EP3898574A1

EP3898574A1 - Process for preparing substituted anilines

Info

Publication number: EP3898574A1
Application number: EP19816767.8A
Authority: EP
Inventors: Andreas REMBIAK; Florian ERVER; Günter Hömberger
Original assignee: Bayer AG
Current assignee: Elanco Animal Health GmbH
Priority date: 2018-12-20
Filing date: 2019-12-12
Publication date: 2021-10-27
Also published as: WO2020126819A1; IL284128A; US20220048847A1; MX2021007511A; BR112021009727A2; TW202039415A; CN113227035A; KR20210105932A; CA3123956A1; JP2022514304A

Abstract

The present invention relates to a process for preparing compounds of the formula (I), starting from compounds of the formula (II), wherein R¹, R², R³ and R^3' are defined according to the invention.

Description

Process for the preparation of substituted anilines

The present invention relates to a process for the preparation of compounds of the formula (I)

(I), starting from compounds of the formula (II)

(II), wherein R ¹ , R ² , R ³ and R ^{3 have} the meanings described below.

A possible process for the preparation of compounds of the formula (I) or their precursors is described, for example, in EP1380568 and WO2016 / 174052. The preparation is carried out by perfluoroalkylation in the para position of anilines which are already substituted in the ortho and meto position. The processes described have the disadvantage that, depending on the substitution, the products are obtained in fluctuating, sometimes only moderate yields, or can be obtained in good yields exclusively by means of very waste-prone Fenton oxidation. In addition, the compounds of formula (I) have to be prepared in multi-stage processes. Further possible processes for the preparation of compounds of the formula (I) are also described in WO2016 / 174052 and also in US2010 / 0204504, EP2319830 and EP2325165. In a two-stage process, perfluoroalkylated anilines, which can optionally also be substituted in the ortho position, are first prepared and isolated in the para position. These can then be halogenated in a further step in the meta or in the meta and orf / zo position to give compounds of the formula (I). A disadvantage of the processes described is in particular the need to isolate the perfluoroalkylated intermediates. On the one hand, this makes a complex, two-stage process with a higher amount of energy, time and waste necessary. In addition, because of their structure, the intermediates tend to decompose through polymerization and thus have only limited stability in concentrated form. All processes described in the prior art also have the disadvantage that they are carried out in solvents which are undesirable for industrial processes, such as dimethylformamide, dichloromethane or chloroform. Substituted anilines of the formula (I) are of great importance as a building block for the synthesis of new agrochemical active ingredients. The object of the present invention was therefore to provide a process for the preparation of compounds of the general formula (I) which can be used on an industrial scale and inexpensively and avoids the disadvantages described above. It is also desirable to obtain the compounds of formula (I) in high yield and high purity, so that the target compounds preferably do not have to be subjected to any further, possibly complex purification.

This object was achieved according to the invention by a process for the preparation of compounds of the formula (I)

wherein

R ^{1 represents} chlorine or bromine,

R ^{2 represents} Ci-C ₄ haloalkyl and

R ^{3 represents} cyano, halogen, optionally substituted by halogen or CN Ci-C ₄ alkyl or represents optionally substituted by halogen Ci-C ₄ alkoxy, starting from compounds of formula (II),

wherein R ^{3 'represents} hydrogen, cyano, halogen, optionally substituted with halogen or CN-substituted C ₁ -C ₄ -, alkyl or optionally substituted with halogen Ci-C ₄ alkoxy, comprising the following steps (1) and (2)

(1) reacting compounds of the formula (II) with compounds of the formula R ² -Y,

where Y is iodine or bromine, to compounds of the formula (III), wherein R ² and R ^{3 'have} the meanings given above and

(2) chlorination or bromination of compounds of the formula (III) with a chlorination or brominating agent to give compounds of the formula (I),

characterized in that the compounds of formula (III) are not isolated from the reaction mixture of step (1) before step (2).

The process according to the invention has the advantage over the process described above that the desired compounds of the formula (I) are obtained in high yields and purities and at the same time the waste streams and process steps are reduced and the overall process can thus be operated more simply, more efficiently and therefore more cost-effectively. In addition, the method according to the invention enables the continuous avoidance of solvents which are undesirable in industrial processes in all steps.

The preferred embodiments described below relate, if applicable, to all formulas described herein.

The term flalogen in the context of this invention preferably stands for chlorine, fluorine, bromine or iodine, particularly preferably for chlorine, fluorine or bromine.

In a preferred embodiment of the invention, R ² represents C ¹ -C ⁴ -alkyl substituted with fluorine.

Is particularly preferred

R ² for perfluoro-Ci-C ₃ alkyl (CF ₃ , C ₂ F ₅ or C ₃ F ₇ (n- or iso-propyl)).

R ² very particularly preferably represents Fleptafluoro-iso-propyl.

In a further preferred embodiment

R ³ for a substituent selected from CI, Br, F, Ci-C3-alkyl, C1-C3-alkyl substituted with flalogen, Ci-C3-alkoxy or Ci-C3-alkoxy substituted with flalogen. In a particularly preferred embodiment

R ³ for CI, Br, Ci-C ₃ alkyl or fluorine-substituted Ci-C ₃ alkyl, Ci-C ₃ alkoxy or fluorine-substituted Ci-C ₃ alkoxy.

R ³ very particularly preferably represents CI, trifluoromethyl, trifluoromethoxy or difluoromethoxy.

In a particularly advantageous embodiment of the invention, R ¹ and R ³ both represent chlorine or bromine, particularly preferably chlorine.

In a further particularly advantageous embodiment of the invention

R ¹ for chlorine or bromine,

R ² for perfluoro-Ci-C ₃ alkyl and

R ³ represents halogen, Ci-C ₃ alkyl or fluoro substituted Ci-C ₃ alkyl, Ci-C ₃ alkoxy or fluoro substituted Ci-C ₃ alkoxy.

In a very particularly advantageous embodiment of the invention, R ^{1 represents} chlorine or bromine,

R ² for heptafluoro-iso-propyl and

R ³ for CI, trifluoromethyl, trifluoromethoxy or difluoromethoxy.

In a further preferred embodiment

R ^{3 '} for a substituent selected from hydrogen, CI, Br, F, Ci-C ₃ alkyl, halogen-substituted Ci-C ₃ alkyl, Ci-C ₃ alkoxy or halogen-substituted Ci-C ₃ alkoxy.

In a particularly preferred embodiment R ^{3 '} for hydrogen, CI, Br, Ci-C3-alkyl or Ci-C3-alkyl substituted with fluorine, Ci-C3-alkoxy or Ci-C3-alkoxy substituted with fluorine.

Is very particularly preferred

R ^{3 '} for hydrogen, CI, trifluoromethyl, trifluoromethoxy or difluoromethoxy.

The anilines of the formula (II) used as starting products are commercially available.

The following anilines of the formula (II) are preferred: aniline,

2-methylaniline,

2-chloroaniline,

2-trifluoromethylaniline,

2-trifluoromethoxyaniline and

2-difluoromethoxyaniline.

The following compounds are particularly preferred: aniline,

2-chloroaniline,

2-trifluoromethylaniline,

2-trifluoromethoxyaniline and

2-difluoromethoxyaniline.

The following compounds of the formula (I) preferably result from these compounds:

2,6-dichloro-4- (l, 1, 1, 2,3,3,3-heptafluoropropan-2-yl) aniline,

2-chloro-6-methyl-4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) aniline,

2-bromo-6-methyl-4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) aniline,

2-chloro-4- (l, 1, 1, 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethyl) aniline,

2-chloro-4- (l, 1, 1, 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethoxy) aniline, 2-chloro-6- (difluoromethoxy) -4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) aniline,

2-bromo-4- (1,1,1,3,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethyl) aniline and

2-bromo-4- (1,1,1,3,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethoxy) aniline;

Are particularly preferred

2,6-dichloro-4- (l, 1, 1, 2,3,3,3-heptafluoropropan-2-yl) aniline,

2-chloro-4- (l, 1, 1, 2,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethoxy) aniline,

2-chloro-6- (difluoromethoxy) -4- (1,1,1, 2,3,3,3-heptafluoropropan-2-yl) aniline and

2-bromo-4- (1,1,1,3,3,3,3-heptafluoropropan-2-yl) -6- (trifluoromethoxy) aniline.

