Specification
FORM 2
The Patent Act 1970,
(39 of 1970) &
The Patent rule 2003
Complete Specification
(See Section 10 and Rule 13)
1. TITLE OF THE INVENTION
A NOVEL PROCESS FOR PREPARING 2,6-DICHLORO-4-TRIFLUORO- METHYLANILINE USING AMMONIA
2. APPLICANT (S)
(a) Name: GHARDA HORMUSJI KEKI
(b) Nationality: INDIAN
(c) Address: GHARDA HOUSE, 48 HILL ROAD, BANDRA (WEST),
MUMBAI 400 050, INDIA
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.
A NOVEL PROCESS FOR PREPARING 2.6-DICHLORO-4-TRIFLUORO- METHYLANILINE USING AMMONIA
FIELD OF THE INVENTION;
The invention relates to a novel process for preparing 2, 6-dichloro-4- trifluoromethyl-aniline, an important intermediate used in the synthesis of N- Phenylpyrazole derivatives. The product of the inventive method is obtained by the action of anhydrous ammonia on polyhalogenated para- trifluoromethylbenzene. Accordingly, it provides an improved method of preparing 2,6-dichloro-4-trifluoromethylaniline from 4-chlorobenzotrifluoride as precursor.
BACKGROUND OF THE INVENTION;
p-Chlorobenzotrlffuoride is easily available In commercial quantity and can be used as a source for grafting monomethylamine or dialkylamine onto a deactivated aromatic ring.
p-Chlorobenzotrifluoride can be aminated in an essentially non aqueous solvent medium which is nonreactive with the reactants under the reaction condition in the presence of a catalytically effective amount of catalyst system comprising of a selected copper compound and a selected alkaline halide salt at a pressure and at elevated temperature in the range of 150 to 240°C to produce p- aminobenzo-trifluoride. However, the conversion is low and yields are correspondingly very less to accept it as an industrial process. Thus, synthesis of p-aminobenzotrifluoride from p-chlorobenzotrifluoride is uneconomical at commercial scale.
p-Chlorobenzotrifluoride can be selectively chlorinated to 3,4-dichlorobenzo- trifluoride in high yield and purity. Amination of 3,4-dichlorobenzotrifluoride and 3,4,5-trichlorobenzotrifluoride proceed much more easily as compared to that of
p-chlorobenzotrifluoride. There is therefore need for preparing polychlorinated p- trifluoromethylanilines, namely 2,6-dichloro-4-trifluoromethylaniline in a simple and economical manner at industrial level, with high yields and purities.
DESCRIPTION OF THE PRIOR ART:
Aryl halides, especially activated aryl halides have been ammonolyzed using aqueous ammonia in the presence of copper salt as catalyst to get the corresponding aromatic amines. However, the same prior art is not applicable for the ammonolysis of p-chlorobenzotrifluoride as p-aminobenzotrifluoride is readily hydrolyzed to p-aminobenzoic acid or aniline in the aqueous medium. Ammonolysis of p-chlorobenzotrifluoride in non-aqueous medium using copper compounds as sole catalyst significantly reduces the hydrolysis problems but produces only small amount of the desired p-aminobenzotrifluoride.
U.S.Patent No. 3,484,487 by James S. Dix discloses the use of copper chloride and non-polar organic solvents such as dimethylacetamide, dimethylformamide, N-methylpyrrolidone for amination of aryl halides. These solvents are not suitable for the preparation of p-aminobenzotrifluoride since transamination occurs to a significant extent to form unwanted N,N-dimethylaminobenzotrifluoride.
The synthesis of anilines has generally been performed by hydrogenation of aromatic nitro compounds. However, the technique is not appropriate in presence of substituents on the benzene ring which are sensitive to hydrogenolysis thus leading to number of side reactions. Moreover, 4-nitro- benzotrifluoride is very difficult to make since nitration of benzotrifluoride yields the meta isomer almost exclusively.
p-Aminobenzotrifluoride is also made by ammonolysis of p-chlorobenzotrifluoride in the presence of copper (I) chloride and potassium fluoride (J. Org. Chem. 44,4731 (1970)). However, the reaction conditions are too drastic, the conversions are low and yields are, correspondingly very low for an industrial process.
