FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION (See Section 10 and Rule 13)
PROCESS FOR THE PREPARATION OF DEFERASIROX
M/S AMOLI ORGANICS PVT. LTD,
407 Dalamal House, J.B.Road,
Nariman Point, Mumbai-400021,
INDIA
The following specification particularly describes the invention and the manner in
which it is to be performed

PROCESS FOR THE PREPARATION OF DEFERASIROX
OBJECT OF THE INVENTION
The main object of the invention is to provide an improved process for the preparation of key intermediate "2-(2-hydroxyphenyl)-4H-benzo(e)[l,3]oxazin-4-one" and further preparation of Deferasirox from the above intermediate.
BACKGROUND OF THE INVENTION
Deferasirox is an iron chelating agent and sold under the brand name Exjade. Exjade tablets for oral suspension contain 125 mg, 250 mg, or 500 mg deferasirox. Deferasirox is designated chemically as 4-[3,5-Bis(2-hydroxyphenyl)-lH-l,2,4-triazol-lyl]-benzoic acid and its structural formula is:

Deferasirox is a white to slightly yellow powder. Its molecular formula is C21H15N3O4 and its molecular weight is 373.4.
Deferasirox, its pharmaceutically acceptable salts and process for their preparation were disclosed in US 6465504. The disclosed process involves reaction of
osalicyloyl chloride with salicylamide at 170oC to obtain 2-(2-hydroxyphenyl)benze[e] [1,3]oxazin-4-one as slightly yellow crystals having
o
melting point 206-208 C, which is then reacted with 4-hydrazinobenzoic acid in ethanol under reflux conditions to obtain 4-[3,5-Bis (2-hydroxyphenyl)-lH-l,2,4-triazol-lyl]-benzoic acid (Deferasirox) as colorless crystals having melting point
o
264-265 C. Deferasirox was obtained as crystalline polymorphic Form-I. However, the obtained material does not meet the quality parameters such as

chromatographic purity, residue on ignition, and appearance as per the ICH guidelines.
Process requires cyclodehydration of 2-Hydroxy-N-(2-hydroxy-benzoyl)benzamide to (2-hydroxyphenyl)-Benz[e] [l,3]oxazin-4-one to be carried

out at a temperature of 170 oC -180 oC entails specific installation of hot oil heaters to obtain the high temperature which requires additional space, investment and operating cost. Besides it causes adverse effect on the environment by higher emissions. In addition during this reaction, 5-chloro-2-hydroxy-N-(2-hydroxybenzoyl)benzamide is produced as a side product in addition to 2-hydroxy=N=(2=hydroxybcnzoyl)benzamide. This 5-chloro-2-hydroxy-N-(2-hydroxybenzoyl)benzamide further results into undesired products.This reaction also generates uncyclised derivative; 2-hydroxy-N-(2-hydroxybenzoyl) benzamide compound (bis-salicylamide) which is difficult to remove from desired product. Though in the gram scale reactions the above said impurity formed is more than 10%; in the scale up reactions this impurity formed, is about >20%. Hence, controlling the formation of this bis-salicylamide to minimum possible levels is essential. These undesired products cause contamination of the final product. The undesired impurities reduce the purity of the API in the pharmaceutical product and often decrease the stability and shelf life of the pharmaceutical product.
Reaction of salicylic acid with p-tolylsulfonyl chloride and salicylamide in presence of pyridine and chlorobenzene to form obtain 2-(2'-Hydroxyphenyl)-4H-[l,4]benzoxazinone has also been reported in Geigy patent US3544567A which has been expired. If instead of p-toluene sulphonyl chloride, the equivalent amount of methane sulphonyl chloride is used under otherwise the same conditions, then 2-(2-hydroxyphenyl)-4H-[l,3]benzoxazinone is obtained.
Reaction of salicylic acid with salicylamide in presence of thionyl chloride, pyridine and xylene to form 2-(2-hydroxyphenyl)-benzo-4H-[l,3]oxazin-4-one has been exemplified in Ciba PCT application WO2003053986.

