Field of the Invention This invention, in general relates to a process for producing 4-(3,5-bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl)benzoic acid (Deferasirox). More particularly the present invention provides a crystalline form of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one, process for preparing the same and employing the same for producing 4-(3,5-bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl)benzoic acid (Deferasirox).
Background of the Invention The excess of iron (metal) deposited in body tissues can cause severe damage to organs such as liver, the heart and the endocrine organs and can lead to death. Iron chelators are able to excrete the iron deposited in the organs and thus, lower the iron related morbidity and mortality. Deferasirox is one of such iron chelating agent, designated chemically as 4-(3, 5-bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid. It is a tridentate ligand and binds iron with high affinity i.e. 2:1 ratio.
Deferasirox (ICL670) is a novel once-daily oral iron chelator for the treatment of chronic iron overload from blood transfusions. This study evaluated the safety and tolerability of deferasirox in pediatric patients with transfusion-dependent P-thalassemia major. It was approved by the United States Food and Drug Administration (USFDA) in November 2005.
US 6,465,504 Bl is a product patent of deferasirox assigned to Novartis AG. The patent discloses a process for preparing deferasirox wherein the process includes reacting salicyloyl chloride with salicylamide at 170°C to obtain 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one (Formula II), and further crystallization in ethanol to obtain slight yellow color crystals of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one (Formula II). 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one is further reacted with 4-hydrazinebenzoic acid in presence of ethanol to give deferasirox having M.P: 264-265°C. The process is schematically represented below in Scheme -1.

The condensation reaction between salicyloyl chloride and salicylamide is carried out at high temperature in the absence of a solvent to obtain 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one of formula (II) which is dark in color and resulting in formation of large amount of impurities. The 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one so obtained requires a number of purification steps in different solvents to get desired quality of the intermediate. Further, the salicyloyl chloride employed in the preparation of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one is highly unstable.
Existing processes for the preparation of deferasirox require cumbersome steps for the preparation and purification of deferasirox. Further the reactants used in the process steps are highly unstable and difficult to handle during commercial production. The high

temperature and reaction conditions employed for the production of deferasirox results in formation of dark colored intermediates and a large amount of impurities.
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. Further, the process involves use of reactants that are stable and hence easy to handle during large scale production.
The subject matter claimed herein is not limited to embodiments that overcome any disadvantages as those described above. Rather, this background is only provided to illustrate one exemplary process where some embodiments described herein may be practiced.
Objects and Summary of the Invention It is an object of the present invention to provide a crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one and process thereof.
It is another object of the present invention to provide an improved process for the producing 4-(3,5-bis(2-hydroxyphenyl)-lh-l,2,4-triazol-l-yl)benzoic acid employing the crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one.
It is yet another object of the present invention to provide an improved process for large scale production of 4-(3,5-bis(2-hydroxyphenyl)-lh-l,2,4-triazol-l-yl)benzoic acid, wherein the process involves minimum steps and time.
It is still another object of the present invention to provide a high yielding process for the preparation of 4-(3,5-bis(2-hydroxyphenyl)-lh-l,2,4-triazol-l-yl)benzoic acid, wherein the process employs stable reactants and produces minimal by-products.

The above and other objects of the present invention are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to the described embodiments herein after.
In accordance with one preferred embodiment of the present invention there is provided a crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one, wherein said crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one is characterized by an X-ray powder diffraction pattern having peaks at 12.58,13.21 and 24.72 ±0.2 29°.
In accordance with another preferred embodiment of the present invention, there is provided a compound 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid prepared by employing said crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one, wherein the 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid is characterized by having the hydrazino benzoic acid content less than 5.0 ppm.
In accordance with one other preferred embodiment of the present invention, there is provided a process for producing a crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one, wherein the process comprises of reacting salicyloyl chloride with salicylamide employing a solvent 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-hydroxy phenyl)benz[e] [l,3]oxazin-4-one.
In accordance with yet another embodiment of the present invention, there is provided a process for producing a crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one, wherein the process further comprises of purifying said 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one employing a solvent to produce pure crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one.
In accordance with still another embodiment of the present invention, there is provided a process for producing 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid, the process comprises of reacting salicyloyl chloride with salicylamide employing a

