WO2012032540A1 - Process for preparation of fluorinated triazole compound - Google Patents

Abstract

The present invention discloses a process for the preparation of 1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4-carboxamide of Formula (I), comprising regioselective cycloaddition of 2,6-difluorobenzyl halide of Formula (II), wherein X is chloride, bromide or iodide; with a compound of Formula (IX); in which R is -COOR₁, wherein R₁ is hydrogen, C₁-C₄ linear or branched alkyl group, or-CN, or-CONH₂ or -CH₂OR₂j wherein R₂ is hydrogen or hydroxyl protecting group; in presence of an azide, Cu(I) species and a catalyst.

Description

"PROCESS FOR PREPARATION OF FLUORINATED TRIAZOLE

COMPOUND"

RELATED APPLICATION:

This invention claims priority from its Indian provisional application No. 2477/MUM/2010 filed on 06.09.2010.

FIELD OF INVENTION:

The present invention relates to an improved process for the preparation of 1 -[(2,6- difluorophenyl)methyl]- 1H- 1 ,2,3-triazole-4-carboxamide of Formula I,

Formula I

BACKGROUND AND PRIOR ART:

The compound l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide of Formula I having International non - proprietary name Rufinamide is an anticonvulsive drug. The compound was first described in US 4789680, wherein 2,6-difluorobenzyl bromide of Formula IIB is reacted with sodium azide in presence of dimethyl sulfoxide to obtain 2,6-difluorobenzyl azide of Formula III. The compound of Formula III is reacted with propiolic acid Formula IV in toluene at 70°C to get l-(2,6-Difluorobenzyl)-lH- l,2,3-triazole-4-carboxylic acid of Formula V. The compound of Formula V is reacted with thionyl chloride and distilling out excess of thionyl chloride to get residual mass of 1 -(2,6-difluorobenzyl)- lH-l,2,3-triazole-4-carbonyl chloride of Formula VI. The compound of formula VI is further taken in toluene and reacted with aqueous ammonia to isolate Rufinamide.

Another process is also disclosed in US 4789680, wherein the compound 1 -(2,6- Difluorobenzyl)-lH-l,2,3-triazole-4-carboxylic acid of Formula V is reacted with methanol in presence of sulfuric acid to get methyl l -(2,6-Difluorobenzyl)-lH- 1,2,3- triazole-4-carboxylate of Formula VII, which on reaction with methanolic ammonia results in the compound Rufinamide of Formula I. The reaction sequence can be represented as in scheme - 1 below;

Formula ΠΒ Formula III

Formula V

Formula VII

Formula I Formula VI

Scheme 1

Another process disclosed in the patent application WO9802423; wherein 2,6- difluorobenzyl azide of Formula III is reacted with 2-chloroacrylonitrile of Formula VIII in water for 24 hours. The excess of 2-chloroacrylonitrile is distilled out up to 113°C and hydrolysed the intermediate cyano compound with sodium hydroxide solution in presence of toluene to obtain the compound of Formula I. The reaction sequence is as given in scheme 2 below;

Formula I

Scheme 2

Another process disclosed in patent application WO2010043849; wherein the compound 2,6-difluorobenzyl bromide of Formula IIB is reacted with sodium azide in water at 70- 75°C for about 30 hours to get 2,6-difluorobenzyl azide of Formula III. To the cooled reaction mass methyl propiolate of Formula IX is added and maintained at 60-65°C for 4- 5 hours to get intermediate compound methyl l-(2,6-difluorobenzyl)-lH-l,2,3-triazole-4- carboxylic acid of Formula VII. To the reaction mass ammonia solution is charged to get Rufinamide of Formula I. The reaction sequence is as per scheme 3 below;

Formula IIB Formula III Formula VII

Formula I

Scheme 3

In the above prior arts, the yield of Rufinamide obtained is low as the reaction requires heating which results in poor regioselectivity at the time of cyclisation giving a mixture of 1,4 and 1,5 disubstituted isomers of l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4- carboxamide of Formula I and l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-5- carboxamide of Formula IA.