European Journal of Inorganic Chemistry 2004, 4177-4192 disclosed a process that 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.
As per 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 there is a need in the art for a process which avoids the formation of bis(salicyl)imide impurity or the process in which this bis(salicyl)imide impurity can be converted into 2-(2-hydroxyphenyl)-benz[e][l,3]oxazin-4-one. Although this process is more technological than the one based on molding salicylamide in salicyloyl chloride, the overall yield is still moderate (40-45%). The moderate yield can be attributed to the formation of by-products - a mixture of the linear and cyclic polyesters formed as a result of intermolecular reaction of salicyloyl chloride.Therefore, there is a need for a process, in which no significant heating is required and formation of polyesters as well as corrosive and hazardous gases such as HC1 is minimized or avoided.
Helvetica Chimica Acta Vol.55, 1 (1972), 152-153, 1566-1594 discloses 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 of 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 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. This impurity could not be completely removed by conventional purification methods; hence it was important to control this impurity.

Indian patent application of Matrix Laboratories ltd 2119/CHE/2008 discloses crystalline form of 2-(2-hydroxyphenyl) benz[e][1,3]oxazin-4-one prepared by reacting salicyloyl chloride with salicylamide employing a solvent selected from oxylene, anisole and diphenylether, or mixture thereof, preferably the o-xylene to give acyl compound 2-hydroxy-N-(2-hydroxybenzyl) benzamide; and heating the acyl compound in-situ to obtain the crystalline form of 2-(2-hydroxyphenyl)benz[ e][ 1 ,3]oxazin-4-one. Advantages of the above process are improved yield and color. In addition this process involves heating 2-hydroxy-N-(2-hydroxybenzyl)benzamide is in-situ to temperature between 100-180°C, preferably between 120-160oC. At this temperature 2-hydroxy-N-(2-hydroxybenzyl)benzamide is cyclized and completely converted into 2-(2-hydroxy phenyl) benz[e] [1,3]oxazin-4-one with a very small quantity of un-reacted 2-hydroxy-N-(2-hydroxybenzyl) benzamide and other impurities.
Indian patent application of MSN 1909/CHE/2009 discloses reaction of salicylic acid with salicylamide in presence of suitable base selected from pyridine, trimethylamine, triethylamine in a suitable solvent selected from toluene, cyclohexane, heptane, chlorobenzene, xylene or a mixture thereof in presence of thionyl chloride at reflux temperature, followed by crystallization from a suitable alcoholic solvents selected from methanol, ethanol, isopropanol or mixtures thereof, to provide the 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one.This reaction also generates uncyclised derivative; 2-hydroxy-N-(2-hydroxybenzoyl)benzamide compound (bis-salicylamide). However in this process, formation of the uncyclised derivative 2-hydroxy-N-(2hydroxybenzoyl)benzamide was well controlled to the level below 10%. If the uncyclized derivative is present in a concentration less than 10% in the mixture, then it completely reacts with 4-hydrazinobenzoic acid 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.
Indian patent application of Wockhardt 1673/MUM/2012 involves treatment of salicylic acid chloride with salicylamide in hydrocarbon in the presence of

bronsted acid / lewis acid catalyst at 120-130°C. This process overcomes disadvantage of prior art by allowing cyclodehydration reaction to occur at much reduced temperature of 120-130°C by making use of bronsted acid / lewis acid catalyst
Indian patent of Biocon IN 295896 discloses reaction of salicyloyl chloride with salicylamide in presence of a catalyst to obtain 2-(2-hydroxyphenyl)benz[e]oxazin-4-one having less than 1% of uncyclized impurity.
Therefore, it is desirable to develop an improved process for the preparation of Deferasirox that provides intermediates and products with improved yield, color and quality with minimal impurities. The present invention provides novel and improved process for preparation of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one; a key intermediate of Deferasirox and further preparation of Deferasirox from the above intermediate.
According to the present invention, reaction of salicylic acid and salicylamide is carried out at 100-110 oC; i.e. at significantly low temperature than that reported in US 6465504. 2-hydroxy-N-(2-hydroxybenzoyl) benzamide (bis-salicylamide) impurity is converted back into (2-hydroxyphenyl)benz[e] [1,3]oxazin-4-one which is intermediate of Deferasirox. In addition, as per the present invention, salicylic acid and salicylamide are reacted in presence of thionyl chloride, pyridinium p-toluenesulfonate as a catalyst and thionyl chloride is added in three lots and not in single lot. Hence, formation of unknown impurity which was detected in final API which showed peak in HPLC at 2.06 - 2.1 RRT and other uncyclized derivatives were on lower side as compared with pyridine as a catalyst and without any catalyst where addition of thionyl chloride was in single lot.
SUMMARY OF THE INVENTION
In an aspect, the present invention relates to the process for the preparation of Deferasirox, comprising the steps of

