The present invention provides a process for preparation of fluorine-containing benzylamine derivatives of formula I and intermediates thereof.

F
Formula I
Background of the invention
The present invention provides a process to produce a fluorine-containing benzylamine derivative and intermediates thereof. These compounds have widely been used as a raw material for photosensitive materials, pharmaceuticals and agrochemicals. Various methods are known in the art for preparation of 2,4,6 trifluorobenzyl amine.
U.S. Patent Publication No. 6,452,056 provides a process for preparation of 2,4,6-trifluorobenzyl amine from 2,4,6-trifluorobenzonitrile by reducing with Raney—Ni washed with 99% ethanol in presence of hexane at a hydrogen pressure of 30 to 40 kg/cm2 and at a reaction temperature of 130°C for 2.5 hours. The high hydrogen pressure at a high temperature of above 100°C posses safety concerns at a commercial scale.
Chinese Patent Publication No. 106349083 discloses a process for preparation of 2,4,6-trifluorobenzylamine by reducing 2,4,6-trifluorobenzonitrile methanolic solution in presence of ammonia under the action of the catalyst at the temperature of 25-120°C. The present inventors have found that the use of ammonia affects the yield and the selectivity of the product.

Thus there is an urgent need to develop a cost effective, economic, high yielding, safe and robust process for preparation of 2,4,6-trifluorobenzyl amine.
Summary of the invention
In first aspect, the present invention provides a process for preparation of a compound of formula 1,

F
Formula I
comprising the steps of:
a) contacting a compound of formula 5,

F Formula 5 wherein X represents -CI, -Br or -I. with an acid to obtain a compound of formula 4,

Formula 4 wherein X represents -CI, -Br or -I.

b) dehalogenating the compound of formula 4, to obtain a compound of formula 3,

F Formula 3
c) dehydrating the compound of formula 3 into the compound of formula 2,
and
CN
V
F Formula 2
d) reducing the compound of formula 2 using hydrogenation catalyst and
ammonium buffer to obtain the compound of formula 1.
In second aspect, the present invention provides a process for preparation of a compound of formula 2,

F Formula 2 comprising the steps of: a) converting the compound of formula 3,

O^NH2

Formula 3 to the compound of formula 2.
In third aspect, the present invention provides a process for preparation of a compound of formula 4,
O^NH2

Formula 4 wherein X represents -CI, -Br or -I. comprising the steps of: contacting a compound of formula 5,
CN F^ ^L ^F

x' ^r "x
F
Formula 5 with an acid to obtain the compound of formula 4.
In fourth aspect, the present invention provides a process for preparation of a compound of formula 3,

O^NH2

F Formula 3 comprising the step of: dehalogenating the compound of formula 4,
VNH2

F
Formula 4 wherein X represents -CI, -Br or -I. to obtain the compound of formula 3.
In fifth aspect, the present invention provides a process for preparation of a compound of formula 1,

F
Formula I comprising the step of: reducing the compound of formula 2 using hydrogenation catalyst and ammonium buffer to obtain the compound of formula 1.

Object of the invention
The present invention provides a cost effective, economic, high yielding, safe and robust process for preparation of 2,4,6-trifluorobenzyl amine.
Detailed description of the invention
As used herein, the term "acid" refers to the acid selected from sulfuric acid, phosphoric acid, hydrochloric acid, methane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid and the like or a mixture thereof.
The step of dehalogenation is carried out using hydrogen in presence of catalyst and a buffer.
The catalyst for the step of dehalogenation is selected from palladium on carbon, platinum on carbon, Raney nickel or the like.
The buffer used in the step of dehalogenation is a phosphate buffer selected from dipotassium hydrogen phosphate, ammonium dihydrogen phosphate, ammonium hydrogen phosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate, calcium phosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate or hydrates thereof.
The step of hydrogenation is carried out using a hydrogen pressure of 15 kg/cm2 at a temperature range of 125-130°C.
The step of dehydration is carried out using dehydrating agents selected from phosphorous pentaoxide, phosphorous oxychloride, thionyl chloride, titanium tetrachloride, sodium borohydride, aluminum chloride/potassium iodide, diethylchlorophosphate or the like.
The step of dehydration is preferably carried out using thionyl chloride.
The step of reduction is carried out using hydrogen in presence of catalyst and an ammonium buffer.
The catalyst for the step of dehalogenation is selected from palladium on carbon, platinum on carbon, Raney nickel or the like.