Unless otherwise defined elsewhere, the term “alkyl”, according to the invention, either alone or in combination with other terms, such as haloalkyl, for the purposes of the present invention, preferably a residue of a saturated, aliphatic hydrocarbon group having 1 to 12 1 to 6 and particularly preferably 1 to 4 carbon atoms understood, which can be branched or unbranched. Examples of C1-C12 alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl.

The term “alkoxy”, either alone or in combination with other terms, such as, for example, haloalkoxy, is understood here to mean an O-alkyl radical, the term “alkyl” having the meaning given above.

Unless otherwise defined elsewhere, the term “aryl” is understood according to the invention to mean an aromatic radical having 6 to 14 carbon atoms, preferably phenyl, naphthyl, anthryl or phenanthrenyl, particularly preferably phenyl.

Residues substituted by halogen, for example haloalkyl (= haloalkyl), are halogenated one or more times to the maximum possible number of substituents. In the case of multiple halogenation, the halogen atoms can be the same or different. If nothing else is mentioned, optionally substituted radicals can be mono- or polysubstituted, and in the case of multiple substitutions the substituents can be the same or different. The general or priority areas listed above apply accordingly to the overall process. These definitions can be combined with one another, i.e. also between the respective preferred areas.

Processes in which a combination of the meanings and ranges listed above as preferred are preferably used according to the invention.

Processes in which a combination of the meanings and ranges listed above as particularly preferred are particularly preferably used according to the invention.

Processes in which a combination of the meanings and ranges listed above as very particularly preferred are used with particular preference in accordance with the invention.

According to the invention, methods are used in particular in which there is a combination of the meanings and ranges specified above as particularly.

Processes highlighted according to the invention are used in which there is a combination of the meanings and ranges listed above as highlighted.

Procedure description

Step 1):

According to the invention, the compounds of the formula (II) are converted into compounds of the formula (III) using compounds of the formula R ² -Y, where Y is iodine or bromine,

(III), where R ² and R ^{3 have} the meanings given above, implemented.

According to the invention, preferably between 0.9 and 2.0 equivalents, particularly preferably between 1.0 and 1.8 equivalents, very particularly preferably between 1.0 and 1.5 equivalents, based on the total amount of the compounds of the formula ( II), of the compounds of the formula R ² -Y. The use of larger surpluses is chemically possible, but is not economically feasible.

The compounds of the formula R ² -Y are preferably in pure form or as a solution in the solvent preferred for the reaction in concentrations of 40-95% by weight, particularly preferably in Pure form or as a solution in a preferred organic solvent in concentrations of 60-90% by weight and very particularly preferably in pure form or as a solution in a preferred solvent in concentrations of 60-85% by weight.

In a preferred embodiment of the invention

Y for iodine.

Preferred compounds of the formula R ² -Y are, in particular, pentafluoroiodethane, heptafluoro-1-iodopropane, heptafluoro-2-iodopropane and heptafluoro-2-bromopropane, and heptafluoro-2-iodopropane and heptafluoro-2-bromo are particularly preferred -propane, heptafluoro-2-iodo-propane is very particularly preferred.

The compounds of the formula (III) in step (1) can be prepared, for example, from the corresponding anilines in analogy to the methods described in JP 2012/153635 A and CN 106748807 A.

A suitable organic solvent is preferably used in step (1). Suitable solvents are, for example: aromatic or aliphatic halogenated hydrocarbons, in particular aromatic or aliphatic chlorinated hydrocarbons, such as tetrachloroethane, dichloropropane, dichloromethane, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichlorethylene, pentachloroethane, difluorobenzene, chlorobenzene, bromobenzene, bromobenzene, bromobenzene, bromobenzene, bromobenzene, bromobenzene, bromide and trichlorobenzene; Esters, especially methyl acetate, ethyl acetate, propyl (n- and iso) acetate or butyl acetate; Ethers, especially tetrahydrofuran (THF), 2-methyl-THF, cyclopentyl methyl ether, tert-butyl methyl ether or diethyl ether; optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbons, in particular pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, ligroin, benzene, toluene, anisole, xylene, mesitylene or nitrobenzene; and nitriles, especially acetonitrile or propionitrile.

Preferred solvents are acetonitrile, methyl acetate, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, THF and methyl-THF. Acetonitrile, tert-butyl methyl ether, ethyl acetate and isopropyl acetate are very particularly preferred.

The solvents can be used alone or in combination of two or more.

Step (1) is preferably carried out in a two-phase system composed of one of the above-mentioned organic solvents and water according to the invention, for example in a ratio of 5: 1 to 1: 5 (organic solvent water), particularly preferably in a ratio of 5: 1 to 1: 2, very particularly preferably in a ratio of 2: 1 to 1: 2. Step (1) is preferably carried out in the presence of a phase transfer catalyst, which is preferably selected from quaternary ammonium salts (in particular tetra-n-butylammonium hydrogen sulfate, chloride or bromide) and tetraalkyl-phosphonium salts (in particular tri-n-butyl (tetradecyl ) butylphosphonium chloride or trihexyl-tetradecylphosphonium chloride). The phase transfer catalyst is particularly preferably selected from tetra-n-butylammonium hydrogen sulfate or tri-n-hexyl-tetradecylphosphonium chloride.

According to the invention, the phase transfer catalyst is preferably used in a proportion between 0.005 and 0.06 equivalents, particularly preferably in a proportion between 0.01 and 0.05 equivalents, based on the total amount of compound (II) used. The catalyst is preferably used in pure form.

Step (1) is preferably carried out in the presence of a reducing agent, for example sodium or potassium dithionite, particularly preferably sodium dithionite. According to the invention, preference is given to using between 0.9 and 2.0 equivalents, particularly preferably between 1.0 and 1.8 equivalents, very particularly preferably between 1.0 and 1.5 equivalents, based on the total amount of compound (II) used. , used. The reducing agent is preferably used in pure form.

Step (1) is preferably carried out at an ambient temperature in the range from -10 ° C. to 80 ° C., particularly preferably in the range from 0 ° C. to 60 ° C., very particularly preferably in the range from -5 ° C. to 40 ° C.

Step (1) is preferably carried out in the range of normal pressure (1013 hPa), e.g. B. in the range of 300 hPa to 5000 hPa or from 500 hPa to 2000 hPa, preferably as in the range of 1013 hPa ± 200 hPa.

The reaction time of the pefluoroalkylation in step (1) is preferably in the range from 3 to 48 hours, particularly preferably between 3 and 24 hours, very particularly preferably between 6 and 24 hours.

The compounds R ² -Y are preferably added by continuous dosing over a period of 2 to 10 hours, particularly preferably between 3 and 6 hours.

Step (1) is preferably carried out under pH control. The pH of the reaction solution is preferably kept in a pH range between 3 and 7, particularly preferably in a pH range between 4 and 7. The pH control is preferably carried out both during the addition of the compounds R ² -Y and during the subsequent reaction over the entire reaction time and by adding a suitable base known to the person skilled in the art, for example as a pure substance or aqueous solutions of (earth) Alkali carbonates, (earth) alkali hydrogen carbonates or (earth) alkali hydroxides. If appropriate, it can be advantageous to adjust the pH of the reaction mixture before starting to meter in the compounds R ² -Y by adding a suitable acid which is well known to the person skilled in the art, for example, carboxylic acids, such as acetic acid or propionic acid, mineral acids, such as hydrochloric acid or sulfuric acid, or sulfonic acids, such as methanesulfonic acid, to a preferred pH, in particular a pH of 4 to 5.