U.S.Patent No. 4,096,185 talk about synthesis of p-aminobenzotrifluoride starting from p-chlorobenzotrifluoride in the presence of unique catalyst combination containing alkali metal halides and copper compounds in presence of nonaqueous solvents like alkanols, aromatic nitriles, aliphatic dinitriles, glycol ethers etc. at a superatmospheric pressure, at a temperature range of about 150 to 240°C.
U.S.Patent Nos.2,194,925 and 2,194,926 show the reaction of certain nitro-halo- benzotrifluorides with ammonia in a solvent medium and in the presence of a copper salt to produce nitro-amino-benzotrifluorides.
Polyhalogenated trifluoromethylanilines are also made by ammonolysis of polyhalogenated benzotrifluoride in the presence of alkaline halide at a temperature ranging between 150 to 350°C. WO 00/35851/2000 talk about synthesis of 2,6-Dichloro-4-trifluoromethylaniline starting from 3,4,5-trichloro- benzotrifluoride in the presence of alkaline fluorides like lithium fluoride and anhydrous ammonia in the presence of N-methylpyrrolidone at 250°C to give 97% conversion and 87% selectivity. The main drawback of the above process is the synthesis of 3,4,5-trichlorobenzotrifluoride in high yield and purity. Chlorination of p-chlorobenzotrifluoride gives a mixture of 3,4,5- trichlorobenzotrifluoride in 72% GLC conversions with two other trichloro isomers in 23% and 5% ratio respectively apart from 3,4-dichloro and tetrachlorobenzotrifluoride. To get pure 3,4,5-isomer from this mixture by fractionation followed by crystallization is very tedious and industrially unviable. Moreover in-spite of using very pure intermediate, substantial amount of wrong isomer (3-amino-4,5-dichlorobenzotrifluoride) is obtained in 17% isomer ratio.
Another approach to generate 3,4,5-trichlorobenzotrifluoride in high yield and purity is to do denitrochlorination of 4-chloro-3,5-dinitrobenzotrifluoride in the presence of a catalyst as described in GB Patent 2154581 A. Even though the process produces 3,4,5-trichlorobenzotrifluoide in high yield and purity, reaction conditions are too drastic for an industrial process.
British Patent No. 1,164,223 by Farbenfabriken Bayer A.-G. describes the preparation of trifluoromethylaniline by hydrolysis of the corresponding trifluoromethylphenyl isocyanates.
T.Cohen and J.G.Tirpak, Tetrahedron Letters, 1975,143 discuss Ullman couplings and ammonolysis of activated aryl halides catalyzed by copper compounds. No alkali metal or ammonium halide is used in their system and also aryl iodides and bromides are used which are known to aminate more readily than aryl chlorides.
In 1995, Jean -Marc Ricca, Lyons, France, U.S. Patent Nos. 5,401,882 presented the invention of synthesis of deactivated anilines by reacting 3,4- dichlorobenzotrifluoride with dimethylformamide in presence of alkali metal hydroxide at temperature ranging between 150 to 250°C. The same patent talk about chlorination of the dialkyl derivative followed by dealkylation of the dialkylaniline by chlorination under UV light or using stoichiometric quantity of pyridine salt at elevated temperature.
None of the above prior art talk about the synthesis of 2,6-dichloro-4- trifluoromethylaniline by reacting ammonia and 3,4-dichlorobenzotrifluoride to get the desired molecule.
OBJECT OF THE INVENTION:
The main object of the present invention relates to the process for the preparation of 2,6-dichloro-4-trifluoromethylaniline, an important intermediate used in the synthesis of N-phenylpyrazole pesticides, using commercially available raw material like p-chlorobenzotrifluoride or 3,4-dichlorobenzotrifluoride, which can be manufactured by selective chlorination of p-chlorobenzotrifluoride in high yield and purity.
It is another object of the present invention to achieve synthesis of p- aminobenzotrifluoride derivative by direct ammonolysis of 3,4- dichlorobenzotrifluoride with ammonia which is not reported so far in the literature. This will avoid the step of dealkylation of the N-alkylanilines which comprises the steps of free radical halogenation or reacting the N-alkylaniline in the presence of a catalytic amount of a pyridine salt which often gives lower yield.
