WO2014072992A1

WO2014072992A1 - A process for preparing triazole compounds

Info

Publication number: WO2014072992A1
Application number: PCT/IN2013/000640
Authority: WO
Inventors: Parimal Hasmukhlal DESAI; Narendra Jagannath Salvi; Seetharaman Subramanian
Original assignee: Aarti Industries Limited
Priority date: 2012-11-12
Filing date: 2013-10-18
Publication date: 2014-05-15

Abstract

The present invention relates to process for preparing triazole compounds used in the treatment of epilepsy. The process comprises of reacting compound of 2, 6 difluoroazide (II) with 2, 3 dihalo compound (III) to form compound of formula I, which on further treatment with an aminating agent gives Rufinamide (IV). 2, 6 difluoroazide (II) is reacted with 2, 3 dihalo compound (III) in the presence of a solvent. The reaction can be carried out in a single pot without isolation of intermediates.

Description

A PROCESS FOR PREPARING TRIAZOLE COMPOUNDS

TECHNICAL FIELD OF THE INVENTION

The present invention relates to process for preparing triazole compounds for treating epilepsy or convulsions.

BACKGROUND OF THE INVENTION

World Health Organization defines epilepsy as a chronic disorder characterized by recurrent seizures, which may vary from a brief lapse of attention or muscle jerks, to severe and prolonged convulsions. The seizures are caused by sudden, usually brief, excessive electrical discharges in a group of brain cells (neurones). In most cases, epilepsy can be successfully treated with anti-epileptic drugs. In developed countries, annual new cases are in between 40 to 70 per 100000 people in the general population. Close to 80% of epilepsy cases worldwide are found in developing regions. The risk of premature death in people with epilepsy is two to three times higher than it is for the general population. Epilepsy accounts for 0.5% of the global burden of disease. Epilepsy has significant economic implications in terms of health-care needs, premature death and lost work productivity. An Indian study calculated that the total cost per epilepsy case was US$ 344 per year (or 88% of the average income per capita). The total cost for an estimated five million cases in India was equivalent to 0.5% of gross national product. Barbiturates, Carbamates, GABA analogs, Hydantoins, Oxazolidinediones, Pyrimidinediones, Triazines, Valproylamides, etc are some of the drugs used for treating epilepsy.

Rufinamide, chemically described as l -(2, 6-difluorobenzyl)-lH-l, 2, 3-triazole- 4-carboxamide is a triazole having antiepileptic activity. It is particularly used in the treatment of Lennox-Gastaut syndrome and other seizure disorders.

US4789680 discloses Rufinamide and a process for preparing the same. In the scheme covered by this patent, 2, 6-difluoro benzyl azide is treated with propiolic acid to form an intermediate, which on further treatment with thionyl chloride and methanolic ammonia gives Rufinamide. The reaction disclosed in this patent uses expensive reagents like propiolic acid. Also, the control of 5- carboxylic acid amide and tetrazole impurities on commercial scale is very difficult. WO2010043849 describes the process for preparation of Rufinamide by reaction of 2,6-difluorobenzyl azide with methyl propiolate to obtain methyl l-(2,6- difluorobenzyl)-l H-l,2,3-triazole-4-carboxylate, which on reaction with ammonia forms Rufinamide. The reaction uses expensive reagents like methyl propiolate.

US6277999 and US6156907 disclose the process for the preparation of Rufinamide by reacting 2, 6-difluorobenzyl azide and 2-chloroacrylonitrile in the presence of aqueous sodium hydroxide and toluene to form Rufinamide. The reaction disclosed in this patent uses expensive reagents like 2- chloroacrylonitrile.

WO2012/025936 discloses a process for preparing Rufinamide by reacting 2,6- difluoro benzyl azide with alkyl 2-bromo acrylate to form 1 -(2,6- difluorobenzyl)- 1 H- 1 ,2,3 -triazole-4-carboxylate ester which is then converted to Rufinamide. The route is as shown below.