Step (2), chlorination / bromination:

According to the invention, the compounds of formula (III) are reacted with a chlorinating or brominating agent to give compounds of formula (I).

In the context of this description of the invention, the term halogenating agent is used to represent chlorinating or brominating agents.

In the following section of the description relating to step (2), the term halogen represents chlorine or bromine.

Suitable halogenating agents are those known to those skilled in the art, such as e.g. Chlorine, bromine, an inorganic salt containing chlorine or bromine, or an organic molecule containing chlorine or bromine, in which the binding of an organic radical to the halogen atom is polarized, so that the chlorine or bromine atom has a partial support is positive thread, such as V-halosuccinimides, 1,3-dihalogen-5-5-dimethylhydantoins or halogenated cyanuric acids (organic halogenating compounds).

Suitable halogenating agents are preferably chlorine, bromine or organic halogenating agents, which are particularly preferably selected from V-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), 1,3-dichloro-5-5-dimethylhydantoin (DCDMH), 1,3 -Dibromo-5-5-dimethylhydantoin (DBDMH), l, 3,5-trichlor-l, 3,5-triazine-2,4,6-trione (TCCA), l, 3,5-tribromo-l, 3rd , 5-triazine-2,4,6-trione or 1,3-dibromo-1,3,5-triazine-2,4,6-trione. The halogenating compounds are very particularly preferably selected from chlorine, bromine, 1,3-dichloro-5-5-dimethylhydantoin (DCDMH), 1,3-dibromo-5-5-dimethylhydantoin (DBDMH), 1,3,5-trichloro -l, 3,5-triazine-2,4,6-trione,

1.3.5-tribromo-l, 3,5-triazine-2,4,6-trione or 1,3-dibromo-l, 3,5-triazine-2,4,6-trione, chlorine being particularly preferred, Bromine, l, 3-dibromo-5-5-dimethylhydantoin (DBDMH) or l, 3,5-trichloro-l, 3,5-triazine

2.4.6-trione (TCCA).

The halogenating agents can be used alone or in combination of two or more, as long as the compounds used carry the same halogen.

According to the invention, the halogenating agent can be used in a proportion between 1.0 and 3.0 equivalents (mono-halogen compounds) or between 0.5 and 1.5 equivalents (dihalogen compounds) or 0.3 and 1.0 equivalents (trihalogen compounds) and preferably between 1.0 and 2.5 equivalents (monohalogen compounds) or between 0.5 and 0.8 equivalents (dihalogen compounds) or between 0.33 and 0.75 equivalents (Trihalogen compounds), based on the total amount of compound (III) used. If necessary, an excess of the halogenating agent can be neutralized after complete conversion determined by HPLC ^a by adding a reducing agent which is well known to the person skilled in the art, for example (earth) alkali metal sulfites, (earth) alkali metal dithionites or (earth) alkali metal thiosulfates. The reducing agents can preferably be used as a pure substance or as an aqueous solution, for example as a saturated aqueous solution.

According to the invention, the halogenating agent can be present in pure form as a solid or as a suspension or solution in a suitable organic solvent which is inert under the reaction conditions, in particular in the solvent selected for the reaction, preferably in a concentration of 40-90% by weight, particularly preferably in a Concentration of 60-95% by weight. Suitable organic solvents are in particular the preferred solvents mentioned below for step (2).

Special catalysts are not necessary for step (2). It may be advantageous to use acids in catalytic amounts for activation, but this is not absolutely necessary in the reactions claimed here. This is particularly advantageous when using organic chlorinating agents such as V-chlorosuccinimide (NCS) and 1,3-dichloro-5-5-dimethylhydantoin (DCDMH).

Suitable acids could preferably be selected from the mineral acids familiar to the person skilled in the art, for example sulfuric acid, hydrochloric acid and hydrofluoric acid, sulfonic acids, for example methanesulfonic acid, trifluoromethanesulfonic acid and 4-toluenesulfonic acid, carboxylic acids, for example trifluoroacetic acid and trichloroacetic acid and Lewis acids, for example iron (III) - and Scandium (III) trifluoromethanesulfonate.

The reaction is preferably carried out in a temperature range from -78 to 200 ° C., particularly preferably at temperatures between -20 to 100 ° C. and very particularly preferably between 0 ° C. and 50 ° C.

The reaction can be carried out under elevated or reduced pressure. However, it is preferably carried out under normal pressure, for example in the range from 1013 hPa + 300 hPa, or in the range from 1013 hPa + 100 hPa, or in the range from 1013 hPa ± 50 hPa. Step (2) is preferably carried out in a suitable organic solvent. Suitable diluents or solvents for carrying out step (2) are in principle all organic solvents which are inert under the specific reaction conditions.

Examples include: aromatic or aliphatic halogenated hydrocarbons, in particular aromatic or aliphatic chlorinated hydrocarbons, such as tetrachloroethane, dichloropropane, dichloromethane, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichlorethylene, pentachloroethane, difluorobenzene, 1, 2-chlorobenzene, bromobenzene, 1, 2-chlorobenzene, bromobenzene, bromobenzene Chlorotoluene or trichlorobenzene; Nitriles, especially acetonitrile, propionitrile, butyronitrile, isobutyronitrile, benzonitrile or m-chlorobenzonitrile; optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbons, in particular pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, ligroin or nitrobenzene; Esters, especially methyl, ethyl, isopropyl, butyl, isobutyl acetate, dimethyl, dibutyl or ethylene carbonate; Amides, especially N, N-dimethylformamide (DMF), N, N-dipropyl-formamide, N, N-dibutyl-formamide (DBF), N, N-dimethylacetamide (DMAC) or N-methyl-pyrrolidine (NMP) ; aliphatic or cycloaliphatic ethers, especially 1,2-dimethoxyethane (DME), diglyme, tetrahydrofuran (THF), 2-methyl-THF, 1,4-dioxane, tert-butyl methyl ether or cyclopentyl methyl ether and carboxylic acids, especially acetic acid, n-propanoic acid or / ? - Butanoic acid.

Preferred diluents or solvents are aromatic or aliphatic halogenated hydrocarbons, in particular chlorobenzene, dichlorobenzene, dichloromethane, chloroform, 1,2-dichloroethane or carbon tetrachloride; Esters, especially ethyl acetate, isopropyl acetate and butyl acetate; Amides, especially DMF, DMAC and NMP; Ethers, especially tetrahydrofuran (THF), 2-methyl-THF, tert-butyl methyl ether or cyclopentyl methyl ether; Nitriles, especially acetonitrile or propionitrile or carboxylic acids, especially acetic acid or n-propanoic acid.

In a particularly preferred embodiment, the solvent is selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, THF, 2-methyl-THF or acetonitrile. Acetonitrile, tert-butyl methyl ether, ethyl acetate and isopropyl acetate are very particularly preferred.

The solvents can be used alone or in combination of two or more.

The duration of the halogenation of the compounds of the formula (III) is preferably in the range from 0.5 h to 10 h, particularly preferably in the range from 0.25 h to 5 h. A longer reaction time is possible, but not useful from an economic point of view.

The halogenating agent can be added to the other reactants in one portion or by metering over a longer period of time. Under certain circumstances, it may also be advantageous to convert a solution of the compound (III) into a solution or suspension in a solvent mentioned for step (2) of the halogenating agent in a preferred solvent for step (2). The duration of the metering can be in a preferred range from 0.5 to 6 hours, particularly preferably from 1 to 4 hours. Longer dosing times are also possible from a technical point of view, but are not sensible from an economic point of view.

