The present invention provides a process for preparation of substituted benzylbromides of formula 1. The substituted benzylbromides are very useful in a wide range of applications.
BACKGROUND OF THE INVENTION
Substituted benzylbromides are used as intermediate for synthesis of complex organic molecules in pharmaceutical and agricultural industries.
There are several methods known in the art for the preparation of substituted benzylbromides.
CN102070398A discloses a process for preparation of 2,6-difluorobenzylbromide by illuminating 2,6-difluorotoluene using tungsten-iodine lamp of 1000W in presence of hydrogen bromide and hydrogen peroxide in an aqueous or an organic solvent. The process uses high energy tungsten-iodine lamp that is not suitable for commercial exploitation. In addition, the raw material used for the preparation of 2,6-difluorobenzylbromide in the given processes is costly and not easily available.
WO2018187336A discloses a process for preparation of alkyl bromide by reacting a solution of methyl 2,6-difluorobenzoate in tetrahydrofuran with lithium aluminium hydride, triphenylphosphine and carbon tetrabromide in presence of an alcohol. The reducing agent used in the process are expensive and unstable in nature, hence difficult to handle at commercial scale.
The above processes are non-selective, requires high energy and non-feasible for commercial scale-ups.
The present invention provides a commercially viable and cost-effective process for preparation of substituted benzylbromide of formula 1.

OBJECT OF THE INVENTION
The main object of the present invention is to provide a cost effective process for preparation of substituted benzylbromide of formula 1 from corresponding benzyl acetate of formula 2.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of a substituted benzylbromides of Formula 1,

Formula 1
wherein X represents C1-C4 alkyl, fluoro, chloro, or bromo groups; n is 1-5, comprising the step of brominating a compound of Formula 2,

Formula 2
wherein X and n are as defined above and R is COR', SO2R, and wherein R is CI-
C4 alkyl group,

with hydrobromic acid.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, "hydrobromic acid" refers to an anhydrous or aqueous form of hydrobromic acid.
In an embodiment, the present invention provides a process for preparation of substituted benzylbromides of formula 1 comprising the step of brominating a compound of Formula 2,
6-
Formula 2
wherein X and n are as defined above and R is COR', SO2R, and wherein R is Cl-
C4 alkyl group,
with hydrobromic acid.
In an embodiment, the step of bromination is carried out in anhydrous conditions.
In an embodiment, the step of bromination is carried out under anhydrous conditions, having the moisture level less than 0.5% and preferably, less than 0.3% and more preferably between 0.1-0.25%) The use of anhydrous condition helps to prevent the formation of undesired impurities.
In an embodiment, the present invention provides an anhydrous process for preparation of benzylbromide of formula 1, comprising brominating a compound of formula 2 with anhydrous hydrobromic acid.

In an embodiment, the present invention provides an anhydrous process for preparation of benzylbromide of formula 1, comprising brominating a compound of formula 2 with anhydrous hydrobromic acid in acetic acid.
The concentration of hydrobromic acid in given solution is 20-33% and preferably 33%.
In preferred embodiment, the present invention provides an anhydrous process for preparation of 2,6-difluorobenzylbromide using anhydrous hydrobromic acid.
In another embodiment, the present invention provides a process for preparation of substituted benzylbromides of formula I, comprising reacting a compound of formula 2 in aqueous conditions.
In another embodiment, the present invention provides a process for preparation of substituted benzylbromide of formula 1, comprising reacting a compound of formula 2 with an aqueous hydrobromic acid.
In another embodiment, an aqueous solution of hydrobromic acid is used for bromination. The concentration of hydrobromic acid is 40-47% in the aqueous solution and preferably 47%.
In an embodiment of the present invention the step of bromination is carried out optionally in presence of a dehydrating agent.
In another embodiment, the step of bromination is carried out using an aqueous hydrobromic acid in presence of a dehydrating agent selected from a group consisting of sulphuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid or an organic compound selected from N,N-dicyclohexylcarbodiimide.
In an embodiment, step of reacting a compound of formula 2 with hydrobromic acid is carried out in a solvent. The solvent is selected from a group consisting of chlorinated

