FIELD OF THE INVENTION

The present invention provides an improved process for preparation of fluorinated benzyl amine of formula I.

Formula I
wherein n=1-5

BACKGROUND OF THE INVENTION
Fluorinated benzylamine are very useful intermediates in agrochemical and pharmaceutical industry.
US5,068,371 discloses a process of hydrogenation of 2,4-difluorobenzonitrile in ethanol in presence of ammonia at 75-80°C to obtain 66% of 2,4-difluorobenzylamine.
US6,452,056 provides a process for preparation of 2,6-difluorobenzylamine from 2,6-difluorobenzonitrile using hydrogen and raney nickel catalyst in presence of hexane solvent. The hexane solvent is highly flammable in nature. The process requires hydrogen pressure of 30-40Kg/cm2 and temperature of above 130°C to achieve better yield, but these reaction parameters may increase safety risk at industrial scale.
Thus, there remains an urgent need to develop an industrially viable process for preparation of fluorinated benzylamine.

SUMMARY OF THE INVENTION
In first aspect, the present invention provides an improved process for preparation of a compound of formula I,

Formula I
wherein n=1-5
comprising the steps of:
a) fluorinating a compound of formula III with pre-heated fluoride source in presence of aprotic polar solvent to obtain a compound of formula II;

Formula III Formula II
wherein n=1-5 wherein n=1-5
b) hydrogenating the compound of formula II in presence of an alcohol, wherein process is carried out in absence of a base.
The second aspect of present invention provides an improved process for preparation of a compound of formula II, comprising fluorinating a compound of formula III with pre-heated fluoride source in presence of aprotic polar solvent to obtain a compound of formula II.

Formula III Formula II
wherein n=1-5 wherein n=1-5

OBJECT OF THE INVENTION
The main object of present invention is to provide an industrially viable process for preparation of fluorinated benzylamine of formula I by improving reaction parameters.

