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

“A PROCESS FOR PURIFICATION OF SUBSTITUTED BENZYL HALIDES”

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

The following specification particular describe the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a process for purification of substituted benzyl halides.

BACKGROUND OF THE INVENTION
The present invention relates to a process for purification of substituted benzyl halides, that are important intermediate in the synthesis of pharma molecules and specifically Rufinamide, an anticonvulsant.
CN102070398A provides a method for preparation of 2,6-difluorobenzyl bromide using hydrogen bromide and hydrogen peroxide and isolating it by giving saturated sodium bisulfite solution washing, water washing, anhydrous sodium sulfate drying and silica gel column chromatography to isolate 2,6-difluorobenzylbromide.
China Journal of Pharmaceutical Industry, 2010, 41(4): 247-249 discloses synthesis of 2,6-difluorobenzyl bromide by bromination of 2,6-difluorotoluene using N-bromosuccinimide and azobisisobutyronitrile in ethyl acetate. The method uses expensive N-bromosuccinimide, azobisisobutyronitrile, and involves formation of impurities that needs exhaustive work up for their removal.
WO2018187336A1 discloses a process using lithium aluminium hydride, triphenylphosphine and carbon tetrabromide for preparation of alkyl bromide from 2,6-difluorobenzoate. The product is isolated by using a tedious purification process, flash chromatography, with ethylacetate and hexane.
RU2596872C1 gives a method for producing mono- and difluoro benzyl chlorides by reacting mono- and difluorobenzyl alcohol with tetra-chloromethane in alcohol solvent. The process uses iron chloride or iron bromide activated by formamide as catalyst at 180°C.
The processes reported in literature for the preparation and purification of substituted benzyl halides are tedious and commercially less viable. The product of present invention is an intermediate in pharma industry and need to be of high purity. Hence, there is a need in the art to develop a process for isolation of compound of formula I by using simple purification technique.
The present invention provides a simpler and feasible purification process for the isolation of substituted benzyl halides that is environment friendly and commercially feasible.

OBJECT OF THE INVENTION
The present invention provides an eco-friendly and economical process for purification of substituted benzyl halides.

SUMMARY OF THE INVENTION
The present invention provides a process for purification of substituted benzyl halides, comprising the steps of:
a) vaporizing crude substituted benzyl halide in a first heating zone; and
b) moving the vapours to a second heating zone to collect the substituted benzyl halide of purity more than 98%, wherein the second heating zone is maintained at a temperature lower than the first heating zone.

DETAILS DECRIPTION OF THE INVENTION
As used herein, a substituted benzyl halide refers to 2,6-difluorobenzyl chloride, 2,6-difluorobenzyl bromide, 2,6-dichlorobenzyl chloride (36-39?), 2,6-dichlorobenzyl bromide (54-56?), 2,6-dibromobenzyl bromide (80-81?), 2-bromo-6-chlorobenzyl bromide (58-60?), 3,5-dichloro-benzyl chloride (36?) or like.
The substituted benzyl halides of the present invention are volatile in nature and can be directly vaporized at ambient temperatures, without converting to liquid phase.
As used herein, crude substituted benzyl halides refer to substituted benzyl halides having purity between 60 to 85%. The crude substituted benzyl halides contains impurities that do not get vaporized at a temperature of first heating zone.
As used herein, the pure substituted benzyl halides refers to the substituted benzyl halides having purity between 90 to 99.9%.
The step of vaporising crude substituted benzyl halide to obtain pure substituted benzyl halide is carried out in the time period selected in the range from 1-4 hours or 1-3 hours.
In an embodiment of the present invention, the step of moving the vapours to a second heating zone is performed in a tube maintained at a temperature higher than the second heating zone. The temperature of the tube is maintained using a heater cover.
In another embodiment of the present invention, the step of moving the vapours to a second heating zone is performed in a tube maintained at a temperature higher than the second heating zone by using a heater cover.
In an embodiment of the present invention, the tube used to move the vapours to the second heating zone is made of glass or quartz tube or a metal alloy.
The present inventors have carried out multiple experiment studies for confirming the concept as given below in Table 1 and Table 2.
TABLE 1: Purification of 2,6-difluorobenzyl chloride via vaporisation
Temperature of first heating zone: 25-26?, Temperature of tube: 20-25?,
Temperature of second heating zone: 10-15?,Pressure: Atmospheric,
Weight of 2,6-difluorobenzyl chloride: 1.004g
S. No Hours Reduced wt. of 2,6-difluorobenzyl chloride (g)
during vaporisation Remaining wt. of 2,6-difluorobenzyl chloride (g) during vaporisation
1 0.00 0.00 1.004
2 1.00 0.683 0.321
3 1.50 0.859 0.145
4 2.00 0.958 0.046
5 2.50 0.986 0.018
6 3.00 1.000 0.004

Table 2: Purification of 2,6-difluorobenzyl bromide via vaporisation
Temperature of first heating zone: 45-55?, Temperature of tube: 20-25?,
Temperature of second heating zone: 10-15?, Pressure: Atmospheric,
Weight of 2,6-difluorobenzyl chloride: 10.063g
S. No Hours Reduced wt. of 2,6-difluorobenzyl bromide (g)
during vaporisation Remaining wt. of 2,6-difluorobenzyl bromide (g) during vaporisation
1 0 0 10.063
2 4.5 4.5 5.563
3 6.5 6.5 3.563
4 7.8 7.8 2.263
5 9.4 9.4 0.663
6 10 10.0 0.063

