FIELD OF INVENTION:
The present invention relates to a process for preparation and purification of 4-heptafluoroisopropyl-2-methyl aniline.
BACKGROUND OF THE INVENTION:
Perfluoroalkylanilines work as a valuable starting materials for preparing agrochemicals. Known process for the preparation of 4-heptafluoroisopropyl-2-methyl aniline includes the following process:
European patent EP0936212 discloses a process, which involves introducing heptafluoroisopropyl group by replacing the halogen atom of a halogenated nitrobenzene in the presence of metallic copper and then reducing the nitro group into amino group. This process is industrially disadvantageous because the previous introduction of halogen to an appropriate position of nitrobenzene is necessary. Excess of copper is required for the reaction and further uie reaction temperature is unfavorably high.
European patents EP-A 206951 and FR-A 2660923 describes the preparation of some perfluoroalkylanilines by reacting aniline with perfluoroalkyl iodide or bromide in aprotic solvents, either in the presence of metals and sulphur dioxide (EP-A 206951 and FR-A 2660923) or in the presence of alkali metal dithionite (EP-A 298803). The disadvantage of these processes is that they give poor to moderate yield.
EP 1006102 discloses a process for preparation of 4-heptafluoroisopropyl-2-methyl aniline by reacting ortho toluidine with heptafluoroisopropyl iodide in a biphasic system in the presence of alkali metal dithionite and phase transfer catalyst. However, the heptafluoroisopropyl iodide is not only expensive, but also, as a consequence of their high molecular weight, causes low atom economy.
EP 1418169 describes a process for the preparation of 4-heptafluoroisopropyl-2-methyl aniline by reacting ortho toluidine with heptafluoroisopropyl bromide in a biphasic system in the presence of alkali metal dithionite and phase transfer catalyst. This process is not economic due to the poor yield.
Thus, there arise a need to develop a new economic process for the preparation of 4-heptafluoroisopropyl-2-methyl aniline that involves direct synthesis of 4-heptafluoroisopropyl-2-
methyl aniline in a good yield in the absence of phase transfer catalyst
OBJECTIVE OF THE PRESENT INVENTION:
An object of the present invention is to provide an industrially feasible process for the preparation of 4-heptafluoroisopropyl-2-methyl aniline in absence of any phase transfer catalyst.
Another object of the present invention is to provide a cost effective process for the preparation of 4-heptafluoroisopropyl-2-methyl aniline.
Still another object of the present invention is to provide a process with out any effluent load.
Yet another object of the present invention is to provide a high purity product by the purification of 4-heptafluoroisopropyl-2-methyl aniline by precipitation of the salt.
SUMMARY OF THE INVENTION:
The present invention provides an industrially feasible process for the preparation of 4-heptafluoroisopropyl-2-methyl aniline by the reaction of ortho toluidine with heptafluoroisopropyl bromide in a homogeneous mixture of a polar aprotic solvent or in mixture of polar aprotic solvent and water in presence of reducing agent as reaction initiator at a lower temperature to provide product in a good yield in the absence of any phase transfer catalyst. The reducing agent is added to the reaction in one portion or in multiple portions. Organic amine is used as base to neutralize hydrogen bromide gas evolved during the course of reaction maintaining pH below 5.0. Further the process also involves the purification of crude product by the selective precipitation of salt of 4-heptafluoroisopropyl-2-methyl aniline with organic or inorganic acid followed by hydrolysis with a base.
