DESC:TECHNICAL FIELD OF INVENTION
The present invention generally relates to a method for preparation of substituted aniline. More particularly, the invention relates to a two-step process for preparation of 2,6-dichloro-para-trifluoromethylaniline with reduced reaction time.
BACKGROUND OF THE INVENTION
2,6-dichloro-para-trifluoromethylaniline is a valuable intermediate for preparation of pesticides. It is used in the synthesis of pyrazole based compounds such as pyrazole type pesticide “Fipronil”. Various processes and studies have already been carried out with the aim of developing processes for the preparation of 2,6-dichloro-para-trifluoromethylaniline. Prior arts disclose different processes for the preparation of 2,6-dichloro-para-trifluoromethylaniline for instance:
WO 201512155A1 discloses a process for the preparation of 2,6-dihalo-para-trifluoromethylanilines as intermediates for pyrazoles comprising the halogenation of para-trifluoromethylaniniline with dihalogen.
US 7553993 discloses a process for the preparation of a compound of 2,6-dihalo-para-trifluoromethylaniline, by reaction of para-trifluoromethylaniline with a dihalogen X2, the two compounds being introduced simultaneously into a polar aprotic solvent in a dihalogen/compound (II) molar ratio ranging from 1.9 to 2.5 and at a temperature ranging from 100 to 300° C.
US6479703B1 discloses a method for preparing polyhalogenated paratrifluormethylanilines.. The products are obtained by the action of ammonia on polyhalogenated para-trifluoromethylbenzene at a temperature ranging between 150 and 350° C. However, the existing processes result in impurities that make it difficult to use 2,6-dichloro-para-trifluoroaniline for further continuation of the preparation of pesticidal compounds of phenylpyrazole type. Further the reaction time for the known process is long and tedious Therefore, there is a continued need in the art to develop an economical process, with reduced reaction time for the preparation of 2,6-dichloro-para-trifluoromethylaniline having higher purity. The present invention teaches synthesis of 2,6-dichloro-para-trifluoromethylaniline using 4-chlorobenzotrifluoride as a starting material that results in enhanced purity of 99% or greater.
OBJECTIVES OF THE INVENTION
The main objective of this invention is to overcome the conventional problems in the prior art.
Another objective of the present invention is to provide process for the preparation of 2,6-dichloro-para-trifluoromethylaniline.
Another objective of the present invention is to develop reaction parameters for the reaction that results in product with negligible impurities and high yield.
Another objective of the present invention is to provide a two-step process for the preparation of 2,6-dichloro-para-trifluoromethylaniline.
Another objective of the present invention is to prevent polymerization of 4-trifluoromethyl aniline in subsequent processing.
Another objective of the present invention is to develop optimum reaction conditions for the chlorination step with catalyst that substantially reduces the reaction time.
Yet another objective of the present invention is to provide a commercial process that scavenges the free fluoride formed during chlorination reaction by adding oxides and salts of GROUP IVA elements which increases the life of the equipment.
SUMMARY OF THE INVENTION
In accordance with an embodiment of the invention, there is provided a process for the preparation of 2,6-Dichloro-para-trifluoromethylaniline, said process comprising the steps of:
(a) reacting 4-Chlorobenzotrifluoride with ammonia in the presence of a polar aprotic solvent to obtain 4-Trifluoromethylaniline;
(b) isolating and washing 4-Trifluoromethylaniline;
(c) reacting the 4-Trifluoromethylaniline with Cl2 in the presence of a catalyst and fluorine scavanger to obtain 2,6-Dichloro-para-trifluoromethylaniline;
wherein the purity of 2,6-Dichloro-para-trifluoromethylaniline is =99%, wherein the reaction of step (c) is over in about 4 to 5 h, and wherein fluorine scavengers react with fluorine to prevent reactor corrosion.
In accordance with an embodiment of the invention, step (a) of the process is carried out in the presence of a polar aprotic solvent, selected from the group consisting of Dimethylformamide, hexamethylphosphoramide, dimethylsulfoxide, sulfolane and combinations thereof. More preferably, step (a) is carried out in the presence of sulfolane as a polar aprotic solvent.
In accordance with another embodiment of the invention, the reaction mixture of step (a) comprises either copper acetatemonohydrate, copper powder, lime, or combinations thereof.
Step (a) of the process is carried out at a temperature in the range of 130 to 135 °C, a pressure of <55 bar, and the reaction time is about 20 h.
In accordance with yet another embodiment of the invention, the product of step (a) is washed with sodium bicarbonate solution, preferably 10% sodium bicarbonate solution.
Step (c) of the process is carried out in ethylene dichloride solvent. In accordance with an embodiment of the invention, the catalysts in step (c) are selected from the group consisting of iron powder, iron salts, aluminium chloride, and combinations thereof. More preferably, the catalyst in step (c) of the process is Fe/FeCl3.
In accordance with still another embodiment of the invention the fluorine scavenger is silica, or salts and oxides of Group IVA of the periodic table, and the reaction of step (c) is carried out at a temperature of 80 to 85 °C.
DETAILED DESCRIPTION OF INVENTION:
Discussed below are some representative embodiments of the present invention. The invention in its broader aspects is not limited to the specific details and representative methods. Illustrative examples are described in this section in connection with the embodiments and methods provided.
It is to be noted that, as used in the specification, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a composition containing “a compound” includes a mixture of two or more compounds. It should also be noted that the term "‘or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
The expression of various quantities in terms of “%” or “% w/w” means the percentage by weight of the total solution or composition unless otherwise specified.

