FIELD OF THE INVENTION
The present invention provides an improved process for preparation of 2,4,6-trifluorobenzylamine using a continuous flow reactor.

BACKGROUND OF THE INVENTION
Halogenated benzylamine such as 2,4,6-trifluorobenzylamine are widely used as raw material for pharmaceutical intermediates, agrochemicals, drugs, and dyes etc. It is an intermediate for N-(2,4,6- trifluorobenzoyl)-N'-[3,5-dichloro-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy) phenyl] urea, useful for controlling various kinds of insect pests.
Various methods are known in the art for preparation of halogenated benzyl amine.
Chinese Patent No. 106349083 provides a process for preparation of 2,4,6-trifluoro- benzylamine using 2,4,6-trifluorobenzonitrile in presence of Raney nickel and aqueous ammonia. It has been observed by present inventors that addition of aqueous ammonia in the 2,4,6-trifluorobenzonitrile in presence of Raney nickel affects the yield and selectivity of the product.
Indian Patent Application No. 201911003239 filed by the inventors of the present invention provides a process for preparation of halogenated benzylamine by hydrogenating halogenated benzonitrile using a hydrogenating catalyst and ammonia in an alcohol solvent in a batch process.
The inventors of the present invention have realised that carrying out the hydrogenation of benzonitrile in an ammoniacal alcohol in a continuous flow reactor further improves the selectivity, yield and reduces the impurities. It also improves the safety of the hydrogenation process. There is no need to filter the catalyst which simplifies the workup process.

OBJECT OF THE INVENTION
The present invention provides an industrially viable process for preparation of 2,4,6-trifluorobenzylamine under mild reaction conditions and using a continuous flow reactor that improves the yield and reduces impurities upto a level of below 1000 ppm.

SUMMARY OF THE INVENTION
First aspect of the present invention provides 2,4,6-trifluorobenzylamine, having less than 1000 ppm of 2,4-difluorobenzylamine and 2,6-difluorobenzylamine impurities, Preferably, having the impurities in a range of 0-50 ppm.
Second aspect of the present invention provides a process for preparation of halogenated benzylamine, comprising the step of hydrogenating halogenated benzonitrile using a continuous flow reactor.

DESCRIPTION OF DRAWING
Figure 1 describes a continuous flow reactor.
A continuous flow reactor consists of a cylinder R1 packed with Raney nickel catalyst viz. equipped with dosing pump P1 and control valve P2 having pressure gauge P. P1 and P2 are used to introduce 2,4,6-trifluorobenzylamine and hydrogen gas respectively, P2 is further connected with mass flow controller MFC. The reactor is further equipped with another pressure gauge P and back pressure regulator B1. The back pressure regulator is further connected with a sample collector and an outlet for product collection.