STATEMENT OF THE INVENTION:
Accordingly, the present invention provides a process for preparation and purification of 4-heptafluoroisopropyl-2-methyl aniline comprising the steps of:
(a) reacting ortho toluidine with heptafluoro isopropyl bromide in a homogeneous mixture of a polar aprotic solvent and water;
(b) cooling the reaction mixture obtained in step (a);
(c) adding a reducing agent to the cold reaction mixture obtained in step (b);
(d) adding an organic amine to the reaction mixture obtained in step (c) to neutralize
evolved HBr;
(e) boiling off the reaction mixture obtained in step (d) to obtain a crude product;
(f) purifying the crude product obtained in step (e) by selective precipitation of the salt with
organic or inorganic acid in the presence of a solvent followed by hydrolysis with a base to obtain pure 4-heptafluoroisopropyl-2-methyl aniline.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention provide an industrially feasible process for the preparation and purification of 4-heptafluoroisopropyl-2-methyl aniline by the reaction of ortho toluidine with heptafluoro isopropyl bromide in a homogeneous mixture of a polar aprotic solvent and water in absence of a phase transfer catalyst. 4-heptafluoroisopropyl-2-methyl aniline is formed by reacting ortho toluidine with heptafluoro isopropyl bromide ranging from 0.9 to 1.1 mole equivalent of the ortho toluidine in a homogeneous mixture of a polar aprotic solvent selected from the group consisting of acetonitrile, tetrahydrofuran, monoglyme, diglyme, dimethylformamide and dioxane. The percent ratio of the polar aprotic solvent and water ranges from 40- 90% : 60-10% by volume, preferably 70- 90%: 30-10% by volume and more preferably 80-90% : 20-10% by volume. The reaction mixture obtained is cooled to 10°C.
A reducing agent selected from dithionous acid salt or mixture of zinc dust and sodium hydrogen sulphite or mixture of zinc dust and sodium metabisulphite or sodium hydroxymethylsulfinate is added to the reaction mixture in one portion or in multiple portions to the cold reaction mixture. The quantity of dithionous acid salt can be used from 0.1 to 2.0-mole equivalent of ortho-toluidine. The quantity of Zinc dust used ranges from 0.1 to 2.0-mole equivalent of ortho toluidine. The quantity of sodium hydrogen sulphite used ranges from 0.2 to 4.0-mole equivalent of ortho toluidine. The quantity of sodium metabisulphite is used in the range of 0.1 to 2.0-mole equivalent of ortho toluidine. The quantity of sodium hydroxymethylsulfinate used ranges from 0.2 to 4.0-mole equivalent of ortho toluidine. The mole ratio of sodium hydrogen sulphite to zinc in the reducing mixture is from 1.5 to 2.5. The mole ratio of sodium metabisulphite to zinc in the reducing mixture is
from 0.75 to 1.25.
After the reduction, an organic amine such as methylamine ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, butylamine, tributylamine, pyridine, isopropyl amine tetramethylguanidine and N,N-dimethylaniline is added as a base, ranging from 0.6 to 1.25 mole equivalent of ortho-toluidine in one portion or in parts to the reaction mixture to neutralize the evolved HBr maintaining the pH below 5. The mixture is then boiled, to obtain crude 4-heptafluoroisopropyl-2-methyl aniline. The reaaion is conduaed at a reaction temperature ranging from -10°C to 100°C, preferably at temperature ranging from -10°C to 40°C. The time period for the reaaion ranges from 30 minutes to 25 hours.
The crude product is purified by seleaive precipitation of the salt of the produa with inorganic or organic acids seleaed from aliphatic or aromatic, carboxylic and sulphonic acid. The aliphatic or aromatic, carboxylic acids are seleaed from halogen substituted acetic acids such as chloroacetic acid, fluoroacetic acid, bromo acetic acid, trichloroacetic acid, dichloroacetic acid, difluoroacetic acid, cholrodifluoroacetic acid, trifluoroacetic acid and nitro acetic acid. Aliphatic or aromatic sulphide acids are selected from methyl sulphonic acid and para-toluene sulphonic acid or inorganic acid seleaed from hydrogen halides, halogen oxy acids, sulphur oxy acids and nitrogen oxy acids.