solvents such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride and hydrocarbon solvent such as hexane, toluene or the like.
In another embodiment, the present invention provides an anhydrous process for preparation of benzyl bromides, wherein the compound of formula 2 is brominated with a solution of 33% hydrobromic acid in acetic acid.
In another embodiment, the present invention provides an anhydrous process for preparation of benzyl bromides, wherein the compound of formula 2 is brominated with an aqueous solution of 47% hydrobromic acid.
In another embodiment, the present invention provides an anhydrous process for preparation of 2,6-difluorobenzyl bromide, wherein 2,6-difluorobenzyl acetate is brominated with a solution of 33% hydrobromic acid in acetic acid. The acidic solution of hydrobromic acid aids in increasing the selectivity and reducing the formation of undesired impurities.
In another embodiment, the step of bromination is carried out at a temperature range of 0 to 50°C. Preferably, reaction is carried out at a temperature range of 10 to 30°C.
In another embodiment, the molar ratio of hydrobromic acid with compound of formula 2 is in the range from 1.1 to 2.5:1.
In another embodiment, the present invention provides a process for preparation of 2,6-difluorobenzylbromide, comprising a step of reacting 2,6-difluorobenzyl acetate with an aqueous solution of hydrobromic acid in presence of a solvent.
In another embodiment, the present invention provides an anhydrous process for preparation of 2,6-difluorobenzylbromide, comprising a step of brominating 2,6-difluorobenzyl acetate with a solution of hydrobromic acid in acetic acid in presence of solvent.

The compound of Formula 1 is isolated by using techniques known in the art for example distillation, evaporation, column chromatography and layer separation or combination thereof.
The compound of Formula 1 so obtained by the present invention has a purity greater than 99% by gas chromatography.
In an embodiment, the present invention provides a process for preparation of 2,6-difluorobenzylbromide, having yield greater than 90%, preferably, greater than 95% and purity of greater than 99%.
The compound of Formula I can be converted to rufinamide using the methods known in art.
While the present invention has been described in terms of its specific embodiments, 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. The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1: Preparation of 2,6-difluorobenzyl bromide.
2,6-difluorobenzyl acetate (10 g, 0.0537 mol), aqueous hydrobromic acid (47%, 19 g, 0.1103 mol) and dichloromethane (8 g, 0.0942 mol) were added in 250 mL four neck round bottomed flask equipped with mechanical stirrer and condenser cooled by circulation chiller at 0°C. The reaction mixture was cooled to 10°C. The concentrated sulphuric acid (22 g, 0.2198 mol) was taken and added dropwise by dropping funnel over a period of one hour in a reaction mixture. After complete addition, the reaction mixture was heated to 30°C and maintained for 24 hours. The reaction was monitored by GC. After completion of the reaction, ice cold water (31 g, 1.722 mol) was added dropwise, and the reaction mass was cooled to 10°C. Thereafter, dichloromethane (42

g, 0.494 mol) was added, and the reaction mass was stirred for 30 min. The layers were separated, and organic layer was washed with sodium bisulphite solution (4%, 31 g, 0.011 mol) and distilled to obtain the titled compound.
Purity: 99.5 %; Yield: 93 %
Example 2: Preparation of 2,6-difluorobenzyl bromide.
2,6-Difluorobenzyl acetate (10 g, 0.0537 mol), a solution of hydrobromic acid in acetic acid (33%, 19 g, 0.1103 mol) and dichloromethane (8 g, 0.0942 mol) were added in 250 mL four neck round bottomed flask equipped with mechanical stirrer and condenser was cooled by circulation chiller at 0°C. After complete addition, the reaction mixture was heated to 30°C and maintained the reaction for 8 hours. The reaction was monitored by GC. After completion of the reaction, ice cold water (31 g, 1.722 mol) was added dropwise, and the reaction mass was cooled to 10°C. Thereafter, dichloromethane (42 g, 0.494 mol) was added and the reaction mass was stirred for 30 min. The layers were separated, organic layer was washed with sodium bisulphite solution (4%, 31 g, 0.011 mol) and distilled to obtain the titled compound.
Purity: 99.7 %; Yield: 92 %

WE CLAIM

1. A process for the preparation of a substituted benzylbromide of Formula 1,

Formula 1
wherein X represents C1-C4 alkyl, fluoro, chloro, or bromo groups; n is 1-5, comprising the step of brominating a compound of Formula 2,


xn

Formula 2
wherein X and n are as defined above and R is COR', SO2R, and wherein R is Cl-
C4 alkyl group,
with hydrobromic acid.
2. The process as claimed in claim 1, wherein the bromination is carried out with anhydrous hydrobromic acid.
3. The process as claimed in claim 1, wherein the step of bromination is carried out with anhydrous hydrobromic acid in acetic acid.
4. The process as claimed in claim 1, wherein the step of bromination is carried out using an aqueous hydrobromic acid in presence of a dehydrating agent selected from a

group consisting of sulphuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfomc acid, p-toluenesulfonic acid or an organic compound selected fromN,N-dicyclohexylcarbodiimide.
5. The process as claimed in claim 1, wherein the step of bromination is carried out in a solvent selected from a group consisting of dichloromethane, dichloroethane chloroform, carbon tetrachloride, hexane, and toluene.
6. The process as claimed in claim 1, wherein the step of bromination is carried out at a temperature in the range selected from 0°C to 50°C.