Formula I

Formula IA

Other drawbacks in the above prior arts are:

i. involves multiple process steps to get Rufinamide;

ii. heating of the reactants resulting in decomposition of the reaction mass resulting in the impurities;

iii. use and handling of hazardous alkyl azide compounds.

It is evident from the prior art that there remains a need for an improved process to prepare the compound l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide of Formula I which has good regioselectivity of the reaction, avoids multiple process steps, avoids handling of alkyl azide compounds and formation of impurities during the reaction, thus resulting in improved yield of the compound of Formula I.

The present inventors have now come out with an improved process which involves "click chemistry" concept using catalyst during the reaction, ameliorates the drawbacks in prior art and avoids high temperature of reaction, handling of hazardous alkyl azide compounds, formation of regio isomer and impurities.

OBJECT OF THE INVENTION:

The object of the present invention is to prepare the compound l-[(2,6- difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide of Formula I with an improved, efficient process and reduced number of steps with good yield.

Another object of the present invention is regiocontrolled synthesis of the compound l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide of Formula I, substantially free from the regio isomer and the impurities. Yet another object of the present invention is the preparation of intermediate compound of Formula XA

Formula XA

SUMMARY OF THE INVENTION:

Accordingly, the present invention provides an improved process for the preparation of the compound l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide of Formula I;

Formula I

comprising regioselective cycloaddition of 2,6-difluorobenzyl halide of Formula II, wherein X is chloride, bromide or iodide;

Formula II

with a compound of Formula IX,

Formula IX

where R is -COORi, wherein R_\ is hydrogen, d-C4 linear or branched alkyl group, or -CN, or -CONH₂ or -CH₂-OR₂, where R₂ is hydrogen or hydroxyl protecting group, in presence of an azide, Cu(I) species and a catalyst.

Accordingly the compound 2,6-difluorobenzyl halide of Formula II, wherein X is chloride, bromide or iodide is reacted with the compound of Formula IX in presence of an azide, Cu(I) species and catalyst, undergoing cycloaddition reaction to give an intermediate compound of Formula X;

Formula X

where R is -COORj_, wherein Rj is hydrogen, C1-C4 linear or branched alkyl group or -CN or -CH₂-OR_2j wherein R₂ is hydrogen or hydroxyl protecting group; and converting the intermediate compound of Formula X to Rufinamide of Formula I.

In another aspect, the present invention discloses preparation of [l-(2,6-difluorobenzyl)- lH-l,2,3-triazol-4-yl]methanol, compound of Formula XA which comprises regioselective cycloaddition of 2,6-difluorobenzyl bromide of Formula IIA with propargyl alcohol of Formula IXB, in presence of an azide, Cu(I) species, phase transfer catalyst, potassium iodide and solvent at a moderate temperature condition.

In another aspect, the compound of Formula XA is further subjected to oxidation reaction in presence of a buffer, a catalyst, an oxidizing agent and solvent to get the compound 1- (2,6-difluorobenzyl)-lH-l,2,3-triazole-4-carboxylic acid of Formula XB which is then further converted to Rufinamide as per the prior art process.

In an aspect, the present invention discloses the novel compound [l-(2,6-difluorobenzyl)- lH-l,2,3-triazol-4-yl]methanol, of Formula XA;

Formula XA

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. DETAILED DESCRIPTION OF THE INVENTION:

The present invention describes the process in detail for the preparation of the compound l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide of Formula I, involving "click chemistry" by carrying out regiocontrolled cycloaddition reaction of the compound of Formula II and Formula IX in presence of an azide, Cu(I) species, a catalyst, and solvent.

In one embodiment of the present invention, the compound 2,6-difluorobenzyl halide of Formula II, wherein X is selected from chloride, bromide or iodide undergoes regioselective cycloaddition reaction with the compound of Formula IX, where R is COOR], wherein R] is hydrogen, C₁-C4 linear or branched alkyl group, or -CN or CH₂-OR_2j wherein R₂ is hydrogen or hydroxyl protecting group, in presence of an azide, Cu(I) species, a catalyst, a reducing agent and solvent at a moderate temperature condition.