Formula I
wherein n=1-5

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an economical process for preparation of a compound of formula I comprising fluorination and hydrogenation reaction.
The fluorination is carried out using a fluoride ion source selected from a group consisting of metal fluoride such as sodium fluoride, potassium fluoride, cesium fluoride, lithium fluoride, zinc fluoride, aluminium fluoride, nickel fluoride.
In one embodiment, the fluoride source is pre-heated at a temperature of 100-160°C.
In another embodiment, the fluoride source is pre-heated at a temperature of 100°C-160°C under reduced pressure.
The molar equivalent of fluoride source to compound of formula III is in the range of 1-3.
The drying/heating of fluoride source at high temperature to obtain pre-heated fluoride source enables removal of impurities formed due to the presence of moisture during the reaction. It is observed by present inventors that maintaining fluoride source in hot condition helps in improving selectivity and yield of final product.
In one embodiment, a solution of compound of formula III in an aprotic polar solvent was added to pre-heated fluoride source in the process to prevent moisture.
In one embodiment, fluorination is carried out in presence of a catalyst. The catalyst for fluorination may be selected from a group consisting of tetrabutylammonium bromide, tetramethylammonium bromide, triethylmethylammonium bromide, tetrabutylammonium chloride, tetramethylammonium choride, triethylmethylammonium chloride, tetrabutylammonium fluoride, tetramethylammonium fluoride, triethylmethylammonium fluoride or like.
The molar equivalent of fluorination catalyst to the compound of formula III is taken in the range of 0.01-0.05.
The aprotic solvent is selected from a group consisting of sulfolane, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidine or the like.
The molar ratio of solvent to compound of formula III is in the range of 5-10 times.
In one embodiment, present invention provides a process for preparation of a compound of formula II comprising
a) heating fluoride source under reduced pressure;
b) adding a solution of a compound of formula III in an aprotic solvent to pre-heated fluoride source of step-a) to obtain a reaction mixture;
c) heating the reaction mixture of step b) to obtain a compound of formula II.
In one embodiment, fluorination reaction is carried out at a temperature of 150-220°C.
In one embodiment, hydrogenation is carried out in presence of a polar solvent in absence of a base.
As used herein, a base refers to ammonia, aliphatic amine, and aromatic amine.
It is observed that use of ammonia in hydrogenation process may result in impurities formed by substitution of ring fluorine. The present invention eliminates use of ammonia to prevent impurity formation during the process, which otherwise can affect the yield of process. Further, it avoids use of hydrocarbon solvent that are highly flammable.
The polar solvent for hydrogenation reaction is selected from a group consisting of methanol, ethanol, propanol, n-butanol, and tert-butanol or like.
The molar ratio of polar solvent to compound of formula II for hydrogenation is in the range of 5-10 equivalents.
In one embodiment, hydrogenation is carried out in presence of a catalyst selected from a group consisting of carbon on palladium, palladium on carbon, carbon, zinc, raney-nickel etc.
The mole ratio of catalyst to the compound of formula II is in the range of 0.1-0.5 equivalents.
The hydrogen pressure for present invention is in the range of 10-16 kg/cm2.
In one embodiment, hydrogen for hydrogenation is added in lots during the hydrogenation.
To avoid high-pressure range, hydrogen is added in lots during the process. After initial addition of hydrogen to obtain 15kg/cm2 hydrogen pressure, it was added periodically to maintain 10-15kg/cm2 pressure over the reaction. This technique avoids use of high pressure range and reduce safety risk of process.
In specific embodiment, hydrogenation is carried out in presence of methanol at 10-15kg/cm2.
In one embodiment, hydrogenation is carried out at a temperature below 80°C and more preferably below 70°C.
In another embodiment, present invention provides a process for preparation of a compound of formula I comprising;
a) heating fluoride source under reduced pressure;
b) adding a solution of a compound of formula III in an aprotic solvent to pre-heated fluoride source of step-a) to obtain a reaction mixture;
c) heating the reaction mixture of step b) to obtain a compound of formula II;
d) hydrogenating the compound of formula II in presence of alcohol solvent without using a base to obtain the compound of formula I.
The purity of compound of formula I of present invention is greater than 95%. More preferably, the purity of compound of formula I is greater than 99%.
The yield of compound of formula I of present invention is greater than 75%.
In a preferred embodiment, the reagents used for present invention are anhydrous.
The compound of formula I may be isolated or can be used in situ for preparation other compounds used in agrochemical and pharmaceutical industry.
After reaction, reaction mixture was cooled to room temperature and filtered to remove solid byproducts. The filtrate was proceeded for isolation of compound of formula I.
In one embodiment, hydrogenation mixture was filtered through celite after reaction completion.
In another embodiment, compound of formula II and I are isolated by fractional distillation.
The compound of formula III may be prepared by any method available in the prior art.
The present invention provides a very simple process for isolation of compound of formula II. The reaction mixture of fluorination was cooled to room temperature and filtered to remove solid byproducts. The product was isolated using fractional distillation.
The compound of formula II may be isolated or be used insitu for preparation of compound of formula I.
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
Example 1: Preparation of 2,4-difluorobenzylamine.
To a stainless steel reactor, 2,4-difluorobenzonitrile (1.0eq.), raney nickel (0.2eq.) and methanol (7eq.) were added. Hydrogen was added to the reactor till pressure of 15kg/cm2 was attained. The reaction mass was heated to 65°C and stirred at same temperature. Hydrogen pressure was reduced to 5kg/cm2 over stirring. Hydrogen was added periodically to the reactor to maintain pressure of 15kg/cm2. After completion of reaction, hydrogen pressure was vented off and reaction mass was cooled to room temperature. The reaction mass was filtered through celite and filtrate was purified by fractional distillation to isolate the titled product.
Purity: 99%; Yield: 80%
Example 2: Preparation of 2,4,6-trifluorobenzylamine.
To a stainless steel reactor 2,4,6-trifluorobenzonitrile (20g), raney nickel (2.4g) and ethanol (100) were added. Hydrogen was added in the reactor till pressure of 15kg/cm2 was attained. The reaction mass was heated to 60-68°C and stirred at the same temperature. Hydrogen pressure was reduced to 5kg/cm2 over stirring. Hydrogen was added in lots to the reactor to maintain pressure of 15kg/cm2. After completion of the reaction, hydrogen pressure was vented off and reaction mass was cooled to room temperature. The reaction mass was filtered through celite and filtrate was purified by fractional distillation to isolate the titled product.
Purity: 99.2%; Yield: 82%
Example 3: Preparation of 2,4-difluorobenzonitrile.
Potassium fluoride (100g) was taken into 2 litre round bottom flask at 140°C and dried for 1 hour at 140-150°C. 2,4-dichlorobenzonitrile (105g), tetrabutylammonium bromide (8.5g) and sulfolane (500g) were added to pre-heated potassium fluoride at 170-180°C. The temperature of the reaction mixture was raised to 205°C over a period of one hour. The reaction mixture was maintained at 200-210°C and analysed on gas chromatography. After completion of reaction, the reaction mass was cooled to room temperature (20-30°C). The reaction mixture was filtered to remove potassium chloride and unreacted potassium fluoride. Filtered solid was washed with 500ml sulfolane. The filtrate was taken for fractional distillation to obtain pure product.
Yield: 80%; Purity: 99.4%
Example 4: Preparation of 2,6-difluorobenzylamine.
To a stainless steel reactor, 2,6-difluorobenzonitrile (1.0eq.), raney nickel (0.2eq.) and methanol (6eq.) were added. Hydrogen was added in the reactor till pressure of 15kg/cm2 was attained. The reaction mass was heated to 65°C and stirred at the same temperature. Hydrogen pressure was reduced to 5kg/cm2 over stirring. Hydrogen pressure was added periodically to the reactor to maintained pressure of 15kg/cm2. After completion of reaction, hydrogen pressure was vented off and reaction mass was cooled to room temperature. The reaction mass was filtered through celite and filtrate was purified by fractional distillation.
Purity: 99.23%; Yield: 84%
Example 5: Preparation of 4-fluorobenzonitrile.
Potassium fluoride (48g) was dried for an hour at 140-150°C. The potassium fluoride was maintained at same temperature and 4-chlorobenzonitrile (50g) in dimethylsulfoxide (250g) was added to pre-heated potassium fluoride at 140°C. Tetrabutylammonium bromide (TBAB) was added and the reaction mixture was heated to 180°C over a period of an hour. Reaction mass was maintained at 180°C and analysed on gas chromatography. After completion of reaction, the reaction mass was cooled to room temperature and was filtered to remove by-product potassium chloride and unreacted potassium fluoride. The solid was washed with 50ml dimethylsulfoxide. The filtrate was taken for fractional distillation to isolate product.
Yield: 86%; Purity: 98.7%
Example 6: Preparation of 2,4-difluorobenzylamine.
Potassium fluoride (95g) was heated to 150°C for 2 hours. A solution of 2,4-dichlorobenzonitrile(100g) in sulfolane (550g) was added to pre-heated potassium fluoride. Tetrabutylammonium bromide (8g) was added to the mixture and the temperature was raised to 205°C over a period of an hour. Reaction mass was maintained at 205-210°C and sample was analysed on gas chromatography. After completion of reaction, reaction mixture was cooled to room temperature (30-35°C). The reaction mass was filtered to remove solid by-product potassium chloride and unreacted potassium chloride. The filtered solid was washed with 100ml sulfolane. The filtrate was concentrated to obtain crude product. The crude product was dissolved in methanol (180g) and charged to a reactor. Raney nickel (15g) was added to reactor. Hydrogen pressure was added to the reactor to attain a pressure of 15kg/cm2. The reactor was heated at 60°C and stirred for 1-4 hours. Hydrogen was added periodically to the reactor to maintain pressure of 15kg/cm2. After completion of reaction, hydrogen pressure was vented off and reaction mass was cooled to room temperature. The reaction mass was filtered through celite and filtrate was purified by fractional distillation to isolate 2,4-difluorobenzylamine.
Yield: 75%; Purity: 98.2%
Example 7: Preparation of 4-fluorobenzonitrile.
Potassium fluoride (48g) was dried for an hour at 140-150°C under vacuum. The potassium fluoride was maintained for 1-2 hours at same temperature. 4-chlorobenzonitrile (50g) in sulfolane (230g) was added to pre-heated potassium fluoride at 140°. Tetrabutylammonium bromide was added to mixture and heated to 200°C over a period of an hour. Reaction mass was maintained at 205-210°C and analysed on gas chromatography. After completion of reaction, reaction mass was cooled to room temperature. The reaction mixture was filtered to remove by-product potassium chloride and unreacted potassium fluoride. The filtered solid was washed with 50ml sulfolane. The filtrate was taken for fractional distillation to isolate the titled product.
Yield: 86%; Purity: > 99%
Example 8: Preparation of 2-fluorobenzonitrile.
Potassium fluoride (144g) was dried for an hour at 140-150°C under vacuum. The potassium fluoride was maintained for 2 hours at same temperature. 2-chlorobenzonitrile (150g) in dimethylsulfoxide (450g) was added to pre-heated potassium fluoride at 140°. Tetrabutylammonium bromide was added to the mixture and heated to 180°C over a period of an hour. Reaction mass was maintained at 180°C and analysed on gas chromatography. After completion of reaction, reaction mass was cooled to room temperature and was filtered to remove by-product potassium chloride and unreacted potassium fluoride. The filtered solid was washed with 100ml dimethylsulfoxide. The filtrate was taken for fractional distillation to isolate the titled product.
Yield: 87%; Purity: 99%
Example 9: Preparation of 2,4,6-trifluorobenzylamine.
To a Stainless steel reactor, 2,4,6-trifluorobenzonitrile (1.0eq.), raney nickel (0.2eq.) and methanol (6.5eq.) were added. Hydrogen was added in the reactor till pressure of 15kg/cm2 was attained. The reaction mass was heated to 65°C and stirred for some time. Hydrogen pressure was reduced to 5kg/cm2 over stirring. Hydrogen was added periodically to the reactor to maintain pressure of 15kg/cm2. After completion of reaction, hydrogen pressure was vented off and reaction mass was cooled to room temperature. The reaction mass was filtered through celite and filtrate was purified by fractional distillation.
Purity: 99%; Yield: 81%