Scheme P_d Rufinamide

Alkyl bromo acrylate compound used in the above reaction is prone to polymerization and needs the storage at -20°C. Thus special precaution is needed during handling and storage of alkyl bromo acrylate compound.

The preparation of azide by various known processes is time consuming, thereby making the process tedious.

Thus, there is a need for a process for preparing Rufinamide and its intermediates, which is less time consuming, avoids the use of expensive reagents and forms the product with higher purity and yield.

SUMMARY OF THE INVENTION An aspect of the present invention relates to a process for preparing triazole compound of formula I. The process comprises reacting 2,6-difluorobenzyl azide (II) with 2,3-dihalo compound (III) to form compound of fomiula I.

wherein,

Xi is chlorine, fluorine, bromine or iodine

X is chlorine, fluorine, bromine or iodine

R is -OR1 or -NH2 and Rl is H or C,-C₆ alkyl.

Another aspect of the invention relates to a process for preparing Rufinamide (IV), the process comprises of reacting 2,6-difluorobenzyl azide (II) with 2,3- dihalo compound (III) to form compound of formula I, which is further treated with an animating agent to form Rufinamide (IV).

IV

wherein,

Xi is chlorine, fluorine, bromine or iodine X₂ is chlorine, fluorine, bromine or iodine R is -ORi, Ri is H or Ci-C₆ alkyl. In an aspect of the present invention Rufinamide (IV) is prepared by condensin 2,6-difluorobenzyl azide (II) with 2,3-dihalo compound (III).

wherein,

X) is chlorine, fluorine, bromine or iodine

X₂ is chlorine, fluorine, bromine or iodine

R is NH2.

Another aspect of the invention relates to a process for preparing 2, 6 difluorobenzyl azide (II) by reacting 2, 6 difluorobenzyl halide (V) and an azide in the presence of an activating agent to form 2, 6 difluorobenzyl azide (II).

V

II wherein, X is chlorine, bromine or iodine DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

An embodiment of the present invention relates to a process to prepare triazole compound of formula I, the process comprising the steps of reacting 2,6- difiuorobenzyl azide (II) with 2,3-dihalo compound (III) to form compound of formula I. The reaction scheme is represented as follows:

wherein,

Xi is chlorine, fluorine, bromine or iodine

X₂ is chlorine, fluorine, bromine or iodine

R is -OR_! or -NH₂, and Rl is H, C_rC₆ alkyl

In a preferred embodiment of the present invention, a process to prepare Rufinamide (IV) comprises reacting 2,6-difluorobenzyl azide (II) with 2,3- dihalo compound (III) to form compound of formula I, which is further treated with an aminating agent to form Rufinamide (IV).

IV wherein,

Xi is chlorine, fluorine, bromine or iodine

X₂ is chlorine, fluorine, bromine or iodine

R is -OR._!, and Ri is H or C C₆ alkyl.

The reaction between 2, 6 difluorobenzyl azide (II) and 2, 3 dihalo compound (III) is carried out at a temperature in the range of 70-140°C. In a further embodiment of the present invention, 2, 6 difluorobenzyl azide (II) is reacted with 2, 3 dihalo compound (III) in the presence of a solvent selected from 1 , 4 dioxane, isopropyl alcohol, ethylene glycol, diethylene glycol, diglyme or diethyl ether. The aminating agent is liquid or gaseous ammonia, preferably methanolic ammonia.

In an embodiment of the present invention, the above reactions can be carried out in the presence of an organic base selected from triethyl amine, tetramethylethylenediamine, bis[2-(N,N-dimethylamino)ethyl] ether, 1 ,8- Diazabicycloundec-7-ene (DBU), l,4-Diazabicyclo[2.2.2]octane (DABCO), or an inorganic base selected from sodium methoxide, sodium t-butoxide, potassium t-butoxide, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

In one embodiment of the present invention, the above reactions can be carried out in the presence of an activating agent selected from trimethyl silyl chloride, trimethyl silyl bromide, trimethyl silyl iodide, trimethyl silyl fluoride, trimethylsilyl trifluoromehtanesulfonate (TMSOTf), trimethyl silyl cyanide and N, N-bis (trimethylsilyl)-trifluoroacetamide. The use of an activating agent reduces the reaction time and gives a better yield.