solvent to give acyl compound 2-hydroxy-N-(2-hydroxybenzyl) benzamide, heating the resultant acyl compound 2-hydroxy-N-(2-hydroxybenzyl) benzamide in situ to obtain 2-(2-hydroxy phenyl) benz[e] [l,3]oxazin-4-one, reacting the resultant 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one with 4-hydrazino benzoic acid in presence of a solvent to obtain the 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid and isolating the 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2,4-triazol-l-yl) benzoic acid.
In accordance with still another embodiment of the present invention, wherein the process further comprising of purifying 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid by employing a solvent.
Brief Description of the Drawings Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures, wherein:
Fig. 1 shows the X-ray diffraction pattern of 2-(2-Hydroxy phenyl) benz[e][l,3]oxazin-4-one.
Detailed Description Of The Invention While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
The present invention discloses a crystalline form of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one. The crystalline form of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one is characterized by X-ray powder diffraction pattern.
Further, the present invention discloses an improved process for the preparation of the 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one. In addition the present invention describes

an improved process for the preparation of 4-(3,5-bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl)benzoic acid employing 2-(2-hydroxyphenyl) benz [e] [1,3] oxazin-4-one employing the crystalline form of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one .
Powder X-rav Diffraction (PXRD)
The crystalline form of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one of the present invention is characterized by its X-ray powder diffraction pattern. Thus, the X-ray diffraction pattern of said crystalline form of the invention was measured on PAnalytical, X'Pert PRO powder diffractometer equipped with goniometer of G/0 configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40 KV and 30 mA. The experiments were conducted over the 26 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.
The crystalline form of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one is characterized by X-ray powder diffraction pattern as shown in Figure 1 having peaks at about 10.70, 12.58 ,13.21, 17.04, 22.56, 24.72, 27.82 and 28.63 ± 0.2 9.
According to the present invention, the improved process for the preparation of crystalline form of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one of formula II, wherein the process involves a condensation reaction between salicyloyi chloride and salicylamide in the presence of a solvent to give acyl compound 2-hydroxy-N-(2-hydroxybenzyl) benzamide of formula (Ha) and heating the acyl compound in-situ resulting in cyclization of 2-hydroxy-N-(2-hydroxybenzyl) benzamide to obtain the crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one of formula II, as shown in the following scheme:


The solvent for condensation reaction between salicyloyl chloride and salicylamide is selected from o-xylene, anisole or diphenyl ether and preferred solvent is o-xylene.
According to the present invention the 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one of
formula (II) is further purified by crystallization in a solvent to give crystalline form of 2-
(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one of formula (II) with improved yield and
P color. The solvent used in the purification is selected from methanol, ethanol, isopropyl
alcohol, n-butanol or mixtures thereof.
The crystalline form of 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one is employed as an intermediate for the production of 4-(3, 5-bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid of formula III. The crystalline 2-(2-hydroxyphenyl) benz [e] [1, 3] oxazin-4-one according to the above process is further reacted with 4-hydrazino benzoic acid in presence of a solvent to obtain 4-(3,5-bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl)benzoic acid. The solvent is selected from methanol, ethanol, isopropyl alcohol, n-butanol or mixtures thereof, preferably ethanol.

Further, the 4-(3,5-bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl)benzoic acid obtained is subjected to purification in a solvent or mixture of solvent with water to give 4-(3,5-bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl)benzoic acid, wherein the 4-(3,5-bis(2-hydroxyphenyl)-lH-l,2,4-triazol-l-yl)benzoic acid having 4-hydrazino benzoic acid content less than 5 ppm, more preferably less than 2ppm. The solvent used in purification is selected from methanol, ethanol, 1-propanol, isopropyl alcohol, butanol, acetone, methyl ethyl ketone, water or mixtures thereof.
According to a preferred embodiment of the invention, the reaction is carried out at a temperature between 40-180°. The condensation reaction between salicyloyl chloride and salicylamide is carried out at a temperature around 40-80° C to form acyl compound 2-hydroxy-N-(2-hydroxybenzyl) benzamide. The 2-hydroxy-N-(2-hydroxybenzyl) benzamide is in-situ heated to temperature between 100-180° C, preferably between 120-160° C. At this temperature 2-hydroxy-N-(2-hydroxybenzyl) benzamide is cyclized and completely converted into 2-(2-hydroxy phenyl) benz[e] [l,3]oxazin-4-one of formula (II) with a very small quantity of un-reacted 2-hydroxy-N-(2-hydroxybenzyl) benzamide and other impurities.
The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.
Example 1
Preparation of Salicyloyl chloride
Salicylic acid (0.362 moles) was dissolved in 150ml ortho xylene at room temperature. The reaction mass was cooled to 0-5°C and charged with 1 ml of dimethyl formamide at the same temperature and maintained for 10 minutes followed by addition of 0.3981 of thionyl chloride at the same temperature over a period of 60-90 min. After completion of addition, the reaction temperature was raised to 35-40°C and maintained for 3-4 hours to produce xylene solution of salicyloyl chloride.

