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 SUBSTITUTED BENZYL HALIDES”

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

The following specification particular describes 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 substituted benzyl halides represented as a compound of formula I,

Formula I
wherein X represents independent halogens, R represents halogen, C1-C2 alkyl optionally substituted with halogen, n and m represents an integer from 0-3 and 0-4 respectively.

BACKGROUND OF THE INVENTION
The substituted benzyl halides are very useful intermediates in preparation of pharmaceuticals and agro chemicals.
Various methods are known for preparation of substituted benzyl halide compounds.
WO2002064538 discloses a process for preparation of 4-trifluoromethoxybenzyl chloride by reacting trifluoromethoxybenzene in paraformaldehyde with thionyl halide, phosphoric acid aqueous solution and zinc chloride in the presence of cetyltrimethylammonium bromide to yield 80% of desired compound.
The above process has high effluent and low selectivity and yield. Considering the drawbacks of foregoing process, there is a need to develop an alternate commercially and economically viable process for manufacture of substituted benzyl halides with high selectivity and yield.
Therefore, the present invention provides a solution to the aforesaid problems of the prior art by employing an improved process to produce substituted benzyl halides with minimum impurities and high selectivity towards the desired compound.

OBJECT OF THE INVENTION
The main object of the present invention is to provide a simple, safe, and economical process for preparation of substituted benzyl halides represented as a compound of formula I,

Formula I
wherein X represents independent halogens, R represents halogen, C1-C2 alkyl optionally substituted with halogen, n and m represents an integer from 0-3 and 0-4 respectively.

SUMMARY OF THE INVENTION
The present invention provides an improved process for preparation of a compound of formula I,

Formula I
wherein X represents independent halogens, R represents halogen, C1-C2 alkyl optionally substituted with halogen, n and m represents an integer from 0-3 and 0-4 respectively,
comprising a step of:
a) reacting a compound of formula II with thionyl halide and halomethylating agent in presence of a hindered catalyst to obtain the compound of formula I,

