The process of the present invention provides a process for preparation of 4-halomethylbenzene derivatives of formula I.

Formula I
wherein R1 represents an alkyl group; R2 represents an alkyl or an alkoxy group.
and X represents a halogen.
BACKGROUND OF THE INVENTION
The 4-(halomethyl)-1 -alkoxy-2-(trifluoromethyl)benzene is used as intermediate in the pharmaceutical or agricultural industries.
PCT application No. 2011109471 describes a process for preparation of 4-(chloromethyl)-l-isopropoxy-2-(trifluoromethyl)benzene by reacting 4-fluoro-3-(trifluoromethyl)benzonitrile with isopropanol in presence of a base to form 4-isopropoxy-3-(trifluoromethyl)benzonitrile, which upon hydrolysis forms 4-isopropoxy-3-(trifluoromethyl)benzoic acid, which upon reduction followed by chlorination using thionyl chloride gives 4-(chloromethyl)-l-isopropoxy-2-(trifluoromethyl)benzene. This involves costly raw material and multiple steps, therefore not a commercially viable alternative for preparation of 4-(chloromethyl)-l-isopropoxy-2-(trifluoromethyl)benzene.
Thus, there is the need in the art to develop a simpler process for preparation of 4-(hal om ethyl)-1 -alkoxy -2-(trifluoromethyl)benzene.

The present invention provides a convenient as well as an economical and a novel process for the preparation of 4-halomethylbenzene derivatives such as 4-(halomethyl)-l-alkoxy-2-(trifluoromethyl)benzene.
OBJECT OF THE INVENTION
The object of the present invention is to provide simpler and safe process for preparation of 4-halomethylbenzene derivatives.
SUMMARY OF THE INVENTION
In first aspect, the present invention provides a process for preparation of a compound of formula I,

Formula I
wherein R1 represents an alkyl group; R2 represents an alkyl or an alkoxy group
and X represents a halogen
Formula II
comprising a step of reacting a compound of formula II with a methylating agent in the presence of a Lewis acid, a protic acid, and a homogenizer;


wherein R1 represents an alkyl group; R2 represents an alkyl or an alkoxy
group.
In second aspect, the present invention provides a process for preparation of a compound of formula I,

Formula I
wherein R1 represents an alkyl group; R2 represents an alkyl or an alkoxy group and X represents a halogen
comprising the steps of:
a) reacting a compound of formula III with an alcohol in presence of a base to obtain a compound of formula II;

Formula III

Formula II

wherein R1 represents an alkyl group; R2 represents an alkyl or an alkoxy group and X' represents a halogen b) reacting the compound of formula II with a methylating agent in the presence of a Lewis acid, a protic acid, and a homogenizer to obtain the compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, an "alkyl group" is selected from a group consisting of C1-C4 alkyl and C1-C4 haloalkyl. The C1-C4 alkyl is selected methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tertiary butyl or the like and C1-C4 haloalkyl is selected from difluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl or like. The preferred alkyl group for compound of formula I is trifluoromethyl.
As used herein, an "alkoxy group" is selected from a group consisting of methoxy, ethoxy, propoxy, iso-propoxy, butoxy, sec-butoxy, tertiary butoxy or the like
As used herein, a "halogen" is selected from a group consisting of fluoro, chloro or bromo.
In an embodiment of the present invention, the methylating agent is selected from a group consisting of paraformaldehyde or chloromethyl methyl ether.
In an embodiment of the present invention, the Lewis acid is selected from a group consisting of zinc chloride, ferric chloride, aluminium chloride, boron trifluoride or the like.
In an embodiment of the present invention, the homogenizer is selected from an organic acid selected from a group consisting of acetic acid, trifluoroacetic acid, benzene sulfonic and, p-toluenesulfonic acid or the like and mixture thereof.
In an embodiment of the present invention, the protic acid is selected from a group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, chlorosulphonic acid and mixture thereof.
In an embodiment, the mole ratio of Lewis acid or protic acid and homogenizer is used in the range from 2 to 30 mole% preferably 2-5 mole% w.r.t compound of formula II.
In an embodiment, the mole ratio of methylating agent is used in the range from 1 to 10 moles with respect to a compound of formula II, preferably from 1 to 3 moles with respect to the compound of formula II.