Example 2
Preparation of Salicvlovl chloride
Salicylic acid (0.362 moles) was dissolved in 150 ml anisole at room temperature. The reaction mass was cooled to 0-5°C and charged with 1 ml of dimethyl formamide at the same temperature and maintained for 10 minutes followed by addition of 0.3981 moles of thionyl chloride at the same temperature over a period of 60-90 min. After completion of addition, the reaction temperature was raised to 35-40°C and maintained for 3-4 hours to produce xylene solution of salicyloyl chloride.
Example 3
a) Preparation of 2-(2-Hvdroxy phenyl) benz [e] [1. 3] oxazin-4-one
Salicylamide (0.2552 moles) was heated at 140-160°C and slowly added to the xylene solution of Salicyloyl chloride (Example-1) over a period of 90-120 minutes at the same temperature and maintained for 3-5 hours. Reaction mass was cooled to 25-30°C and maintained for 60 minutes, followed by Alteration and washing with 50 ml ortho xylene. The compound was dried under vacuum at 40-45°C for 2-3 hours to produce crude product of 2-(2-Hydroxy phenyl) benz[e] [ 1,3]oxazin-4-one (Deferasirox Intermediate).
The obtained crude product was suspended in 175 ml ethanol at 25-30°C. The temperature was raised to 75-80°C and maintained for 60 minutes. The reaction mass was cooled to 25-30°C and maintained for another 60 minutes. The resultant mass was filtered and washed with 70 ml ethanol, dried under vacuum at 45 °C and maintained for 4-6 hours to produce 45 gm of pure 2-(2-Hydroxy phenyl) benz[e] [l,3]oxazin-4-one.
Example -4
Preparation of 2-(2-Hydroxy phenyl) benz[e"lf 1.3]oxazin-4-one (Stage-1)
0.255 moles of Salicylamide was dissolved in 70 ml of O-xylene and the temperature was raised to 130-160°C. Xylene solution of Salicyloyl chloride (prepared in example-1) was

added to the resulting solution over a period of 90-120 minutes at the same temperature and maintained for 3-5 hours till salicylamide disappears. After reaction is over, the reaction mass was maintained for 2-3 hours at 130-160°C. Subsequently, xylene was distilled out completely at atmospheric pressure. To the resultant compound 35 ml of ethanol was added, distilled off under vacuum and fresh ethanol was again added. The reaction temperature was raised to 75-80°C and maintained for 60 minutes followed by cooling of the reaction mass to 0-5°C and maintained for 60 minutes. The resultant mixture was then filtered, washed with 35 ml ethanol and dried under vacuum at 45°C for 4-6 hours to produce 52 gm of 2-(2-Hydroxy phenyl) benz[e] [1,3] oxazin-4-one.
Example- 5
Preparation of 2-(2-Hydroxy phenyl) benz[e][1.3]oxazin-4-one (Stage-1)
0.255 moles of Salicylamide was dissolved in anisole and the temperature was raised to 140-180°C. To the resultant solution anisole solution of Salicyloyl chloride (prepared in example-1 A) was added over a period of 90-120 minutes at the same temperature and maintained for 3-5 hours till salicylamide disappears. After reaction is over, the reaction * mixture was maintained for 2-3 hours at 140-160°C. Anisole was distilled off completely at atmospheric pressure and 35 ml of ethanol was added to the resultant compound. Subsequently, ethanol was distilled off under vacuum and fresh ethanol was again added. The reaction temperature was raised to 75-80°C and maintained for 60 minutes, cooled to 0-5°C and maintained for 60 minutes, filtered and washed with 35 ml ethanol and dried under vacuum at 45 °C for 4-6 hours to produce 52 gm of 2-(2-Hydroxy phenyl) benz[e] [1, 3] oxazin-4-one.
Example 6
Preparation of 4-(3, 5- bis (2-hydroxvphenyl)-lH-l, 2.4-triazol-l-vl) benzoic acid 0.1945 moles of 2-(2-Hydroxy phenyl) benz[e] [1, 3] oxazin-4-one was dissolved in 750 ml of methanol and 0.2305 moles of 4-Hydrazino benzoic acid was added at 25-30°C. Subsequently, the temperature of the reaction mixture was raised to 65-70°C and maintained for 3-4 hours at the same temperature. The reaction mass was cooled to 25-