In another embodiment of the present invention, the above reactions can be carried out in the presence of a base and an activating agent. An embodiment of the present invention relates to a process for preparing compound of formula II by reacting 2,6-difluorobenzyl halide (V) and an azide in the presence of an activating agent to form 2,6-difluorobenzyl azide (II).

wherein,

X is chlorine, bromine or iodine.

R" is:

an alkali metal, preferably sodium or potassium

R₂ Si- , wherein R₂ is Ci-C₆ alkyl, preferably trimethyl silyl azide or

P(0)(0- CrC₆ alkyl) or diphenyl phosphoryl azide.

The activating agent is preferably hydrazine hydrate and the reaction is carried out at a temperature in the range of 70-90° C to obtain 2,6-difluorobenzyl azide (II). The addition of an activating agent reduces the reaction time to few hours. In a preferred embodiment, 2,6-difluorobenzyl azide (II) is further treated with 2,3 -dihalo compound (III) to form triazole compound of formula I having R as - OR1 , which is further treated with an aminating agent, to form Rufinamide (IV). 2,6-difluorobenzyl azide (II) is reacted with 2,3 -dihalo ^'compound (III) in the presence of a solvent selected from 1 , 4-dioxane, isopropyl alcohol, ethylene glycol, diethylene glycol, diglyme or diethyl ether. The aminating agent is liquid or gaseous ammonia, preferably methanolic ammonia.

In an embodiment of the present invention, the process of preparing Rufinamide (IV) can be carried out in the presence of an organic base selected from triethyl amine, tetramethylethylenediamine, bis[2-(N,N-dimethylamino)ethyl] ether, 1,8- Diazabicycloundec-7-ene (DBU), l ,4-Diazabicyclo[2.2.2]octane (DABCO), or inorganic base selected from sodium methoxide, sodium t-butoxide, potassium t- butoxide, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

In one embodiment of the present invention, the process of preparing Rufinamide (IV) can be carried out in the presence of an activating agent selected from trimethyl silyl chloride, trimethyl silyl bromide, trimethyl silyl iodide, trimethyl silyl fluoride, trimethylsilyl trifluoromehtanesulfonate (TMSOTf), trimethyl silyl cyanide and N, N-bis (trimethylsilyl)- trifluoroacetamide. The use of an activating agent reduces the reaction time and gives a better yield.

In another embodiment of the present invention, the process of preparing Rufinamide (IV) can be earned out in the presence of a base and an activating agent.

The reactions can proceed without the isolation of triazole of formula I or formula II, thus making the process a one pot synthesis of compound of formula IV.

Rufinamide (IV) can be further purified in accordance with the known methods.

The following examples illustrate the invention, but are not limiting thereof.

EXAMPLES

Example 1 :

Preparation of 2, 6-difluorobenzyl azide

To a mixture of sodium azide (34 g) and water (1 lit), 2, 6- difluorobenzylbromide (100 g) was charged. The reaction mixture was heated to 70-75°C for 30 hours. After completion of the reaction, the contents were cooled to room temperature. The layers of the reaction mixture were separated to obtain an upper water layer and a lower azide intermediate layer. The lower layer was extracted with dichloromethane (300 ml) and further washed with brine (10 ml). The layer is dried with sodium sulphate (15 g). The organic layer thus obtained was then evaporated under vacuum below 40°C to obtain 81.6 g of the product.