The addition or metering is preferably carried out in a temperature range from -78 to 200 ° C., particularly preferably at temperatures between -20 to 100 ° C. and very particularly preferably between 0 ° C. and 50 ° C. In an advantageous embodiment, the temperature at which metering is carried out corresponds to the reaction temperature.

In a particularly advantageous embodiment of the invention, the same organic solvent is used in step (1) and step (2).

In the context of this embodiment of the invention, the solvent in both steps is preferably selected from the group of the esters, the ethers or the nitriles, particularly preferably the solvent is selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, THF, methyl-THF and acetonitrile . Acetonitrile, tert-butyl methyl ether, ethyl acetate and isopropyl acetate are very particularly preferred.

The solvents mentioned can be used alone or in combination of two or more.

The process according to the invention is characterized in that the compounds of the formula (III) are not isolated from the reaction mixture from step (1) before step (2).

The term “isolating” in the context of the present invention means a complete separation of the compounds of the formula (III) from the reaction mixture, that is to say, for example, from all solvents and salts by means of separation processes which are generally known to the person skilled in the art. In addition, “isolating” in the sense of the present invention means that after step (1) and before step (2), the entire organic solvent from step (1) is never removed.

The compounds of the formula (III) from step (1) are preferably used directly as a solution in the organic solvent of step (1) in step (2).

In the process according to the invention, reaction volumes in the form of solids, liquids or suspensions, for example in the form of solid, dissolved or suspended halogenating agents, or solvents (the same solvent as in the first step or a further solvent) can be added during the reaction sequence. In particular, the addition of acids or bases and the partial or complete removal of aqueous constituents of the reaction mixture between reaction steps (1) and (2) are possible. It is further preferred according to the invention that less than 30% by volume, particularly preferably less than 20% by volume and very particularly preferably less than 10% by volume, of the organic solvent of step (1), based on the volume of organic solvent used Start of step (2) is removed.

It is particularly advantageous if no organic solvent is actively removed after step (1). The active removal of the organic solvent is generally the removal of the organic solvent by means of distillation, if appropriate with thermal action on the reaction mixture, under normal or reduced conditions! Pressure understood.

In a further preferred embodiment of the invention, step (1) and step (2) take place in the same reaction vessel. In this case, the person skilled in the art will choose from the start a reaction vessel which can hold all the volumes for reaction (1) and (2).

In other words, it is preferred that the reaction sequence is a telescoped reaction in one or more vessels, preferably one vessel.

The method according to the invention preferably consists of steps (1) and (2).

Optionally, step (1) and / or step (2) can also be carried out several times, for example two or three times, in the same reaction vessel without further working up. The reaction mixture from step (1), for example after complete conversion according to HPLC ^{a, can} again be mixed with the compound of the formula (II) and a reducing agent according to the invention and by metering in a compound R ² -Y under pH control to give a compound of the formula (III) be implemented. This process can be repeated again or the reaction mixture can be treated further according to the invention. After complete conversion according to HPLC ^{a, the} reaction mixture from step (2) can again be mixed with compound of the formula (III) and then further converted into compounds of the formula (I) by adding a halogenating agent according to the invention.

The work-up and isolation of the compounds (I) can, after complete reaction, take place, for. B. by removing the solvent, washing with water and extraction with a suitable organic solvent and separation of the organic phase and removal of the solvent under reduced pressure. The residue can also be subjected to vacuum distillation at 0.05-1 mbar using a canned column and crystallization in a solvent which is well known to those skilled in the art. Scheme 1: Halogenating agent

Step 2)

(II) (III)

Scheme 1 gives an overall schematic representation of the method according to the invention with both steps. Reaction conditions and reactants are selected in accordance with the preferred and preferred embodiments of the invention described above. All variables in formulas (I), (II), (III) and R ² -Y are defined as described above.

A preferred embodiment of the method according to the invention is the following:

The compounds of formula (II) are placed in a mixture of an organic solvent and water and after adding a phase transfer catalyst according to the invention, for example tetra-n-butylammonium hydrogen sulfate or tri-n-hexyl (tetradecyl) phosphonium chloride, and a reducing agent according to the invention, for. B. sodium dithionite, preferably at -10 ° C to 80 ° C, particularly preferably 0 ° C to 60 ° C for 2 h to 10 h, after which the pH before starting the metering by a suitable acid, for example acetic acid 4 to 5 was set, with a perfluoroalkylating agent according to the invention, e.g. B. heptafluoro-2-iodo-propane. The pH of the reaction mixture is preferably kept in a range from 3 to 7 during the entire reaction period by adding a suitable base, as a solid or as an aqueous solution, for example 40% by weight aqueous potassium carbonate solution. After preferably 3 h to 48 h, the aqueous phase is separated off, the organic phase optionally with water or aqueous hydrochloric acid, for. B. 5 wt.% Or 25 wt.%, Washed and the organic phase, containing compounds of formula (III) preferably at -20 ° C to 100 ° C, particularly preferably at 0 ° C to 50 ° C, with a halogenating agent , e.g. B. as a solid or solution in an organic solvent according to the invention, preferably over 0.5 h to 6 h. After conversion is complete (HPLC ^a ), any excess halogenating agent which may be present is neutralized by adding a reducing agent, for example as a pure substance or aqueous solution, and the compounds of the formula (I) are isolated. (Steps (1) and (2))

In a further advantageous embodiment, the compounds of the formula (II) are introduced in a mixture of an organic solvent and water and, after adding a phase transfer catalyst according to the invention, for. B. tetra-n-butylammonium hydrogen sulfate or tri-n-hexyl (tetradecyl) phosphonium chloride, and a reducing agent according to the invention, for. B. Sodium dithionite, preferably at -10 ° C. to 80 ° C., particularly preferably 0 ° C. to 60 ° C., for 2 hours to 10 hours, after which the pH may be reduced to 4 to 4 to by means of a suitable acid, for example acetic acid, before metering begins 5 was set, with a perfluoroalkylating agent according to the invention, for example heptafluoro-2-iodopropane. The pH of the reaction mixture is preferably kept in a range from 3 to 7 during the entire reaction period by adding a suitable base, as a solid or as an aqueous solution, for example 40% by weight aqueous potassium carbonate solution. After preferably 3 h to 48 h after adding a further portion of the compound of formula (II) and a reducing agent according to the invention, for. B. sodium dithionite, preferably at -10 ° C to 80 ° C, particularly preferably 0 ° C to 60 ° C over 2 h to 10 h with a perfluoroalkylating agent according to the invention, for example heptafluoro-2-iodo-propane. The pH of the reaction mixture is preferably kept in a range from 3 to 7 during the entire reaction period by adding a suitable base, as a solid or as an aqueous solution, for example aqueous potassium carbonate solution. After preferably 3 h to 48 h, the process can optionally be repeated again or the aqueous phase separated, the organic phase optionally washed with water or aqueous hydrochloric acid, for example 5% by weight or 25% by weight, and the organic phase containing compounds of Formula (III) preferably at -20 ° C to 100 ° C, particularly preferably at 0 ° C to 50 ° C, with a halogenating agent, for. B. as a solid or solution in an organic solvent according to the invention, preferably over 0.5 h to 6 h. After conversion is complete (HPLC ^a ), any excess halogenating agent which may be present is neutralized by adding a reducing agent, for example as a pure substance or aqueous solution, and the compounds of the formula (I) are isolated. (Step (1) (double) and (2))

A particularly preferred embodiment of the method according to the invention is the following:

The compounds of the formula (II) are initially introduced into a mixture of ethyl acetate and water and, after addition of tetra-n-butylammonium hydrogen sulfate and sodium dithionite, at 0 ° C. to 60 ° C., after which the pH, if necessary, before starting the dosing with acetic acid 4 to 5 was set, heptafluoro-2-iodopropane was added over 3 h to 6 h. The pH of the reaction mixture is kept in a range from 4 to 7 during the entire metering and reaction period by adding a 40% by weight aqueous potassium carbonate solution. After preferably 3 h to 24 h, the aqueous phase is separated off, the organic phase optionally with water or aqueous hydrochloric acid, for example. 5% by weight or 25% by weight, and the organic phase, containing compounds of the formula (III), preferably at 0 ° C. to 50 ° C., with chlorine or 1,3,5-trichloro-1,3,5- triazine-2,4,6-trione (TCCA) (chlorination) or bromine or 1,3-dibromo-5-5-dimethylhydantoin (DBDMH) (bromination) over 1 h to 4 h. After complete conversion (HPLC ^a ), any excess halogenating agent which may be present is neutralized by the addition of sodium sulfite, as a pure substance or as an aqueous solution, and the compounds of the formula (I) are isolated. (Steps (1) and (2)) Examples

The following examples explain the process according to the invention in more detail without restricting the invention to these.