In an embodiment, the methylation of compound of formula II is carried out at a temperature in the range of 25 to 30°C.
In another embodiment, the reaction of the compound of formula III with an alcohol is carried out using a base in a solvent.
The alcohol is selected from a group consisting of methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tertiary-butanol or the like.
In another embodiment, the reaction of the compound of formula III with an alcohol is carried out using a base selected from a group consisting of sodium ethoxide, sodium methoxide, sodium butoxide, potassium butoxide, sodium hydride, potassium hydride, butyl lithium, sodium metal, potassium metal, lithium (hexamethylsilyl)amide, potassium (hexamethylsilyl)amide or like.
In another embodiment, the reaction of the compound of formula III with an alcohol is carried out in a solvent selected from a group consisting of dimethyl sulfoxide, dimethyl sulfone, sulfolane, N-methylpyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, and hexamethylphosphoric triamide.
In another embodiment, reaction of the compound of formula III with an alcohol is carried out at a temperature of 0 to 70°C.
The compound of formula I is isolated with a purity of 90-99% and gives a yield of 70-90%.
The compound of formula II is isolated with a purity more than 90% and more preferably 95% and yield of more than 80% and preferably more than 85% and most preferably 90%.
In another embodiment, the present invention provides a process for preparation of 4-(chloromethyl)-l-isopropoxy-2-(trifluoromethyl)benzene, comprising the steps of:
a) reacting l-fluoro-2-(trifluoromethyl)benzene with isopropanol in presence of a base to form l-isopropoxy-2-(trifluoromethyl)benzene;

b) methylating l-isopropoxy-2-(trifluoromethyl)benzene in the presence of a Lewis acid, a protic acid and a homogenizer to give 4-(chloromethyl)-1-isopropoxy-2-(trifluoromethyl)benzene.
The compound of formula III may be selected from l-fluoro-2-(trifluoromethyl)benzene, 1 -chloro-2-(trifluoromethyl)benzene, 1 -bromo-2-(trifluoromethyl)benzene, 1 -fluoro-2-(dichlorofluoromethyl)benzene, 1 -fluoro-2-(chlorodifluoromethyl)benzene, 1 -chloro-2-(dichlorofluoromethyl)benzene, 1 -chloro-2-(chlorodifluoromethyl)benzene, or the like.
The compound of formula II may be selected from a group consisting of 1-methoxy-
2-(trifluoromethyl)benzene, 1 -(ethoxy)-2-(trifluoromethyl)benzene, 1 -
(isopropoxy)-2-(trifluoromethyl)benzene, l-(butoxy)-2-(trifluoromethyl)benzene,
1 -(tert-butoxy)-2-(trifluoromethyl)benzene, 1 -isopropoxy-2-
(dichlorofluoromethyl)benzene, 1 -methoxy-2-(dichlorofluoromethyl)benzene, 1 -
methoxy-2-(chlorodifluoromethyl)benzene, 1 -ethoxy-2-
(chlorodifluoromethyl)benzene, 1 -propoxy-2-(chlorodifluoromethyl)benzene, or the like.
In an embodiment, present invention provides a process for preparation of 1-isopropoxy-2-(trifluoromethyl)benzene from 1 -Fluoro-2-(trifluoromethyl)benzene.
The compound of formula I may be selected from a group consisting of:
4-(chloromethyl)-l-methoxy-2-(trifluoromethyl)benzene,
4-(chloromethyl)-l-isopropoxy-2-(trifluoromethyl)benzene,
4-(chloromethyl)-l-ethoxy-2-(trifluoromethyl)benzene,
4-(bromomethyl)-l-methoxy-2-(trifluoromethyl)benzene,
4-(bromomethyl)-l-(isopropoxy)-2-(trifluoromethyl)benzene,
4-(bromomethyl)-l-(ethoxy)-2-(trifluoromethyl)benzene,
4-(chl orom ethyl)-l-(tert-butoxy)-2-(trifluorom ethyl )benzene,
4-(chloromethyl)-l-methoxy-2-(dichlorofluoromethyl)benzene,
4-(bromomethyl)-l-methoxy-2-(dichlorofluoromethyl)benzene,
4-(chloromethyl)-l-methoxy-2-(chlorodifluoromethyl)benzene,

4-(chloromethyl)-l-ethoxy-2-(chlorodifluoromethyl)benzene,
4-(bromomethyl)-l-propoxy-2-(chlorodifluoromethyl)benzene,
4-(bromomethyl)-l-methoxy-2-(chlorodifluoromethyl)benzene,
4-(bromomethyl)-l-ethoxy-2-(chlorodifluoromethyl)benzene,
4-(bromomethyl)-l-propoxy-2-(chlorodifluoromethyl)benzene, or the like.
In an embodiment, present invention provides a process for preparation of 4-
(chloromethyl)-l-isopropoxy-2-(trifluoromethyl)benzene from l-isopropoxy-2-
(trifluoromethyl)benzene.
In an embodiment, present invention provides a process for preparation of 4-(chloromethyl)-l-isopropoxy-2-(trifluoromethyl)benzene from l-fluoro-2-(trifluoromethyl)benzene.
In an embodiment, present invention provides a process for preparation of 4-(bromomethyl)-l-isopropoxy-2-(trifluoromethyl)benzene from l-fluoro-2-(trifluoromethyl)benzene.
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.
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 l-isopropoxy-2-(trifluoromethyl)benzene
N,N-Dimethylformamide (52 g, 0.708 moles) and isopropanol (7.3 g, 0.122 moles) were charged to round bottom flask at room temperature and cooled to a temperature of 0°C. Sodium hydride (5 g, 0.122 moles) was added to the reaction mass in parts while maintaining the temperature to 0-5°C. The temperature of the reaction mass was gradually raised to 25°C. l-Fluoro-2-(trifluoromethyl)benzene (4 g, 0.024 moles) was added dropwise to the reaction mass while maintaining the temperature between 25-30°C. After complete addition, the reaction mixture was stirred for further 2 hours. After completion of the reaction, the reaction mass was quenched into ice cooled water and extracted with ethyl acetate to get titled compound.
Yield:90%; Purity:95%.
Example 2: Preparation of 4-(chloromethyl)-l-isopropoxy-2-(trifluoromethyl)benzene
l-Isopropoxy-2-(trifluoromethyl)benzene (2 g, 0.0098 moles) was charged at room temperature (25-30°C) into round bottom flask and cooled to 0°C. Paraformaldehyde (0.353 g, 0.01176 moles), sulphuric acid (7.55 g, 0.0539 moles, 70%), acetic acid (3.09 g, 0.0515 moles), zinc chloride (1.48 g, 0.0108 moles) and concentrated hydrochloric acid (11.7 g, 0.112 moles) were added to the reaction mass while maintaining the mass temperature between 0 to 5°C. After complete addition, reaction mass temperature was raised to 30°C and the reaction mixture was stirred for 30 hours. After completion of the reaction, the reaction mixture was quenched into ice cooled water and extracted with dichloromethane to product. Yield: 75%; Purity: 98%
Example 3: Preparation of 4-(bromomethyl)-l-isopropoxy-2-(trifluoromethyl)benzene

l-Isopropoxy-2-(trifluoromethyl)benzene (2 g, 0.0098 moles) was charged at room temperature (25-30°C) into round bottom flask and cooled to 0°C. Paraformaldehyde (0.353 g, 0.01176 moles), sulphuric acid (7.55 g, 0.0539 moles, 70%), acetic acid (3.09 g, 0.0515 moles), zinc chloride (1.48 g, 0.0108 moles) and concentrated hydrobromic acid (11.7 g, 0.112 moles) were charged to the reaction mass while maintaining the mass temperature between 0 to 5°C. After complete addition, reaction mass temperature was raised to 30°C and the reaction mixture was stirred for 30 hours. After completion of the reaction, the reaction mass was quenched into ice cooled water and extracted with dichloromethane to get titled product.
Yield: 75%; Purity: 98%

WE CLAIM:

1. A process for preparation of a compound of formula I,

Formula I
wherein R1 represents an alkyl group; R2 represents an alkyl or an alkoxy group and X represents a halogen
comprising a step of reacting a compound of formula II,

Formula II wherein R1 and R2 are as defined above
with a methylating agent in the presence of a Lewis acid, a protic acid, and a homogenizer to obtain the compound of formula I.
2. The process as claimed in claim 1, wherein the methylating agent is selected from a group consisting of paraformaldehyde or chloromethyl methyl ether.
3. The process as claimed in claim 1, wherein the Lewis acid is selected from a group consisting of zinc chloride, ferric chloride, aluminium chloride, and boron trifluoride.

4. The process as claimed in claim 1, wherein the protic acid is selected from a group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, chlorosulphonic acid and mixture thereof.
5. The process as claimed in claim 1, wherein the homogenizer is selected from an organic acid selected from a group consisting of acetic acid, trifluoroacetic acid, benzene sulfonic and, p-toluenesulfonic acid, and mixture thereof.
6. The process as claimed in claim 1, wherein the compound of formula II is prepared by reacting a compound of formula III
x
&
Formula III wherein X and R2 are as defined above with an alcohol in presence of a base to obtain a compound of formula II.
7. The process as claimed in claim 6, wherein the alcohol is selected from a group consisting of methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, and tertiary-butanol.
8. The process as claimed in claim 6, wherein the base is selected from a group consisting of sodium ethoxide, sodium methoxide, sodium butoxide, potassium butoxide, sodium hydride, potassium hydride, butyl lithium, sodium metal, potassium metal, lithium (hexamethylsilyl)amide, potassium (hexamethylsilyl)amide.
9. The process as claimed in claim 6, wherein the reaction of the compound of formula III with an alcohol is carried out in a solvent.

10. The process as claimed in claim 6, wherein the reaction of the compound of formula III with an alcohol is carried out in a solvent selected from a group consisting of dimethyl sulfoxide, dimethyl sulfone, sulfolane, N-methylpyrrolidinone, N,N-dimethylacetamide, N,N-dimethylformamide, and hexamethylphosphoric triamide.