It is another object of the present invention to achieve synthesis of 2,6-dichloro-4- trifluoromethylaniline directly by chlorination of 2-chloro-4-trifluoromethylaniline without incorporating the step of dealkylation.
Advantage of the this process over those reported in the prior arts include: ability to effect ammonolysis of 3,4-dichlorobenzotrifluoride at moderate reaction condition with high conversion to achieve 2-chloro-4-trifluoromethylanilne; and to achieve 2,6-dichloro-4-trifluoromethylaniline directly by chlorination without incorporating dealkylation, a step which gives lower yield due to side reactions.
SUMMARY OF THE INVENTION:
The present invention relates to a novel process for the preparation of 2,6- dichloro-4-trifluoromethyl aniline, which comprises the step of reacting a compound of formula (I) with anhydrous ammonia in the presence of alkali metal halides and copper catalyst at elevated temperatures,
Wherein,
R1 constitute leaving groups such as chlorine or bromine.
R2 and R4 which may be the same or different, are chosen from hydrogen,
hydrocarbon chains, and halogens
R3 is chosen from groups which are electron attracting through an inductive effect rather than a mesomeric effect.
Preferably, the electron attracting groups are perhaloalkyl, more preferably the electron attracting groups are trihalomethyl, most preferably the electron attracting groups are trifluoromethyl.
A second embodiment of the present invention is directed to a process for the halogenation of the substituted p-trifluoromethylaniline with halogenating agents like chlorine, sulfuryl chloride, thionyl chloride, phosphorus pentachloride (PCI5), mixture of phosphorus trichloride and chlorine (PCI3+CI2) etc. to get the desired 2,6-dichloro-4-trifluoromethylaniline without dealkylation.
DETAILED DESCRIPTION OF THE INVENTION:
The process for the synthesis of 2,6-dichloro-4-trifluoromethylaniline was improved upon from the prior art process by doing ammonolysis of 3,4- dichlorobenzotrifluoride in high conversion rate at moderate reaction conditions as compared to that of p-chlorobenzotrifluoride. The resultant 2-chloro-4- trifluoromethylaniline is further chlorinated to get the desired molecule without incorporating the step of dealkylation.
In a preferred embodiment of the process, 3,4-dichlorobenzotrifluoride is manufactured in high yield and purity by chlorination of commercially available p- chlorobenzotrifluoride. Ammonolysis of 3,4-dichlorobenzotrifluoride and 3,4,5- trichlorobenzotrifluoride is much easy and facile as compared to that of p- chlorobenzotrifluoride which gives much higher conversions as compared to that of p-chlorobenzotrifluoride. 3,4-Dichlorobenzotrifluoride is ammonolyzed with anhydrous ammonia in the presence of polar solvents which is non reactive with the reactants under the reaction condition. Ammonolysis is conducted in the presence of a catalytically effective amount of a catalyst system comprising of a selected copper compound and a selected salt of alkaline halides under pressure at 20 to 50 kg/cm2, more preferably 35 to 42 kg/cm2 and at a temperature range of 200 to 300°C, more preferably in the temperature range of 240 to 250°C.
In a preferred embodiment, anhydrous ammonia is used in excess of 5-6 m/m to start with. As the reaction proceeds, more ammonia is fed in to maintain the reactor pressure and to minimize side reactions, which predominates at higher temperature due to lowering of ammonia concentration.
In a preferred embodiment, the solvent employed in the present process can be any solvent or mixture of solvent, which does not decompose under the reaction condition and is inert with respect to the reactants. Preferably the solvent used is polar solvent. N-methylpyrrolidone is the solvent of choice as it does not interact with the reactants at the same time it solubilises potassium fluoride.
According to the present invention, it is possible to prepare p- trifluoromethylaniline derivatives in a single step from the corresponding p- halobenzotrifluorides. However, results obtained are generally better when
starting material is dihalogenated or trihalogenated derivatives of p- benzotrifluoride.