Methods:

The NMR data of the examples are listed in classic form (d values, multiplet splitting, number of H atoms).

The solvent and the frequency at which the NMR spectrum was recorded are given in each case. ^a) HPLC (High Performance Liquid Chromatography) on a phase reversal column (C18). Agilent 1100 LC system; Phenomex Prodigy 100 x 4mm ODS3; Eluent A: acetonitrile (0.25mL / L) l; Eluent B: water (0.25mL TFA / L); linear gradient from 5% acetonitrile to 95% acetonitrile in 7.00 min, then 95% acetonitrile for a further 1.00 min; Oven temperature 40 ° C; Flow: 2.0 mL / min.

Step 1: preparation of the compounds of formula (III)

4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] aniline (III-la)

60.0 g (0.64 mol, 1.0 eq) of aniline were placed in 450 mL water and ethyl acetate and successively with 4.5 g (13.0 mmol, 0.02 eq) tetra-n-butylammonium hydrogen sulfate and 144.0 g (0.70 mol, 1.1 eq, 85% by weight ) Sodium dithionite added. 214.0 g (0.70 mol, 1.1 eq) of heptafluoro-2-iodopropane were metered in at room temperature over 3 h and the pH was kept at 6.0-7.0 during the metering by adding 40% by weight of aqueous K2CO3. After the addition was complete, the mixture was stirred for a further 3 h at approx. 21 ° C. at the same pH, then the phases were separated and the organic phase was washed with a solution of 40 ml of 20% by weight NaCl and 2.5% by weight HCl. A conversion of 98% to the desired product was detected by means of HPLC ^a) . The organic phase was then used in step (2) without further treatment.

An analytical sample of the pure compound was obtained after isolation by removing the solvent by distillation.

'H NMR (CDC1 ₃ , 400 MHz) d (ppm) = 7.35 (d, J = 8.9 Hz, 2H), 6.72 (d, / = 7.7 Hz, 2H), 3.91 (br s, 2H). 4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (III-lb)

7.5 g (79.8 mmol, 1.0 eq) of aniline were placed in 60 mL water and ethyl acetate each and successively with 0.1 g (0.4 mmol, 0.005 eq) tetra-n-butylammonium hydrogen sulfate and 17.9 g (87.8 mol, 1.1 eq, 85% by weight ) Sodium dithionite added. 26.8 g (87.8 mmol, 1.1 eq) of heptafluoro-2-iodo-propane, diluted with 8 mL of ethyl acetate, were metered in over 4 h at 20-22 ° C., and the pH was metered in during the metering by adding 40% by weight of aqueous K2CO3 kept at 6.0-7.0. After the addition was complete, the mixture was stirred for a further 1.5 h at approx. 20-22 ° C at the same pH. A conversion of 98% to the desired product was detected by means of HPLC ^a) . The phases were separated and the organic phase was washed with 75 ml of 10% by weight HCl. The organic phase was then used in step (2) without further treatment.

'H NMR (CDCI3, 400 MHz) d (ppm) = 7.35 (d, J = 8.9 Hz, 2H), 6.72 (d, / = 7.7 Hz, 2H), 3.91 (br s, 2H).

4- [1,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] aniline (III-lc)

7.5 g (79.8 mmol, E0 eq) of aniline were placed in 60 mL water and ethyl acetate and successively with 1.4 g (1.6 mmol, 0.02 eq) tri-n-butyl (tetradecyl) phosphonium chloride and 17.9 g (87.8 mol, 1.1 eq, 85% by weight) of sodium dithionite. 26.8 g (87.8 mmol, 1.1 eq) of heptafluoro-2-iodo-propane, diluted with 8 ml of ethyl acetate, were metered in over 3 h at 20-22 ° C., and the pH was metered in during the metering by adding 40% by weight of aqueous K2CO3 kept at 6.0-7.0. After the addition was complete, the mixture was stirred for a further 4 h at approx. 20-22 ° C at the same pH. A conversion of 96% to the desired product was detected by means of HPLC ^a) . The phases were separated and the organic phase was washed with 75 ml of 10% by weight HCl. The organic phase was then used in step (2) without further treatment.

'H NMR (CDCL, 400 MHz) d (ppm) = 7.35 (d, J = 8.9 Hz, 2H), 6.72 (d, / = 7.7 Hz, 2H), 3.91 (br s, 2H).

4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] aniline (III-Id)

15.0 g (150.0 mmol, 1.0 eq) of aniline were placed in 120 mL water and isopropyl acetate and successively with 3.3 g (9.7 mmol, 0.06 eq) tetra-n-butylammonium hydrogen sulfate and 35.9 g (170.0 mol, 1.1 eq, 85% by weight ) Sodium dithionite added. 53.51 g (170.0 mmol, 1.1 eq) of heptafluoro-2-iodo-propane were metered in at 20-22 ° C. over 3 h and the pH during the metering by adding 40% by weight aqueous K2CO3 kept at 6.0-7.0. After the addition was complete, the mixture was stirred for a further 5 h at approx. 20-22 ° C at the same pH. A conversion of 94% to the desired product was detected by means of HPLC ^a) . The phases were separated and the organic phase was then used in step (2) without further treatment.

4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] aniline (III-le)

30.0 g (0.31 mol, 1.0 eq) of aniline were placed in 240 mL water and ethyl acetate and successively with 2.2 g (6.2 mmol, 0.02 eq) tetra-n-butylammonium hydrogen sulfate and 71.9 g (0.35 mol, E l eq, 85 wt. %) Sodium dithionite added. 90.0 g (0.35 mol, 1.1 eq) of heptafluoro-2-bromopropane were metered in via a gas inlet tube at -5 ° C. over 3 h and the pH was kept at 6.0-7.0 during the metering by adding 40% by weight of aqueous K2CO3 . After the addition was complete, the mixture was stirred for a further 3 h at approx. -5 ° C at the same pH and then warmed to 20 ° C overnight. A conversion of 96% to the desired product was detected by means of HPLC ^a) . The phases were separated, the organic phase washed with a solution of 40 mL 20% by weight NaCl and 2.5% by weight HCl. The organic phase was then used in step (2) without further treatment.

2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (III-2a)

10.0 g (78.3 mmol, 1.0 eq) 2-chloroaniline were placed in 100 mL water and ethyl acetate and successively with 0.5 g (1.6 mmol, 0.02 eq) tetra-n-butylammonium hydrogen sulfate and 19.3 g (94.0 mmol, 1.2 eq, 85 wt .%) Sodium dithionite added. The pH was adjusted to 5 by adding 1.25 g (20.8 mmol, 0.3 eq) of acetic acid. 26.3 g (86.2 mmol, 1.1 eq) of heptafluoro-2-iodo-propane, diluted with 6 mL of ethyl acetate, were metered in over 3 h at 20-22 ° C., and the pH was metered in during the metering by adding 40% by weight of aqueous K2CO3 kept at 4.0-5.0. After the addition was complete, the mixture was stirred for a further 4 h at approx. 20-22 ° C at the same pH. A conversion of 94% to the desired product was detected by means of HPLC ^a) . The phases were separated, the organic Phase washed with 75 mL 10 wt.% HCl. The organic phase was then used in step (2) without further treatment.