Example 2:

Preparation of 2, 6-difluorobenzyl azide

To a mixture of 1.7 g of sodium azide, 60 ml of water and 0.363 g of hydrazine hydrate, 5g of 2, 6-difluorobenzylbromide was added. The mixture was heated to 70-75°C for 3 hours. After completion of the reaction, the contents were cooled to room temperature to obtain an upper water layer and a lower azide intermediate layer. The lower layer was extracted with 20ml dichloromethane and further washed with 10 ml brine. The layer was dried with 2 g sodium sulphate. The organic layer thus obtained was then evaporated under vacuum below 40°C to obtain 3.6 g of 2, 6-difluorobenzyl azide.

Example 3 :

Preparation of 2,3-Dibromo- methyl propionate

Bromine (102 g) in dichloromethane (220ml) was added drop wise to the solution of the methyl acrylate (50 g) in dichloromethane (250ml) previously cooled to -10°C over 1 hour. The mixture was stirred by maintaining the internal temperature below 20-25°C for 7 hours at which stage orange color persisted. A saturated solution of sodiumdithionate (200 ml) was added until a persistent colorless solution was observed. The solution was extracted with dichloromethane (100ml). The organic phase was dried over sodium sulphate, filtered & vacuum treated to remove the solvent to obtain 2,3-Dibromo- propionic acid methyl ester (104g) as an oil.

Example 4:

Preparation of 2,3-Dibromo-propionamide

Bromine (246 g) in chloroform (514ml) was added dropwise to the solution of the acrylamide (100 g) in chloroform (700ml) previously cooled to -10°C over 1 hour. The mixture was stirred by maintaining the internal temperature below 20- 25°C, for 7 hours at which stage orange color persisted. 1% sodium sulfite solution (150 ml) was added to the mixture, which was stirred & filtered to obtain a solid. The solid was dissolved in ethylacetate (1.5 lit), washed with brine and dried over sodium sulphate. After removal of the solvent in vacuum, 2,3-dibromopropionamide (273.6 g) was obtained as a white solid.

Example 5:

Preparation of methyl l-(2, 6-difmorobenzyl)-lH-l,2,3-triazole- 4-carboxylate 2,6-difluorobenzyl azide (20 g), 2,3-dibromo methyl propionate (43.63 g), tri ethyl amine (19.36 g) and isopropyl alcohol (200 ml) were charged in a reaction vessel. The reaction mixture was heated to 75-80°C for 25 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, isopropyl alcohol was evaporated in vacuum to give brown solid to which water was added and extracted using dichloromethane (150 ml). The organic layer was washed with brine, dried on sodium sulphate and evaporated in vacuum below 40°C to give brown solid. This solid was slurried in n-heptane, filtered and dried at 60-65°C to give methyl l-(2, 6-difluorobenzyl)-lH-l,2,3- triazole- 4-carboxylate (19.3g) as light brown solid.

Example 6:

Preparation of Rufinamide

Methyl l-(2, 6-difIuorobenzyl)-lH-l,2,3-triazole- 4-carboxylate (19 g) was dissolved in methanol (285 ml) at 65-70°C. Added dropwise 20% liq NH₃ (150 ml) over a period of 30 min. The mixture was then stirred at 65-70°C for 5-6 hours. After the completion of reaction, as monitored by TLC, the reaction mixture was cooled to room temperature. The solid was filtered, washed with water and dried under vacuum at 65°C to give rufinamide (13.3 g).

Example 7:

Preparation of Rufinamide

To the mixture of 2,6-diftuorobenzyl azide (4.75 g) and 2,3- dibromopropionamide (5 g), triethyl amine (2.18 g) and 1 ,4-dioxane (30 ml) were charged. The reaction mixture was heated to 100 ^" 105°C for 25 to 30 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, water (50 ml) was added; the solid was filtered by suction and washed with water (50 ml). This solid was added in methanol (30 ml), filtered and dried at 60-65°C to give Rufinamide (2.5g) as a light brown solid.