Accordingly, the present process for the preparation of l-[(2,6-difluorophenyl)methyl]- lH-l,2,3-triazole-4-carboxamide, compound of Formula I;

Formula I

comprises the steps of regioselective cycloaddition of 2,6-difluorobenzyl halide of Formula II, wherein X is chloride, bromide or iodide;

Formula II

with a compound of Formula IX, in presence of an azide, Cu(I) species, catalyst and solvent at a moderate temperature condition,

Formula IX where R is -COOR^ wherein R\ is hydrogen, C1-C4 linear or branched alkyl group, or -CN, or- CONH₂ or -CH₂-OR_2j where R₂ is hydrogen or hydroxyl protecting group.

The azide compound used in regioselective cycloaddition reaction is selected from a metal azide or an alkyl silyl azide. The metal azide used is selected from sodium azide or potassium azide and the alkyl silyl azide is trimethylsilyl azide. The preferred azide compound used for the regioselective cycloaddition reaction is metal azide selected from sodium azide or potassium azide, wherein the most preferred metal azide used is sodium azide.

The Cu(I) species used for the reaction is generated insitu by reaction of Cu(II) species with reducing agent selected from sodium bisulfite, sodium metabisulfite, ascorbic acid or its salts preferably sodium ascorbate. The Cu (II) species used for the reaction are selected from CuS0₄.5H₂0, CuCl₂, Cul₂, Cu/AlO (OH) or Cu (II) salts supported on carbon, silica and alumina. Alternatively, Cu (I) species can be obtained directly from Cul, CuCl or any other cuprous salt. The preferred Cu (II) species used in the reaction is CuS0₄.5H₂0 with sodium ascorbate.

The catalyst used in the regioselective cycloaddition reaction is phase transfer catalyst selected from tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, benzyl triethyl ammonium chloride and benzyl triethyl ammonium bromide. The preferred phase transfer catalyst used is tetrabutyl ammonium bromide [TBAB].

The solvent used for the regioselective cycloaddition reaction is selected from polar solvents such as water, Cj-C₄ linear or branched alcohol, acetone, ethyl acetate, methyl ethyl ketone and methyl isobutyl ketone, acetonitrile, dimethyl sulfoxide, N,N- dimethylformamide either single or mixture thereof. The preferred polar solvents used for the regioselective cycloaddition reaction is water and Ci-C₄ linear or branched alcohol either single or mixture thereof, wherein CrC₄ linear or branched alcohol are methanol, ethanol, w-propanol, w-butanol, isopropanol, and tert-butanol. The most preferred solvent used for the regioselective cycloaddition reaction is mixture of water and tert-butanol. The ratio of solvent mixture of water and tert-butanol used for the reaction is 1: 15 or 15: 1 v/v. The regioselective cycloaddition reaction is carried out at moderate temperature in the range of 10°C to 50°C. The preferred temperature range for the reaction is 15°C to 35°C, wherein the most preferred temperature range used for the reaction is 25°C to 30°C.

The regioselective cycloaddition reaction is carried out in presence of potassium iodide used as an initiator. The general reaction sequence can be represented as shown in the scheme 4 below;

Formula X

Scheme 4

Wherein "X" and "R" are as defined above.

In another embodiment of the present invention, the compound 2,6-difluorobenzyl bromide of Formula IIA, undergoes regioselective cycloaddition reaction with the compound methyl propiolate of Formula IXA, in presence of an azide, Cu(I) species, phase transfer catalyst, potassium iodide and solvent at a moderate temperature condition to give the compound l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide of Formula I in a two step process.

The azide compound used in regioselective cycloaddition reaction is sodium azide. The Cu(I) species used for the reaction is generated insitu by reaction of Cu(II) species with reducing agent selected from sodium bisulfite, sodium metabisulfite, ascorbic acid or its salts preferably sodium ascorbate. The Cu(II) species used for the reaction are selected from CuS0₄.5H₂0, CuCl₂, Cul₂, Cu A10(OH) or Cu(II) salts supported on carbon, silica or alumina. Alternatively Cu (I) species can be obtained directly from Cul, CuCl or any other cuprous salt. The preferred Cu (II) species used in the reaction is CuS0₄.5H₂0 with sodium ascorbate.

The catalyst used in the regioselective cycloaddition reaction is phase transfer catalyst selected from tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, benzyl triethyl ammonium chloride and benzyl triethyl ammonium bromide. The preferred phase transfer catalyst used is tetrabutyl ammonium bromide.

The solvent used for the regioselective cycloaddition reaction is selected from polar solvents such as water, C]-C₄ linear or branched alcohol, acetone, ethyl acetate, methyl ethyl ketone and methyl isobutyl ketone, acetonitrile, dimethyl sulfoxide, N,N- dimethylformamide either single or mixture thereof. The preferred solvent used for the reaction is selected from water and Q-C4 linear or branched alcohol, wherein C1-C4 linear or branched alcohol are selected from methanol, ethanol, n-propanol, M-butanol, isopropanol, and tert-butanol. The most preferred solvent used for the regioselective cycloaddition reaction is mixture of water and ter/-butanol. The ratio of solvent mixture of water and fert-butanol used for the reaction is 1: 15 or 15: 1 v/v, wherein the preferred ratio of water and tert-butanol is in the ratio of 1 : 9 v/v.

The regioselective cycloaddition reaction is carried out at moderate temperature in the range of 10°C to 50°C. The preferred temperature range for the reaction is 15°C to 35°C, wherein the most preferred temperature range used for the reaction is 25°C to 30°C. The reaction is maintained under stirring for 4 to 6 hours. After the reaction, the solid product separated may be filtered and taken in water or the reaction is continued as such without filtration. Ammonia in the form of gaseous ammonia or aqueous ammonia is added to the reaction mass for amide formation. The reaction is carried out at a temperature in the range of 50-80°C. The time for the completion of the amidation reaction is 4-12 hours. The compound l-[(2,6-difluorophenyl)methyl]-lH-l,2,3-triazole-4-carboxamide (Rufinamide) of Formula I is isolated by filtration at 25-30°C and dried till constant weight.

In yet another embodiment of the present invention 2,6-difluorobenzyl bromide of Formula IIA, undergoes regioselective cycloaddition reaction with propargyl alcohol of Formula IXB, in presence of an azide, Cu(I) species, phase transfer catalyst, potassium iodide and solvent at a moderate temperature condition to get [l-(2,6-difluorobenzyl)-lH- l,2,3-triazol-4-yl]methanol of Formula XA.

The azide compound used in regioselective cycloaddition reaction is sodium azide. The Cu(I) species used for the reaction is generated insitu by reaction of Cu(II) species with reducing agent selected from sodium bisulfite, sodium metabisulfite, ascorbic acid or its salts preferably sodium ascorbate. The Cu(II) species used for the reaction are selected from CuS0₄.5H₂0, CuCl₂, Cul₂, Cu/A10(OH) or Cu(II) salts supported on carbon, silica or alumina. Alternatively Cu(I) species can be obtained directly from Cul, CuCl or any other cuprous salt. The preferred Cu(II) species used in the reaction is CuS0₄.5H₂0 with sodium ascorbate.

The catalyst used in the regioselective cycloaddition reaction is phase transfer catalyst selected from tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, benzyl triethyl ammonium chloride and benzyl triethyl ammonium bromide. The preferred phase transfer catalyst used is tetrabutyl ammonium bromide.

The solvent used for the regioselective cycloaddition reaction is selected from polar solvents such as water, C C₄ linear or branched alcohol, acetone, ethyl acetate, methyl ethyl ketone and methyl isobutyl ketone, acetonitrile, dimethylsulfoxide, N,N- dimethylformamide either single or mixture thereof. The preferred solvent used for the reaction is selected from water and C1-C4 linear or branched alcohol, wherein Ci-C₄ linear or branched alcohol are selected from methanol, ethanol, w-propanol, n-butanol, isopropanol, and tert-butanol. The most preferred solvent used for the regioselective cycloaddition reaction is mixture of water and tert-butanol. The ratio of solvent mixture of water and tert-butanol used for the reaction is 1 : 15 or 15: 1 v/v, wherein the preferred ratio of water and tert-butanol is in the ratio of 1 : 9 v/v.

