FORM 2
THE PATENT ACT 1970 (39 of 1970)
& The Patents Rules,2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
A process for the preparation of Rufinamide
2. APPLICANT (S)
(a) NAME: Enaltec Labs Pvt. Ltd.
(b) NATIONALITY:
An Indian Company incorporated under the Indian Companies ACT 1956
(c) ADDRESS:
Enaltec Labs Pvt. Ltd., 17th Floor, Kesar Solitaire, Plot No. 5, Sector 19, Sanpada, Navi Mumbai- 400705, Maharashtra, India.

Technical field of the invention:
Present invention relates to a process for the preparation of Rufinamide; the compound represented By structural formula I.

Background of the invention:
Rufinamide is chemically known as l-[(2,6-difluorophenyl)methyl]-lH-1,2,3-triazole-4 carboxamide and was first disclosed in U.S. patent number 4,789,680 and is represented by following structural formula I.

Rufinamide is well tolerated and effective anti-epileptic drug indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in children 4 years and older and adults.
U.S. Patent Number 4,789,680 discloses a process for the preparation of Rufinamide; the compound represented by structural formula I as depicted below in Scheme I, wherein l-(2,6-difluorobenzyl)-lH-l,2,3-triazole-4-carboxylic acid; the compound represented by structural formula II is treated with thionyl chloride at reflux

temperature to provide the compound represented by structural formula III which is further treated with aqueous ammonia solution to give Rufinamide; the compound represented by structural formula I.

U.S. Patent Number 6,740,669 discloses a process for the preparation of Rufinamide; the compound represented by structural formula I as depicted below in Scheme II, wherein hydrolysis of 4-cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole; the compound represented by structural formula IV is carried out by using 1 N sodium hydroxide solution in presence of water as solvent at temperature of 95-100°C to give Rufinamide; the compound represented by structural formula I.

Journal ACS Catal. 2014, 4, 1901-1910 discloses a process for the preparation of Rufinamide; the compound represented by structural formula I as depicted below in Scheme III, wherein rhodium (I) complex [RhCl(COD){P(NMe2)3}] is used for the reaction.


The preparation method disclosed in U.S. Patent Number 4,789,680 is disadvantageous as preparation of compound of formula III involves the reaction of the compound of formula II with thionyl chloride at reflux temperature, which is very unsafe at commercial scale.
The preparation method disclosed in U.S. Patent Number 6,740,669 is disadvantageous as preparation of compound of formula I involves hydrolysis of 4-cyano-1 -(2,6-difluorobenzyl)-1H-1,2,3-triazole; the compound represented by structural formula IV by using 1 N sodium hydroxide solution in presence of water as solvent at temperature of 95-100°C to give Rufinamide; the compound represented by structural formula I, which promotes formation of impurity represented by following structural formula II.

The preparation method disclosed in journal ACS Catal. 2014, 4, 1901-1910 is disadvantageous as preparation of compound of formula I involves use of rhodium (I) complex [RhCl(COD){P(NMe2)3}] which is expensive and therefore not viable at commercial scale.

European patent EP0199262 teaches transformation of cyano compounds to amide compounds using alkali metal such as sodium or potassium hydroxide, if necessary in the presence of peroxy compounds, including hydrogen peroxide analogously.
Accordingly there is a need in the art to develop a process of preparing Rufinamide; the compound represented by structural formula I, which is simple, economic, safe and industrially viable.
Object of the invention:
i) The main object of the invention is to provide a simple, economic, safe
and industrially viable process for preparation of Rufinamide; the compound represented by structural formula I.

ii) Another object of present invention is to provide a process for preparation of Rufinamide; the compound represented by structural formula I comprising hydrolysis of 4-cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole; the compound represented by structural formula IV by using peroxide followed by treatment with alkali metal hydroxide in polar aprotic solvent,


Summary of the invention:
A first aspect of the present invention is to provide a simple, economic, safe and industrially viable process for preparation of Rufmamide; the compound represented by structural formula I.

A second aspect of the present invention is to provide a simple, economic, safe and industrially viable process for preparation of Rufmamide; the compound represented by structural formula I.

comprises,
hydrolysis of 4-cyano-1 -(2,6-difluorobenzyl)-1H-1,2,3-triazole; the compound represented by structural formula IV by using peroxide followed by treatment with alkali metal hydroxide in polar aprotic solvent.


Third aspect of the present invention is to provide a process for preparation of Rufinamide compound represented by structural formula I.

comprises,
hydrolysis of 4-cyano-1-(2,6-difluorobenzyl)-1H-1,2,3-triazole compound represented by structural formula IV by using peroxide followed by treatment with alkali metal hydroxide in polar aprotic solvent at a temperature in the range of 15°C to 35°C.

Fourth aspect of the present invention is to provide a process for preparation of Rufinamide compound represented by structural formula I.


comprises,
hydrolysis of 4-cyano-l-(2,6-difluorobenzyl)-lH-l,2,3-triazole compound represented by structural formula IV by using peroxide selected from hydrogen peroxide and hydrogen peroxide - urea followed by treatment with alkali metal hydroxide in polar aprotic solvent at a temperature in the range of I5°C to 35°C.

