Purification of Deferasirox.

To a solution of aqueous sodium hydroxide (10%, 250ml) added of deferasirox (25g).

Stirred for fifteen minutes and filtered it. The filtrate was extracted with dichloromethane, and to the filtrate added hydrose (1.25 grams) and stirred for 10-15 min. The pH of this solution is adjusted to 2, using dilute hydrochloric acid with constant stirring to precipitate a solid. The precipitated solid was filtered, washed with water and dried to provide pure deferasirox.

Yield: 21 grams;

Purity by HPLC: 99.83 %.

Example-8: Purification of Deferasirox.

Deferasirox (25 grams) was suspended in 500 ml of methanol and refluxed for lhr. The reaction mixture was cooled to 0-5° C with stirring. The solid was filtered and dried to get pure deferasirox.

Yield: 23 grams;

Purity by HPLC: 99.89 %

Example-9: Preparation of deferasirox methylamine amine salt compound of formula-8a.

Added 30 ml of ethyl acetate to the crude deferasirox (3 grams) followed by 40% aqueous methyl amine (0.74ml) at 25-30°C. Stirred the reaction mixture for 2 hours at 25- 30°C. Filtered the precipitated solid and washed with ethyl acetate. Dried the material for 5 hours. Added 40 ml of acetone to the above obtained dried material and heated to reflux. Stirred the reaction mixture for 30 minutes and cooled the reaction mixture to 25- 35°C. Stirred the reaction mixture for 6 hours at 25-35°C. Filtered the precipitated solid and dried the material at 50-55°C to get the title compound.

Yield: 3.1 grams. Example-10: Preparation of deferasirox isopropyl amine salt compound of formula-8b.

Added 100 ml of ethyl acetate to the crude deferasirox (10 grams) followed by isopropyl amine (1.5 ml) at 25-30°C. Stirred the reaction mixture for 2 hours at 25-30°C. Filtered the precipitated solid and washed with ethyl acetate. Added 100 ml of ethyl acetate to the above solid and heated to reflux. Stirred the reaction mixture for 30 minutes and cooled the reaction mixture to 25-35°C. Stirred the reaction mixture for 6 hours at 25-35°C. Filtered the precipitated solid and dried the material at 50-55°C to get the title compound.

Yield: 9.4 grams.

Example-11: Preparation of deferasirox n-butyl amine salt compound of formula-8c.

Added 100 ml of ethyl acetate to the crude deferasirox (10 grams) followed by n-butyl amine (2 ml) at 25-30°C.Stirred the reaction mixture for 2 hours at 25-30°C. Filtered the precipitated solid and washed with ethyl acetate. Dried the material for 6 hours. Added ^* 100 ml of ethyl acetate to the above obtained dried material and heated to reflux. Stirred the reaction mixture for 30 minutes and cooled the reaction mixture to 25-35°C. Stirred ' the reaction mixture for 6 hours at 25-35°C. Filtered the precipitated solid and dried the- material at 50-55°C to get the title compound.

Yield: 9.8 grams

Example-12: Preparation of deferasirox dicyclohexylamine salt compound of formula-8d.

Added 50 ml of ethyl acetate to the crude deferasirox (5 grams) followed by dicyclohexylamine (2 ml) at 25-30°C. Stirred the reaction mixture for 2 hours at 25-30°C. Filtered the precipitated solid and washed it with ethyl acetate. Dried the solid material for 6 hours. Added 60 ml of toluene to the above obtained dried material and heated to reflux. Stirred the reaction mixture for 30 minutes and cooled the reaction mixture to 25-35°C. Stirred the reaction mixture for 6 hours at 25-35°C. Filtered the precipitated solid and dried the material at 50-55⁰C to get the title compound.

Yield: 4.9 grams Example-13: Preparation of deferasirox from its methylamine salt.

Deferasirox methyl amine salt(2.0 grams) was taken in methanol (20ml) and added water (40ml) and stirred for 15 minutes. The pH of the solution was adjusted to around 2 using dilute hydrochloric acid and stirred the solution for 30 minutes. Filtered the precipitated solid washed with methanol and dried to provide pure deferasirox.

Yield: 1.6 grams; HPLC Purity: 99.90 %

Example-14: Purification of Deferasirox.

Deferasirox (5 grams) was suspended in 15 ml of dimethyl formamide and stirred for ten minutes at 25-35°C. Water (20ml) was added to the solution and stirred for one hour. The solid precipitated was filtered and dried to get pure deferasirox.