'H NMR (CDC1 ₃ , 400 MHz) d (ppm) = 7.47 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.13 (br s, 2H).

2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (III-2b)

40.0 g (0.31 mol, 1.0 eq) 2 -chloraniline were placed in 400 mL water and ethyl acetate and successively with 2.2 g (6.3 mmol, 0.02 eq) tetra-n-butylammonium hydrogen sulfate and 77.1 g (0.38 mmol, 1.2 eq, 85 wt .%) Sodium dithionite added. The pH was adjusted to 5 by adding 4.8 g (79.9 mmol, 0.25 eq) of acetic acid. 114.8 g (0.38 mol, 1.2 eq) of heptafluoro-2-iodopropane, diluted with 26 mL of ethyl acetate, were metered in over 3 h at 20-22 ° C., and the pH was metered in during the metering by adding 40% by weight of aqueous K ₂ CO _{3 kept} at 4.0-5.0. After the addition was complete, the mixture was stirred for a further 4 h at approx. 20-22 ° C at the same pH. A conversion of 99% to the desired product was detected by means of HPLC ^a) . The phases were separated, the organic phase washed with 300 mL 10% by weight HCl. The organic phase was then used in step (2) without further treatment.

'H NMR (CDCI ₃ , 400 MHz) d (ppm) = 7.47 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.13 (br s, 2H).

2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (III-2c)

10.0 g (78.3 mmol, 1.0 eq) of 2-chloroaniline were placed in 100 mL water and tert-butyl methyl ether and successively with 0.5 g (1.6 mmol, 0.02 eq) tetra-n-butylammonium hydrogen sulfate and 19.3 g (94.0 mmol, 1.2 eq, 85% by weight) of sodium dithionite. The pH was adjusted to 5 by adding 1.0 g (16.6 mmol, 0.2 eq) of acetic acid. 26.3 g (86.2 mmol, 1.1 eq) of heptafluoro-2-iodo-propane, diluted with 6 ml of ethyl acetate, were metered in over 3 h at 20-22 ° C., and the pH was metered in during the metering by adding 40% by weight of aqueous K ₂ CO _{3 kept} at 4.0-5.0. After the addition was complete, the mixture was stirred for a further 4 h at approx. 20-22 ° C at the same pH. A conversion of 82% to the desired product was detected by means of HPLC ^a) . The phases were separated and the organic phase was washed with 75 ml of 10% by weight HCl. The organic phase was then used in step (2) without further treatment. An analytical sample of the pure compound was obtained after isolation by removal of the solvent by distillation.

2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (III-2d)

15.0 g (0.12 mol, E0 eq) 2-chloroaniline were placed in 120 mL water and 90 mL ethyl acetate and successively with 0.8 g (2.4 mmol, 0.02 eq) tetra-n-butylammonium hydrogen sulfate and 28.9 g (0.14 mmol, 1.2 eq, 85% by weight) of sodium dithionite. The pH was adjusted to 5 by adding 1.9 g (31.6 mmol, 0.3 eq) of acetic acid. 40.1 g (0.13 mmol, 1.1 eq) of heptafluoro-2-iodopropane, diluted with 7 ml of ethyl acetate, were metered in over 3 h at 20-22 ° C., and the pH was metered in during the metering by adding 40% by weight of water K2CO3 kept at 4.0-5.0. After the addition was complete, the mixture was stirred for a further 4 h at approx. 20-22 ° C at the same pH. A conversion of 94% to the desired product was detected by means of HPLC ^a) . The phases were separated and the organic phase was washed with 75 ml of 10% by weight HCl. The organic phase was then used in step (2) without further treatment.

'H NMR (CDCL, 400 MHz) d (ppm) = 7.47 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.13 (br s , 2H).

4- [1,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -2- (trifluoromethoxy) aniline (III-3a)

40.0 g (0.22 mol, 1.0 eq) 2-trifluoromethoxyaniline were placed in 400 mL water and 250 mL ethyl acetate and successively with 1.55 g (4.4 mmol, 0.02 eq) tetra-n-butylammonium hydrogen sulfate and 68.0 g (0.33 mol, 1.5 eq) sodium dithionite transferred. 100.2 g (0.33 mol, 1.5 eq) of heptafluoro-2-iodopropane are metered in at room temperature over 2.5 h and the pH is kept at 4.0-5.0 during the metering by adding 40% by weight of aqueous K2CO3. After the addition was complete, the mixture was stirred at about 21 ° C. for 1 h, then the phases were separated. The organic phase was diluted with 100 ml of n-heptane, then washed in each case with 250 ml of 20% by weight HCl, 250 ml of saturated NaCl solution and 250 ml of water. The organic phase was then used in step (2) without further treatment.

An analytical sample of the pure compound was obtained after isolation by removing the solvent by distillation. 'H NMR (DMSO-d _ö , 400 MHz) d (ppm) = 7.51 (d, / = 9.0 Hz, 1H), 7.44 (s, 1H), 7.43 (d, J = 9.0 Hz, 1H), 6.38 (br s, 2H).

4- [1,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -2- (trifluoromethoxy) aniline (III-3b)

40.0 g (0.22 mol, 1.0 eq) 2-trifluoromethoxyaniline were placed in 600 mL water and 360 mL ethyl acetate and successively with 4.6 g (13.5 mmol, 0.06 eq) tetra-n-butylammonium hydrogen sulfate and 59.0 g (0.29 mol, 0.4 eq, 85 % By weight) sodium dithionite. 100.2 g (0.34 mol, 1.5 eq) of heptafluoro-2-iodopropane, dissolved in 20 g of ethyl acetate, were metered in over 1.5 h at 25 ° C., and the pH was metered in during metering by adding 40% by weight of aqueous K2CO3 kept at 4.0-4.9. After the addition was complete, the mixture was stirred for a further 2 h at approx. 21 ° C. at the same pH. Using HPLC ^a) , a conversion of> 95% to the desired product was detected. Then again 40.0 g (0.22 mol, 1.0 eq) 2-trifluoromethoxyaniline and 59.0 g (0.29 mol, 0.4 eq, 85% by weight) sodium dithionite were added and then 100.2 g (0.34 mol, 1.5 eq) Heptafluoro-2-iodo-propane, dissolved in 20 g of ethyl acetate, was metered in and the pH was kept at 4.0-4.9 during the metering by adding 40% by weight of aqueous K2CO3 and again at about 21 ° C. for 2 h stirred the same pH. A conversion of> 97% to the desired product was detected by means of HPLC ^a) . The process was repeated once more with 40.0 g (0.22 mol, 1.0 eq) 2-trifluoromethoxyaniline, 59.0 g (0.29 mol, 0.4 eq, 85% by weight) sodium dithionite and 100.2 g (0.34 mol, 1.5 eq) heptafluoro-2-iodine -propane, dissolved in 20 g ethyl acetate, repeated over 1.5 h at a pH of 4.0 - 4.9, then stirred at a pH of 4.0 to 4.9 for 3 h. A conversion of> 97% to the desired product was detected by means of HPLC ^a) . The phases were separated and the organic phase after the addition of 400 ml of n-heptane was washed twice with 300 ml of 20% by weight HCl and once with 300 ml of saturated, aqueous NaCl solution. The organic phase was then used in step (2) without further treatment.

'H NMR (DMSO-d _ö , 400 MHz) d (ppm) = 7.51 (d, / = 9.0 Hz, 1H), 7.44 (s, 1H), 7.43 (d, J = 9.0 Hz, 1H), 6.38 (br s, 2H).

