Description
The present invention relates to cyclo dehydration of 2-Hydroxy-N-(2-hydroxy-benzoyl)-benzamide in the presence of bronsted acid/lewis acid catalyst at a reduced temperature of 1200C -1300C to yield 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one.

Deferasirox is a novel oral iron chelator for the treatment of chronic iron overload from blood transfusions represented by Formula I.

Formula I
US 6 465 504 B1 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 1700C to obtain 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one (Formula II) and its further conversion to Deferasirox.

Formula II

WO 2010023685 relates to a crystalline form of 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one.

US 3 554 567 disclose a process for the preparation of 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one.

The prior art process for the preparation of 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one disclosed in US ‘504 and WO/10/23685 comprises (a) reacting salicylic acid with thionyl chloride in the presence of a solvent to produce an acid chloride solution; (b) preparing a suspension of salicylamide in the presence of a solvent and heating the suspension to 100- 1100C; (c) mixing and heating the acid chloride solution of step(a) with suspension of step (b) to 1700C to cause cyclo dehydration of 2-Hydroxy-N-(2-hydroxy-benzoyl)-benzamide to -(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one.

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.

Prior art process steps require cyclo dehydration of 2-Hydroxy-N-(2-hydroxy-benzoyl)-benzamide to - (2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one to be carried out at a temperature of 1700C -1800C 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.

2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one is the key raw material in the synthesis of 4-[3  5-bis (2-hydroxyphenyl)-[1  2  4] triazol-1-yl]-benzoic acid or Deferasirox- an oral tridentate iron chelator. According to prior art the synthesis of 2-(2-hydroxyphenyl)benz[e] [1 3]oxazin-4-one by cyclo dehydration of 2-Hydroxy-N-(2-hydroxy-benzoyl)-benzamide requires high temperatures  usually in the range of 150 to 170 ºC. Maintaining such high temperatures at plant scale requires installation of special facilities including hot oil circulation. Such high temperatures are difficult to achieve using the low or high pressure steam generation boilers which are more commonly used in pharmaceutical manufacturing plants.

The present inventors while developing a process for the preparation of key intermediate raw material 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one (Formula II) for the preparation of Deferasirox have developed a process where in the cyclo dehydration of acyl compound 2-hydroxy-N-(2-hydroxybenzoyl) benzamide of (Formula III) may be converted to 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one by carrying out the reaction in the presence of bronsted acid/lewis acid at a much reduced temperature of 1200C -1300C.

In one of the embodiment of the invention use of bronsted acid/lewis acids catalyzes the cyclo dehydration of acyl compound 2-hydroxy-N-(2-hydroxybenzoyl) benzamide of (Formula III) 

Formula III
at a much reduced temperature of 1200C to 1300C requiring industrially easily available low or medium pressure steam of 3 to 4 kg/cm2g as against the steam pressure requirement of 7 to 9 kg/cm2g if the cyclo dehydration were to be carried out at 1700C to 1800C as per the prior art process or hot oil.

In second embodiment of the invention 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one (Formula II) may be obtained in good yield (0.9 – 1 kg/kg) and of good purity (96-97% rel by HPLC).

In third embodiment of the invention Eliminates higher capital investment  operating expenses and releases additional space which otherwise would be required for installation of hot oil heaters or higher pressure boilers.

In fourth embodiment of the invention use of low or moderate pressure steam means a favorable impact on green house gas effect.

In fifth embodiment of the invention the intermediate obtain the process of invention is used to prepare deferasirox.

In one of the aspects of the invention may be a process for the preparation of key intermediate raw material 2-hydroxyphenyl Benz[e] [1  3] oxazin-4-one (Formula II) wherein the cyclo dehydration of acyl compound 2-hydroxy-N-(2-hydroxybenzoyl) benzamide of (Formula III) may be carried out the in the presence of bronsted acid/lewis acid at a much reduced temperature of 1200C -1300C.

According to the present invention Salicylic acid  N  N-dimethyl formamide and thionyl chloride may be allowed to react in the presence of a hydrocarbon at 40-45ºC for 3 hours. The suspension of salicylamide in hydrocarbon may be prepared separately and heated to 100-110ºC. The concentrated acid chloride solution may then be added to this suspension over a period of 2-3 hours. To this a small quantity of bronsted acid or lewis acid may be added.