Formula II
wherein X, R ,n, and m represented as above.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, “X” represents halogens and may be selected from a group consisting of fluoro, and bromo. “X'” represents halogens and may be selected from a group consisting of fluoro, chloro, bromo and iodo. The most preferred “X” and “X'” for present invention is chloro. “R” represents halogen, C1-C2 alkyl optionally substituted with halogen, halogen refers chloro, fluoro, iodo and bromo, C1-C2 alkyl refers to methyl and ethyl or optionally substituted with halogen such as trifluoromethyl, difluoromethyl, fluoromethyl, dichloromethyl, difluoroethyl, trifluoroethyl, monofluoroethyl or like.
The “R” may be substituted at ortho and meta position in formula II compound.
As used herein, ‘thionyl halide’ refers to the thionyl iodide, thionyl bromide and thionyl chloride either used as such or generated in-situ.
In embodiment, the process of the present invention provide a compound of formula I may be selected from the group consisting of 1-(chloromethyl)-4-methoxybenzene, 1-( chloromethyl)-4-(chloromethoxy)benzene, 1-(chloromethyl)-4-(dichloromethoxy)benzene, 1-(chloromethyl)-4-(trichloromethoxy)benzene, 1-(chloromethyl)-4-[chloro(fluoro)methoxy]benzene, 1-(chloromethyl)-4-[dichloro(fluoro)methoxy]benzene, 1-(chloromethyl)-4-[chloro(difluoro)methoxy]benzene, 1-(chloromethyl)-4-(trifluoromethoxy)benzene, 1-(chloromethyl)-4-(difluoromethoxy)benzene, 1-(chloromethyl)-4-(fluoromethoxy)benzene, 1-(chloromethyl)-4-(tribromomethoxy)benzene, 1-(chloromethyl)-4-(dibromomethoxy)benzene, 1-(chloromethyl)-4-(bromomethoxy)benzene, 1-(chloromethyl)-4-[dibromo(chloro)methoxy]benzene, 1-(bromomethyl)-4-methoxybenzene, 1-(bromomethyl)-4-(chloromethoxy)benzene, 1-(bromomethyl)-4-(dichloromethoxy)benzene, 1-(bromomethyl)-4-(trichloromethoxy)benzene, 1-(bromomethyl)-4[dichloro(fluoro)methoxy]benzene, 1-(bromomethyl)-4-(trifluoromethoxy)benzene, 1-(bromomethyl)-4-(difluoromethoxy)benzene, 1-(bromomethyl)-4-(fluoromethoxy)benzene, 1-(bromomethyl)-4-(tribromomethoxy)benzene, 1-(bromomethyl)-4-(dibromomethoxy)benzene, 1-(bromomethyl)-4-[dibromo(fluoro)methoxy]benzene, 1-(bromomethyl)-4-[dibromo(chloro)methoxy]benzene, 1-(iodomethyl)-4-(dichloromethoxy)benzene, 1-(iodomethyl)-4-(trichloromethoxy)benzene, 1-(iodomethyl)-4-(trifluoromethoxy)benzene, 1-(iodomethyl)-4-(chloromethoxy)benzene, 1-(chloromethyl)-4-(trifluoromethoxy)-2-(trifluoromethyl)benzene, 1-(bromomethyl)-4-(trifluoromethoxy)-2-(trifluoromethyl)benzene, 1-(bromomethyl)-2-chloro-4-(trifluoromethoxy)benzene, 1-(chloromethyl)-2-chloro-4-[chloro(difluoro)methoxy]benzene, and 1-(bromomethyl)-3-chloro-4-(dichloromethoxy)benzene.
In embodiment, the process of the present invention provide a compound of formula II may be selected from the group consisting of anisole, (chloromethoxy)benzene, (dichloromethoxy)benzene, (trichloromethoxy)benzene, (fluoromethoxy)benzene, (difluoromethoxy)benzene, (trifluoromethoxy)benzene, [chloro(fluoro)methoxy]benzene, [dichloro(fluoro)methoxy]benzene, [chloro(difluoro)methoxy]benzene, (tribromomethoxy)benzene, (bromomethoxy)benzene, (dibromomethoxy)benzene, [bromo(chloro)methoxy]benzene, [bromo(fluoro)methoxy]benzene, [bromo(chloro)fluoromethoxy]benzene, [dibromo(fluoro)methoxy]benzene, [bromo(difluoro)methoxy]benzene, [dibromo(chloro)methoxy]benzene, [bromo(dichloro)methoxy]benzene, 1-chloro-2-[chloro(difluoro)methoxy]benzene, 1-chloro-2-(trifluoromethoxy)benzene, 1-chloro-2-methoxybenzene, 1-bromo-2-(dichloromethoxy)benzene, 1-fluoro-2-(bromomethoxy)benzene.
The ‘hindered catalyst’ refers to ammonium or phosphonium having at least two long carbon chains of more than 6 carbon atoms (>C6) attached to the nitrogen or phosphorous atom. Examples of such catalyst includes methyltrioctylammonium bromide, methyltrioctylammonium chloride, didecyldimethylammonium bromide, tributyl hexadecyl phosphonium bromide, hexadecyltrimethylammonium bromide, didecyldimethylammonium chloride, tributyl hexadecyl phosphonium chloride and hexadecyltrimethylammonium chloride.
In an embodiment, the reaction of the compound of formula II with thionyl halide and halomethylating agent in presence of hindered catalyst is carried out at a temperature in the range from 40 to 80?.
As used herein, ‘halomethylating agent’ is selected from a formaldehyde, paraformaldehyde, halomethyl ether and bishalomethyl ether either used as such or generated in-situ.
In an embodiment, the reaction of the compound of formula II with thionyl halide in presence of halomethylating agent using hindered catalyst is carried out using Lewis’s acid and protic acid.
The ‘Lewis’s acid’ catalyst is selected from an aluminum chloride, iron (III) chloride, zinc chloride, zinc bromide, zinc iodide and titanium (IV) chloride or a like.
The protic acid is selected from an orthophosphoric acid, pyrophosphoric acid, metallic acid, triphosphoric acid, tetraphosphoric acid, polyphosphoric acid, aqueous phosphoric acid, sulfuric acid, oleum, hydrochloric acid, hydrobromic acid and acetic acid, or a mixture thereof.
In an embodiment, compound of formula II may be charged directly or added dropwise.
In an embodiment, the present invention provides a process with maximum conversion, minimum impurity and thereby increases the selectivity towards the desired product significantly.
In an embodiment, the reaction of compound of formula II was treated with hydrogen fluoride in activation of fluorination reaction conducted in-situ.
In preferred embodiment, the fluorination of (trifluoromethoxy)benzene was treated with hydrogen fluoride conducted in-situ.
In an embodiment, the present invention provides less than 0.5% of isomeric impurity in the final compound.
In preferred embodiment, the process of the present invention provides a process for the preparation of 1-(chloromethyl)-4-(trifluoromethoxy)benzene by reacting the trifluoromethoxy benzene with thionyl chloride and paraformaldehyde in the presence of zinc chloride, ortho phosphoric acid and N-methyl-N,N,N-trioctylammonium chloride.
In an embodiment, the molar ratio of thionyl halide w.r.t formula II is the range from 1.0 to 2.0.
In an embodiment, the molar ratio of compound of halomethylating agent w.r.t formula II is in the range from 1.0 to 2.0.
In an embodiment, the molar ratio of Lewis’s acid w.r.t formula II is the range from 0.25 to 1.0.
In an embodiment, the present invention provides a process for preparation of compound of formula I, having yield greater than 84%.
In an embodiment, the present invention provides a process for preparation of compound of formula I, having purity greater than 98%.
In an embodiment, the present invention provides a process for preparation of compound of formula I, having selectivity greater than 90%.
In an embodiment, after completion of the reaction, the reaction mass is separated into layers, top layer washed with water, followed by washing with aqueous base solution and as such or distilled to obtain pure product and bottom layer recycled in further batches.
The compound of formula II which is used as a starting material in step a) can be prepared by any method known in the art or may be obtained commercially.
The compound of the present invention can be isolated using various isolation techniques known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
The completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), gas chromatography (GC), liquid chromatography (LC) and alike.
The reagents used in the above process are obtained commercially.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes 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 following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.