The regioselective cycloaddition reaction is carried out at moderate temperature in the range of 10°C to 50°C, wherein the preferred temperature for the reaction is 15°C to 35°C and the most preferred temperature used for the reaction is 25°C to 30°C.

Accordingly, the reaction temperature is maintained at 25°C to 30°C under stirring for 4 to 6 hours. After the completion of the reaction, ammonia in the form of gaseous ammonia or aqueous ammonia is added to the reaction mass and stirred for 2 to 4 hours at 0°C to 10°C. Filtered the solid compound of [l-(2,6-difluorobenzyl)-lH-l,2,3-triazol-4- yl]methanol of Formula XA. In another embodiment of the present invention, the compound [l-(2,6-difluorobenzyl)- lH-l,2,3-triazol-4-yl]methanol of Formula XA is subjected to oxidation reaction in presence of a buffer, a catalyst, an oxidizing agent and solvent to get the compound 1- (2,6-difluorobenzyl)-lH-l,2,3-triazole-4-carboxylic acid of Formula XB.

The buffer used for the oxidation reaction is selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, and ammonium acetate, either single or mixture thereof. The preferred buffer used for the reaction is mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate. The molar ratio of the mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate used is 0.5: 1.0 to 1.0: 0.5. The preferred molar ratio of sodium dihydrogen phosphate and disodium hydrogen phosphate used is 1.0: 0.9.

The catalyst used for the oxidation reaction is (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl [TEMPO]. The oxidizing agent used is mixture of sodium chlorite and sodium hypochlorite in the molar ratio of 2.5: 0.5.

The solvent used for the oxidation reaction is selected from acetonitrile, N,N- dimethylformamide, Ν,Ν-dimethylacetamide, dimethylsulfoxide and tetrahydrofuran. The preferred solvent used for the oxidation reaction is selected from acetonitrile and tetrahydrofuran, wherein the most preferred solvent used for the oxidation reaction is tetrahydrofuran.

The oxidation reaction is carried out at temperature in the range of 20°C to 40°C, wherein the preferred temperature of the oxidation reaction is between 35°C to 40°C. The time for completion of oxidation reaction is 4 to 6 hours. After completion of oxidation reaction the pH of the reaction mass is adjusted to 8 - 9 using aqueous sodium hydroxide solution. The reaction solution is extracted with toluene or diethyl ether and separated the organic layer. The pH of the aqueous layer is adjusted to 1 - 2 using dilute aqueous hydrochloric acid. The reaction mass is cooled to 0°C to 5°C and maintained 2 - 3 hours under stirring. Filtered the solid product of l-(2,6-difluorobenzyl)-lH-l,2,3-triazole-4-carboxylic acid of Formula XB. The compound l-(2,6-difluorobenzyl)-lH-l,2,3-triazole-4-carboxylic acid of Formula XB can be converted to rufinamide as per the process disclosed in the prior art process US pat. No.4789680

The reaction sequence of the present invention can be represented as in scheme 5;

Fopnula IIA Formula IXB Formula XA

Formula I

Formula XB

Scheme 5

In one of the embodiment, for the compound of Formula IX wherein R is -CN, the corresponding compound of Formula X can be hydrolysed, with aqueous sodium hydroxide at temperature of 90°C to 100°C to isolate the final compound Rufinamide of Formula I.

In yet another embodiment, the compound of Formula IX where R is -CH₂OR₂, wherein R₂ is hydroxyl protecting group selected from acetyl, benzyl or benzoyl groups results in an intermediate triazole compound which is first deprotected by suitable deprotecting method to get the compound of Formula XA. This is followed by a process for the preparation of Rufinamide of Formula I as per the reaction scheme 5 described above.

In another embodiment, the present invention discloses the novel compound [l-(2,6- difluorobenzyl)-lH-l,2,3-triazol-4-yl]methanol, of Formula XA;

Formula XA

Thus the present invention demonstrates an improved, efficient process for the preparation of Rufinamide which is substantially free from the regio isomer impurities, with reduced number of steps and giving good yield.