The bronsted acid in small quantity may be added to catalyze the cyclo dehydration of 2-Hydroxy-N-(2-hydroxy-benzoyl)-benzamide to 2-(2-hydroxyphenyl)benz[e] [1 3]oxazin-4-one at a reduced temperature. The reaction mass may be heated to at 1200C -1300C for 6 to 8 hours. At the end of the reaction  the resulting slurry is filtered off and washed with methanol to get the 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one compound as a yellow crystalline solid in good yield.

The intermediate 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one is converted to deferasirox by the process known in the prior art via US 6 465 504 and WO WO/10/23685.

The hydrocarbon used for the reaction may not be limited to but include of touene  o-xylene  m-xylene or mixture of xylene.

The bronsted acids may be one or more of hydrofluoric acid  hydroiodic acid  hydrobromic acid  hydrochloric acid  sulfuric acid  phosphoric acid  perchloric acid and organic acids like formic acid  acetic acid  propionic acid  p-toluene sulfonic acid  acidic compounds like phosphoryl chloride and thionyl chloride and the like.

The lewis acids may be one or more of aluminium chloride  ferric chloride  zinc chloride  and zirconium oxychloride

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example 1

Preparation of 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one
1 kg of salicylic acid  catalytic quantity (0.02 kg) of N N-dimethyl formamide and 0.64 L thionyl chloride were allowed to react in 3 L of o-xylene s solvent at 40-45ºC for 3 hours. At the end of reaction  toluene was distilled off partially to about half the original volume. In a separate flask  a suspension of 0.993 kg salicylamide was prepared in1 L o-xylene  and heated to 100-110ºC. The concentrated acid chloride solution was then added to the suspension over a period of 2-3 hours. The 5 ml of concentrated sulfuric acid is added and the reaction mass is heated at 120-130 ºC for 6 to 8 hours. At the end of the reaction  the resulting slurry was filtered off and washed with methanol to get the title compound as a yellow crystalline solid.
Yield: 0.9 kg.

Example 2

Preparation of 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one
An experiment is carried out similar to example 1 except that 5 ml of p-toluene sulfonic acid is used as the acid catalyst in place of sulfuric acid. Yield of 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one: 0.86 kg

Example 3

Preparation of 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one
An experiment is carried out similar to example 1 except that 10 ml of concentrated hydrochloric acid (36.0 % w/v) is used as the acid catalyst in place of sulfuric acid. Yield of 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one: 0.72 kg

Example 4

Preparation of 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one
An experiment is carried out similar to example 1 except that 5 ml of phosphoric acid is used as the acid catalyst in place of sulfuric acid. Yield of Oxazinone: 0.78 kg.

We claim:

1. A process for the preparation of 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one of Formula II  the process comprising treating salicylic acid chloride with salicylamide in hydrocarbon in the presence of bronsted acid/Lewis acid catalyst at 120-1300C.

Formula II
2. The process of Claim1  wherein hydrocarbon is one or more from toluene  o-xylene  m-xylene or mixture of xylene.
3. The process of Claim 1  wherein the bronsted acid is one or more of hydrofluoric acid  hydroiodic acid  hydrobromic acid  hydrochloric acid  sulfuric acid  phosphoric acid  perchloric acid  formic acid  acetic acid  propionic acid  p-toluene sulfonic acid phosphoryl chloride and thionyl chloride.
4. The process of Claim 3  wherein the sulfuric acid used as bronsted acid.
5. The process of Claim 1  wherein the lewis acids is one or more of aluminium chloride  ferric chloride  zinc chloride and zirconium oxychloride.
6. The process of Claim 5  wherein the zirconium oxychloride is used as Lewis acid.
7. The process of Claim 1  wherein obtained 2-(2-hydroxyphenyl) Benz[e] [1  3] oxazin-4-one (Formula II) is converted to Deferasirox.

Dated this 7th day of June  2012 For Wockhardt Limited

(Dr Mandar Kodgule)
Authorized Signatory