FIELD OF THE INVENTION
The present invention relates to a process for preparing substituted benzyl bromide using hydrobromic acid in presence of a dehydrating agent.
BACKGROUND OF THE INVENTION
2,6-Difluorobenzyl bromide is an important pharmaceutical intermediate and is 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.
WO2009129365A1 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 literature for the preparation of substituted benzyl bromide are not efficient as they involves lot of corrosive reagents and also pose difficulties in purification. The present invention provides a simpler and feasible process for the preparation of substituted benzyl bromide.
Thus, the present invention provide a simple, economical process for the preparation of substituted benzyl bromide.
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 the steps of;
a) reacting a substituted benzylamine of Formula 3;

Formula 3
wherein X represents C1-C4 alkyl, fluoro, chloro, and bromo groups; n is 1-5,
with sodium nitrite in presence of an acid to give a reaction mixture;
b) reacting the reaction mixture obtained in step a) with a base to form a compound of Formula 2;

Formula 2
wherein X and n are as defined above and R is hydrogen, COR?, SO2R?, and wherein R? is C1-C4 alkyl group,
c) reacting the compound of Formula 2 with hydrobromic acid in presence of a dehydrating agent to obtain a compound of Formula 1.

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 presence of a solvent.
A solvent used in the step of reacting a compound of formula 2 with hydrobromic acid is selected from a group consisting of chlorinated agents such as dichloromethane, chloroform, carbon tetrachloride, alcohols such as methanol, ethanol, isopropanol, esters such as ethyl acetate, methyl acetate, isopropyl acetate, ethers such as diethyl ether, methyltertiarybutylether, methylisopropylether, tetrahydrofuran, dioxane, nitriles such as acetonitrile, isopropylnitrile, hydrocarbons such as hexanes, toluene, benzene or the like.
The step of reacting a compound of formula 2 with hydrobromic acid is carried out at a temperature ranging from 0°C to 40°C.
The step of reacting a benzyl amine of formula 3 with sodium nitrite is carried out in presence of an acid selected from a group consisting of sulphuric acid, acetic acid, hydrochloric acid, hydrobromic acid or the like.
The base used in step b) is selected from a group consisting of sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate or mixture(s) thereof.
In another embodiment, the present invention provides a process wherein the compound of formula 2 formed by the reaction of the substituted benzyl amine with nitrite in presence of an organic acid, followed by base, is reacted with hydrobromic acid in situ, without isolation of the compound of formula 2.
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 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 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
Preparation of 2,6-difluorobenzyl amine
2,6-difluorobenzonitrile (198 g), methanol (313.1g) and Raney nickel(19.8 g wet) (washed with methanol to remove water) were charged at room temperature and pressurised to 20kg/cm2 with hydrogen and heated to 60-65°C. Hydrogen gas was passed continuously till the pressure becomes constant, to form 2,6-difluorobenzyl amine.

Preparation of 2,6-difluorobenzyl alcohol
2,6-difluorobenzyl amine (35g) was added dropwise to acetic acid (69 g) by maintaining the mass temperature around 30°C. After complete addition, the reaction mass was stirred for an hour to get a clear solution (to solubilise amine salt in acetic acid). After dissolution, the reaction mass was cooled to 0°C and sodium nitrite (25.34 g)was added portion wise by maintaining the mass temperature between 0-5°C. After addition, the reaction mass was stirred at the same temperature for another one hour and then it was allowed to raise for decomposition (mass temp gone upto 37°C). 50% Sodium hydroxide solution (196 g) was added to the reaction mass keeping the temperature below 40°C and heated to 80°C for an hour. The reaction mass was cooled and extracted with dichloromethane (300g) followed by concentration to get 2,6-difluorobenzyl alcohol.
Preparation of 2,6-difluorobenzyl bromide
2,6-difluorobenzyl alcohol (27g) and hydrobromic acid (23g) solution 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 10% sodium bisulphite solution 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%