Example 10: Preparation of 2,4-difluorobenzylamine.
Potassium fluoride (95g) was heated to 150°C for 2 hours. A solution of 2,4-dichlorobenzonitrile (100g) in dimethylformamide (550g) was added to pre-heated potassium fluoride. Tetrabutylammonium bromide (8g) was added to the mixture and was heated to 150°C over a period of an hour. Reaction mass was maintained at 150°C and sample was analysed on gas chromatography. After completion of reaction, reaction mixture was cooled to room temperature (30-35°C). The reaction mass was filtered to remove solid by-product potassium chloride and unreacted potassium fluoride. The filtered solid was washed with 100ml dimethylformamide. The filtrate was concentrated to obtain crude product. The crude product was dissolved in methanol (180g) and charged in reactor. Raney nickel (16g) and hydrogen were added to the reactor to attain a pressure of 15kg/cm2. The reactor was heated to 60°C and stirred for 1-4 hours. Hydrogen was added periodically to the reactor to maintained pressure of 15kg/cm2. After completion of reaction, hydrogen pressure was vented off and reaction mass was cooled to room temperature. The reaction mass was filtered through celite and filtrate was purified by fractional distillation to isolate 2,4-difluorobenzyl amine.
Yield: 75%; Purity: 98.2%
COMPARATIVE EXAMPLES:
Example 1: Preparation of 2,6-difluorobenzonitrile.
Potassium fluoride (165g), 2,6-dichlorobenzonitrile (150g) and sulfolane (450g) were charged to a reactor. Tetrabutylammonium bromide was added to mixture and heated to 180°C over a period of an hour. Reaction mass was maintained at 180°C and analysed on gas chromatography. After completion of reaction, reaction mass was cooled to room temperature and was filtered to remove by-product potassium chloride and unreacted potassium fluoride. The filtered solid was washed with 100ml dimethylsulfoxide. The filtrate was taken for fractional distillation to isolate the titled product.
Yield: 55%; Purity: 97%
Example 2: Preparation of 2,6-difluorobenzylamine.
2,6-difluorobenzonitrile (1.0eq.), raney nickel (0.2eq.) and methanol (7eq.) were added to a reactor, followed by addition of ammonia (1 eq.) to the reactor. Hydrogen was added in the reactor till pressure attained 20 kg/cm2. The reaction mass was heated to 70°C and stirred for completion. After completion of reaction, hydrogen pressure was vented off and reaction mass was cooled to room temperature. The reaction mass was filtered through celite and filtrate was purified by fractional distillation to isolate the titled produet.
Purity: 95%; Yield: 60%

