Field of the Invention

The present invention provides an improved process for the preparation of Rufmamide of formula (I) or its pharmaceutical acceptable salts. The present invention specifically relates to an improved process for the preparation of compound of formula (II) which is an important intermediate in the synthesis Rufmamide.

Background of the Invention

Rufmamide is chemically known as l-(2,6-difluorobenzyl)-lH-1,2,3-triazole-4-carboxamide used as an anticonvulsant medication.

US 4,789,680 claims Rufmamide and its analogues having anticonvulsive action and discloses the preparation of Rufmamide by reacting 2,6-difluorobenzyl azide with propiolic acid to give corresponding carboxylic acid followed by esterification and then treated with ammonia.

US 4,789,680 also discloses the preparation of Rufmamide by reacting 2,6-difluorobenzyl azide with propiolic acid to give corresponding carboxylic acid which is treated with thionyl chloride and subsequently with ammonia.

US 6,156,907 discloses the process for the preparation of Rufinamide which involves reacting 2,6-difluorobenzyl azide with 2-chloroacrylonitrile.

US 20100234616 disclose the process for the preparation of Rufinamide which involves reacting 2,6-difluorobenzyl azide with propiolic acid in presence of monovalent copper catalyst to do the reaction at low temperature.

WO 20100443 849(2190/MUM/2008) discloses the process for the preparation of Rufinamide which involve reacting 2,6-difluorobenzyl azide with methyl propoilate.

Despite of these improvements in prior art process, a need to find out alternate process for Rufinamide synthesis and considering the commercial importance of Rufinamide, applicant focused developing a simple process for Rufianmide with an enhanced purity and reduced impurity.

Objectives of the Invention

An objective of the present invention is to provide an improved process for the preparation of Rufinamide of formula (I) or its pharmaceutical acceptable salts with good purity and yield.

Another objective of the present invention is to provide an improved process for preparation of compound of formula (II).

Yet another objective of the present invention is to provide an improved and industrially simple and advantageous process for preparation of compound of formula (I).

Summary of the Invention

Accordingly, the present invention directed to an improved process for the preparation of compound of formula (II)

Wherein R is C1_10 straight chain or branched alkyl group; which comprising: reacting 2,6-difluorobenzyl azide of formula (III) with compound of formula (IV)

wherein X is leaving group.

The above invention is illustrated as shown in the following scheme:

Detailed Description of the Invention

In an embodiment of the present invention, X in compound of formula (IV) represents a leaving group selected from group of halogen atoms such as chloro, bromo or iodo; and R represents alkyl groups such as methyl, ethyl, propyl, n-propyl, isopropyl, n-butyl, isobutyl.

In another embodiment of the present invention, reaction of compound of formula (III) with compound of formula (IV) is conducted in the presence or absence of solvent at a temperature in the range of 10° C to reflux temperature of the solvent used to yield the compound of formula (II), wherein the improvement consists the use compound of formula (IV) which results the reduction of number of steps involved and improved yield. The solvent used for this reaction is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butyl alcohol, acetone, methylisobutylketone, 2-pentanone, ethyl methylketone, diethylketone, ethyl acetate, n-butyl acetate, tert-butyl acetate, isopropylacetate, diethylether, isopropylether, methyltert-butyl ether or a mixture thereof.

In yet another embodiment of the present invention, compound of formula (II) prepared according to present invention is converted to Rufinamide or its pharmaceutically acceptable salts by following conventional method or by reacting the compound of formula (II) with an ammonium source like ammonia.

Considering the importance of Rufinamide, the present invention provides novel process which is easy to implement in plant, associated with low cost of manufacture, and providing good yield with high purity.
Further Rufinamide obtained as per the present invention can be further micronized, milled or sieved to get the desired particle size (d90 less than 50 micron, preferably less than 10 micron) required for pharmaceutical composition to achieve the desired dissolution profile. Rufinamide prepared by the present invention is a free flow solid and suitable for pharmaceutical composition.

The starting material used in the present invention is prepared by utilizing the process available in the literature.

Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure. The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.

The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.

Example 1 Methvl-l-(2.6-difluorobenzvn-lH-1.2.3-triazole-4-carboxvlate(ID
To a solution of 2, 6-difluorobenzyl azide (0.5 g) in water (5 mL), methyl-2-chloroacrylate (0.35 g) was added at 25 to 35°C. The reaction mass was heated to 80-85°C and maintained till the completion of the reaction. The reaction mass was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with water and distilled out ethyl acetate completely under vacuum to yield the title compound. The residue was used as such for the next stage. Yield: 0.4 g

Reference example 1

Preparation of 2,6-difluorobenzvl azide (III)

To a solution of 2, 6-difluorobenzylbromide (25 g) in N,N-dimethylacetamide (87 mL), sodium azide (8.64 g) was added at 25-30°C and stirred the reaction mass at 25-30°C till the completion of reaction. Reaction mass was quenched into water and extracted with cyclohexane. The organic layer was washed with water and concentrated completely under vacuum to yield the title compound. The residue was used as such for the next stage. Yield: 19.27 g

Reference example 2

Preparation of l-(2,6-difluorobenzvl)-1H-l,2,3-triazole-4-carboxamide (I) (Rufinamide)

Aqueous ammonia solution (102 mL) was added to the residue obtained from example 1 (17.0 g) and heated the reaction mass to 70 to 75°C till completion of the reaction. The reaction mass was cooled to room temperature, filtered the solid, washed with water and dried at 60-65 °C. Yield: 11 g

We Claim:

1. An improved process for preparation of compound of formula (II)

wherein R represents methyl, ethyl, propyl, n-propyl, isopropyl, n-butyl, or isobutyl; the said process comprises reacting 2,6-difluorobenzyl azide of formula (III) with compound of formula (IV)
wherein X represents chloro, bromo or iodo.

2. The process according to claim 1, wherein the reaction is performed in the present of solvent.

3. The process according to claim 2, wherein solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butyl alcohol, acetone, methylisobutylketone, 2-pentanone, ethyl methylketone, diethylketone, ethyl acetate, n-butyl acetate, tert-butyl acetate, isopropylacetate, diethylether, isopropylether, methyltert-butyl ether or a mixture thereof.

4. The process according to claim 1, wherein the reaction is carried out at the temperature in the range of 10° C to reflux temperature of solvent used.

5. The process as claimed in claim 1 further comprises reacting the compound of formula (II) with an ammonium source to yield Rufinamide or its pharmaceutically acceptable salts.