The present invention is further illustrated in detail with reference to the following examples. It is desired that the example be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.

EXAMPLES:

Example 1: Preparation of [l-(2,6-difluorobenzyl)-lH-l,2,3-triazol-4-yl] methanol:

In a 100 ml 4 neck flask was charged 2, 6-difluorobenzyl bromide (lOg), sodium azide (6.26 gm), propargyl alcohol (5.4 g), copper sulfate pentahydrate (0.6g), sodium ascorbate( 1.9g), TBAB (1.54g), potassium iodide (0.8g) and a mixture of solvent tert- butanol and water (lOOml).The reaction mixture was stirred for 4 hrs at 25 - 30°C. On completion of the reaction, was charged aqueous ammonia (100 volumes) to the reaction mass and stirred for 2 hours at 25 - 30°C. Charged water (100 ml), stirred for 30 minutes and cooled to 5 - 10°C. Maintained at 5 - 10°C for 1 hour and filtered the product [l-(2,6- difluorobenzyl)-lH-l,2,3-triazol-4-yl]methanol, dried at 50-55°C till constant weight, m.p.: 1 17-121°C.

Ή-NMR (DMSO-de) 400 MHz: 5(ppm) 7.97 (s, 1H), 7.50 (m, 1H), 7.15 -7.22 (d, 2H),

5.63 (s, 2H), 5.19 (t, OH), 4.50 (d, 2H); ¹³C-NMR (DMSO-de): d (ppm) 40.70, 54.9,

1 1 1.50, 1 1 1.9, 1 12.0, 122.98, 131.7, 148.2, 159.6, 162.1.

IR (cm '): 3230.61, 1460, 1473.99, 1200, 1272, 1 150, 1 130.2, 1030.68

MS (M+l): 226.

Yield = 9.0 g;

HPLC purity = 99.50%. Example 2: Preparation of l-(2,6-difluorobenzyl)-lH-l,2,3-triazole-4-carboxylic acid:

To a 500 ml 4 neck RB flask was charged [l-(2,6-difluorobenzyl)-lH-l,2,3-triazol-4- yl]methanol (5.0g), tetrahydrofuran (50 ml) ,ΤΕΜΡΟ (0.23g), mixture of NaH₂P0₄ and Na₂HP0₄ buffer (125 ml). Stirred the reaction mass at 30 - 35°Cfor 15 minutes. Charged simultaneously 20 % of the mixture of aqueous solution of sodium chlorite (4.96 gm in 33 ml water) and sodium hypo chlorite (20 ml, in 20 ml of water). After completion of addition, maintained the reaction mass for 4 - 6 hours at temperature 35 - 40°C. After completion of the reaction adjusted pH of the reaction mass to 8 - 9 with aqueous 2N sodium hydroxide solution. Quenched the reaction mass in sodium sulfite solution (12 gm in 50 ml of water) and extracted with 50 ml of toluene, separated the organic layer. Adjusted pH of the reaction mass to 1 - 2 with 2N hydrochloric acid and cooled the reaction mass to 0 to 5°C. Maintained at 0 to 5°C for 2 hrs and filtered the compound 1- (2,6-difluorobenzyl)-lH-l,2,3-triazole-4-carboxylic acid and dried till constant weight. Yield = 5.0 g;

HPLC purity = 99.80%.

Example 3: Preparation of Rufinamide:

In a 100 ml flask was charged l-(2,6-difluorobenzyl)-lH-l,2,3-triazole-4-carboxylic acid (1.5 gm) and thionyl chloride (15 ml). Refluxed the reaction mass for 2.0 hours. Distilled out excess of thionyl chloride using toluene under vacuum. Diluted the reaction mass with toluene and quenched the solution slowly over 30 minutes in pre cooled aqueous ammonia (15 ml) maintaining temperature at 5 - 10°C. Stirred the reaction mass for 30 minutes and diluted the reaction mass with ethanol (30 ml). Filtered the solid l-[(2,6- difluorophenyl)methyl]- 1 Η- 1 ,2,3-triazole-4-carboxamide [Rufinamide] .

Yield = 1.3 g;

HPLC purity = 99.40%.