Detail description of the invention:
Present invention provides a process for preparation of Rufinamide compound represented by structural formula I.

comprises,
hydrolysis of 4-cyano-l-(2,6-difluorobenzyl)-lH-l,2,3-triazole compound represented by structural formula IV by using peroxide followed by treatment with alkali metal hydroxide in polar aprotic solvent.


The 4-cyano-1 -(2,6-difluorobenzyl)-1H-1,2,3-triazole compound represented by structural formula IV can be prepared by following the methods disclosed in the art such as those described in US Patent Number 6,740,669, which is incorporated herein by reference only.

The hydrolysis of 4-cyano-1 -(2,6-difluorobenzyl)-1H-1,2,3-triazole compound represented by structural formula IV can be carried out by using peroxide followed by treatment with alkali metal hydroxide in polar aprotic solvent.

The example of peroxide can include but not limited to hydrogen peroxide and hydrogen peroxide - urea.
The example of alkali metal hydroxide can include but not limited to sodium hydroxide, potassium hydroxide and lithium hydroxide.
The examples of polar aprotic solvent can include but not limited to dimethyl sulfoxide, dimethylformamide, acetonitrile, N-methylpyrrolidone, tetrahydrofuran, acetone, ethyl acetate or mixture(s) thereof.

The peroxide is added to the solution of 4-cyano-l-(2,6-difluorobenzyl)-lH-l,2,3-triazole compound represented by structural formula IV in polar aprotic solvent at a temperature in the range of 15° C-35° C.
The reaction mixture after addition of peroxide is stirred at a temperature in the range
o o
of 15 C-35 C for a period of 15 minutes to 1 hour.
The alkali metal hydroxide is added to reaction mixture at a temperature in the range of l5°C-35°C.
The reaction mixture after addition of alkali metal hydroxide is stirred at a temperature in the range of 15°C-35° C for a period of 30 minutes to 5 hours.
The Rufinamide compound represented by structural formula I can be isolated by addition of water and acid followed by steps of filtration, centrifugation, washing, drying or combinations thereof.
The example of acid can include but not limited to organic acid such as acetic acid, formic acid, etc. or inorganic acid such as hydrochloric acid, sulfuric acid, etc.
The isolated Rufinamide compound represented by structural formula I is having impurity represented by structural formula II less than 0.1%.


Example:
In the following example, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of l-(2,6-Difuorobenzyl)-1H-1,2,3-triazole-4-carboxamide (Rufinamide):
To a solution l-(2,6-difluorobenzyl)-lH-l,2,3-triazole-4-carbonitrile (25gm) in dimethyl sulfoxide (375 ml) was added 30% hydrogen peroxide (50 ml) at 25-30°C, and the mixture was stirred for 30 minutes at 25-30°C. Then, to the reaction mixture 20% sodium hydroxide solution (50 ml) was added and the mixture was stirred for 90 minutes at 25-30°C. The mixture was diluted with water (50ml) and to the reaction mixture acetic acid (38ml) was added. The reaction mixture was stirred for 30 min at 25-30°C. Solid was filtered washed with water and dried under reduced pressure at 45-50°C.
Yield: 25 g (96%)
Purity: 99.80% (by HPLC)
Impurity represented by structural formula II content: 0.06% (by HPLC)

We claim:
1. A process for preparation of Rufinamide compound represented by structural formula I.

comprises,
hydrolysis of 4-cyano-1 -(2,6-difluorobenzyl)-1H-1,2,3-triazole compound represented by structural formula IV by using peroxide followed by treatment with alkali metal hydroxide in polar aprotic solvent.

2. A process as claimed in claim 1 wherein peroxide is selected from hydrogen peroxide and hydrogen peroxide - urea.
3. A process as claimed in claim 1 wherein alkali metal hydroxide is selected from the group consisting of sodium hydroxide, potassium hydroxide and lithium hydroxide.
4. A process as claimed in claim 1 wherein polar aprotic solvent is selected from the group consisting of dimethyl sulfoxide, dimethylformamide, acetonitrile, N-methylpyrrolidone, tetrahydrofuran, acetone, ethyl acetate or mixture(s) thereof.
5. A process as claimed in claim 1 wherein hydrolysis of 4-cyano-1-(2,6-difluorobenzyl)-lH-l,2,3-triazole compound represented by structural formula IV is carried out by steps of:

a. adding peroxide to a solution of 4-cyano-l-(2,6-difluorobenzyl)-lH-
1,2,3-triazole compound represented by structural formula IV in polar
aprotic solvent at a temperature in the range of 15°C-35°C;
b. stirring reaction mixture obtain in step-a for a period of 15 minutes to
1 hour;
c. adding alkali metal hydroxide to reaction mixture of step-b at a
temperature in the range of 15°C-35°C;
d. stirring reaction mixture obtain in step-c for a period of 30 minutes to
5 hours.
e. isolating Rufinamide compound represented by structural formula I.
6. A process as claimed in claim 5 wherein Rufinamide compound represented by structural formula I is isolated by addition of water and acid followed by steps of filtration, centrifugation, washing, drying or combinations thereof.
7. A process as claimed in claim 6 wherein acid is selected from group consisting of organic acid such as acetic acid and formic acid or inorganic acid such as hydrochloric acid and sulfuric acid.