DESC:
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 HALOSUBSITUTED BENZYL CHLORIDES”

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 provides a process for preparation of halosubstituted benzyl chloride of formula I.

Formula I
wherein X is a halogen independently selected from chloro, bromo and fluoro, and n is 1-5.

BACKGROUND OF THE INVENTION
The present invention relates to a process for preparation of a compound of formula I, that are important intermediate in the synthesis of pharmaceutical ingredients such as Rufinamide, an anticonvulsant medication.
Yanbian Daxue Yixue Xuebao, 27(4), 264-266; 2004 discloses a halogenation reaction of 2,6-difluorobenzyl alcohol with thionyl chloride at refluxing in diethylether to produce 2,6-difluorobenzyl chloride. The use a volatile and extremely flammable solvent such as diethyl ether is not viable at industrial scale.
CN104610068B provides a process for preparation of 2,4,6-trifluorobenzyl chloride by chlorinating 2,4,6-triflurobenzyl alcohol using thionyl chloride in presence of pyridine.
RU2596872C1 provides a process for preparing mono and difluoro benzyl chlorides by reacting corresponding benzyl alcohols with tetra-chloromethane in an alcohol solvent in presence of iron chloride or iron bromide activated by formamide as catalyst at 180°C.
Organic Process Research & Development, Volume 20, Issue 2, 568-573, 2016 provides a process for preparation of 2,6-difluorobenzyl chloride from 2,6-difluorobenzyl alcohol using hydrochloric gas at temperature greater than 100?. Owing to corrosive nature of hydrogen chloride, the process necessitates use of a complex set-up involving expensive reactor.
Journal of Fluorine Chemistry, 226,109346, 2019 discloses a process of mono and difluorobenzyl chloride by chlorination of mono and difluoro toluenes with tetrachloromethane and tert-butyl hypochlorite, in presence of iron-containing catalysts.
The processes known in the literature are carried out either in presence of a solvent or a metal catalyst, that increases cost and number of operations during industrial scale up. In light of the drawbacks of foregoing processes and increasing demand the present invention provides an environment friendly process for preparation of compounds of formula I by eliminating the use of solvent and catalyst. Additionally, the present invention provides a process for the purification of compound of formula I thereby eliminating formation of impurities.

OBJECT OF THE INVENTION
The present invention provides an economical, environment friendly and highly purified process for preparation of compounds of formula I that is carried out in absence of any solvent and catalyst.

SUMMARY OF THE INVENTION
In first aspect, the present invention provides a process for preparation of compound of formula I,

Formula I
wherein X is a halogen independently selected from chloro, bromo and fluoro, and n is 1-5;
by chlorinating a compound of formula II using a chlorinating agent in absence of solvent,

Formula II
wherein X is a halogen independently selected from chloro, bromo and fluoro, and n is 1-5.
In second aspect, the present invention provides a process for obtaining pure compound of formula I,

Formula I
wherein X is a halogen independently selected from chloro, bromo and fluoro, and n is 1-5;
a) chlorinating a compound of formula II using a chlorinating agent in absence of solvent and catalyst to obtain a crude compound of formula I,

wherein X is a halogen independently selected from chloro, bromo and fluoro, and n is 1-5.
b) purifying the crude obtained in step a) using the method of sublimation; and
c) isolating the compound of formula I, having purity greater than 99.8%.