Regio Isomer = Not detected

Example 4: Preparation of Rufinamide:

In a 50ml R.B flask, 2,6-Difluorobenzyl bromide (l .Og), sodium azide (0.344g), propiolamide (0.33g), copper sulfate pentahydrate (0.12g), sodium ascorbate (0.191g), a mixture of water and tert-butanol (1 :1,15ml) were added. The reaction mixture was stirred at R.T (25 °C) for 15 hours. On completion of reaction, the reaction mass was filtered, washed with water and dried under vacuum till constant weight to get

Rufinamide.

Yield = 0.9 g;

HPLC purity =99.53%.

Regio Isomer = Not detected

Example 5: Preparation of Rufinamide:

In a 50ml R.B flask, 2,6-Difluorobenzyl bromide (lg), sodium azide (0.344g), methylpropiolate (0.406g), copper sulfate pentahydrate (0.12g), sodium ascorbate (0.191g), a mixture of water and ter/-butanol (1 :1,15ml) were added. The reaction mixture was stirred at 25-30°C for 20 hours. On completion of reaction 30 ml water was added and the solid product was filtered. The solid was suspended in 7.5 ml water and to this 7.5 ml aqueous ammonia solution (25%) was added. The reaction mixture was stirred at 60-70°C for 4 hours. On completion of reaction (TLC), the reaction mass was cooled to 25-30°C, filtered , washed with water and dried under vacuum till constant weight to get Rufinamide.

Yield = 0.82 g;

HPLC purity = 99.57%.

Regio Isomer = Not detected

Example 6: Preparation of Rufinamide

In a 2.5 litre R.B flask was charged 2,6-difluorobenzyl bromide (lOOg), sodium azide (34.4g), propiolamide (33g), copper sulfate pentahydrate (12g), sodium ascorbate (19.1g,), TBAB (15.55 g), KI (8.02g) in the mixture of water and tert-butanol (1:1, 1.5 It). The reaction mixture was stirred at 25 °C - 30°C for 15 hours. On completion of reaction (TLC), the reaction mass was filtered, washed with water and dried under vacuum till constant weight to yield Rufinamide.

Yield: 90.0 g

HPLC purity: 99.53%

Regioisomer: Not detected Example7: Preparation of Rufinamide

In a 5.0 litre R.B flask, was charged 2,6-difluorobenzyl bromide (lOOg), sodium azide (34.4g), methylpropiolate (40.6g), copper sulfate pentahydrate (12g), sodium ascorbate (19.1g), TBAB (15.55 g), KI (8.02g) in the mixture of water and r/-butanol (1:1,1.5 It). The reaction mixture was stirred at 25°C - 30°C for 20 hours. On completion of reaction, charged 1.0 It DM water and the solid product was filtered. The solid was suspended in 750 ml water and to this 750 ml aqueous ammonia solution (25%) was added. The reaction mixture was stirred at 60-70°C for 4 hours. On completion of reaction (TLC), the reaction mass was cooled, filtered, washed with water and dried the compound Rufinamide under vacuum till constant weight.

Yield: 82.0 g

HPLC purity: 99.55%

Regioisomer: Not detected

Claims

We Claim,

1. A process for the preparation of Rufinamide of Formula I,

Formula I

comprising;

regioselective cycloaddition of 2,6-difluorobenzyl halide of Formula II,

Formula II

wherein X is chloride, bromide or iodide;

with a compound of Formula IX;

Formula IX

where R is -COORi, wherein Ri is hydrogen, C₁-C4 linear or branched alkyl group, or -CN, or -CONH2 or

where R₂ is hydrogen or hydroxyl protecting group; in presence of an azide, Cu(I) species and a catalyst.

2. The process as claimed in claim 1 ; wherein the azide is selected from metal azide or alkyl silyl azide.

3. The process as claimed in claim 2; wherein the metal azide is sodium azide or potassium azide and alkyl silyl azide is trimethylsilyl azide.

4. The process as claimed in claim 1 ; wherein the Cu(I) species is generated insitu by reaction of Cu(II) species with a reducing agent.