WE CLAIM:

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

Formula I
wherein n=1-5
comprising the steps of:
a) fluorinating a compound of formula III with pre-heated fluoride source in presence of an aprotic polar solvent to obtain a compound of formula II; and

Formula III Formula II
wherein n=1-5
b) hydrogenating the compound of formula II in an alcohol solvent, wherein process is carried out without using any base.
2. A process for preparation of a compound of formula II, comprising fluorinating a compound of formula III with pre-heated fluoride source in presence of an aprotic polar solvent to obtain the compound of formula II.

Formula III Formula II
wherein n=1-5
3. The process as claimed in claim 1 and claim 2, wherein the fluoride source is a metal fluoride selected from a group consisting of sodium fluoride, potassium fluoride, cesium fluoride, lithium fluoride, zinc fluoride, aluminum fluoride and nickel fluoride or a mixture thereof.
4. The process as claimed in claim 1 and claim 2, wherein the fluorination reaction is carried out in presence of a catalyst.
5. The process as claimed in claim 4, wherein the fluorination catalyst is selected from a group consisting of tetrabutylammonium bromide, tetramethylammonium bromide, triethylmethylammonium bromide, tetrabutylammonium chloride, tetramethylammonium chloride, triethylmethylammonium chloride, tetrabutylammonium fluoride, tetramethylammonium fluoride, triethylmethylammonium fluoride or a mixture thereof.
6. The process as claimed in claim 1, wherein the hydrogenation is carried out in presence of a catalyst.
7. The process as claimed in claim 6, wherein the hydrogenation catalyst is selected from a group consisting of carbon on palladium, palladium on carbon, carbon, zinc and raney nickel.
8. The process as claimed in claim 1 and claim 2, wherein the aprotic solvent is selected from a group consisting of sulfolane, dimethylsulfoxide, dimethylformamide and N-methylpyrrolidine or a mixture thereof.