Yield: 4.3 grams; HPLC Purity: 99.82 %

1

Example-15: 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 iml) 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%; Methyl ester impurity: 0.05%

Particle size distribution:

D(0.1):4.02 μm; D(0.5):10.39 μm; D(0.9):23.10 μm; D(l.OO): 59.09 μm. Example-16 to 18: Purification of Deferasirox.

The deferasirox compound of formula- 1 was purified in a similar manner to example-15 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-19: Purification of deferasirox compound of formula-1:

Deferasirox (100 ,gram) was dissolved in tetrahydrofuran (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 IL 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

Particle size distribution: D(0.1):6.74 μm; D(0.5): 17.32 μm; D(0.9):41.50 μm; D(LOO): 107.37 μm.

Example-20: Preparation of methyl ester of deferasirox compound of formula-9a:

A mixture |of deferasirox (5 grams), methanol (100 ml) and sulphuric acid (0.5 ml) was heated to reflux temperature. The reaction mixture was stirred at reflux for an hour. The reaction mixture was cooled to 0-5⁰C and stirring for 30 minutes. The solid was filtered and dried to get the title compound.

Yield: 4.8 grams

Claims

We Claim:

1. An improved process for the preparation of deferasirox compound of formula- 1 which comprises of the following steps,

a) Reacting the salicylic acid compound of formula- 2

Formula-2

with salicylamide compound of formula-3

Formula-3

in presence of a suitable base selected from pyridine, trimethylamine, triethylamine, in a suitable solvent selected from toluene, cyclohexane, heptane, chlorobenzene, xylene or a mixture thereof, in the presence of thionyl chloride at reflux temperature, followed by crystallization from a suitable alcoholic solvents like methanol, ethanol, isopropanol a mixture thereof, characterized in that the thionyl chloride is used in the mole ratio of 1.7-1.9 and is added in two lots at reflux temperature, wherein the second lot is added after maintaining the reaction mixture for some time after the addition of first lot of thionyl chloride, to provide the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4,

Formula-4

b) reacting the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4 with 4-hydrazinobenzoic acid compound of formula-5

HOOC -<\ /)— N- NH₅

Formula-5 in a suitable alcoholic solvents selected from methanol, ethanol, isopropanol, butanol or mixtures thereof at reflux temperature to provide the deferasirox compound of formula- 1,

c) purifying the compound of formula- 1 by treating it with a base and optionally ^"5 extracting the mixture with a suitable water immiscible solvent, followed by treatment with an acid to provide the pure deferasirox

2. An improved process for the preparation of deferasirox compound of formula- 1 which comprises of the following steps,

0 a) Reacting the salicylic acid compound of formula-2 with salicylamide compound of formula-3 in the presence of a pyridine in xylene and in the presence of thionyl chloride at reflux temperature, followed by crystallization of the obtained compound from a methanol, to provide the 2-(2-hydroxyphenyl)-benz[e][l,3] oxazin-4-one compound of formula-4, characterized in that the thionyl chloride is5 used in the mole ratio of 1.7-1.9 and is added in two lots at reflux temperature, ^' wherein the second lot is added after maintaining the reaction mixture for some time after the addition of first lot of thionyl chloride,

b) reacting the 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of formula-4 with 4-hydrazinobenzoic acid compound of formula-5 in methanol at0 60-65° C to for 3-5 hours to provide the deferasirox compound of formula- 1,

c) optionally purifying the compound of formula- 1 by treating it with aqueous sodium hydroxide, followed by hydrose and subsequently with an acid to provide the pure deferasirox. 5 3. One-pot process for the preparation of deferasirox compound of formula- 1, which comprises of reacting the salicylic acid compound of formula-2 with salicylamide compound of formula-3 in the presence of a suitable base selected from pyridine, trimethylamine and triethylamine, in a suitable solvent selected from toluene, cyclohexane, heptane, chlorobenzene, xylene or a mixture thereof and in presence of0 thionyl chloride, to provide the 2-(2-hydroxyphenyl)-benz[e][l,

3]oxazin-4-one compound of formula-4, which on in-situ reaction with 4-hydrazinobenzoic acid compound of formula-5 in a suitable solvent selected from alcoholic solvents like methanol, ethanol, isopropanol, butanol or a mixture thereof, at reflux temperature to provide deferasirox compound of formula- 1.

4. A process of claim 1 to 3, wherein deferasirox compound of formula- 1, having a purity greater than 99% by HPLC and having an impurity at 2.1 RRT in a concentration less than 0.10 %.

5. A process of claim 1 to 4, wherein 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one compound of¹ formula-4 containing the uncyclised derivative 2-hydroxy-N-(2- hydroxybenzoyl) benzamide compound of formula-6, in a concentration below 10% and the unknown impurity with molecular mass of 508, in a concentration less than 0.15%.

Formula-6

6. A process according to claim 3, wherein thionyl chloride is added in two lots at reflux temperature. ,

7. Novel amine salts of deferasirox compound of general formula-8,

Formula-8

wherein NRiR₂R₃ is an amine and Ri_; R₂ and R₃ are same or different and are each independently 'selected from either hydrogen, Ci_-I2 alkyl, C_3-7 cycloalkyl, aryl-Ci_-6 alkyl, aryl and the like.

8. The deferasirox amine salts compound of general formula-8 of claim 7, wherein NRjR₂R₃ is an iamine and is selected from a group which includes but is not limited to methylamine, ' ethylamine, n-propylamine, isopropylamine n-butylamine, isobutylamine, tertiary butyl amine, diethyl amine, octylamine, 2-ethylhexylamine, benzylamine, phenethylamine, dibenzylamine, N-methylbenzylamine, N- ethylbenzylamine, dibenzylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine,

N-ethylcycloheptylamine, dicyclohexylamine, pyrrolidine, N-methylpyrrolidine, N- methylpiperidine, piperidine, morpholine and the like.

9. A process for i the preparation of deferasirox amine salts, compounds of general formula- 8

Formula-8

wherein NRiR₂R₃ is an amine wherein Ri₁ R₂ and R₃ are same or different and are each independently selected from either hydrogen, C_M2 alkyl, C_3-7 cycloalkyl, aryl- '^; Ci_-6 alkyl, aryl and the like: which comprises of the following steps;

a) Treating the crude deferasirox with an amine NRiR₂R₃ compounds of general formula-7, wherein Ri₁ R₂ and R₃ as defined above; in a suitable solvent selected from ester solvents and/or hydrocarbon solvents and/or ketone solvents, or their mixtures thereof,

c) separating the solid by filtration and washing with suitable solvent,

e) drying the solid to get the pure amine salt of deferasirox.

10. A process for the preparation of methylamine salt of deferasirox compound of formula-8a, comprising of;

a) Treating the crude deferasirox with an methylamine in ethyl acetate,

b) stirring the reaction mixture for 2 hours at 25-35°C, i

c) separating the solid by filtration and washing with ethyl acetate,

d) purifying the solid using ethyl acetate,

e) drying the solid formed to provide deferasirox methyl amine salt .

11. The use of deferasirox amine salts compound of general formula-8 as claimed in claim 7 for the preparation of highly pure deferasirox.

12. A process for the preparation of pure deferasirox from deferasirox amine salt which comprises of;

a) suspending deferasirox amine salt in an suitable solvent selected from a group consisting of water, alcoholic solvents namely methanol ethanol, n-propanol, isopropanol, n-butanol and the like; chlorinated hydrocarbons like dichloromethane, chloroform etc., ester solvents for example ethyl acetate, isopropyl acetate and the like; or their mixtures thereof,

b) treating it with an acid selected from an inorganic acid like hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids like acetic acid, propionic acid, acetic acid and the like,

c) filtering the solid obtained and washing with suitable solvent selected from methanol, ethanol, isopropanol, n-propanol, butanol and the like, and drying it to provide highly pure deferasirox.

13. A process for the purification of deferasirox compound of formula- 1, which comprises of the following steps,

a) Treating the deferasirox with a suitable aqueous base like sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, sodium bicarbonate, potassium bicarbonate and ammonia, in absence or presence of a solvent, which is selected from alcoholic solvents like methanol, ethanol, isopropanol, n-propanol and butanol and stirring the reaction mixture to provide solution,

b) filtering the solution, and optionally extracting the filtrate with a suitable water immiscible solvent selected from ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, toluene, xylene, cyclohexane, hexane, heptane and the like, to remove the impurities,

c) treating the filtrate with hydrose,

d) treating the reaction mixture with suitable acid selected from a group consisting of ^"5 hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and acetic acid and filtering the precipitated solid,

e) suspending the wet solid in a suitable water miscible solvent selected from alcoholic solvents like methanol, ethanol, isopropanol, n-propanol, butanol and heating the suspension to reflux,

0 f) cooling the reaction mixture and filtering the precipitated solid to get pure deferasirox.