EXAMPLES
EXAMPLE 1: Preparation of 1-(chloromethyl)-4-(trifluoromethoxy)benzene
Trifluoromethoxybenzene (1 equivalent), paraformaldehyde (1.2 equivalents) zinc chloride (0.25 equivalents), ortho phosphoric acid (0.5 equivalents) and N-methyl-N,N,N-trioctylammonium chloride (0.01 equivalents) were added into the round-bottomed flask equipped with a mechanical stirrer, thermos pocket and double surface condenser at 25-28°C. Thionyl chloride (1.1 equivalents) was added dropwise in the reaction mixture in 30-60 minutes under stirring (350 rpm) at 30-35°C. After addition completed, the reaction mixture was heated to 60-75°C. Thereafter, layers were separated, and top layer was taken for distillation after washing using water (2-4 equivalents), followed by aqueous sodium carbonate (0.5 equivalents, 1-2%) and bottom layer was recycled back in the process.
Conversion: 99%; Selectivity: 92%.
Yield: 86%; Purity: 98.7%.
EXAMPLE 2: Preparation of 1-(chloromethyl)-4-(trifluoromethoxy)benzene
Trifluoromethoxybenzene (1 equivalent), chloromethyl ethyl ether (1.2 equivalents) zinc chloride (0.25 equivalents), ortho phosphoric acid (0.5 equivalents) and N-methyl-N,N,N-trioctylammonium chloride (0.01 equivalents) were added into the round-bottomed flask equipped with a mechanical stirrer, thermos pocket and double surface condenser at 25-28°C. Thionyl chloride (1.1 equivalents) was added dropwise in the reaction mixture in 30-60 minutes under stirring (350 rpm) at 30-35°C. After addition completed, the reaction mixture was heated to 60-75°C. Thereafter, layers were separated, and top layer was taken for distillation after washing using water (2-4 equivalents), followed by aqueous sodium carbonate (0.5 equivalents, 1-2%) and bottom layer was recycled back in the process.
Yield: 85%; Purity: 98%.
EXAMPLE 3: Preparation of 1-(chloromethyl)-4-(dichlorofluoromethoxy)benzene
Dichlorofluoromethoxybenzene (1equivalent), paraformaldehyde (1.5 equivalents), zinc chloride (0.25 equivalents), ortho phosphoric acid (0.25 equivalents) and tributyl hexadecyl phosphonium chloride (0.05 equivalents) were added into the round-bottomed flask equipped with a mechanical stirrer, thermos pocket and double surface condenser at 10-20?. Thionyl chloride (1.1 equivalents) was added dropwise in the reaction mixture in 60-90 minutes under stirring (350 rpm) at 30-35°C. After addition completion, the reaction mixture was heated to 35-45°C. Thereafter, layers were separated, and top layer was taken for distillation after washing using water (2-4 equivalents) followed by aqueous sodium carbonate (0.1 equivalents, 1-2%).
Conversion: 99%; Selectivity: 98%.
Yield: 92%; Purity: 99%.
EXAMPLE 4: Preparation of 1-(chloromethyl)-4-(trichloromethoxy)benzene
Trichloromethoxybenzene (1equivalent), paraformaldehyde (1.5 equivalents), zinc chloride (0.25 equivalents), ortho phosphoric acid (0.25 equivalents) and N-methyl-N,N,N-trioctylammonium chloride (0.05 equivalents) were added into the round-bottomed flask equipped with a mechanical stirrer, thermos pocket and double surface condenser at 10-20?. Thionyl chloride (1.1 equivalents) was added dropwise in the reaction mixture in 60-90 minutes under stirring (350 rpm) at 30-35°C. After addition completion, the reaction mixture was heated to 35-45°C. Thereafter, layers were separated, and top layer was taken for distillation after washing using water (2-4 equivalents) followed by aqueous sodium carbonate (0.1 equivalents, 1-2%).
Conversion: 99%; Selectivity: 98%.
Yield: 92%; Purity: 99%.
EXAMPLE 5: Preparation of 1-(chloromethyl)-4-(chloromethoxy)benzene
Chloromethoxybenzene (1 equivalents), paraformaldehyde (2.0 equivalents) zinc chloride (0.5 equivalents), ortho phosphoric acid (0.25 equivalents) and N-methyl-N,N,N-trioctylammonium chloride (0.02 equivalents) were added into the round-bottomed flask equipped with a mechanical stirrer, thermos pocket and double surface condenser at 25-28°C. Thionyl chloride (1.1 equivalents) was added dropwise in the reaction mixture in 60-90 minutes under stirring (350 rpm) at 30-35°C. After reaction completion, the reaction mixture was heated to 50-65°C. Thereafter, layers were separated, and top layer was taken for distillation after washing using water (2-4 equivalents) followed by aqueous sodium carbonate (0.1-0.5 equivalents, 1-2%).
Conversion: 99%; Selectivity: 90%.
Yield: 86%; Purity: 99.5%.
EXAMPLE 6: Preparation of 1-[bromo(difluoro)methoxy]-4-(bromomethyl)benzene
Bromo(difluoro)methoxybenzene (1eq.), paraformaldehyde (1.0eq.) zinc bromide (0.5eq.), ortho phosphoric acid (0.5 eq.) and hexadecyltrimethylammonium bromide (0.05eq.) were added into the round-bottomed flask equipped with a mechanical stirrer, thermos pocket and double surface condenser at 25-28°C. Thionyl bromide (1.2eq.) was added dropwise in the reaction mixture in 60-90 minutes under stirring (350 rpm) at 10-15°C. After reaction completion, the reaction mixture was heated to 35-40°C. Thereafter, layers were separated, and top layer was taken for distillation after washing using water (2-4 eq.), followed by aq. sodium hydroxide (0.1-0.5 eq., 1-2%).
Conversion: 99%; Selectivity: 92%.
Yield: 85%; Purity: 98%.
,CLAIMS:WE CLAIM:
1. An improved process for preparation of a compound of formula

