Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2000-11-06
2001-12-25
Siegel, Alan (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
Reexamination Certificate
active
06333434
ABSTRACT:
The present invention relates to an improved process for preparing trifluoromethylanilines starting from benzotrichlorides.
Trifluoromethylanilines are important intermediates for preparing pharmaceutically and agrochemically active compounds, for example herbicides, insecticides, infection inhibitors and disinfectants. There is therefore a need for a process for preparing trifluoromethylanilines in a simple and economical manner in industrial quantities in good yields and purities.
Existing processes for preparing trifluoromethylanilines are unsuitable for practice on an industrial scale or have other serious disadvantages.
The use of sulphur tetrafluoride for preparing trifluoromethylanilines on an industrial scale (see J. Org. Chem. 26, 1477 (1961) and 27, 1406 (1962)) is not advisable on account of its extreme toxicity.
The introduction of trifluoromethyl groups by means of sodium trifluoroacetate in the presence of stoichiometric amounts of copper(I) iodide (see J. Chem. Soc. Perk. Trans. 1, 1988, 921) requires costly reagents, and there are problems with the disposal of copper salts.
The fluorination of tribromomethylnitrobenzene with antimony trifluoride and the subsequent reduction of the resulting trifluoromethylnitrobenzene by means of tin chloride (see J. Am. Chem. Soc. 69, 2346 (1947)) likewise requires costly reagents and substantial spending on ecological measures.
The reaction of chlorobenzotrifluoride with ammonia and copper(I) chloride (see J. Org. Chem. 44, 4731 (1979)) requires drastic reaction conditions and provides only low yields.
Nitrating benzotrifluoride and reducing the nitrobenzotrifluoride obtainable provides large amounts of 3-trifluoromethylaniline (around 90%), some 2-trifluoromethylaniline (around 9%) and only little 4-trifluoromethylaniline (around 1%) (see Synthesis 11, 1087 (1992)). The situation is similar with the nitration of substituted benzotrifluorides. The only processes in existence for preparing 3-chloro-6-nitrobenzotrifluoride and 3-fluoro-6-nitrobenzotrifluoride (US-A 2,086,029) provide 3-chloro-4-nitrobenzotrifluoride and 3-fluoro-4-nitrobenzotrifluoride only “to a small extent”. Frequently, however, the 4-trifluoromethylanilines are the more wanted compounds.
Preparing trifluoromethylaniline by catalytic reduction of trifluoromethylnitrobenzene has been known for a long time (see J. Org. Chem. 26, 1477 (1964)), but, as explained above, 4-trifluoromethylnitrobenzene is not conveniently obtainable on an industrial scale.
A more recent process for preparing trifluoromethylaniline comprises reacting trichloromethylphenyl isocyanate first with anhydrous hydrofluoric acid and then with water to obtain trifluoromethylaniline hydrofluoride, from which the free aniline is released using a base (see EP-A 639 556). The starting isocyanate has to be prepared first, for example by chlorination of methylphenyl isocyanate. The particular disadvantage of this process is its many stages.
Another recent process reacts chlorobenzotrifluoride with ammonia or amine in the presence of a palladium catalyst, a cocatalyst and a strong base (see EP-A 846 676). As well as being complex, the process has the disadvantage that even an isomerically pure starting material will give rise to a product that is a mixture of isomers.
This invention now provides a process for preparing trifluoromethylanilines of the formula (I)
where
R
1
is hydrogen, fluorine, chlorine, bromine, methyl, monochloromethyl, dichloromethyl or formyl and
R
2
is hydrogen, fluorine or chlorine and for R
1
=R
2
=hydrogen the amino group is para to the trifluoromethyl group, characterized in that a benzotrichloride of the formula (II)
where
R
1
and R
2
are each as defined for the formula (I),
is nitrated and, in the nitrobenzotrichlorides thus obtainable, the trichloromethyl groups are converted into trifluoromethyl groups by reaction with anhydrous hydrofluoric acid and finally the nitro groups are reduced.
In the formulae (I) and (II) R
1
is preferably hydrogen, fluorine or chlorine and R
2
is preferably hydrogen or chlorine.
The first step of the process according to the invention, the nitration of benzotrichlorides of the formula (II), is preferably carried out using mixtures of nitric acid and sulphuric acid as nitrating agent, the sulphuric acid preferably being at least 96% strength and the nitric acid being fuming nitric acid containing around 100% HNO
3
. The nitric acid is preferably used in excess, for example 1.2 to 5 mol per mole of benzotrichloride of the formula (II). This amount is preferably 1.8 to 2.5 mol. The weight ratio of nitric acid to sulphuric acid can be for example 0.5 to 2:1. It is also possible first to add just nitric acid and then sulphuric acid. An addition of sulphuric acid without initially charging or simultaneously adding nitric acid to benzotrichlorides of the formula (II) is to be avoided.
The nitration can be carried out for example at temperatures in the range −15 to +50° C. It is preferable to use the range from −10 to +35° C. If desired, the nitration may be carried out in the presence of an inert solvent. Examples of useful solvents are dichloromethane and 1,2-dichloroethane.
The nitration can be carried out batchwise of discontinuously or else continuously, for example in a tubular reactor. The use of bundle reactors or microreactors is likewise possible.
The as-nitrated reaction mixture can be worked up, for example, by discharging it onto ice, extracting with an inert organic solvent, washing the combined extracts acid-free (for example with water and/or aqueous sodium bicarbonate solution), drying and removing the extractant.
The second step of the process according to the invention, the reaction with anhydrous hydrofluoric acid, can be carried out using the mixture of isomeric nitrobenzotrichlorides obtained in the first step. However, it is also possible first to separate the isomers, for example by distillation or crystallization, and to react isomerically pure nitrobenzotrichlorides with anhydrous hydrofluoric acid.
For example, 3 to 50 mol of anhydrous hydrofluoric acid can be used per mole of nitrobenzotrichloride, in which case the material commercially available under the name “anhydrous hydrofluoric acid” is sufficiently water-free.
The fluorination can be carried out for example at temperatures in the range 0 to 180° C. and pressures in the range 1 to 50 bar. It is preferable to fluorinate at 10 to 160° C. and 1 to 30 bar. If desired, the fluorination can be carried out in the presence of a catalyst and/or an inert solvent. The catalyst used can be for example boron trifluoride, titanium tetrachloride, antimony pentachloride or antimony pentafluoride, while dichloromethane can be used as solvent.
The anhydrous hydrofluoric acid can be charged first and the nitrobenzotrichloride added, or vice versa. It is advantageous to combine the hydrofluoric acid and the nitrobenzotrichloride at relatively low temperatures, for example, at up to 50° C., within the framework of the abovementioned temperature ranges, and then to increase the temperature. After the reaction has ended, the reaction mixture can be admixed with a suitable solvent, for example dichloromethane, and the organic phase separated off, washed with water, dried and concentrated or distilled.
The fluorination can also be carried out in the gas phase, in which case the reaction temperature can be 200 to 450° C. for example.
To prepare very isomerically pure trifluoromethylanilines of the formula (I), it is advantageous to separate the isomers at the nitrobenzotrifluoride stage. For example, this separation of isomers may be effected by final distillation or a combination of final distillation and crystallization. The final distillation is preferably carried out using such pressures that the liquid phase does not have to be heated to temperatures above 200° C. It is advantageous to carry out the final distillation at pressures in the range 50 to 150 mbar and at liquid phase temperatures in the range from 110 to 180° C. A combination of f
Baumann Käthe
Marhold Albrecht
Bayer Aktiengesellschaft
Gil Joseph C.
Henderson Richard E. L.
Siegel Alan
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