DETAILS DECRIPTION OF THE INVENTION
As used herein, a compound of formula I may refers to 2,4-difluorobenzyl chloride; 2,6-difluorobenzyl chloride; 4-fluorobenzyl chloride; 2-fluorobenzyl chloride; 2,4,6-trifluorobenzyl chloride; 4-chloro-2-fluorobenzyl chloride; 2,4-dichlorobenzyl chloride; 4-chlorobenzyl chloride; 2-chloro-benzyl chloride and 2,3,5,6-tetrafluorobenzyl chloride or the like.
As used herein, a compound of formula II may refer to 2,4-difluorobenzyl alcohol; 2,6-difluorobenzyl alcohol; 4-fluorobenzyl alcohol; 2-fluorobenzyl alcohol; 2,4,6-trifluorobenzyl alcohol; 4-chloro-2-fluorobenzyl alcohol; 2,4-dichlorobenzyl alcohol; 4-chlorobenzyl alcohol; 2-chloro-benzyl alcohol and 2,3,5,6-tetrafluorobenzyl alcohol or the like.
In an embodiment, the chlorination of compound of formula II is carried out in absence of solvent and solvent refers to any organic or aqueous solvent.
In an embodiment, the chlorination of a compound of formula II is carried out in absence of catalyst.
In other embodiment, the chlorination of a compound of formula II is carried out under anhydrous conditions.
The present invention provides a process for preparation of a compound of formula I, by chlorinating a compound of formula II using a chlorinating agent in absence of solvent.
The present invention provides a process for preparation of a compound of formula I, wherein the step of chlorination is further followed by purification using method of sublimation.
In an embodiment, chlorinating agent is added in the compound of formula II at 40-60? and the step of chlorination is carried out at a temperature in the range selected from 40-90?.
In an embodiment, the step of purification is carried out at a temperature in the range selected from 29-30?.
In an embodiment, the process of the present invention is carried out in a continuous flow mode.
As used herein, chlorinating agent may be selected from thionyl chloride, oxalyl chloride, phosphoryl chloride and sulfuryl chloride or the like. The molar ratio of chlorinating agent to the compound of formula II is in the range of 1.1 to 1.5.
In a preferred embodiment, the step of chlorinating a compound of formula II using a thionyl chloride is carried out in absence of a solvent and a catalyst to obtain a compound of formula I.
In a preferred embodiment, the step of chlorinating a compound of formula II using a thionyl chloride is carried out in absence of a solvent and a catalyst to obtain a crude compound of formula I, purifying the obtained crude using sublimation technique to get pure compound of formula I.
In an embodiment, the chlorination of a compound of formula II is carried out at atmospheric pressure under vigorous stirring.
As used herein, “vigorous stirring” refers to a rpm of 500-600. The vigorous stirring helps in achieving high selectivity by removing by-product gases from the reaction mixture. While using thionyl chloride, phosphorus trichloride and sulphur dioxide gases are removed continuously from reaction mixture under vigorous stirring of 400-600ppm. The high concentration of these gases in the reaction mixture, leads to the formation of impurity 1 and impurity 2.

Impurity: 1 (ether-based impurity)

Impurity: 2 (Z is Phosphorous or Sulphur)
The chlorination of 2,6-difluorobenzyl alcohol to obtain 2,6-difluorobenzyl chloride gives ether (impurity 1a) and sulphonyl impurities (impurity 2a) /sulphite, if stirring speed is below 400 rpm then the concentration of ether containing and sulphur dioxide gases in the reaction mixture found higher. Hence, the vigorous stirring is required for removing such impurities and achieving high selectivity.

Impurity: 1a (ether-based impurity)