Example 8:

Preparation of Rufinamide

Trimethyl silyl chloride (TMSC1) (8.35 g) was added to pre-stirred mixture of 2,3-dibromopropionamide (17.8 g) and tetramethylethylenediamine (TMEDA) (10.3 g) and diglyme (80 ml) at room temperature. The temperature of the reaction mixture was increased to 55°C. 2, 6-difluorobenzyl azide (10 g) was added to the reaction mixture at 55°C. The reaction mixture was then heated to 125°C for 3 hours. After completion of the reaction, water (80 ml) and n- Heptane (60 ml) were added and the mixture was stirred for 10 min. The solid obtained was filtered at suction and washed with water (40ml) & n-heptane (40ml). This solid was slurried in methanol (100 ml), cooled to 15°C & filtered. The solid was dried at 60-65°C to give Rufinamide (11.2 g) as light brown solid.

Example 9:

Preparation of Rufinamide

Trimethyl silyl chloride (TMSCl) (4.18 g) was added to pre-stirred mixture of 2,3-dibromopropionamide (8.89 g) and l,8-diazabicycloundec-7-ene (DBU) (5.85 g) and diglyme (50 ml) at room temperature. The temperature of the reaction mixture was increased to 55°C. 2, 6-difluorobenzyl azide (5 g) was added to the reaction mixture at 55°C. The reaction mixture was then heated to 125°C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Water (35 ml) and n-Heptane (20 ml) were added and the mixture was stirred for 10 min. The solid obtained was filtered at suction & washed with water (25 ml) and n-heptane (20 ml). This solid was then slurried in methanol (30 ml), cooled to 15°C, washed with methanol (20 ml) and filtered. The solid was dried at 60-65°C to give Rufinamide (2.5 g) as light brown solid.

Example 10:

Preparation of Rufinamide Trimethyl silyl chloride (TMSCl) (4.18 g) was added to pre-stirred mixture of 2,3-Dibromopropionamide (8.89 g) and sodium methoxide (4.16 g) and diglyme (40 ml) at room temperature. The temperature of the reaction mixture was increased to 55°C. 2, 6-difluorobenzyl azide (5 g) was added to the reaction mixture at 55°C. The reaction mixture was then heated to 125°C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Water (40 ml) and n-Heptane (20 ml) were added and the mixture was stirred for 10 min. The solid obtained was filtered at suction & washed with water (20 ml) & n-heptane (20 ml). This solid was then slurried in methanol (30 ml), cooled to 15°C, washed with methanol (20 ml) and filtered. The solid was dried at 60-65°C to give Rufinamide (2.4 g) as light brown solid.

Example 1 1 :

Preparation of Rufinamide

Trimethyl silyl chloride (TMSCl) (3.34 g) was added to pre-stirred mixture of 2,3-Dibromopropionamide (7.11 g) and potassium tert-butoxide (4.16 g) and diglyme (32 ml) at room temperature. The temperature of the reaction mixture was increased to 55^°C. 2, 6-difluorobenzyl azide (4 g) was added to the reaction mixture at 55 C. The reaction mixture was then heated to 125°C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Water (40 ml) and n-Heptane (30 ml) were added and the mixture was stirred for 10 min. The solid obtained was filtered at suction & washed with water (20 ml) & n-heptane (20 ml). This solid was then slurried in methanol (20 ml), cooled to 15°C, washed with methanol (10 ml) and filtered. The solid was dried at 60-65°C to give Rufinamide (0.6 g) as light hrown solid.

Example 12:

Purification of Rufinamide

Crude Rufinamide (3 g) obtained in above examples and formic acid (12 ml) were heated to 50-55°C to get clear solution. This reaction mass was added to previously cooled methanol (12 ml) at 20°C dropwise through dropping funnel. The reaction mass was stirred for 1 hour at 20-25 °C. The solid was filtered and washed with methanol (3 ml). The solid was dried at 60-65°C to give pure Rufinamide (2.7 g) as a white crystalline solid, with 99.9% purity.