14. A process according to claim 13, wherein the purification comprises of the following steps,

5 a) Treating the deferasirox with a aqueous sodium hydroxide and stirring,

b) filtering the solution,

c) treating the filtrate with hydrose,

d) treating the reaction mixture with hydrochloric acid and filtering the obtained solid,

0 e) suspending the wet solid in methanol and heating the suspension to reflux, '. f) cooling the reaction mixture to 0-5°C and filtering the precipitated solid to get pure deferasirox.

15. A process for the purification of deferasirox compound of formula- 1, which5 comprises of the following steps,

a) Suspending the deferasirox in a suitable alcoholic solvents like methanol, ethanol, isopropanol, n-propanol, butanol or mixtures thereof,

0 c) cooling the reaction mixture, d) filtering, washing the solid with a suitable alcoholic solvent like methanol, ethanol, isopropanol, n-propanol, butanol or mixtures thereof, drying to get the pure compound of formula- 1.

16. A process for the purification of deferasirox compound of formula- 1, which comprises of the following steps,

a) Suspending the deferasirox in a suitable polar aprotic solvent like dimethyl formamide, dimethylacetamide or dimethylsulfoxide and heating it to reflux, b) cooling thei reaction mixture,

c) adding an anti solvent and stirring the reaction mixture,

d) filtering the solid formed, washing the solid with a suitable solvent and drying to get the pure compound of formula- 1.

17. A process according to claim 16, the anti solvent used in step c) is selected from water or ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone and the like or hydrocarbon solvents such as hexane, cyclohexane, n-heptane and the like or ether solvents ,such as diethyl ether, isopropyl ether and the like or their mixtures thereof.

18. Deferasirox compound of formula- 1 having D₉₀ is in the range of 2-100 μm and mean particle size in the range of 2-40 μm.

19. 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 triethylamihe, 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,

^"5 i) cooling thel 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.

20. A process for the purification of deferasirox compound of formula- 1, which0 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 the5 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,

0 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.

5

21. 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,

0 c) adding the filtrate to aqueous alcohol and stirring,

d) filtering the precipitated solid and washing with water,

e) dissolving the wet solid in aqueous base solution, 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,

"5 i) filtering the precipitated solid and washing with suitable solvent,

j) drying the solid to get the highly pure deferasirox compound of formula- 1.

22. A process for the purification of deferasirox compound of formula- 1, which comprises of the following steps,

0 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,

5 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,

0 i) filtering the solid and washing with water,

j) drying the solid to get the highly pure deferasirox compound of formula- 1.

23. A process according to any of the preceding claims, wherein purified deferasirox is having HBA content less than 5 ppm.

5

24. A process according to any of the preceding claims, wherein purified deferasirox is having HBA content less than 2 ppm.

25. A process according to any of the preceding claims, wherein purified deferasirox is0 having purity greater than 99.95% by HPLC, preferably greater than 99.95%.

26. Deferasirox having HBA content less than 5 ppm prepared as per the process claimed in claims 19 to 22.

27. 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, ^"5 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, 0 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 level5 of HBA content.

28. A process for, the reduction of HBA content present in deferasirox compound^of formula- 1 comprises of the following steps,

a) Suspending¹ the deferasirox in a suitable alcohol solvent selected from methanol,0 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 as described in step a),

5 e) drying the solid to get the deferasirox compound of formula- 1 with reduced level of HBA content.

29. Deferasirox methyl amine salt compound of formula-8a. 0

30. Deferasirox isopropyl amine salt compound of formula-8b.

31. Deferasirox n-butyl amine salt compound of formula-8c.

32. Deferasirox dicyclohexyl amine salt compound of formula-8d.

5

33. Compound represented by the following general structural formula-9

Formula-9

Wherein R is Ci_-4 alkyl.

34. A compound according to claim 33, wherein the R is alkyl and is selected from methyl, ethyl, propyl, isopropyl, n-butyl and sec-butyl.

35. The methyl ester of deferasirox compound of formula-9a characterized by ¹H NMR (300 MHz) δ(ppm): 11.28 (b, IH), 9.57 (b, IH), 8.25-8.22 (d, 2H), 8.15-8.12 (dd,

IH), 7.62-7.51 (d, 2H), 7.41-7.32 (m, 2H), 7.16-7.02 (m, 3H), 6.93-6.90 (dd, IH), 6.68-6.63 (t, IH), 3.99 (s, 3H); and its Mass spectra m/z =388 (M+H)⁺. ^