Impurity: 2a (Z is Sulphur)
In present invention, the by-product produced during chlorination is initially scrubbed to water and then in aqueous base for complete quenching.
In present invention, the selectivity of chlorination step is greater than 95% and preferably 97% and the concentration of given impurities in reaction mixture is less than 5%.
In present invention, the purification step reduce the concentration of given impurities in reaction mixture upto 0.01%.
In a preferred embodiment, the present invention provides a process for preparation of pure 2,6-difluorobenzyl chloride by chlorination which is followed by sublimation to form pure 2,6-difluorobenzyl chloride.
In a preferred embodiment, the present invention provides a process for preparation of 2,6-difluorobenzyl chloride by chlorinating 2,6-difluorobenzyl alcohol using a thionyl chloride in absence of solvent.
In a preferred embodiment, the present invention provides a process for preparation of 2,6-difluorobenzyl chloride by chlorinating 2,6-difluorobenzyl alcohol using a thionyl chloride in absence of solvent, further followed by purification using method of sublimation.
In a preferred embodiment, the present invention provides a process for preparation of 2,6-difluorobenzyl chloride by chlorinating 2,6-difluorobenzyl alcohol using sulfuryl chloride in absence of a solvent.
In another preferred embodiment, the present invention provides a process for preparation of 2,3,5,6-tetrafluorobenzyl chloride by chlorinating 2,3,5,6-tetrafluorobenzyl alcohol using thionyl chloride in absence of a solvent.
In an embodiment, the present invention provides a process for preparation of 2-chloro-6-fluorobenzyl chloride by chlorinating 2-chloro-6-fluorobenzyl alcohol using a thionyl chloride in absence of a solvent.
In another preferred embodiment, the present invention provides a process for preparation of 2,4,6-trifluorobenzyl chloride by chlorinating 2,4,6-trifluorobenzyl alcohol using a thionyl chloride in absence of a solvent.
In a preferred embodiment, the present invention provides a process for preparation of 2,4,6-trifluorobenzyl chloride by chlorinating 2,4,6-trifluorobenzyl alcohol using a thionyl chloride in absence of a solvent, further followed by purification using method of sublimation.
The product may be isolated from reaction mixture by layer separation, solvent extraction, distillation, azeotropic distillation, fractional distillation, and reactive distillation.
In an embodiment, chlorinating a compound of formula II, using a chlorinating agent to obtain reaction mixture and adding water to neutralise the reaction mixture. Then, an organic solvent was added to reaction mixture and separated organic phase to obtain compound of formula I. The organic solvent may be selected from dichloromethane, 1,2-dichloroethane, acetone, acetonitrile, xylene, and m-xylene or like.
It is observed that water addition has adverse effect on product yield and purity. Due to water neutralisation, the product may further back convert to the reactant.
In preferred embodiment, chlorinating a compound of formula II using a chlorinating agent to obtain reaction mixture and, then distilling the reaction mixture to obtain a compound of formula I.
In another preferred embodiment, embodiment, chlorinating a compound of formula II using a chlorinating agent to obtain reaction mixture and, then distilling the reaction mixture to obtain a compound of formula I in anhydrous conditions.
In a preferred embodiment, 2,6-difluorobenzyl alcohol is chlorinated using thionyl chloride to obtain reaction mass that is directly distilled to obtain 2,6-difluorobenzyl chloride, wherein distillation is fractional distillation.
In another preferred embodiment, the present invention provides a process for preparation of a compound of formula I, comprising the steps of:
i) reacting a compound of formula II with thionyl chloride at 50-80?;
ii) vigorously stirring the reaction mass at 60-80? for 4-5 hours;
iii) distilling step-ii) reaction mass to obtain a crude compound of formula I.
iv) purifying the resultant crude at 29-30?; and
v) isolating the pure compound of formula I.
The purity of compound of formula I obtained in present invention is 95-99.9% and in a yield of 85-90%.
Unless stated to the contrary, any of the words “comprising”, “comprises” mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
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 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.
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 chloride
2,6-Difluorobenzyl alcohol (190 g) was charged in a reactor and added thionyl chloride (189 g) slowly at temperature of 50-80 ?C. The reaction mass was stirred between 550-650 rpm for 10 hours. Reaction progress was monitored by gas chromatography. The reaction mass was fractional distilled to obtain 2,6-difluorobenzyl chloride.
Purity: 99.5%; Yield: 90%
Example 2: Preparation of 2,6-difluorobenzyl chloride (Comparative Example)
2,6-Difluorobenzyl alcohol (190 g) was taken in a reactor and added thionyl chloride (210 g) slowly at 50-80 ?C. The reaction mass stirring was kept between 200 rpm for 10 hours. Reaction progress was monitored by gas chromatography. The reaction mass was fractional distilled to obtain 2,6-difluorobenzyl chloride.
At reaction termination:
Impurity 1 (Bis ether) (%): -5 to 10%
Impurity 2 (Sulphite) (%): -5 to 7%
Purity: 95.3%; Yield: 68%
Example 3: Preparation of 2,4,6-trifluorobenzyl chloride
2,4,6-trifluorobenzyl alcohol (162 g) was charged in a reactor and added sulfuryl chloride (174.2 g) slowly at 50-80 ?C. The reaction mass was stirred at 500-600 rpm for 9 hours. Reaction progress was monitored by gas chromatography. The reaction mass was fractional distilled to obtain 2,4,6-trifluorobenzyl chloride.
Purity: 98.5%; Yield: 85%
Example 4: Preparation of 2,4-difluorobenzyl chloride
2,6-difluorobenzyl alcohol (190 g) was charged in a reactor and added phosphoryl chloride (243 g) slowly at 50-80 ?C. The reaction mass stirring was kept between 500-600 rpm for 10-15 hours. Reaction progress was monitored by gas chromatography. The reaction mass was fractional distilled to obtain 2,4-difluorobenzyl chloride.
Purity: 96%; Yield: 87.4%
Example 5: Purification of 2,6-difluorobenzyl chloride
2,6-difluorobenzyl alcohol (8.0 g) was charged in a reactor and added thionyl chloride (8.9 g) slowly at temperature of 60-65 ?C. The reaction mass was stirred between 550-650 rpm for 10 hours. Reaction progress was monitored by gas chromatography. The reaction mass was fractional distilled to obtain a crude 2,6-difluorobenzyl chloride, further followed by purification using sublimation technique atmospherically at 29-30 ?C to obtain a pure 2,6-difluorobenzyl chloride (8.1 g).
Purity: 99.8%; Yield: 90%.
,CLAIMS:WE CLAIM:
1. A process for preparation of compound of formula I,