Example 13

One pot preparation of Rufinamide from dibromopropionamide

PART-A:-

Sodium azide (1.7g) was added to pre-stirred mixture of 2,6-difluorobenzyl bromide (5g), hydrazine hydrate (0.36g) and diglyme (25ml) at room temperature. The temperature of the reaction mixture was increased to 75^°C for 3 hours. Reaction mass was cooled to room temperature and used as is in the next step without isolation of the product.

PART-B: Trimethyl silyl chloride (TMSCl) (3.4 g) was added to pre-stirred mixture of 2,3-Dibromopropionamide (7.2 g) and Tetramethylethylenediamine (TMEDA) (8.4 g) and diglyme (30 ml) at room temperature. The temperature of the reaction mixture was increased to 45 C. To this was added PART-A solution through dropping funnel in 5 mins. The reaction mixture was then heated to 125°C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Water (40 ml) and n-Heptane (30 ml) were added and the mixture was stirred for 10 min. The solid obtained was filtered at suction & washed with water (20 ml) & n-heptane (20 ml). This solid was then slurried in methanol (20 ml), cooled to 15°C, washed with methanol (10 ml) and filtered. The solid was dried at 60-65°C to give Rufinamide (1.1 g) as light brown solid.

Example 14

One pot preparation of Rufinamide from 2,3-dibromo methyl propionate

2,6-difluorobenzyl azide (20 g), 2,3-dibromo methyl propionate (43.63 g), triethyl amine (19.36 g) & IPA (200 ml) were charged. The reaction mixture was heated to 75-80°C for 25 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, 20% liq N¾ (150 ml) added dropwise over a period of 30 min.

The mixture was then stirred at 75-80°C for 5-6 hours. After the completion of reaction, as monitored by TLC, the reaction mixture was cooled to room temperature. The solid obtained was filtered, washed with water and dried under vacuum at 65°C to give a light brown solid product (13.3 g).

Utility

The compounds of formula I and IV and their compositions are used for the treatment of epilepsy or convulsions, they are particularly used to treat Lennox- Gastaut syndrome and other seizure disorders. The reactions can be carried out in a single pot reaction, thus avoiding the separation of the intermediates, which can be tedious. Also, the use of expensive reagents is avoided, which makes the process industrially advantageous and economical. The yield and purity of the products obtained by the process as defined in the various embodiments is much higher than the known processes.

Claims

Claims :

1. A process for preparing triazole compound of Formula I, the process comprising reacting 2,6-difluorobenzyl azide (II) with 2,3-dihalo compound (III) to form compound of fonnula I.

wherein,

R is -ORi or NH_2; Rj is H or C_rC₆ alkyl group

Xi and X₂, independently is chlorine, fluorine, bromine or iodine

The process as claimed in claim 1 , comprising reacting 2, 6-difluorobenzyl azide (II) with 2, 3-dihalo compound (III) in the presence of a solvent.

The process as claimed in claim 2, wherein the solvent is selected from 1 ,4- dioxane, ethylene glycol, diglyme, diethylene glycol, isopropyl alcohol and diethyl ether.

The process as claimed in any of the preceding claims 1 to 3, comprising carrying out the reaction in presence of a base.

The process as claimed in any of the preceding claims 1 to 3, comprising carrying out the reaction in the presence of an activating agent. The process as claimed in any of the preceding claims 1 to 3, comprising carrying out reaction in presence of a base and an activating agent.

The process as claimed in claim 4 or 6, wherein the base is an organic base selected from triethyl amine, tetramethylethylenediamine, bis[2-(N,N- dimethylamino)ethyl] ether, l ,8-Diazabicycloundec-7-ene (DBU), 1 ,4- Diazabicyclo[2.2.2]octane (DABCO), or an inorganic base selected from sodium methoxide, sodium t-butoxide, potassium t-butoxide, sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

The process as claimed in claim 5 or 6, wherein the activating agent is selected from trimethyl silyl chloride, trimethyl silyl bromide, trimethyl silyl iodide, trimethyl silyl fluoride, trimethylsilyl trifluoromethanesulfonate (TMSOTf), trimethyl silyl cyanide and N,N-bis(trimethylsilyl)- trifiuoroacetamide.