I,

Formula I
wherein X represents independent halogens, R represents halogen, C1-C2 alkyl optionally substituted with halogen, n and m represents an integer from 0-3 and 0-4 respectively,
comprising a step of:
a) reacting a compound of formula II with thionyl halide and halomethylating agent in presence of a hindered catalyst to obtain the compound of formula I,

Formula II
wherein X, R ,n, and m represented as above.
2. The process as claimed in claim 1, wherein thionyl halide is selected from a group consisting of thionyl iodide, thionyl bromide, and thionyl chloride either used as such or generated in-situ.
3. The process as claimed in claim 1, wherein the hindered catalyst refers to ammonium or phosphonium having at least two long carbon chains of more than 6 carbon atoms (>C6) attached to the nitrogen or phosphorous atom.
4. The process as claimed in claim 3, wherein the hindered catalyst includes methyltrioctylammonium bromide, methyltrioctylammonium chloride, didecyldimethylammonium bromide, tributyl hexadecyl phosphonium bromide, hexadecyltrimethylammonium bromide, didecyldimethylammonium chloride, tributyl hexadecyl phosphonium chloride and hexadecyltrimethylammonium chloride.
5. The process as claimed in claim 1, wherein the process of the present invention is carried out at a temperature in the range from 40 to 80?.
6. The process as claimed in claim 1, wherein the halomethylating agent is selected from a group consisting of formaldehyde, paraformaldehyde, halomethyl ether and bishalomethyl ether either used as such or generated in-situ.
7. The process as claimed in claim 1, wherein the process of the present invention is carried out using Lewis’s acid and protic acid.
8. The process as claimed in claim 7, wherein the Lewis’s acid is selected from a group consisting of aluminum chloride, iron (III) chloride, zinc chloride, zinc bromide, zinc iodide and titanium (IV) chloride.
9. The process as claimed in claim 7, wherein the protic acid is selected from a group consisting of orthophosphoric acid, pyrophosphoric acid, metallic acid, triphosphoric acid, tetraphosphoric acid, polyphosphoric acid, aqueous phosphoric acid, sulfuric acid, oleum, hydrochloric acid, hydrobromic acid and acetic acid, or a mixture thereof.

10. The process as claimed in claim 1, wherein the compound of formula I is having yield greater than 85% and purity greater than 99%.

Dated this 26th day of December 2023.