In the second embodiment, the halogenation of the substituted p- trifluoromethylaniline is carried out using halogenating agents like chlorine, thionyl chloride, sulfuryl chloride, PCI5, mixture of PCI3 +CI2, etc. at temperature ranging between 0 to 100°C, preferably at 0 to 70°C. Among various halogens, the preferred halogen is chlorine unless a specific halogen is desired. The amount of halogenating agent used is limited to 10 to 50% excess relative to the stoichiometric amount, preferably about 10-20% of stoichiometric excess. Preferably halogenation is done in chlorinated hydrocarbon solvents with boiling point below 100°C or under reduced pressure to drive the reaction. The preferred solvents are carbon tetrachloride, dichloromethane, chlorobenzene, o- dichlorobenzene etc.
The desired 2,6-dichloro-4-trifluoromethylaniline can be obtained in high purity by fractional distillation of the product post halogenation. Distilled product can be crystallized from a suitable solvent to achieve the desired quality.
SPECIFIC EMBODIMENTS OF THE INVENTION:
The invention is illustrated by the following examples in which the composition of the products is estimated by gas chromatography of reaction mixture sample by area normalization. In the following illustrative examples, all parts are by weight and all temperatures are centigrade unless otherwise specified.
Example-1
1050 ml of N-methylpyrrolidone is charged in an autoclave along with 102 g {1 m/m) anhydrous activated potassium fluoride. 377 g (1.75 mole; GC, 99.9 %) 3,4-dichlorobenzotrifluoride is added and pressure reactor is fitted. 158 g (5.3 m/m) ammonia gas is passed in the reactor from a pressure pot at ambient temperature.
The content of the reactor is heated to 245-250°C over a period of 2 hours to get reactor pressure of 30-32 kg/cm2. Excess NH3 is fed from the pressure pot to maintain the reactor pressure at 38-40 kg /cm2 at 245-250°C liquid temperature. Reaction mixture is maintained at 245-250°C/38-40 kg/cm2 pressure for further 8 hours. Reaction mixture is cooled to ambient temperature, NH3 is vented off and reaction mass sample is checked by gas chromatography: 28.88% 3,4- dichlorobenzotrifluoride; 60.44% 2-chloro-4-trifluoromethylaniline, 6.9% 2-chloro- 5-trifluoromethylaniline and 2.65% high boiler.
After treatment of the reaction medium, 70.5% conversion of 3,4- dichlorobenzotrifluoride was achieved with 0.25 m/m starting material recovered. Fractionation of reaction medium gave 58.3% 2-chloro-4-trifluoromethylaniline with 9.2% 2-chloro-5-trifluoromethylaniline as other isomer with relative ratio of 87:13 and 77% yield of 2-chloro-4-trifluoromethylaniline on 3,4- dichlorobenzotrifluoride consumed.
Example- 2
815 ml on N-methylpyrrolidone is charged in an autoclave along with 292 g 3,4- dichlorobenzotrifluoride (1.35m,GC, 99.9%) and 118g (1.5 m/m) of calcined potassium fluoride. The reactor is fitted and 213 g (9.2 m/m) of ammonia gas is fed in the reactor.
The mixture is gradually heated to 245-250°C liquid temperature to achieve 3840 kg/cm2 reactor pressure initially and then further maintained at 245-250°C/38- 40 kg/cm2/6 hours by feeding ammonia gas to maintain the desired reactor pressure. Gas chromatography of the reaction mixture after 6 hours shows: 36.5% 3,4-dichlorobenzotrifluoride; 52.9% 2-chloro-4-trifluoromethylaniline; 5.7% 2-chloro-5-trifluoromethylaniline and 4.3% high retention signal. The isomer ratio is 90:10%.
After treatment of reaction medium, 0.325 m/m 3,4-dichlorobenzotrifluoride is recovered along with 0.508 m/m 2-chloro-4-trif1uoromethylaniline giving a yield of 75.2 % on 3,4-dichlorobenzotrifluoride consumption.
Example- 3
301 g of a mixture (1.0 mote isomer mixture) containing 57.37% 2-chloro-4- trifluoromethylaniline (0.88m); 7.61% 2-chloro-5-trifluoromethylaniline (0.117m) ; 34% N-methyl pyrrolidone (NMP) is mixed with 500 ml chlorobenzene. 148.4 g (1.1 m/m) of sulfuryl chloride is added at 55-60°C over 4 hours and reaction mixture is maintained at 55-60°C till gas chromatography of the reaction medium shows: 86.76% 2,6-dichloro-4-trifluoromethylaniline; 11.27% trichlorotrifluoro- methylaniline and 1.8% high retension signal.