Preparation of 2,6-difluorobenzyl bromide
2,6-Difluorobenzyl acetate (42g) and hydrobromic acid (116.7g) solution were charged to the reactor at room temperature and cooled to 10°C. Then sulphuric acid (63g) 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 hrs. Then reaction was monitored by gas chromatography to check the absence of 2,6-difluorobenzyl acetate. If 2,6-difluorobenzyl acetate less than 0.2%,the mass was quenched into ice cooled water and extracted with dichloromethane twice and the combined organic layer was washed with 10% sodium bisulphite solution to remove traces bromine and HBr. Dichloromethane was evaporated at 45-50°C in buchi and crude mass was distilled to get desired product.
Yield: 80 %
Purity: 98%
Preparation of 2,4,6-trifluorobenzyl bromide
2,4,6-trifluorobenzyl alcohol (35g) and hydrobromic acid (23g) solution 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. After completion of the reaction, the reaction mass was quenched into ice cooled water and extracted with dichloromethane twice and the combined organic layer was washed with 10% sodium bisulphite solution 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%
Preparation of 2,4,6-trifluorobenzyl bromide
2,4,6-Trifluorobenzyl acetate (50g) and hydrobromic acid (116.7g) solution were charged to the reactor at room temperature and cooled to 10°C.Then sulphuric acid (63g) 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. After comletion of the reaction, the mass was quenched into ice cooled water and extracted with dichloromethane twice and the combined organic layer was washed with 10% sodium bisulphite solution to remove traces bromine and hydrogen bromide. Dichloromethane was evaporated at 45-50°C in buchi and crude mass was distilled to get pure product.
Yield: 80 %
Purity: 98%
Preparation of 2,4-difluorobenzyl bromide
2,4-difluorobenzyl alcohol (25g) and hydrobromic acid (23g) solution 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 5 hours. Then reaction was monitored by gas chromatography. After completion of the reaction, the reaction mass was quenched into ice cooled water and extracted with dichloromethane twice and the combined organic layer was washed with 10% sodium bisulphite solution 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%
Preparation of 2,4-difluorobenzyl bromide
2,4-Difluorobenzyl acetate (50g) and hydrobromic acid (116.7g) solution were charged to the reactor at room temperature and cooled to 10°C. Then sulphuric acid (63g) 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. After completion of the reaction, the mass was quenched into ice cooled water and extracted with dichloromethane twice and the combined organic layer was washed with 10% sodium bisulphite solution to remove traces bromine and HBr. Dichloromethane was evaporated at 45-50°C in buchi and crude mass was to get pure product.
Yield: 80%
Purity: 98%
Preparation of 2,4,6-trifluorobenzyl bromide
Hydrobromic acid (116.7g) solution was charged to a mixture of polyphosphoric acid and 2,4,6-trifluorobenzyl acetate (42g) at room temperature and cooled to 10°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. After completion of the reaction, reaction mass was quenched into ice cooled water and extracted with dichloromethane twice and the combined organic layer was washed with 10% sodium bisulphite solution to remove traces bromine and HBr. Dichloromethane was evaporated at 45-50°C in buchi and crude mass was distilled to get pure product,
Yield: 80%
Purity: 98%

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 the steps of;
a) reacting a substituted benzylamine of Formula 3;

Formula 3
wherein X represents C1-C4 alkyl, fluoro, chloro, and bromo groups; n is an integer 1-5,
with sodium nitrite in presence of an acid to give a reaction mixture;
b) reacting the reaction mixture obtained in step a) with base to form compound of Formula 2;

Formula 2
wherein X and n are as defined above and R is hydrogen, COR?, SO2R?, and wherein R? is C1-C4 alkyl group,
c) reacting the compound of Formula 2 with hydrobromic acid in presence of a dehydrating agent to obtain a compound Formula 1.
2. The process as claimed in claim 1, wherein the acid used in step a) is selected from a group consisting of sulphuric acid, acetic acid, hydrochloric acid, hydrobromic acid or a mixture thereof.
3. The process as claimed in claim 1, wherein the base used in step b) is selected from a group consisting of sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate or mixture(s) thereof.
4. The process as claimed in claim 1, wherein the dehydrating agent used in step c) is selected from a group consisting of sulphuric acid, phosphoric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid and N,N-dicyclohexylcarbodiimide.
3. The process as claimed in claim 1, wherein the bromination is carried out in presence of a solvent.
4. The process as claimed in claim 3, wherein the solvent is 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, benzene or a mixture thereof.
5. The process as claimed in claims 1, wherein the bromination is carried out at a temperature ranging from 0°C to 40°C.