In an embodiment, the present invention provides a process for purification of substituted benzyl halides, wherein the step of vaporizing is carried out at atmospheric pressure.
In an embodiment, the present invention provides a process for purification of substituted benzyl halides, wherein the step of vaporization is carried out under reduced pressure in the range from 760 mbar to 1 mbar or 760 mbar to 5 mbar.
In an embodiment of the present invention, the first heating zone is maintained at a temperature of 20-90?.
In another embodiment of the present invention, the second heating zone is maintained at a temperature of 0-20?.
In another embodiment of the present invention, the tube for moving the vapours to the second heating zone is maintained at a temperature of 25-80?.
In an embodiment, the present invention provides a process for purification of 2,6-difluorobenzyl chloride, comprising the steps of vaporizing crude 2,6-difluorobenzyl chloride at 30-55? and moving the vapours to a second heating zone to collect the 2,6-difluorobenzyl chloride of purity more than 99.1%, wherein the second heating zone is maintained at a temperature of 0-10?.
In an embodiment, the present invention provides a process for purification of 2,6-difluorobenzyl bromide, comprising the steps of vaporizing crude 2,6-difluorobenzyl bromide at a temperature of 40-55? and moving the vapours to a second heating zone to collect the 2,6-difluorobenzyl bromide of purity more than 99.3%, wherein the second heating zone is maintained at a temperature of 5-10?.
In an embodiment, the present invention circumvents use of any solvent for purification wherein “solvent” refers to an organic or aqueous solvent.
The purity of compound of formula I obtained in present invention is >95% and more preferably >99%.
In a preferred embodiment, the preparation of 2,6-difluorobenzyl chloride involves a step of chlorinating 2,6-difluorobenzyl alcohol using a thionyl chloride to obtain 2,6-difluorobenzyl chloride followed by vaporizing crude 2,6-difluorobenzyl chloride at 30-55? and moving the vapours to a second heating zone to collect the 2,6-difluorobenzyl chloride of purity more than 99.1%, wherein the second heating zone is maintained at a temperature of 0-10?.
In an embodiment, the preparation of 2,6-difluorobenzyl bromide involves a step of brominating 2,6-difluorobenzyl alcohol using hydrobromic acid in presence of sulfuric acid to obtain crude 2,6-difluorobenzyl bromide followed by vaporizing crude 2,6-difluorobenzyl bromide at a temperature of 40-55? and moving the vapours to a second heating zone to collect the 2,6-difluorobenzyl bromide of purity more than 99.3%, wherein the second heating zone is maintained at a temperature of 5-10?.
The substituted benzyl halides of formula I of present invention may be prepared by any method known in Indian applications IN201711032191, IN201911003300, IN202111052832, IN202211062424, IN202211046879 of same applicant.
The completion of the reaction can be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure 5 liquid chromatography (UPLC), Gas chromatography (GC) and alike.
Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLE
Example 1: Purification of 2,6-difluorobenzyl chloride
Crude 2,6-difluorobenzyl chloride (10g, 82.71%) was charged in a round bottom flask equipped with thermometer, distillation head connected by a tube to a bent fitted into a second heating zone. The crude 2,6-difluorobenzyl chloride was vaporized at 38-50? for 3-4 hours and collected in the second heating zone kept at 5-10?. Purity: 99.1%
Example 2: Purification of 2,6-difluorobenzyl chloride
Crude 2,6-difluorobenzyl chloride (10g, 85.15%) was charged in a round bottom flask equipped with thermometer, distillation head connected by a tube to a bent fitted into a second heating zone. The crude 2,6-difluorobenzyl chloride was vaporized at 38-50? for 3-4 hours and collected in the second heating zone maintained at 5-10?. Purity: 99.3%
Example 3: Purification of 2,6-difluorobenzyl bromide
Crude 2,6-difluorobenzyl bromide (11.5g, 83%) was charged in a round bottom flask equipped with thermometer, distillation head connected by a tube to a bent fitted into a second heating zone. The crude 2,6-difluorobenzyl bromide was vaporized at 45-55? for 4-5 hours and collected in the second heating zone maintained at 5-10?. 2,6-difluorobenzyl bromide: Purity: 99.64%

,CLAIMS:
WE CALIM:
1. A process for purification of substituted benzyl halides, comprising the steps of:
a) vaporizing crude substituted benzyl halide in a first heating zone; and
b) moving the vapours to a second heating zone to collect the substituted benzyl halide of purity more than 98%, wherein the second heating zone is maintained at a temperature lower than the first heating zone.

2. The process as claimed in claim 1, wherein the substituted benzyl halides are volatile in nature and can be directly vaporized at ambient temperatures without converting to liquid phase.

3. The process as claimed in claim 1, wherein the crude substituted benzyl halides is having purity between 60 to 85%.

4. The process as claimed in claim 1, wherein the pure substituted benzyl halide is having purity between 90 to 99.9%.

5. The process as claimed in claim 1, wherein the step of vaporizing is carried out at atmospheric pressure.

6. The process as claimed in claim 1, wherein the step of vaporizing is carried out under reduced pressure, selected in the range from 760 mbar to 1 mbar.

7. The process as claimed in claim 1, wherein the first heating zone is maintained at a temperature of 20-90?.
8. The process as claimed in claim 1, wherein the second heating zone is maintained at a temperature of 0-20?.

9. The process as claimed in claim 1, wherein the tube for moving the vapours to the second heating zone is maintained at a temperature of 25-80?.

Dated this 27th day of January 2023.