A process for the preparation of Deferasirox comprising the steps of:
step 1) reacting Salicyclic acid, thionyl chloride and Salicylamide in the
presence of a catalyst and solvent to obtain a mixture of 2-(2-
hydroxyphenyI-benz[e] [ 1,3]oxazin-4-one and 2-hydroxy-N-(2-
hydroxybenzoyl) benzamide;
step 2) reacting the mixture of product obtained in step 1) with a catalyst in presence of a solvent to obtain 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one;
step 3) reacting 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one obtained in step 2) with 4-hydrazinobenzoic acid in a suitable solvent and
step 4) purifying the Deferasirox obtained in step 3).
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the process for the preparation of Deferasirox, comprising the steps of
A process for the preparation of Deferasirox comprising the steps of:
step 1) reacting Salicyclic acid, thionyl chloride and Salicylamide in the
presence of a catalyst and solvent to obtain a mixture of 2-(2-
hydroxyphenyl-benz[e] [1,3]oxazin-4-one and 2-hydroxy-N-(2-
hydroxybenzoyl) benzamide;
step 2) reacting the mixture of product obtained in step 1) with a catalyst in presence of a solvent to obtain 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one;
step 3) reacting 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one obtained in step 2) with 4-hydrazinobenzoic acid in a suitable solvent and
step 4) purifying the Deferasirox obtained in step 3).

In one embodiment of the invention, catalyst used in step 1) and 2) is pyridinium para-toluenesulfonate.
In another embodiment of the invention, solvent used in step 1) is selected from toluene, xylene, o-xylene, dimethyl formamide or mixtures thereof.
In preferred embodiment of the invention, solvent used in step 1) is o-xylene.
In further preferred embodiment of the invention, step 1) is carried out by reacting Salicylic acid with Salicylamide in presence of thionyl chloride, catalytic amount of pyridinium para-toluenesulfonate and using o-xylene as a solvent to form a mixture of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 2-hydroxy-N-(2-hydroxybenzoyl) benzamide as a product.
In another preferred embodiment of the invention, reaction mass containing o-xylene, Salicylamide, pyridinium para-toluenesulfonate and Salicylic acid is first heated to 65-80°C and then slow addition of thionyl chloride is started at 65-80°C for 40-60 min under nitrogen.
In further preferred embodiment of the invention, after addition of thionyl chloride, reaction is carried out at temperature of 100-130 C preferably 100-110 C for 3 hours under nitrogen.
In another embodiment of the invention, thionyl chloride is added in three lots.
In additional embodiment of the invention, product obtained in step 1) may be further purified by employing a solvent selected from C1-C4 alcohols; preferably methanol.
In further embodiment of the invention, in step 1) along with 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one, an uncyclized derivative namely 2-hydroxyl-N-(2-hydroxybenzoyl)benzamide was also formed. If uncyclized derivative is present in a concentration less than 10% in a mixture, then it completely reacts with 4-hydrazinobenzoic acid to get Deferasirox. But, if it is present in concentration above 10% then it is not consumed completely, and hence