DETAILED DESCRIPTION OF THE INVENTION
Halogenated benzonitrile as used herein refers to 2,4,6-trifluorobenzonitrile,
2,4,6-trichlorobenzonitrile, 2,4-difluorobenzonitrile, 4-fluorobenzonitrile, 2,6-
difluorobenzonitrile, 2,3,4,5,6-pentafluorobenzonitrile and 2,3,5,6-tetrafluorobenzonitrile or the like.
Halogenated benzylamine as used herein refers to 2,4,6-trifluorobenzylamine, 2,4,6-trichlorobenzylamine, 2,4-difluorobenzylamine, 4-fluorobenzylamine, 2,6-difluorobenzylamine, 2,3,4,5,6-pentafluorobenzylamine and 2,3,5,6-terafluorobenzylamine or the like.
In an embodiment, the hydrogenation is carried out using a hydrogenation catalyst in a solvent. The hydrogenation catalyst is selected from palladium on carbon, platinum on carbon and Raney nickel or the like. The molar ratio of catalyst may be selected in the range from 0.05 to 0.3. The Raney nickel contains nickel in the range from 70-95% and more preferably 80-90%.
In another embodiment, weight% of catalyst with respect to halogenated benzonitrile is in the range of 1-10% and more preferably in the range of 5-10%.
The solvent for hydrogenation is either water or an alcohol selected from a group consisting of methanol, ethanol, 2-propanol, propanol, butanol, t-butanol, hexanol and pentanol or the like and a mixture thereof. It has been found that alcohols comprising C-3 or more are preferred.
In preferred embodiment, hydrogenation is carried out in an alcohol solvent selected from 2-propanol, propanol, t-butanol, hexanol and pentanol.
In a specific embodiment, hydrogenation is carried out using Raney nickel in a range of around 0.14 to 0.2 molar equivalents.
The halogenated benzonitrile may be used as such, molten form or as alcoholic solution and more preferably as alcoholic solution.
In an embodiment, hydrogenation of halogenated benzonitrile is carried out using anhydrous ammonia to obtain halogenated benzylamine. It prevents formation of azeotropic mixture of water and alcohol which need azeotropic distillation.
The ammonia is used in pure gaseous form or solution form selected from anhydrous ammonia, aqueous ammonia and alcoholic ammonia solution. The molar ratio of ammonia is in the range of 1-5 by mass.
The temperature range and the lower hydrogen pressure during the hydrogenation of halogenated benzonitrile enables the process to be carried out at a commercial scale without jeopardizing the safety.
In preferred embodiment, hydrogenation of halogenated benzonitrile is carried out using molecular hydrogen in presence of Raney nickel and solution of ammonia in isopropanol.
In an embodiment, present invention provides a process for preparing 2,4,6-trifluorobenzyl amine using catalyst in continuous flow reactor.
In an embodiment, hydrogenation of halogenated benzonitrile is carried out using 0.2 to 0.7 M ammonical isopropanol.
In an embodiment, hydrogenation of halogenated benzonitrile is carried out using a hydrogen pressure of 3 to 3.5kg/cm2 at a temperature range of 65-70°C.
In another embodiment of the present invention, the hydrogen is purged in reactor at a pressure of 3.5 kg/cm2 to generate high selectivity towards the desired product.
In an embodiment, hydrogenation of halogenated benzonitrile is carried out using anhydrous ammonia to obtain halogenated benzylamine. It prevents formation of azeotropic mixture of water and alcohol which need azeotropic distillation.
In a preferred embodiment, hydrogenation is carried out using ammonia in the range of 2.0 to 4.0 molar equivalents.
In an embodiment, the process for preparation of halogenated benzylamine, comprising the steps of hydrogenating halogenated benzonitrile in presence of anhydrous ammonia in a continuous flow mode.
In another embodiment, the continuous flow mode is maintained using a continuous flow reactor.
The process of the present invention is carried out in a continuous flow reactor. In continuous flow reactor, the feed of halogenated benzonitrile and hydrogen gas is continuously and simultaneously supplied to the flow reactor, and pure compound having no unwanted impurities is continuously separated from the flow reactor.
In an embodiment, the halogenated benzonitrile is added continuously in the reaction mixture. The addition rate of halogenated benzonitrile is from 0.5-2ml/min, through HPLC pump.
The present invention for preparation of halogenated benzylamine has following advantages over the known methods:
1. The use of mild reaction condition in form of using low pressure range prevents degradation of product and improves yield significantly.
2. The mode of addition of reactant and reagent used in the reaction positively affects the product selectivity. The present inventors observed an improvement in the selectivity with slow and continuous addition of hydrogen to the reaction mixture.
3. Use of continues flow reactor for the reaction to get 100% conversion, minimizes the impurity and thereby increases the selectivity towards the desired product significantly.
4. The process of present invention provides efficient recycling and recovery of solvents.
5. The process of present invention is safe at commercial scale.
The results obtained for continuous addition of an alcoholic solution of 2,4,6-trifluorobenzonitrile in the reaction mixture containing alcohol, catalyst and ammonia are given in Table 1.
S. N. Component Experiment Selectivity %
Aqueous
25%
Ammonia Ammonium
Acetate Continuous addition of
2,4,6-benzonitrile Continuous flow reactor
Aqueous
Ammonia Anhydrous
Ammonia Anhydrous ammonia
1 2,4,6-
Trifluorobenzylamine 45-50 75-85 91-95 91-94 95-98
2 Alkoxy impurity 30-35 0 0-1 0-1 0
3 Dimer impurity 14-15 13-15 0-2 0-2 0-1

The halogenated benzylamine so obtained by the present invention has a purity greater than 95 %, more preferably greater than 98 %, most preferably greater than 99.6 % by gas chromatography.
The halogenated benzylamine is isolated by any method known in the art, for example, chemical separation, extraction, acid-base neutralization, distillation, evaporation, column chromatography and filtration or a mixture thereof.
High-pressure dosing pump is made of different material of construction, pressure rating and flow rate were used for dosing the feeds.
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.