The seleaive precipitation can be carried out efficiently in a solvent or a mixture of solvents having Snyder polarity index 1 to 4, preferably 2.25 to 2.75. Some solvents that can be used for selective precipitation are benzene, toluene, xylene, chlorobenzene, dichlorobenzene, carbon tetrachloride, chloroform, dichloromethane, methyl tert-butyl ether, diethyl ether, di-isopropyl ether and ethylene chloride. A mixture of solvents can also be prepared by mixing two or more solvents of different polarity index to get a suitable medium having polarity index 1 to 4. Low polarity index solvent like n-pentane, n-hexane, n-heptane, isooctane cyclohexane can be mixed with high polarity index solvents like ethanol, methanol, n-propanol, ethylacetate, isopropanol, dioxane, tetrahydrofuran and acetonitrile. The aforementioned solvents can also be used in preparing the suitable mixture for seleaive precipitation. The pure 4-heptafluoroisopropyl-2-methyl aniline can be obtained by hydrolysis of the salt with a base such as dry ammonia, aqueous ammonia, aqueous alkali metal hydroxide or alkaline earth metal hydroxide.
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.
Example 1
Charged ortho toluidine (10.7 gms, 0.1 mole), heptafluoroisopropyl bromide (24.9 gms, 0.1 mole), water (20 ml) and acetonitrile (80 ml) in a 250 ml round bottom flask equipped with condenser and temperature sensor. Cooled the round bottom flask using ice bam to 10°C . A mixture of zinc dust (1.6g .025 mole) and sodium hydrogen sulphite (5.2g, 0.05 mole) is added to the cold reaction mixture. The evolved HBr is neutralized by slow addition of triethylamine maintaining me pH below 5.0. The progress of reaction is monitored by Gas Chromatography. At the end of reaction, heptafluoroisopropyl bromide disappear almost completely and almost 10% w/w unreacted ortho toluidine remains in the reaction mixture. The reaction mixture is boiled off to recover the acetonitrile. The residue separated in to two layers. The organic layer is washed with IM HCl (20ml) followed by 20 ml water. Obtained 23.5 gm crude product of 90% w/w purity (77% yield). Obtained 17.9 gm pure 4-heptafluoroisopropyl-2-methyl aniline (purity 99.9 %w/w) by hydrolysis of hydrochloride salt prepared by the selective precipitation from hexane/tert butylmethyl ether by the reaction of crude product and dry HCl.
Example 2
The reaction is conducted in the same manner as in example 1 except that excess heptafluoroisopropyl bromide (31 gms, 0.125 mole) is charged. At die end of reaction starting materials disappear almost completely. Obtained 27 gms crude product of 87% w/w purity (85% yield). Obtained 20.6 gms pure 4-heptafluoroisopropyl-2-methyl aniline (purity 99.9 %w/w) by hydrolysis of trifluoroacetate salt prepared by the selective precipitation from hexane/tert butylmethyl ether by the reaction of crude product and trifluoroacetic acid.
ADVANTAGES:
1. The process involves preparation of 4-heptafluoroisopropyl-2-methyl aniline in single-phase reaction system prepared in the absence of phase transfer catalyst.
2. The process provides improved yield.
3. The process provides highly pure 4-heptafluoroisopropyl-2-methyl aniline.
4. The process is cost effective.
5. The purification of 4-heptafluoroisopropyl-2-methyl aniline is carried out by selective precipitation and crystallization of salt with acid followed by hydrolysis.
6. No effluent load is obtained.

We Claim:
1. A process for preparation and purification of 4-heptafluoroisopropyl-2-methyl aniline
comprising the steps of:
(a) reacting ortho toluidine with heptafluoro isopropyl bromide in a homogeneous mixture of a polar aprotic solvent and water;
(b) cooling the reaction mixture obtained in step (a);
(c) adding a reducing agent to the cold reaction mixture obtained in step (b);
(d) adding an organic amine to the reaction mixture obtained in step (c) to neutralize evolved HBr;
(e) boiling off the reaction mixture obtained in step (d) to obtain a crude product;
(f) purifying the crude product obtained in step (e) by selective precipitation of the salt with organic or inorganic acid in the presence of a solvent followed by hydrolysis with a base to obtain pure 4-heptafluoroisopropyl-2-methyl aniline.