will be present as an impurity in final API. In the present invention the formation of uncyclized derivative is well controlled to the level below 10% by converting uncyclized derivative into 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one in step 2).
In subsequent embodiment of the invention, in step 2) 2-hydroxy-N-(2-hydroxybenzoyl) benzamide is converted into 2-(2-hydroxyphenyl) benz[e][l,3]oxazin-4-one by reacting the mixture of product obtained in step 1) with catalyst in presence of solvent to obtain 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one in step 2).
In further embodiment of the invention, solvent used in step 2) is selected from toluene, xylene, o-xylene, dimethyl formamide or mixtures thereof.
In preferred embodiment of the invention, solvent used in step 2) is toluene.
In preferred embodiment of the invention, in step 2) mixture of product obtained in step 1) along with pyridinium p-toluenesulfonate and toluene is heated to a temperature of 100-130oC preferably 100-120 oC and azeotropic distillation is carried out for 6 hours and then toluene is distilled out under vacuum at 90-110°C.
In an embodiment of the present invention, step 3) is carried out without isolating the compound of step 2) (in-situ).
In further embodiment of the invention, solvent used in step 3) is selected from the group comprising methanol, ethanol, iso-propanol, ethyl acetate, toluene or mixtures thereof.
In another embodiment of the invention, suitable temperatures that may be employed for the condensation in step 3) may be between 10°C - 100°C, preferably 50°C - 70°C, more preferably 60°C-65°C.
In accordance with another embodiment of the invention, in step 4) Deferasirox obtained may be purified by process comprising dissolution of Deferasirox in THF followed by filtration, distilling off THF from filtrate, addition of aqueous

methanol to the filtrate, stirring, filtration of solid, dissolution of wet solid in water and adjustment of pH of the reaction mass to 9.5-11.0 by slow addition of 10% NaOH solution, filtration, treatment with methanol, acidification of reaction mass with aq HC1 solution, stirring, filtration and drying to get highly pure deferasirox.
In accordance with one embodiment of the invention, the deferasirox obtained has a purity of about 99% to about 99.99%.
In accordance with one further embodiment of the invention, the deferasirox contains 4-hydrazinobenzoic acid in an amount of less than about 10 parts per million.
The present invention can be illustrated by the following examples, which do not limit the scope of invention.
Examples:
Example 1: Preparation of 2-(2-hydroxyphenyl)benz[e][l,3]oxazin-4-one
o-xylene (3600 ml) and Salicylamide (300 g) were charged into 4 necked round

bottom flask at 25-35 oC under nitrogen and reaction mass was stirred for 10-20 minutes. Salicylic acid (317 g), and pyridinium para-toluenesulfonate (82.4 g) were then charged into the reaction mass and temperature of the reaction mass

was raised to 65-80 oC. Thionyl chloride (79.4 ml) was added slowly at 65-80 oC for 40-60 min under nitrogen. Temperature of the reaction mixture was raised to

100-110 oC and maintained for 3 hours. The reaction mass was cooled to 65-80°C and thionyl chloride (79.4 ml) was added slowly at 65-80C for 40-60 min under
onitrogen. The temperature of the reaction mixture was raised to 100-110 oC and maintained for 3 hours. The reaction mass was cooled to 65-80°C and thionyl

chloride (79.4 ml) was added slowly at 65-80 oC for 40-60 min under nitrogen.The

temperature of the reaction mixture was raised to 100-110 oC and maintained for 3 hours. After completion of reaction, o-xylene was distilled out under vacuum up to 9-11 V at 90-110°C. Reaction mixture was cooled to 40-50°C. Methanol

(1200.0 ml) was charged into the reaction mixture and stirred for 60 min at 40-
50 oC. The reaction mass was cooled to 25-35°C and stirred for 60-90 minutes at 25-35°C. The product was filtered, washed with methanol (600.0 ml) and dried in vacuum tray dryer for 8 hours at 50-60°C.
Example 2: Preparation of Deferasirox
Toluene (1680 ml), 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one (280.0 g) (product of example 1) and pyridinium para-toluenesulfonate (14.7 g) were
o
charged in 4 necked round bottom flask at 25-35 C. The temperature of the

reaction mixture was raised to 110-120 oC and azeotropic distillation was carried out for 6 hrs. Toluene was distilled out under vacuum at 90-110°C. After cooling the reaction mass to 25-35°C, methanol (4200 ml), 4-hydrazinobenzoic acid (187
o
g), were charged to reaction mass at 25-35 C. The temperature of the reaction

mixture was raised to 60-65 oC and maintained at the same temperature for 2 hours. Reaction mixture was cooled to 5-10°C and stirred for 60-90 minutes at 5-10°C. The crude product obtained was filtered, washed with methanol (560.0 ml) and suck dried well.
Example 3: Purification of Deferasirox
Tetrahydrofuran (1575 ml), Deferasirox from example 2 along with previous batch second crop (10-17 g) were charged in 4 necked round bottom flask at 25-

35 oC. Reaction mixture was stirred for 15-20 min at 25-35 oC. After addition of

activated charcoal PF-33 (A) (35.0) gm to the reaction mass at 25-35 oC, the temperature of the reaction mixture was raised to 50-60 C and maintained at the
same temperature for 45-60 min. The reaction mass was cooled to 25-35 oC and filtered through Hyflo. The Hyflo bed was washed with tetrahydrofuran (350 ml). The filtrate was taken into round bottom flask, temperature of the filtrate was

raised to 65-70 oC and tetrahydrofuran was distilled out atmospherically at 65-

70 oC. The reaction mass was cooled to 50-60 oC and mixture solution of methanol (2450 ml) and water (2450 ml) was added to the reaction mass at 50-60 oC. The reaction mass was maintained at 50-60 oC for 30-45 min, cooled to 25-35 oC and

maintained at the same temperature for 90-120 min. The solid obtained was filtered, washed with mixture of water (350 ml) and methanol (350 ml) and suck dried well. The obtained solid along with water (2800 ml) were charged at 25-

30 oC and pH of the reaction mixture was adjusted to about 9.5 -11.0 by slow addition of 10% NaOH solution. After pH was complied, reaction mass was filtered through Hyflo, the Hyflo bed was washed with DM water at 25-35°C. Methanol (1750.0 ml) was added into the reaction mixture at 25-35 C. The

temperature of the reaction mass was raised to 50-60 oC and maintained at the

same temperature for 3-4 hrs. The reaction mass was cooled to 25-35 oC and pH of the reaction mixture was adjusted to about 2.0 - 3.0 by slow addition of 50 % aq
o
HC1 solution at 25-35 C. The reaction mixture was stirred for 30-45 min and
o
maintained for 90-120 min at 25-35 C. . The product was filtered, washed with water (350 ml) and methanol (350 ml). The product was suck dried well. The above wet cake and water (2800 ml) was charged into the 4-neck, heated to 50-
o
60 C and maintained for 90-120 minutes at 50-60 oC. The reaction mixture was cooled to 25-35°C, maintained for 30-45 min at 25-35°C, filtered and washed with water (350 ml) and methanol (350 ml) and suck dried well. The wet solid was dried in vacuum tray dryer at 70-80 C for 12 hrs.

We Claim:
1. A process for the preparation of Deferasirox comprising the steps of:
step 1) reacting Salicyclic acid, thionyl chloride and Salicylamide in the
presence of a catalyst and solvent to obtain a mixture of 2-(2-
hydroxyphenyl-benz[e][l,3]oxazin-4-one and 2-hydroxy-N-(2-
hydroxybenzoyl) benzamide;
step 2) reacting the mixture of product obtained in step 1) with a catalyst in presence of a solvent to obtain2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one;
step 3) reacting 2-(2-hydroxyphenyl)bcnz[e][l,3]oxazin-4-one obtained in step 2) with 4-hydrazinobenzoic acid in a suitable solvent and
step 4) purifying the Deferasirox obtained in step 3).
2. The process as claimed in claim 1 wherein the catalyst used in step 1) & 2) is Pyridinium para toluene sulfonate (PPTS)
3. The process as claimed in claim 1, wherein the solvent in step 1) & 2) is selected from the group comprising toluene, xylene, o-xylene, dimethyl formamide or mixtures thereof.
4. The process as claimed in claim 1, wherein step 3) is carried out without isolating the compound of step 2).
5. The process as claimed in claim 1, wherein the solvent in step 3) is selected from the group comprising methanol, ethanol, iso-propanol, ethyl acetate, toluene or mixtures thereof.
6. A process for the preparation of intermediates of Deferasirox comprising of reacting Salicyclic acid, thionyl chloride and Salicylamide in the presence of a catalyst and solvent to obtain a mixture of 2-(2-hydroxyphenyl-benz[e][1,3]oxazin-4-one and 2-hydroxy-N-(2-hydroxybenzoyi) benzamide.

7. The process as claimed in claim 6, wherein the catalyst used is Pyridinium para toluene sulfonate (PPTS)
8. The process as claimed in claim 6, wherein the solvent is selected from the group comprising toluene, xylene, o-xylene, dimethyl formamide or mixtures thereof.