The following 4-perfluoroalkylanilines of the general formula (III) could be prepared analogously to Examples (III-la) and (III-Ib):

4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] -2- (trifluoromethyl) aniline (III-4)

'H NMR (DMSO-d ₆ , 400 MHz) d (ppm) = 7.51 (d, J = 9.0 Hz, 1H), 7.43 (br s, 1H), 7.01 (d, J = 9.0 Hz, 1H), 6.38 (br s, 2H). 2-ethyl-4- [1,2,2,2-tetrafluoro-1 - (trifluoromethyl) ethyl] aniline (III-5)

'H NMR (CDCL, 400 MHz) d (ppm) = 7.63 (d, J = 8.3 Hz, 1H), 7.53 (br s, 1H), 7.43 (d, / = 8.3 Hz, 1H), 2.92 (q , / = 7.6 Hz, 2H), 1.35 (t, / = 7.6 Hz, 3H).

Step (2): preparation of the compounds of the formula (I)

2,6-dichloro-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] aniline (I-la)

180.0 g (0.64 mol, 1.0 eq) 4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (III-1) as a solution in 450 mL ethyl acetate from step (1) (example (III - 1 a)), were diluted with a further 150 mL ethyl acetate and, after adding 100 mL water at 0-5 ° C for 5 h, 96.0 g (128.0 mmol, 2.0 eq) chlorine gas was added. The phases were then separated and the aqueous phase was extracted in succession with a mixture of 100 ml of ethyl acetate and 50 ml of n-heptane and a mixture of 50 ml of ethyl acetate and 25 ml of n-heptane. The combined organic phases were washed twice with 100 mL 20% by weight NaCl solution and the product obtained as a red-brown oil after removal of the solvent: yield 200.0 g (95% of theory).

'H NMR (CDCL, 400 MHz) d (ppm) = 7.41 (s, 2H), 4.76 (br s, 2H).

2,6-dichloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (I-lb)

41.5 g (0.15 mol, 1.0 eq) 4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (III-1) as a solution in 120 mL isopropyl acetate from step (1) (example (III-Id)), 27.0 g (0.38 mol, 2.5 eq) of chlorine gas were added at 0-5 ° C over 4 h. Then 40 mL ice water was slowly added, the phases separated, the aqueous phase extracted with 40 mL isopropyl acetate. The combined organic phases were washed twice with 40 mL 20% by weight NaCl solution and the product was obtained as a red-brown oil after removal of the solvent: yield 42.5 g (86% of theory).

'H NMR (CDCL, 400 MHz) d (ppm) = 7.41 (s, 2H), 4.76 (br s, 2H).

2,6-dichloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (I-lc)

20.8 g (79.7 mmol, 1.0 eq) 4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (III-1) as a solution in 50 mL ethyl acetate from step (1) (example (III -lc)), were over 2 h at 0-5 ° C with a solution of 13.1 g (55.7 mmol, 0.7 eq) l, 3,5-trichloro-l, 3,5-triazine-2,4,6- trion (TCCA) in 40 mL ethyl acetate. The reaction was heated to 20-25 ° C over 2.5 h and stirred at this temperature for 1 h. The resulting solid was filtered off, 10 ml of aqueous, saturated Na2S03 solution and 30 ml of water were added to the clear solution. After separating the phases, wash the organic phase with 20 mL each Water and 20 mL saturated NaCl solution, removal of the solvent under reduced pressure gave the product as a light brown-red oil which solidifies on cooling: yield 26.1 g (89.9% of theory).

'H NMR (CDC1 ₃ , 400 MHz) d (ppm) = 7.41 (s, 2H), 4.76 (br s, 2H).

2,6-dichloro-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] aniline (I-Id)

46.3 g (0.16 mol, 1.0 eq) 2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (III-2) as a solution in 100 mL ethyl acetate from step (1) (Example (III-2a)) were with a solution of

12.9 g (54.8 mmol, 0.35 eq) l, 3,5-trichlor-l, 3,5-triazine-2,4,6-trione (TCCA) in 50 mL ethyl acetate. The reaction was heated to 20-25 ° C over 2.5 h and stirred at this temperature for 1 h. The resulting solvent was filtered off, the clear solution was mixed with 40 ml of aqueous, saturated NaiSCL solution and 120 ml of water. After separating the phases, washing the organic phase with 80 mL water and 80 mL saturated NaCl solution, removing the solvent under reduced pressure, the product was obtained as a light, brown-red oil, which solidifies on cooling: yield 50.7 g (88.6 % of theory).

'H NMR (CDCI3, 400 MHz) d (ppm) = 7.41 (s, 2H), 4.76 (br s, 2H).

2,6-dichloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (I-le)

23.1 g (78.3 mol, 1.0 eq) 2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (III-2) as a solution in 100 mL tert-butyl methyl ether from step ( 1) (Example (III-2c)), were over 2 h at 0-5 ° C to a suspension of 6.4 g (27.4 mmol, 0.35 eq) l, 3,5-trichloro-l, 3,5-triazine 2,4,6-trione (TCCA) dosed in 50 mL tert-butyl methyl ether. The reaction was heated to 20-25 ° C over 2.5 h and stirred at this temperature for 1 h. The resulting solvent was filtered off, 20 ml of aqueous, saturated NaiSCL solution and 60 ml of water were added to the clear solution. After separating the phases, washing the organic phase with 40 mL water and 40 mL saturated NaCl solution, removing the solvent under reduced pressure, the product was obtained as a reddish-brown oil: yield

20.9 g (67.7% of theory).

'H NMR (CDCI3, 400 MHz) d (ppm) = 7.41 (s, 2H), 4.76 (br s, 2H).

2,6-dichloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (I-lf)

8.8 g (29.9 mmol, 1.0 eq) 2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (III-2) as a solution in 30 mL ethyl acetate from step (1) (Example (III-2b)), 96 wt.% H2SO4 were obtained at 0-5 ° C with 0.15 g (1.5mmol, 0.05 eq) and then in portions with 3.16 g (15.7 mmol, 0.53 eq) over 1 h - Added dichloro-5,5-dimethylhydantoin (DCDMH). The ice bath was removed and the reaction at 2 h Room temperature stirred. The slightly cloudy solution was then mixed with 10 mL aqueous, saturated Na2SC> 3 solution and 30 mL water. After separating the phases, diluting the organic phase with 50 mL ethyl acetate and then washing the organic phase with 30 mL water, and removing the solvent under reduced pressure, the product was obtained as a beige-orange solid: yield 9.7 g (98% of theory ).

'H NMR (CDCL, 400 MHz) d (ppm) = 7.41 (s, 2H), 4.76 (br s, 2H).

2,6-dichloro-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] aniline (I-Ig)

20.0 g (33.9 mmol, 1.0 eq) 2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] aniline (III-2) as a solution in 40 mL ethyl acetate from step (1) (Example (III-2a)), 4.86 g (35.6 mmol, 1.05 eq) / V-chlorosuccinimide (NCS) were added in one portion at room temperature. The mixture was then heated to 50 ° C. and stirred at this temperature for 3 h. The slightly cloudy solution was then mixed with 10 mL aqueous, saturated NaiSCL solution and 30 mL water. After dilution of the organic phase with 40 mL ethyl acetate, subsequent separation of the phases and removal of the solvent under reduced pressure, the product was obtained as a beige-orange solid: yield 10.4 g (93% of theory).

'H NMR (CDCL, 400 MHz) d (ppm) = 7.41 (s, 2H), 4.76 (br s, 2H).

