Description:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF SUBSTITUTED BENZYL BROMIDE”
This patent application is a modification of Indian Patent application IN201911003300 filed on 28/01/2019.

SRF LIMITED, AN INDIAN COMPANY,
SECTOR 45, BLOCK-C, UNICREST BUILDING,
GURGAON – 122003,
HARYANA (INDIA)

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention relates to a process for preparing substituted benzyl bromide using hydrobromic acid in absence of a dehydrating agent.

BACKGROUND OF THE INVENTION
The substituted benzyl bromide derivatives are important pharmaceutical intermediates and are used for preparing anticonvulsant drug such as rufinamide.
Journal of Pharmaceutical Sciences, 2009, 44(11):1233-1243 discloses synthesis of a new drug “TMC125”, a non-nucleoside reverse transcriptase inhibitor (NNRTI) from 2,6-dihalobenzylbromide.
WO2009129365 uses 2,6-dihalobenzylbromide as a raw material to synthesize 1-cyano-3-pyrrolidinyl-N-substituted sulfonamides for the treatment of diseases such as obstructive pulmonary disease and chronic rheumatoid arthritis.
Zhongguo Yiyao Gongye Zazhi,41,(4),247-248,2010, discloses synthesis of rufinamide from 2,6-difluorotoluene.
China Journal of Pharmaceutical Industry, 2010, 41(4): 247-249 discloses synthesis of 2,6-difluorobenzyl bromide by bromination of 2,6-difluorotoluene. The reaction uses N-bromosuccinimide as brominating reagent and azobisisobutyronitrile as the initiator in ethyl acetate in 81.2% yield.
The method uses relatively expensive N-bromosuccinimide and azobisisobutyronitrile. The use of azobisisobutyronitrile leads to the formation impurities that needs exhaustive work up for their removal.
CN102070398, discloses the synthesis of 2,6-difluorobenzyl bromide prepared by bromination reaction using 2,6-difluorotoluene as a raw material. The reaction uses the hydrobromic acid, methyl chloride and hydrogen peroxide in presence of an organic or inorganic solvent to yield 90.3% of 2,6-difluorobenzyl bromide.
The processes reported in the literature for the preparation of substituted benzyl bromide are not efficient as they involve lot of corrosive reagents and pose difficulties in purification. The present invention provides a simpler and feasible process for the preparation of substituted benzyl bromide.
IN201911003300 filed by the same applicant, discloses a process for preparation of substituted benzyl bromide by reacting substituted benzyl alcohol with hydrobromic acid in presence of a dehydrating agent. The inventors have now evolved a process which can provide good yields of substituted benzyl bromide in absence of any dehydrating agent.

OBJECT OF THE INVENTION
The invention provides a simple and cost-effective method for preparation of substituted benzyl bromide that is viable at commercial scales.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of a substituted benzyl bromide of Formula 1,

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

Formula 2
wherein X and n are as defined above
with hydrobromic acid at a temperature in the range of 70°C to 95°C.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, “dehydrating agents” are selected from the group consisting of acids such as sulphuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and organic compounds such as N,N-dicyclohexylcarbodiimide.
The step of reacting a compound of formula 2 with hydrobromic acid is optionally carried out in a solvent selected from dichloromethane, chloroform, carbon tetrachloride, methanol, ethanol, isopropanol, ethyl acetate, methyl acetate, isopropyl acetate, diethyl ether, methyltertiarybutylether, methylisopropylether, tetrahydrofuran, dioxane, nitriles, acetonitrile, isopropylnitrile, hexanes, toluene and benzene or a mixture thereof.
In another embodiment of the present invention, the step of reacting a compound of formula 2 with hydrobromic acid is carried out in absence of a dehydrating agent.
In another embodiment of the present invention, the step of reacting a compound of formula 2 with hydrobromic acid is carried out at a temperature in the range of 70°C to 95°C.
In another embodiment of the present invention, the step of reacting a compound of formula 2 with hydrobromic acid is carried out at a temperature of in the range of 70°C to 95°C in absence of dehydrating agent. This temperature range not only results in improved yield and purity but also reduces the effluent and the waste salts generated due to the use of the dehydrating agent such as acids, thereby offering an environment friendly process for commercial production of the titled compounds.
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 is crystallized using a solvent selected from a group consisting of methanol, ethanol, propanol, isopropanol, butanol, tertiary butanol, acetone, diethylether and tetrahydrofuran or the mixture thereof.
The compound of Formula 1 so obtained by the present invention has a purity greater than 95%, more preferably greater than 98.8%, most preferably greater than 99% by gas chromatography.
The compound of Formula I can be converted to rufinamide using the methods known in the 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
Comparative Example-1: Preparation of 2,6-difluorobenzyl bromide (Comparative example with dehydrating agent)
2,6-Difluorobenzyl alcohol (27g) and hydrobromic acid solution (61g, 48%) were charged to the reactor at room temperature and cooled to 10°C. After cooling, sulphuric acid (37g) was added dropwise over the period of one hour by maintaining the temperature below 15°C. After addition, the mass temperature was increased to room temperature (30°C) and stirred for 4 hours. Then reaction was monitored by gas chromatography. When 2,6-difluorobenzylalcohol was less than 0.2%, the reaction mass was quenched into ice cooled water and extracted with dichloromethane twice and the combined organic layer was washed with sodium bisulphite solution (10%) to remove traces bromine and hydrobromic acid. The solvent dichloromethane was evaporated at 45-50°C and crude mass was distilled to get pure product.
Yield: 75%; Purity: 99.8%
Comparative Example-2: Preparation of 2,6-difluorobenzyl bromide (Comparative example at lower temperature range)
2,6-Difluorobenzyl alcohol (27g) and hydrobromic acid solution (61g, 48%) were charged to the reactor at 50 to 60°C and stirred for 10-14 hours. Then reaction was monitored by gas chromatography. The reaction mass was quenched into ice cooled water and extracted with dichloromethane twice and the combined organic layer was washed with sodium bisulphite solution (10%) to remove traces of bromine and hydrobromic acid. The solvent dichloromethane was evaporated at 45-50°C and crude mass was distilled to get pure product.
Yield: 75%; Purity: 99.8%