All cited references are incorporated herein by reference in their entireties. Citation of any reference is not an admission regarding any determination as to its availability as prior art to the claimed invention.
The present invention, in all its aspects, is described in detail as follows:
In one embodiment, the present invention relates to a two-step process for the preparation of 2,6-dichloro-para-trifluoromethylaniline. The process comprising the steps of:
1. Preparation of an intermediate 4-trifluoromethylaniline from 4-chlorobenzotrifluoride using ammonia and sulfolane at temperature in the range of 130-135 oC.
2. Isolation and washing of the intermediate i.e. 4-trifluoromethylaniline formed in step 1.
3. Preparation of 2,6-dichloro-para-trifluoromethylaniline from 4-trifluoromethylaniline using dihalogen and a catalyst at temperature in the range of 80-85 oC.
The present invention involves the ammoniation of 4-chlorobenzotrifluoride in presence of ammonia, copper acetatemonohydrate/copper, lime, sodium bicarbonate and sulfolane at temperature in the range of 130-135oC. The present invention involves the isolation of the formed product without any oligomeric impurities. The formed product i.e. 4-trifluoromethylaniline is solubilized in EDC (1,2-Dichloroethane) and washed with 10% of sodium bicarbonate solution in order to prevent trimerisation of 4-trifluoromethylaniline. Isolation of 4-trifluoromethylaniline and washing enhances the purity of the final product and also results in increased rate of conversion of 4-trifluoromethylaniline to 2,6-dichloro-para-trifluoromethylaniline.

The chlorination of 4-trifluoromethylaniline with EDC involves the use of Cl2, silica gel and catalyst such as Fe/FeCl3, Fe/AlCl3, Fe to give 2,6-dichloro-trifluoromethylaniline. The reaction is carried at temperature in the range of 80-85 oC for about 4 hours to about 5 hours. The formed 2,6-dichloro-trifluoromethylaniline has a purity of 99% or greater (GC Purity). Below is the reaction scheme for the instant invention.

The use of catalyst in the chlorination reaction of 4-trifluoroaniline, is likely to show high reaction conversion ratio and yield ratio. Use of catalyst in the instant process leads to significant reduction in reaction time i.e. about 4 hours to about 5 hours. In the chlorination reaction, the elemental chlorine and 4-trifluoromethylaniline react under catalysis of composite catalyst comprising elemental metal and metal halide and reaction temperature in the range of 80-85 oC.
The use of silica and acid scavenger (fluorine scavangers) in the reaction prevents the reactors from corrosion, by reacting with the free fluoride present in the reaction mass and hence avoids the damage of reactors from corrosion. The corrosion test of various material of constructions (MOCs) are shown in Table 1, data mentioned in below table shows the comparative analysis of chlorination reaction with and without the use of silica.
Table 1: CORROSION STUDY FOR EQUIPMENT MATERIAL OF CONSTRUCTION AS BELOW TABLE:

Without Silica chlorination reaction batch
MOC Phase Initial
Wt. in gm Final
Wt. in gm Diff
Wt. in gm %loss in wt.
HC-276 Liquid 36.8015 36.7862 0.0153 0.0416
Vapour 36.4908 36.478 0.0128 0.0351

SS-347 Liquid 38.5426 38.4001 0.1425 0.3697
Vapour 47.4058 46.9011 0.5047 1.0646

Glass dumbells Liquid 40.3709 40.3381 0.0328 0.0812

W/W 1% Silica used in reaction with respect to TFMA quantity

MOC Phase Initial
Wt. in gm Final wt. in gm Diff wt. in gm % loss in wt.
HC-276 Liquid 36.786 36.7599 0.0261 0.0710
Vapour 36.4779 36.4675 0.0104 0.0285