The ammonium buffer is selected from salt of ammonia and a weak acid selected from acetic acid, formic acid, lactic acid, citric acid, or the like.
The ammonium acetate is preferred as an ammonium buffer for the step of reduction.
The step of reduction is carried out using a hydrogen pressure of 15 kg/cm2 at a temperature range of 70-90°C.
The temperature range and the lower hydrogen pressure during the step of reduction enables the process to be carried out at a commercial scale without jeopardizing the safety.
The compound of Formula I 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.
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
Step-1: Preparation of 3,5-dichloro-2, 4, 6-trifluorobenzamide
Aqueous sulphuric acid (96%, 1200 g) and 3, 5-dichloro-2, 4, 6-trifluorobenzonitrile (300 g) were charged sequentially in a reaction vessel. The reaction mixture was heated to 110-120°C and stirred at 110-120°C for 2-3 hours. Progress of the reaction was monitored by HPLC. After completion of the reaction, reaction mass was cooled to 25-35° C and quenched into ice water (4000 g) at 10-15°C. After quenching, the reaction mass was maintained at 20-30°C. The reaction mass was filtered and washed with water (300g) and dissolved into ethyl acetate (2500 g). Layers were separated. Organic layer was washed with 1% sodium bicarbonate solution (600 g). The ethyl acetate was recovered from organic layer under vacuum at 40-60°C and dried the bottom mass under vacuum at 50-55°C to obtain the titled compound. Yield: 98% Purity (by HPLC): 98%
Step-2: Preparation of 2,4,6-trifluorobenzamide
3, 5-dichloro-2, 4, 6-trifluorobenzamide (200 g) obtained from step 1, water (1160 g), dipotassium hydrogen phosphate (355 g), and Pd/C (2 g) were charged in a reaction vessel. Reaction vessel was flushed first with nitrogen and then with hydrogen. The reaction mixture was heated to 125-130°C. Hydrogen was charged in reaction vessel at 130°C continuously to 15 kg/cm2. Progress of the reaction was monitored by GC. After completion of the reaction, reaction mass was cooled to 30-35°C and excess hydrogen pressure was released. Ethyl acetate (450 g) was charged into the reaction vessel and stirred. The reaction mass was filtered, and washed with ethyl acetate (250 g) and water (500 g) sequentially. Layers were separated from filtrate. Ethyl acetate was recovered from organic layer under vacuum at 40-60°C and dried the bottom mass under vacuum at 50-55°C. Yield (%): 92% Purity (by GC): 94%

Step-3: Preparation of 2,4,6-trifluorobenzonitrile.
Toluene (625g) and 2, 4, 6-trifluorobenzamide (125 g) were added sequentially in a reaction vessel. Thionyl chloride (150 g) was charged into reaction vessel dropwise. The reaction mixture was heated gradually to 80-85°C and stirred at 80-85°C for 6-7 hours. Progress of the reaction was monitored by GC. After completion of the reaction, the excess of thionyl chloride was recovered from the reaction mass. The reaction mass was distilled under reduced pressure. Yield: 85% Purity (by GC): 98%
Step-4: Preparation of 2,4,6-trifluorobenzyl amine.
2, 4, 6-trifluorobenzonitrile (100 g), methanol (1000 g), Raney Nickel (10 g), and ammonium acetate (147 g) were charged into a reaction vessel. The reaction vessel was flushed once with nitrogen and then with hydrogen. The reaction mixture was heated to 90°C. Hydrogen was charged in reaction vessel at 90°C continuously to 10 kg/cm2. After completion of the reaction, the reaction mass was cooled to 20-25°C and residual pressure was released. Reaction mass was filtered, washed with methanol. Methanol was recovered from filtrate. Bottom mass was cooled to 20-25°C. The pH of bottom mass was adjusted to 9-10 and product was extracted with dichloromethane. Layers were separated. Dichloromethane was recovered from organic layer and product was purified by distillation under reduced pressure. Yield (%): 80% Purity (by GC): 99%
Comparative Examples:
Preparation of 2,4,6-trifluorobenzyl amine.
Aqueous ammonia (170g) was added to a mixture of 2, 4, 6-trifluorobenzonitrile (100 g), Raney Nickel (10 g), in methanol (1000 g). Reactor was flushed once with nitrogen and then with hydrogen. The reaction mixture was heated to 90°C. Hydrogen was charged in reactor at 90°C continuously at 10 kg/cm2. The progress