5. The process as claimed in claim 4; wherein the Cu(II) species is selected from CuS0₄.5H₂0, CuCl₂, Cul₂, Cu/A10(OH) or Cu(II) salts supported on carbon, silica and alumina.

6. The process as claimed in claim 4; wherein the reducing agent is selected from sodium bisulfite, sodium metabisulfite, ascorbic acid or its salts thereof.

7. The process as claimed in claim 1 ; wherein the catalyst for the reaction is phase transfer catalyst selected from tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, benzyl triethyl ammonium chloride and benzyl triethyl ammonium bromide.

8. The process as claimed in claim 1; wherein the regioselective cycloaddition reaction is carried out in presence of polar solvent.

9. The process as claimed in claim 8; wherein the polar solvent is selected from water, Q-C4 linear or branched alcohol, acetone, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, dimethylsulfoxide, N,N- dimethylformamide or mixture thereof.

10. The process as claimed in claim 1 ; wherein the regioselective cycloaddition reaction is carried out in presence of potassium iodide.

11. The process for the preparation of Rufinamide as claimed in claim 1, comprises the steps of;

a. regioselective cycloaddition of 2,6-difluorobenzyl halide of Formula II,

Formula II

wherein X is chloride, bromide or iodide;

with propargyl alcohol of Formula IXB;

Formula IXB

in presence of an azide, Cu(I) species, catalyst and solvent to obtain the compound [l-(2,6-difluorobenzyl)-lH-l,2,3-triazol-4-yl]methanol of Formula XA;

Formula XA Oxidation of the compound of Formula XA with an oxidizing agent in presence of a buffer, a catalyst, and solvent to obtain the compound l-(2,6- difluorobenzyl)-lH-l,2,3-triazole-4-carboxylic acid of Formula XB; and

Formula XB

c. Converting the compound of Formula XB to Rufinamide of Formula I.

12. The process as claimed in claim 11(a); wherein the azide is selected from sodium azide, potassium azide and trimethylsilyl azide.

13. The process as claimed in claim 11(a); wherein the Cu(I) species is generated insitu by reaction of Cu(II) species with a reducing agent.

14. The process as claimed in claim 13; wherein the Cu(II) species for the reaction is selected from CuS0₄.5H₂0, CuCl₂, Cul₂, Cu/A10(OH) or Cu(II) salts supported on carbon, silica and alumina.

15. The process as claimed in claim 13; wherein the reducing agent is selected from sodium bisulfite, sodium metabisulfite, ascorbic acid or its salts thereof.

16. The process as claimed in claim 11(a); wherein the catalyst for the reaction is phase transfer catalyst selected from tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, benzyl triethyl ammonium chloride and benzyl triethyl ammonium bromide.

17. The process as claimed in claim 11(a); wherein the polar solvent is selected from water, C1-C4 linear or branched alcohol, acetone, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, dimethylsulfoxide, N,N- dimethylformamide or mixture thereof.

18. The process as claimed in claim 11(a); wherein the regioselective cycloaddition reaction is carried out in presence of potassium iodide.

19. The process as claimed in claim 11(b); wherein the oxidizing agent is a mixture of sodium chlorite and sodium hypochlorite.

20. The process as claimed in claim 11(b); wherein the buffer is selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, and ammonium acetate, either single or mixture thereof.

21. The process as claimed in claim 20; wherein the buffer is selected from a mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate.

22. The process as claimed in claim 21 ; wherein the molar ratio of the mixture of sodium dihydrogen phosphate and disodium hydrogen phosphate is 0.5: 1.0 to 1.0:

0.5.

23. The process as claimed in claim 1 1 (b); wherein the solvent for the oxidation reaction is selected from acetonitrile, Ν,Ν-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide and tetrahydrofuran.

24. The process as claimed in claim 23; wherein the solvent for the oxidation reaction is acetonitrile and tetrahydrofuran.

25. The process as claimed in claim 1 1(b); wherein the catalyst for the oxidation reaction is (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl.

26. The compound [l-(2,6-difluorobenzyl)-lH-l,2,3-triazol-4-yl]methanol of Formula XA;

Formula XA