Formula I
wherein X is a halogen independently selected from chloro, bromo and fluoro, and n is 1-5;
by chlorinating a compound of formula II using a chlorinating agent in absence of solvent,

Formula II
wherein X is a halogen independently selected from chloro, bromo and fluoro, and n is 1-5.
2. The process as claimed in claim 1 to obtain pure compound of formula I, comprising the steps of:

Formula I
wherein X is a halogen independently selected from chloro, bromo and fluoro, and n is 1-5;
a) chlorinating a compound of formula II using a chlorinating agent in absence of solvent and catalyst to obtain a crude compound of formula I,

Formula II
wherein X is a halogen independently selected from chloro, bromo and fluoro, and n is 1-5.
b) purifying the crude compound of formula I using the method of sublimation; and
c) isolating the compound of formula I, having purity greater than 99.8%.
3. The process as claimed in claim 1 and claim 2, wherein the chlorination is carried out at a temperature in the range selected from 40-90?.
4. The process as claimed in claim 2, wherein the step of purification is carried out at a temperature in the range selected from 29-30?.
5. The process as claimed in claim 1 and claim 2, wherein the chlorinating agent is selected from a group consisting of thionyl chloride, oxalyl chloride, phosphoryl chloride and sulfuryl chloride.
6. The process as claimed in claim 1 and claim 2, wherein the chlorination of a compound of formula II is carried out at atmospheric pressure under vigorous stirring.
7. The process as claimed in claim 1 and claim 2, for preparation of a compound of formula I, comprising the steps of:
i) reacting a compound of formula II with thionyl chloride at 50-80?;
ii) vigorously stirring the reaction mass at 60-80? for 4-5 hours;
iii) distilling step-ii) reaction mass to obtain a crude compound of formula I.
iv) purifying the crude compound of formula I at 29-30?; and
v) isolating the pure compound of formula I.
8. The process as claimed in claim 1 and claim 2, wherein the process is carried out in a continuous flow mode.

Dated this 17th day of August 2022.