SS-347 Liquid 38.4001 38.3093 0.0908 0.2365
Vapour 46.9004 46.7178 0.1826 0.3893

Glass dumbells Liquid 40.3388 40.3294 0.0094 0.0233
Vapour 14.0319 14.0201 0.0118 0.0841

HC-22 Liquid 34.3102 34.2988 0.0114 0.0332
Vapour 35.8088 35.7665 0.0423 0.1181

W/W 1.5% Silica used in reaction with respect to TFMA quantity
MOC Phase Initial
Wt. in gm Final wt. in gm Diff wt. in gm % loss in wt.
HC-276 Liquid 36.7607 36.7321 0.0286 0.0778
Vapour 36.4056 36.3965 0.0091 0.0250

INCO 825 Liquid 14.0045 13.9895 0.015 0.1071
Vapour 14.8744 14.6956 0.1788 1.2021

Glass dumbells Liquid 40.2957 40.2954 0.0003 0.0007
Vapour 13.7961 13.7956 0.0005 0.0036

HC-22 Liquid 34.2988 34.268 0.0308 0.0898
Vapour 35.7664 35.7531 0.0133 0.0372
The invention is now illustrated by way of following non-limiting examples:
The present invention is more particularly described in the following examples that are intended as illustration only, since numerous modifications and variations within the scope of the present invention will be apparent to those of skill in the art. Unless otherwise noted, all parts, percentages, and ratios reported in the following example are on a weight basis, and all reagents used in the examples were obtained or are available from the chemical suppliers.
The following examples illustrates the basic methodology and versatility of the present invention.
Example 1: Ammoniation of 4-chloro benzotrifluoride
5L hastelloy C 276 autoclave was cleaned and dried and further tested for leak test at 50 barg. Charged sulfolane (2000 g), 4-chlorobenzotrifluoride (1000 g), cupric acetate monohydrate (300 g), copper powder (70 g), lime (77 g) and sodium bicarbonate (40 g) was taken in 5 liter autoclave and stirred at 25-30°C. The reaction mass was then cooled up to 10-20°C. Further addition of ammonia was done from cylinder at 10-20°C, and pressure 5 barg. The reaction mass was then heated slowly to 130-140°C and the temperature was maintained for 19 hrs. Auto generated pressure was maximum 55 barg. Reaction was monitored by GC and after completion, the reaction mass is cooled at 40 oC and stirred for 10-15 mins. Ammonia was allowed to release and reaction mass was unloaded, followed by centrifugation of reaction mass at 25-30°C. The solid obtained was then washed with sulfolane at 25-30°C and dried over salt for 15-20 minutes at 25-30°C. Filtrate was distilled with high vacuum fractional distillation. Product obtained from distillation having no sulfolane impurity was mixed with solvent EDC and stirred well followed by addition of 10% sodium bicarbonate solution and stirred for 15 min at 35-40°C.; then the organic layer was separated. Washing with sodium bicarbonate solution was repeated twice. The organic layer separated and use further in continuation for chlorination.
Recovered CBT: 155.68 g
Weight of step I (GC >96%A): 647.7 gm
Yield: 86.0%