30°C followed by 0-5°C and maintained for 60 minutes. The reaction mass was then filtered and washed with chilled 100 ml of methanol.
175 ml of dimethyl formamide was added to the resultant solid and stirred for 15-20 minutes to get a clear solution. The above DMF solution was slowly added to a mixture of 700 ml D M water and 14 ml concentrated HC1 in 60 minutes at 25-35°C and maintained for 60-90 minutes at the same temperature. The mixture was the filtered and washed with water (4 X 140 ml), dried under vacuum at 50-60°C for 4-6 hours to produce 70 gm of crude 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2,4-triazol-l-yl) benzoic acid.
The resultant solid obtained from methanol was suspended in water and heated to 50-100° C, cooled and filtered to give 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid, free from sulfated ash.
Example 7 Purification of 4-C3. 5- bis (2-hydroxvphenyO-lH-l. 2.4-triazol-l-yl) benzoic acid
50 gms of 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid was dissolved in 1250 ml of isopropyl alcohol and maintained for 60 to 90 minutes at 80-85°C. 0.5 gm of activated carbon was added to the reaction mass and maintained for 30 minutes at the same temperature. The reaction mass was then filtered through high flow bed and washed with 50 ml of isopropyl alcohol, which was subsequently distilled off completely and charged with 250 ml of acetone. The reaction mass was then cooled to 15-25°C and maintained for 60 minutes and dried at 50-60°C under vacuum for 4-6 hours to produce 45 gms of pure 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid. Further 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid was suspended in methanol 250 ml and heated to reflux for 3-5 hours. Subsequently resultant mixture was cooled and filtered to obtain pure 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid.
12

Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.

We Claim:
1. A crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one , wherein said crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one is characterized by an X-ray powder diffraction pattern having peaks at 12.58, 13.21 and 24.72 ±0.2 20°.
2. The crystalline form according to claim 1, wherein said 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one is characterized by an X-ray powder diffraction pattern having peaks at 10.70, 12.58,13.21,17.04,22.56,24,72,27.82 and 28.63 ±0.2 20°.
3. The crystalline form according to claim 1, wherein said crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one is having a substantially similar X-ray powder diffraction pattern as depicted in Figure 1.
4. The crystalline form according to claim 1, wherein said crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one is employed to prepare 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2,4-triazol-l-yl) benzoic acid.
5. A process for preparing crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one comprising the steps of:

a) reacting salicyloyl chloride with salicylamide employing a solvent to give acyl compound 2-hydroxy-N-(2-hydroxybenzyl) benzamide; and
b) heating the acyl compound in-situ to obtain the crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one.
6. The process according to claim 5, wherein the solvent is selected from o-
xylene, anisole and diphenylether, or mixture thereof, preferably the o-xylene.
14

7. The process according to claim 5, wherein the process further comprising purifying said 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one employing a solvent to produce pure crystalline form of 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one.
8. The process according to claim 7, wherein the solvent is selected from methanol, ethanol, isopropyl alcohol, n-butanol or mixtures thereof.
9. The process according to claim 5, wherein the heating is performed at a temperature between 100-180° C, preferably between 120-160° C.
10. The process according to claim 5, wherein the process further comprising reacting the 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one with 4-hydrazino benzoic acid in presence of a solvent to obtain 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid.
11. The process according to claim 10, wherein the solvent is selected from methanol, ethanol, isopropyl alcohol, n-butanol or mixtures thereof, preferably ethanol.
12. A process for preparing 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid, the process comprising:

a) reacting salicyloyl chloride with salicylamide employing a solvent to give acyl compound 2-hydroxy-N-(2-hydroxybenzyl) benzamide];
b) heating the acyl compound in situ to obtain 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one;
c) reacting 2-(2-hydroxy phenyl)benz[e] [l,3]oxazin-4-one with 4-hydrazino benzoic acid in presence of a solvent to obtain the 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid; and
d) isolating 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid.

13. The process according to claim 12, wherein the process further comprising
purifying 4-(3, 5- bis (2-hydroxyphenyl)-lH-l, 2, 4-triazol-l-yl) benzoic acid by
employing a solvent.
14. The process according to claim 13, wherein the solvent is preferably
selected from methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, methyl ethyl
ketone, water more preferably selected from isopropyl alcohol, acetone and methyl ethyl
ketone.
15. A compound 4-(3, 5- bis (2-hydroxyphenyl)-1H-1,2,4-triazol-1 -yl) benzoic
acid prepared according to claim 12, wherein the 4-(3, 5- bis (2-hydroxyphenyl)-1H-1, 2,
4-triazol-l-yl) benzoic acid is characterized by having the hydrazino benzoic acid content
less than 5.0 ppm.
16. The process according to claim 12, wherein the solvent employed in step
10(a) is selected from o-xylene, anisole or diphenylether, preferably o-xylene.
17. The process according to claim 12, wherein the heating is performed at a
temperature between 100-180° C, preferably between 120-160° C.
18. The process according to claim 12, wherein the solvent in step 10(c) is
selected from methanol, ethanol, isopropyl alcohol, n-butanol or mixtures thereof.