Comparative Example-3: Preparation of 2,6-difluorobenzyl bromide (Comparative example at higher temperature range)
2,6-Difluorobenzyl alcohol (27g) and hydrobromic acid solution (61g, 48%) were charged to the reactor at 100 to 110°C and stirred for 8-10 hours. Then reaction was monitored by gas chromatography. The reaction mass was quenched into ice cooled water and extracted with dichloromethane twice and the combined organic layer was washed with sodium bisulphite solution (10%) to remove traces bromine and hydrobromic acid. The solvent dichloromethane was evaporated at 45-50°C and crude mass was distilled to get pure product.
Yield: 60%; Purity: 90.8%
Example-1: Preparation of 2,6-difluorobenzyl bromide
2,6-Difluorobenzyl alcohol (27g) and hydrobromic acid solution (61g, 48%) were charged to the reactor at room temperature and heated to a temperature of 80-85°C. The reaction mixture was stirred at same temperature for 10 to 11 hours. The reaction was monitored by GC and after completion of the reaction, the mass was cooled to 40°C and dichloromethane (70g, 0.824 mol) was added and stirred for 30 minutes. The layers were separated. The organic layer was washed with water (25g, 1.38 mol) and concentrated using rota evaporator, concentrated at 50-55°C at 150-200 torr. Finally, the crude mass was crystallized using isopropyl alcohol (25g, 0.41 mol) at 50-55°C. The reaction mass was cooled to 30-35°C and then gradually cooled to 0-5°C. The product was filtered and dried under vacuum at 250300 torr at 45-50°C.
Purity: 99.5 %; Yield: 90 %
Example-2: Preparation of 2,4,6-trifluorobenzyl bromide
2,4,6-Trifluorobenzyl alcohol (35g) and hydrobromic acid solution (61g, 48%) was heated at a temperature of 85 to 90°C for 10-11 hours. The progress of reaction was monitored by GC and after completion of the reaction, the mass was cooled to 40°C and dichloromethane (70 g, 0.824 mol) was added and stirred for 30 minutes. The layers were separated. The organic layer was washed with water (25g, 1.38 mol) and concentrated using rota evaporator, concentrated at 50-55°C at 150-200 torr. Finally, the crude mass was crystallized using isopropyl alcohol (25g, 0.41 mol) at 50-55°C. The reaction mass was cooled to 30-35°C and then gradually cooled to 0-5°C. The product was filtered and dried under vacuum at 250-300 torr at 45-50°C.
Purity: 99.8 %; Yield: 89 %
Example-3: Preparation of 2,4-difluorobenzyl bromide
2,4-difluorobenzyl alcohol (25g) and hydrobromic acid solution (61g, 48%) was heated at a temperature of 85 to 90°C for 10-11 hours. The progress of reaction was monitored by GC and after completion of the reaction, the mass was cooled to 40°C and dichloromethane (70 g, 0.824 mol) was added and stirred for 30 minutes. The layers were separated. The organic layer was washed with water (25 g, 1.38 mol) and concentrated using rota evaporator, concentrated at 50-55°C at 150-200 torr. Finally, the crude mass was crystallized using isopropyl alcohol (25g, 0.41 mol) at 50-55°C. The reaction mass was cooled to 30-35°C and then gradually cooled to 0-5°C. The product was filtered and dried under vacuum at 250-300 torr at 45-50°C.
Purity: 99.8 %; Yield: 90 %
As is evident from the above examples 1-3 and the comparative examples 1-3, the process of the present invention not only results in improved yield and purity but also reduces the effluent and the waste salts generated due to the use of dehydrating agent such as sulfuric acid.
, Claims:

WE CLAIM:
1. A process for preparation of a substituted benzyl bromide of Formula 1,

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

Formula 2
wherein X and n are as defined above,
with hydrobromic acid at a temperature of 70°C to 95°C.
2. The process as claimed in claim 1, wherein the process is carried out in a solvent selected from dichloromethane, chloroform, carbon tetrachloride, methanol, ethanol, isopropanol, ethyl acetate, methyl acetate, isopropyl acetate, diethyl ether, methyltertiarybutylether, methylisopropylether, tetrahydrofuran, dioxane, nitriles, acetonitrile, isopropylnitrile, hexanes, toluene and benzene or a mixture thereof.

Dated this 01st day of November 2022.