Reaction medium on treatment and fractionation gave 0.84 m of 2,6-dichloro-4- trifluoromethylaniline, 95% on 2-chloro-4-trifluoromethylaniline,
Example- 4
276 g of a mixture containing 60.47% 2-chlor-4-trifluoromethylaniline (0.854 m); 10.45% 2-chloro-5-trifluoromethylaniline (0.147 m); 26.27% NMP and 2.66% high retention impurity is mixed with 500 mi chlorobenzene. 135 g (1m) sulfuryl chloride is added at 55-60X deg liquid temperature over 4 hours and reaction temperature is maintained for further 2 hours. Additional 20 .2 g (0.15 m/m) of sulfuryl chloride is added to take the reaction to completion. Gas chromatography of the reaction medium shows: 84.98% 2,6-dichloro-4-trif1uoromethylaniline; 14.28% trichlorotrifluoromethylaniline and 0.33% high retention signal.
Reaction medium on treatment and fractionation gave 0.809 m of 2,6-dichloro-4- trifluoromethylaniline, in 94% yield on 2-chlor-4-trifluoromethylaniline.
I claim :
1. A novel process for the preparation of polyhalogenated p-trifluoromethylaniline derivatives which are useful as an intermediate for the synthesis of agrochemicals comprising reacting a compound of the formula (I)
Wherein:
R'l is chlorine or bromine
R2 and R4 may be the same or different, are chosen from hydrogen, hydrocarbon chains and halogens;
R3 is chosen from groups which are electron attracting through an inductive effect rather than a mesomeric effect;
a) with ammonia in the presence of a polar solvent under pressure and at elevated temperature ranging between 200 to 300°C and at a pressure of 20 to 50 kg/cm2 to form substituted p-trifluoromethylaniline; and
b) reacting substituted p-trifluoromethylaniline formed in step (a) with halogenating agents to form polyhalogenated p-trifluoromethylaniline,
2. A novel process for the synthesis of polyhalogenated p-trifluoromethylaniline according to claim 1 wherein R1 is chlorine.
3. A novel process for the synthesis of polyhalogenated p- trifluoromethylaniline according to claim 1 wherein the said elevated temperature is 240 to 250°C.
4. A novel process for the synthesis of polyhalogenated p-trifluoromethylaniline according to claim 1 wherein the reaction is conducted at a pressure of 20 to 50 kg/cm2.
5. A novel process for the synthesis of polyhalogenated p- trifluoromethylaniline according to claim 1 wherein the reaction is performed in the presence of an alkali metal halides.
6. A novel process for the synthesis of polyhalogenated p- trifluoromethylaniline according to claim 1 wherein the said alkali metal halide is potassium fluoride.
7. A novel process for the synthesis of polyhalogenated p-trifluoromethylaniline according to claim 1 wherein the said electron attracting groups are psedohalogens or perfluoroalkyl groups.
8. A novel process for the synthesis of polyhalogenated p-trifluoromethylaniline according to claim 7 wherein R3 is a perfluoroalkyl group.
9. A novel process for the synthesis of polyhalogenated p- trifluoromethylaniline according to claim 8 wherein R3 is trifluoromethyl.
10. A novel process for the synthesis of polyhalogenated p-trifluoromethylaniline according to claim 1 wherein the amine used for amination is anhydrous ammonia.
11. A novel process for the synthesis of polyhalogenated p- trifluoromethylaniline according to claim 1 wherein the halogenating agents are chlorine, sulfuryl chloride, thionyl chloride, phosphorus pentachloride (PCI5), mixture of phosphorus trichloride and chlorine (PCI3+CI2), etc.
12. A novel process for the synthesis of polyhalogenated p-trifluoromethylaniline according to claim 1 wherein the said polyhalogenated p-trifluoromethyfamfine is 2,6-dichloro-4-trifluoromethylaniline.