of the reaction was monitored by GC. After completion of the reaction, the reaction mass was cooled to 20-25°C and residual pressure was released. Reaction mass was filtered, washed with methanol. Methanol was recovered from filtrate. The pH of bottom mass was adjusted to 9-10 and product was extracted with dichloromethane. Layers were separated. Dichloromethane was recovered from organic layer and product was purified by fractional distillation under reduce pressure. Selectivity toward the desired product, by GC (area %), in the organic layer was found to be in the range of 15-25%.
Preparation of 2,4,6-trifluorobenzyl amine.
Methanolic ammonia solution (35g) was added to a solution of 2, 4, 6-trifluorobenzonitrile (10 g), ammonium acetate (15 g), Raney Nickel (1.8 g) in methanol (65g). Reactor was flushed once with nitrogen and then with hydrogen. The reaction mixture was heated to 90°C. Hydrogen was charged in reactor at 90°C continuously at 10 kg/cm2. After completion, the mass was cooled to 20-25°C and residual pressure was released. Reaction mass was filtered, washed with methanol. Methanol was recovered from filtrate. Adjust the pH of bottom mass to 9-10 and product was extracted with dichloromethane. Layer were separated. Dichloromethane was recovered from organic layer and product was purified by fractional distillation under reduce pressure. Selectivity toward the desired product, by GC (Area %) was found to be in the range of 15-20%.

We Claim:

1. A process for preparation of a compound of formula 1,
^NH2

Formula I
comprising the steps of:
a) contacting a compound of formula 5,
CN

Formula 5 wherein X represents -CI, -Br or -I. with an acid to obtain a compound of formula 4,
0.,NH2

Formula 4 wherein X represents -CI, -Br or -I.
b) selective dehalogenating the compound of formula 4 in presence of a catalyst and a buffer, to obtain a compound of formula 3,

O^NH2
Formula 3
c) dehydrating the compound of formula 3 into the compound of formula 2,
and



Formula 2 d) reducing the compound of formula 2 using hydrogen, a catalyst and an ammonium buffer to obtain the compound of formula 1.
2. A process for preparation of a compound of formula 3,
VNH2
Formula 3 comprising the step of selective dehalogenating the compound of formula 4 in presence of a catalyst and a buffer, to obtain a compound of formula 3,

°^/NH2

F
Formula 4 wherein X represents -CI, -Br or -I.
3. A process for preparation of a compound of formula 1,

F
Formula I
comprising the step of reducing the compound of formula 2

F Formula 2 using hydrogenation catalyst and an ammonium buffer to obtain the compound of formula 1.
4. The process as claimed in claim 1 wherein, acid used in step a) is selected from sulfuric acid, phosphoric acid, hydrochloric acid, methane sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid.

5. The process as claimed in claim 1 wherein, dehydration is carried out using dehydrating agents selected from phosphorous pentaoxide, phosphorous oxychloride, thionyl chloride, titanium tetrachloride, sodium borohydride, aluminum chloride/potassium iodide, diethylchlorophosphate.
6. The process as claimed in claim 1, 2 and 3, wherein, catalyst is selected from a group comprising of palladium on carbon, platinum on carbon, Raney nickel.
7. The process as claimed in claim 1 wherein, buffer is selected from dipotassium hydrogen phosphate, ammonium dihydrogen phosphate, ammonium hydrogen phosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate, calcium phosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate.