FIELD OF INVENTION

The present invention relates to a novel, cost-effective process for preparing the 2-halo-6-(trifluoromethyl)benzylhalide of formula I.
Where X isCl or Br and X1 is CI, Br or F

Background of the Invention

2-Halo-6-(trifluoromethyl)benzyl halide of formula lis used as a key intermediate in the preparation of many active pharmaceutical ingredients used for the treatment of many disorders. Particularly 2-Chloro-6-(trifluoromethyl)benzyl bromide is a key starting material in the preparation of a compound useful in the treatment of disorders such as allergic disorders, inflammatory disorders and disorders of the immune system.
The preparation of 2-halo-6-(trifluoromethyl)benzyl halide is very scarcely reported in the literature, hence there is a need to develop a facile and economical process which will give 2-halo-6-(trifluoromethyl)benzyl halidein high purity and high yield.

The present inventors have developed a novel process for the preparation of 2-halo-6-(trifluoromethyl)benzyl halide which is scalable, eco-friendly, avoids the formation of undesired regioisomers and which provides 2-halo-6-(trifluoromethyl)benzyl halide in high purity and high yield.

SUMMARY OF THE INVENTION

The principal aspect of the present invention is to provide a process for the preparation of2-halo-6-(trifluoromethyl)benzylhalideof formula I, which comprises:

a) converting 3-trifluoromethyl-2-methyl aniline of formula III into 1-halo-2-methyl-3-(trifluoromethyl)benzene of formula II using sodium nitrite in concentrated hydrochloric acid or sulphuric acid and cuprous halide in presence of water with the proviso when X1 is F in compound II, it is obtained by further reacting the obtained compound II having X1 as Br with potassium fluoride; and

b) halogenating l-halo-2-methyl-3-(trifluoromethyl)benzene of formula II with halogenating reagent in presence of a solvent to obtain 2-halo-6-(trifluoromethyl)benzyl halide of formula I.

The process of the present invention may be illustrated by the below scheme:

Where X is CI or Br and Xi is CI, Br or F
In another aspect, the present invention provides a simple and cost effective process for the preparation of 2-Chloro-6-(trifluoromethyl)benzyl bromide comprising:

a) converting 3-trifluoromethyl-2-methyl aniline of formula III into 1-chloro-2-methyl-3-(trifluoromethyl)benzene using sodium nitrite in concentrated hydrochloric acid or sulphuric acid and cuprous chloride in presence of water; and

b) halogenating l-chloro-2-methy 1-3 -(trifluoromethyl)benzene with N-bromosuccinimide in presence of ethylene dichloride to obtain 2-chloro-6-(trifluoromethyl)benzyl bromide.

DETAIL DESCRIPTION OF THE INVENTION

Accordingly in an embodiment of the present invention the conversion of
3-trifluoromethyl-2-methyl aniline of formula III into l-halo-2-methyl-3-
(trifluoromethyl)benzene of formula II is carried out in presence of an acidic
solution of sodium nitrite preferably sodium nitrite in concentrated hydrochloric
acid, cuprous halide selected from cuprous chloride and cuprous bromide in
presence of suitable solvent preferably water, more preferably DM water. 1-Halo-
2-methyl-3-(trifluoromethyl)benzene of formula II can be selected from 1-chloro-
6-methyl-5-(trifluoromethyl)cyclohexa-l,3-diene; l-bromo-6-methyl-5-
(trifluoromethyl)cyclohexa-l,3-diene or l-fiuoro-6-methyl-5-
(trifluoromethyl)cyclohexa-l,3-diene. But when the compound of formula II is 1-fluoro-6-methyl-5-(trifluoromethyl)cyclohexa-l,3-diene, it is prepared by the fluorination of the obtained l-bromo-6-methyl-5-(trifluoromethyl)cyclohexa-l,3-diene with potassium fluoride.

In another embodiment of the presentinvention the halogenation of 1-halo-2-methyl-3-(trifluoromethyl)benzeneof formula II into 2-halo-6-(trifluoromethyl)benzyl halide of formula I is carried out using a halogenating reagent N-bromosuccinimide or N-chlorosuccinimide. 2-Halo-6-(trifluoromethyl)benzyl halide of formula I may be selected from the group consisting of 2-chloro-6-(trifiuoromethyl)benzyl bromide, 2-bromo-6-(trifluoromethyl)benzyl bromide, 2-fluoro-6-(trifluoromethyl)benzyl bromide, 2-chloro-6-(trifluoromethyl)benzyl chloride, 2-bromo-6-(trifiuoromethyl)benzyl chloride, and 2-fiuoro-6-(trifluoromethyl)benzyl chloride. The halogenation in step b) is carried out in an organic solvent selected from acetone, methyl acetate, ethyl acetate, ethylene dichloride and methylene dichloride, preferably ethylene dichloride and a light radiation preferably mercury light radiation obtained by using high pressure mercury lamp in 60-160 Watt range, preferably 160 watt. A good result is obtained without using any catalyst and it has been observed that a low Watt mercury bulb doesn't take reaction to completion.

The preparation of l-halo-2-methyl-3-(trifluoromethyl)benzene of formula II and 2-halo-6-(trifluoromethyl)benzyl halide of formula I reported in prior art are labile to formation of a number of regioisomers, whereas the process
of the present invention produces no regioisomers and in-turn gives high purity of the product.

The present invention can be illustrated by following non-limiting examples.

Example:

(a) Preparation of l-chloro-6-methvl-5-(trifluoromethvDcvclohexa-lt3-dieiie:

3- Trifluoromethyl -2-methyl aniline (150 g)was charged into the flask containing a stirred solution of concentrated hydrochloric acid and DM water. The reaction mixture was stirred for 30-60 minutes at 25-30°C, cooled to -5 to 3°C. Solution of sodium nitrite (0.45 g) in DM water (0.8 ml) was slowly added to the above reaction mass, maintained for 90-120 minutes at -5 to 3°C. After completion of reaction, RM was filtered. To the filtrate heated mixture of concentrated hydrochloric acid and cuprous chloride was slowly added at 95-100°C, stirred and cooled. Methylene dichloride was added, stirred and two layers were separated. The organic layer was washed twice with DM water, layers were separated and the obtained organic layer was further washed with 10% sodium hydroxide solution. The layers were separated, organic layer was washed twice with water and further distilled to remove Methylene dichloride completely. The crude product obtained was further subjected to fractional distillation under vacuum.

Yield: 99.47 %

(b) Preparation of 2-ChIoro-6-(trifluoromethvl)benzyl bromide:

l-chloro-6-methyl-5-(trifluoromethyl)cyclohexa-l,3-diene (5.0 ml) and ethylene dichloride(250 g) were charged into the flask . N-Bromosuccinimide (1.1 g) was added to the above reaction mass at 25-30°C. High pressure mercury lamp of 160 Watt was switched on, reaction mass was heated to 70-75°C and maintained for 2-3 hrs. After completion of reaction, Mercury light was switched off and RM was cooled to 0-5°C .Solid was filtered and washed with ethylene dichloride. The collected filtrate was washed with Sodium meta bisulphate solution (2.0 ml), two layers were separated and collected filtrate was washed with DM water. Collected filtrate was distilled and thick residue obtained was further subjected to fractional distillation under vacuum.

Yield: 95.96 %.

(c) Preparation of 2-Chloro-6-(trifluoromethvl)benzvl bromide:

l-chloro-6-methyl-5-(trifluoromethyl)cyclohexa-l,3-diene (5.0 ml) and ethylene dichloride(250 g) were charged into the flask . N-Bromosuccinimide (1.1 g) was added to the above reaction mass at 25-30°C. High pressure mercury lamp of 40 Watt was switched on, RM was heated to 70-75°C and maintained for 2-3 hrs. Reaction was completed only upto 50% .Even after prolonged time reflux under same condition no much progress was observed. Mercury light was switched off and RM was cooled to 0-5°C . Solid was filtered and washed with ethylene dichloride. The collected filtrate was washed with Sodium meta bisulphate solution (2.0 ml), two layers were separated and collected filtrate was washed with DM water. Collected filtrate was distilled and thick residue obtained was further subjected to fractional distillation under vacuum. Initial fractions contained the unreacted starting material. The later fractions (middle and the third) contained the product.
Yield-45%.

We claim:

1. A process for the preparation of 2-halo-6-(trifluoromethyl)benzyl halide of formula I,
Where X is C1 or Br and X1 is C1, Br or F
which comprises:

a) converting 3-trifluoromethyl-2-methyl aniline of formula III into 1-halo-2-methyl-3-(trifluoromethyl)benzene of formula II using sodium nitrite in concentrated hydrochloric acid or sulphuric acid and cuprous halide in presence of water with the proviso when X1 is F in compound II, it is obtained by further reacting the obtained compound II having X1 as Br with potassium fluoride ; and Where X1 is same as described above

b) halogenating l-halo-2-methyl-3-(trifluoromethyl)benzene of formula II with halogenating reagent in presence of solvent to obtain 2-halo-6-(trifluoromethyl)benzyl halide of formula I.

2. A process according to claim 1 wherein, the cuprous halide in step a) is selected from cuprous chloride and cuprous bromide.

3. A process according to claim 1 wherein, the halogenation in step b) is carried out using a halogenating agent selected from N-Bromosuccinimide and N-chlorosuccinimide.

4. A process according to claim 1 wherein, the solvent for halogenation in step b) is an organic solvent selected from acetone, methyl acetate, ethyl acetate, ethylene dichloride and methylene dichloride, preferably ethylene dichloride.

5. A process according to claim 1 wherein, the halogenation in step b) is carried out using light radiation.

6. A process according to claim 1 wherein, the halogenation in step b) is carried out using light radiation from high pressure mercury lamp.

7. A process for the preparation of 2-Chloro-6-(trifluoromethyl)benzyl bromide comprising:

a) converting 3-trifluoromethyl-2-methyl aniline of formula III into 1-chloro-2-methyl-3-(trifluoromethyl)benzene using sodium nitritein concentrated hydrochloric acid or sulphuric acid and cuprous chloride in presence of water; and

b) halogenatingl-chloro-2-methyl-3-(trifluoromethyl)benzenewith N-bromosuccinimidein presence of ethylene dichloride to obtain 2-chloro-6-(trifluoromethyl)benzyl bromide.

8. A process according to claim 7 wherein, the halogenation in step b) is carried out using light radiation.

9. A process according to claim 7 wherein, the halogenation in step b) is carried out using light radiation from high pressure mercury lamp.