2. The process as claimed in claim 1, wherein the amount of heptafluoro isopropyl bromide ranges from 0.9 to 1.25 mole equivalent of the ortho toluidine.
3. The process as claimed in claim 1, wherein the polar aprotic solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, monoglyme, diglyme, dimethylformamide and dioxane.
4. The process as claimed in claim 1, wherein the percent ratio of the polar aprotic solvent and water ranges from 40- 90% : 60-10% by volume, preferably 70- 90%: 30-10% by volume and more preferably 80-90% : 20-10% by volume.
5. The process as claimed in claim 1, wherein the reducing agent is selected from dithionous acid salt, mixture of zinc dust and sodium hydrogen sulphite or mixture of zinc dust and sodium metabisulphite or sodium hydroxymethylsulfinate.
6. The process as claimed in claim 1, wherein the amount of reducing agent ranges from 0.1 to 2 mole equivalent of ortho-toluidine, added to the reaction mixture in one portion or in multiple portions.
7. The process as claimed in claim 1, wherein the organic amine is selected from the group consisting of methylamine ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, butylamine, tributylamine, pyridine, isopropyl amine tetramethylguanidine and N,N-dimethylaniline.
8. The process as claimed in claim 1, wherein the amount of organic amine ranges from 0.6 to 1.25 mole equivalent of ortho-toluidine, added in one portion or in parts.
9. The process as claimed in claim 1, wherein the reaction is conducted at a temperature ranging from -10°C to 100°C in the reaction mixture, preferably at temperature ranging from -10°C to 40°C.
10. The process as claimed in claim 1, wherein the reaction is conducted at pH below 5.0.
11. The process as claimed in claim 1, wherein the reaction time ranges from 30 minutes to 25 hours.
12. The process as claimed in claim 1, wherein the organic acid is selected from a group consisting of aliphatic carboxylic acid, aromatic carboxylic acid, aliphatic sulphonic acid and aromatic sulphonic acid.
13. The process as claimed in claim 12, wherein the aliphatic carboxylic acid is selected from the group consisting of chloroacetic acid, fluoroacetic acid, bromo acetic acid, trichloroacetic acid, dichloroacetic acid, difluoroacetic acid, cholrodifluoroacetic acid, trifluoroacetic acid and nitro acetic acid, the aliphatic sulphonic acid is chlorosulphonic acid and methyl sulphonic acid and aromatic sulphonic acid is para-toluene sulphonic acid.
14. The process as claimed in claim 1, wherein the inorganic acid is selected from the group consisting of hydrogen halides, halogen oxy acids, sulphur oxy acids and nitrogen oxy acids.
15. The process as claimed in claim 1, wherein the base is selected from dry ammonia, aqueous ammonia, aqueous alkali metal hydroxide or alkaline earth metal hydroxide.
16. The process as claimed in claim 1, wherein the solvent used for selective precipitation have Snyder polarity index in the range of 1 to 4 and preferably ranging from 2.25 to 2.75.
17. The process as claimed in claim 16, wherein the solvent is selected from benzene, toluene, xylene, chlorobenzene, dichlorobenzene, carbon tetrachloride, chloroform, dichloromethane, methyl tert-butyl ether, diethyl ether, di-isopropyl ether and ethylene chloride or a mixture of solvents selected from the group consisting of n-pentane, n-hexane, n-heptane, isooctane cyclohexane, ethanol, methanol, n-propanol, ethylacetate, isopropanol, dioxane, tetrahydrofuran and acetonitrile.
18. A process for preparation and purification of 4-heptafluoroisopropyl-2-methyl aniline substantially as herein described in the specification with reference to the foregoing examples.