Example 2: Chlorination of 4-trifluoromethylaniline in presence of EDC, Cl2, Fe/AlCl3
5L RBF equipped with TP, stirrer, condenser, Y-bend apparatus for chlorine gas spurring in the oil bath with overhead stirrer motor was taken for reaction. Charged EDC (1085 g), iron powder (4 g), aluminium chloride (4 g) and silica gel (6 g) was added in clean and dried round bottom flask and stirred for 10-15 mins at 25-30°C. The reaction mass was heated slowly to 80 °C and added step-I in EDC (step-I - 400 g + EDC 153 g) over a period. Further Cl2 gas was spurged in reaction mass at 80-85°C in 4-5 hrs, and stirred for 20-30minutes at 80 - 85°C. The reaction was monitored by GC. After completion of the reaction, the reaction mass was cooled at 25°C and stirred for 15-20 minutes at 25-30°C. The reaction mass was then filtered and washed with EDC (100 g) at 25-30°C and dried over salt for 15-20 minutes at 25-30°C. The organic layer is then separated and distilled, to give the final product. Reaction Yield: 78.41%
Example 3: Chlorination of 4-trifluoromethylaniline in presence of EDC, Cl2, Fe/FeCl3
5L RBF equipped with TP, stirrer, condenser, Y-bend apparatus for chlorine gas spurging in the oil bath with overhead stirrer motor was taken for reaction. Charged EDC (1355 g), iron powder (5 g), ferric chloride (5 g), silica gel (7.5 g) was taken in clean and dried round bottom flask and stirred for 10-15 mins at 25-30°C. The reaction mass was heated slowly to 80 °C and added step-I in EDC (step-I - 500 g + EDC 190 g) over a period. Further Cl2 gas was spurged in reaction mass at 80-85°C in 4-5 hrs, and stirred for 20-30 minutes at 80 - 85°C. The reaction was monitored by GC. After completion of the reaction, the reaction mass was cooled at 5°C and stirred for 15-20 minutes at 25-30°C. Further ammonia was added (30 g) till pH~8 at <5°C. The reaction mass was then filtered and washed with EDC (100 g) at 25-30°C and dried over salt for 15-20 minutes at 25-30°C. The organic layer was then separated and distilled to give the final product. Reaction Yield: 92.70% and isolated yield is 90.38%
Over all yield from 4-chloro benzotrifluoride to 2,6-dichloro-4-trifluoromethyl aniline is 77.73 %
Example 4: Chlorination of 4-trifluoromethylaniline in presence of EDC, Cl2, Fe powder
5L RBF equipped with TP, stirrer, condenser, Y-bend apparatus for chlorine gas spurging in the oil bath with overhead stirrer motor was taken for reaction. Charged EDC (271 g), iron powder (1 g), silica gel (1.5 g) was taken in clean and dried round bottom flask and stirred for 10-15 mins at 25-30°C. The reaction mass was heated slowly to 80 °C and added step-I in EDC (step-I - 100 g + EDC 38 g) over a period. Further Cl2 gas is spurged in reaction mass at 80-85°C in 4-5 hrs, and stirred for 20-30 minutes at 80 - 85°C. The reaction was monitored by GC. After completion of the reaction, the reaction mass was cooled at 10°C and stirred for 15-20 minutes at 25-30°C. Further ammonia was added (10 g) till pH~8 at 10-15°C. The reaction mass was then filtered and washed with EDC (20 g) at 25-30°C and dried over salt for 15-20 minutes at 25-30°C. The organic layer was then separated and distilled to give the final product. Reaction Yield: 69.45%.
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive.
,CLAIMS:1. A process for the preparation of 2,6-Dichloro-para-trifluoromethylaniline, said process comprising the steps of:
(a) reacting 4-Chlorobenzotrifluoride with ammonia in the presence of a polar aprotic solvent to obtain 4-Trifluoromethylaniline;
(b) isolating and washing 4-Trifluoromethylaniline;
(c) reacting said isolated and washed 4-Trifluoromethylaniline with Cl2 in the presence of a catalyst and fluorine scavenger for a specified period of time to obtain 2,6-Dichloro-para-trifluoromethylaniline;
wherein the purity of obtained 2,6-Dichloro-para-trifluoromethylaniline is =99% and wherein fluorine scavengers react with fluorine to prevent reactor corrosion.
2. The process as claimed in claim 1, wherein step (a) of the process is carried out in the presence of a polar aprotic solvent, selected from the group consisting of Dimethylformamide, hexamethylphosphoramide, dimethylsulfoxide, sulfolane and combinations thereof.
3. The process as claimed in claims 1 and 2, wherein step (a) is carried out in the presence of sulfolane as a polar aprotic solvent.
4. The process as claimed in claims 1 to 3, wherein the reaction mixture of step (a) comprises either copper acetatemonohydrate, copper powder, lime, or combinations thereof.
5. The process as claimed in claims 1 to 4, wherein the reaction of step (a) is carried out at a temperature in the range of 130 to 135 °C.
6. The process as claimed in claims 1 to 5, wherein the reaction of step (a) is carried out at a pressure of <55 bar.
7. The process as claimed in claims 1 to 6, wherein the reaction time of step (a) is about 20 h.
8. The process as claimed in claims 1 to 7, wherein the product of step (a) is washed in step (b) with sodium bicarbonate solution, preferably 10% sodium bicarbonate solution.
9. The process as claimed in claims 1 to 8, wherein step (c) is carried out in ethylene dichloride solvent.
10. The process as claimed in claims 1 to 9, wherein the catalysts in step (c) are selected from the group consisting of iron powder, iron salts, aluminium chloride, and combinations thereof.
11. The process as claimed in claims 1 to 10, wherein the catalyst in step (c) is Fe/FeCl3.
12. The process as claimed in claims 1 to 11, wherein the fluorine scavenger is silica or salts and oxides of Group IVA of the periodic table.
13. The process as claimed in claims 1 to 12, wherein the reaction of step (c) is carried out at a temperature range of 80 to 85 °C.
14. The process as claimed in claims 1 to 13, wherein the specified period of time in step (c) is in the range of 4 to 5 hours.