EXAMPLE:
Example 1: Preparation of 2,4,6-trifluorobenzyl amine
A solution of 2,4,6-trifluorobenzonitrile (70 g) and ammoniacal isopropanol (1000 g) was passed through Raney nickel cartridge (2.25 g) in a continuous flow reactor. The reaction mixture was heated to 70°C. Hydrogen was charged in reaction vessel at 70°C continuously at pressure of 3.5 kg/cm2. The reaction mass was monitored by gas chromatography. After reaction completed, clear mass was obtained from continuous flow reactor. The resultant mass was further isolated by fractional distillation.
Selectivity: 97%
Yield: 90%
Purity (by GC): 99.8%
Example 2: Preparation of 2,4,6-trifluorobenzyl amine
A solution of 2,4,6-trifluorobenzonitrile (70 g) and ammoniacal isopropanol (1000 g) was passed through Raney nickel cartridge (3.0 g) in a continuous flow reactor. The reaction mixture was heated to 70°C. Hydrogen was charged in reaction vessel at 70°C continuously at pressure of 3 kg/cm2. The reaction mass was monitored by gas chromatography. After reaction completed, clear mass was obtained from continuous flow reactor. The resultant mass was further isolated by fractional distillation.
Selectivity: 98%
Yield: 91%
Purity (by GC): 99.7%
Example 3: Preparation of 2,4,6-trifluorobenzyl amine
A solution of 2,4,6-trifluorobenzonitrile (70 g) and ethanolic ammonia (1000 g) was passed through Raney nickel cartridge (2.25 g) in a continuous flow reactor. The reaction mixture was heated to 70°C. Hydrogen was charged in reaction vessel at 70°C continuously at pressure of 3.5 kg/cm2. The reaction mass was monitored by gas chromatography. After reaction completed, clear mass was obtained from continuous flow reactor. The resultant mass was further isolated by fractional distillation.
Selectivity: 96%
Yield: 89%
Purity (by GC): 99.9%

SRF LIMITED NO. OF SHEETS: 1
APPLICATION NO.: 202111043831 SHEET NO. 1 OF 1

Figure 1: Flow reactor.

CLAIMS:

WE CLAIM:
1. A process for preparation of halogenated benzylamine, comprising the steps of hydrogenating halogenated benzonitrile in presence of ammonia in a continuous flow mode.
2. The process as claimed in claim 1, wherein the hydrogenation is carried out using anhydrous ammonia either in pure gaseous form or as alcoholic ammonia solution.
3. The process as claimed in claim 1, wherein the hydrogenation is carried out using a hydrogenation catalyst.
4. The process as claimed in claim 3, wherein the catalyst used is selected from palladium on carbon, platinum on carbon and Raney nickel.
5. The process as claimed in claim 2, wherein the alcoholic ammonia solution comprises a solution of ammonia with an alcohol solvent selected from a group consisting of methanol, ethanol, 2-propanol, propanol, butanol, t-butanol, hexanol and pentanol.
6. The process as claimed in claim 1, wherein the hydrogenation is carried out at a hydrogen pressure of 3 to 3.5kg/cm2 and at a temperature range of 65-70°C.
7. The process as claimed in claim 1, wherein the continuous flow mode is maintained using a continuous flow reactor as illustrated in Figure 1, wherein the feed of halogenated benzonitrile and hydrogen gas is continuously and simultaneously supplied to the flow reactor, and pure compound having no unwanted impurity is continuously separated from the flow reactor.
8. The process as claimed in claim 1, wherein the Halogenated benzylamine comprises 2,4,6-trifluorobenzylamine, 2,4,6-trichlorobenzylamine, 2,4-difluorobenzylamine, 4-fluorobenzylamine, 2,6-difluorobenzylamine, 2,3,4,5,6-pentafluorobenzylamine and 2,3,5,6-terafluorobenzylamine.

9. 2,4,6-Trifluorobenzylamine, having less than 1000 ppm of 2,4-difluorobenzylamine and 2,6-difluorobenzylamine.