The process as claimed in any of the preceding claims 1 to 8, wherein compound of formula I having R as -OR1 is further treated with an animating agent to form Rufinamide (IV).

IV

10. The process as claimed in claim 9, wherein the aminating agent is ammonia, preferably methanolic ammonia.

1 1. The process as claimed in claim 9 or 10, wherein the aminating agent is aqueous ammonia.

12. A process for preparing Rufinamide (IV), the process comprising the steps: reacting 2, 6-difluorobenzyl azide (II) with 2,3-dihalo compound (III) to form compound of formula I; and

reacting compound of formula I with an aminating agent to form Rufinamide (IV).

29

I

wherein,

R is -ORi; Ri is H or C C₆ alkyl group

Xi and X₂ is chlorine, bromine, iodine or fluorine.

13. A process for preparing Rufmamide(IV), the process comprising the steps: reacting 2, 6-difluorobenzyl azide (II) with 2,3-dihalo compound (III) to form compound of formula IV.

IV

wherein,

R is -NH_2;

Xi and X₂ is chlorine, bromine, iodine or fluorine.

14. A process for preparing Ruiinamide (IV), the process comprising the steps: reacting compound of formula V with an azide in the presence of hydrazine hydrate to form 2, 6-difluorobenzyl azide (II);

reacting 2, 6-difluorobenzyl azide (II) with 2, 3-dihalo compound (III) to form compound of formula I; and

reacting compound of formula I with an aminating agent to form Ruiinamide

32

wherein,

R is -ORi_; Rj is H or Ci-C₆ alkyl group

Xi and X₂ is chlorine, bromine, iodine or fluorine

X is chlorine, bromine or iodine

15. The process as claimed in any one of the claims 12 or 14 comprising reacting 2, 6-difluorobenzyl azide (II) with 2, 3-dihalo compound (III) in the presence of a solvent selected from 1, 4-dioxane, ethylene glycol, diglyme, di ethylene glycol, isopropyl alcohol and diethyl ether.

16. The process as claimed in any one of the claims 12 or 14, wherein the aminating agent is liquid or gaseous ammonia, preferably methanolic ammonia.

17. A process for preparing 2, 6-difluorobenzyl azide (II), the process comprising reacting 2, 6-difiuorobenzyl halide (V) and an azide in the presence of an activating agent, hydrazine hydrate to form 2, 6- difluorobenzyl azide (II).

V wherein, X is chlorine, bromine or iodine.

18. The process as claimed in claim 17, wherein the azide is:

an alkali metal azide, selected from sodium or potassium azide,

R2 Si- , wherein R2 is C C₆ alkyl, preferably trimethyl silyl azide, and

P(0)(0- Ci-C₆ alkyl) or diphenyl phosphoryl azide.

19. A one pot process for preparing Rufinamide(IV), the process comprising the steps:

reacting 2, 6-difluorobenzyl azide (II) with 2,3-dihalo compound (III) to form compound of formula I; and

reacting compound of formula I with an aminating agent to form Rufinamide

IV

I

wherein,

R is -ORi_; R\ is H or Ci-C₆ alkyl group

Xi and X₂ is chlorine, bromine, iodine or fluorine.

20. A one pot process for preparing Rufinamide (IV), the process comprising the s:

reacting compound of formula V with an azide in the presence of hydrazine hydrate to form 2, 6-difluorobenzyl azide (II);

reacting 2, 6-difluorobenzyl azide (II) with 2, 3-dihalo compound (III) to form compound of formula I; and reacting compound of fomiula I with an animating agent to form Rufinamide (IV).

wherein,

R is -ORj_; R] is H or C| -C₆ alkyl group

Xi and X₂ is chlorine, bromine, iodine or fluorine

X is chlorine, bromine or iodine