2-bromo-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6- (trifluoromethoxy) aniline (1-2)

A solution of 234.6 g (0.68 mol, 1.0 eq) of 4- [1,2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -2- (trifluoromethoxy) aniline (III-3) as a solution in 360 mL ethyl acetate and 400 mL n-heptane from step (1) (example (III-3b)), was added after adding 200 mL water over 1 h at 25-30 ° C with a solution of 119.0 g (0.75 mol, 1.1 eq) bromine added in 40 mL ethyl acetate. During the entire metering time, the pH was adjusted to 6-8 by adding aqueous, 53% by weight K ^ CCL solution. Complete conversion to the desired product was detected by means of HPLC ^a) . The phases were separated, the organic phase was washed with 400 ml of aqueous 10% by weight sodium thiosulfate solution, dried and the solvent was removed at 40 ° C. under reduced pressure. The product was obtained as a dark red oil: yield 248.0 g (86% of theory).

Ή NMR (CDC1 ₃ , 400 MHz) d (ppm) = 7.59 (s, 1H), 7.34 (s, 1H), 4.65 (br s, 2H). 2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6- (trifluoromethyl) aniline (1-3)

4.0 g (12.1 mmol, 1.0 eq) 4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -2- (trifluoromethyl) aniline (III-4) as a solution in 10 mL ethyl acetate from step ( 1), were over 2 h at 0-5 ° C with a solution of 0.99 g (4.3 mmol, 0.35 eq) l, 3,5-trichloro-l, 3,5-triazine-2,4,6-trione ( TCCA) in 5 mL ethyl acetate. The reaction was heated to 20-25 ° C over 2.5 h and stirred at this temperature for 1 h. The resulting solid was filtered off, 10 ml of aqueous, saturated NaiSCL solution and 10 ml of water were added to the clear solution. After separating the phases, washing the organic phase with 15 mL water and 15 mL saturated NaCl solution, removing the solvent under reduced pressure, the product was obtained as a slightly yellow oil: yield 3.16 g (71% of theory).

'H NMR (DMSO-d _ö , 400 MHz) d (ppm) = 7.72 (br s, 1H), 7.46 (br s, 1H), 6.56 (br s, 2H).

2-bromo-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6- (trifluoromethyl) aniline (I-4a)

20.0 g (60.8 mmol, 1.0 eq) 4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -2- (trifluoromethyl) aniline (III-4) as a solution in 40 mL ethyl acetate from step ( 1), were over 1 h at 20-25 ° C to a suspension of 9.3 g (31.9 mmol, 0.53 eq) l, 3-dibromo-5,5-dimethylhydantoin (DBDMH) and 0.16 g (1.52 mmol, 0.025 eq) 98% by weight of H2SO4 in 100 ml of ethyl acetate. The reaction was stirred at this temperature for 30 min. After adding 25 mL aqueous, saturated NaiSCL solution and 75 mL water, the phases were separated, the organic phase was diluted with 100 mL n-heptane and washed again with 100 mL water. Removal of the solvent under reduced pressure gave the product as a reddish oil: yield 20.4 g (82% of theory).

'H NMR (DMSO-d _ö , 400 MHz) d (ppm) = 7.86 (br s, 1H), 7.50 (br s, 1H), 6.43 (br s, 2H).

2-bromo-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6- (trifluoromethyl) aniline (I-4b)

4.0 g (12.1 mmol, 1.0 eq) 4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -2- (trifluoromethyl) aniline (III-4) as a solution in 10 mL ethyl acetate from step ( 1), were metered in over 1 h at 20-25 ° C to a suspension of 1.9 g (6.4 mmol, 0.53 eq) l, 3-dibromo-5,5-dimethylhydantoin (DBDMH) in 20 mL ethyl acetate. The reaction was stirred at this temperature for 30 min. After adding 5 mL aqueous, saturated Na2S03 solution, 15 mL water and 25 mL n-heptane, the phases were separated and the organic phase was washed with 15 mL water and 15 mL aqueous, saturated NaCl solution. Removal of the solvent under reduced pressure gave the product as an orange oil: yield 4.0 g (80% of theory).

'H NMR (DMSO-d _ö , 400 MHz) d (ppm) = 7.86 (br s, 1H), 7.50 (br s, 1H), 6.43 (br s, 2H). 2-bromo-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6- (trifluoromethyl) aniline (I-4c)

4.0 g (12.1 mmol, 1.0 eq) 4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -2- (trifluoromethyl) aniline (III -4) as a solution in 10 mL ethyl acetate from step ( 1), were metered in over 1 h at 20-25 ° C. to a suspension of 2.3 g (12.7 mmol, 1.05 eq) of N-bromosuccinimide (NBS) in 20 mL of ethyl acetate. The reaction was stirred for 60 minutes at this temperature. After adding 5 mL aqueous, saturated NaiSCL solution, 15 mL water and 25 mL n-heptane, the phases were separated and the organic phase was washed with 15 mL water and 15 mL aqueous, saturated NaCl solution. Removal of the solvent under reduced pressure gave the product as an orange oil: yield 4.0 g (81% of theory).

'H NMR (DMSO-d _ö , 400 MHz) d (ppm) = 7.86 (br s, 1H), 7.50 (br s, 1H), 6.43 (br s, 2H). The following 4-perfluoroalkylanilines of the general formula (I) could be prepared analogously to Example (I-Id):

2-chloro-4- [l, 2,2,2-tetrafluoro-l- (trifluoromethyl) ethyl] -6- (trifluoromethoxy) aniline (1-5)

'H NMR (CDCL, 400 MHz) d (ppm) = 7.45 (s, 1H), 7.30 (s, 1H), 4.59 (s, 2H). 2-Chloro-6-ethyl-4- [1,2,2,2-tetrafluoro-1- (trifluoromethyl) ethyl] aniline (1-6) 'H NMR (CDCL, 400 MHz) d (ppm) = 7.43 s, 1H), 7.17 (s, 1H), 2.54 (q, / = 7.5 Hz, 2H), 1.28 (t, / = 7.5 Hz, 3H).

Claims

Claims:

1. Process for the preparation of compounds of formula (I)

where R ^{1 represents} chlorine or bromine,

R ^{2 represents} Ci-C4-haloalkyl and

R ^{3 represents} cyano, halogen, C 1 -C 4 -alkyl optionally substituted with halogen or CN or C 1 -C 4 -alkoxy optionally substituted with halogen, starting from compounds of the formula (II), wherein R ^{3 represents} hydrogen, cyano, halogen, Ci-C4-alkyl optionally substituted with halogen or CN or for Ci-C4-alkoxy optionally substituted with halogen, comprising the following steps (1) and (2)

(1) reacting compounds of the formula (II) with compounds of the formula R ² -Y, where Y is iodine or bromine, to give compounds of the formula (III), wherein R ² and R ^{3 'have} the meanings given above and

(2) chlorination or bromination of compounds of the formula (III) with a chlorinating or brominating agent to give compounds of the formula (I), characterized in that the compounds of the formula (III) are not isolated from the reaction mixture from step (1) before step (2) and that an organic solvent is used in step (1) and no organic solvent is actively removed after step (1) becomes.

2. The method according to claim 1, characterized in that the compounds of formula (III) from step (1) are used directly as a solution in the organic solvent of step (1) in step (2)

3. The method according to any one of claims 1 or 2, characterized in that step (1) and step (2) take place in the same reaction vessel.

4. The method according to any one of the preceding claims, characterized in that the chlorinating or brominating agent in step (2) is selected from chlorine, bromine, V-chlorosuccinimide (NCS), V-bromosuccinimide (NBS), 1,3-dichloro- 5-5-dimethylhydantoin (DCDMH), l, 3-dibromo-5-5-dimethylhydantoin (DBDMH), l, 3,5-trichloro-l, 3,5-triazine-2,4,6-trione, l, 3,5-tribromo-l, 3,5-triazine-2,4,6-trione or 1,3-dibromo-l, 3,5-triazine-2,4,6-trione.

5. The method according to any one of the preceding claims, characterized in that in step

(1) an organic solvent is used and this is selected from acetonitrile, methyl acetate, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, THF and methyl-THF.

6. The method according to any one of the preceding claims, characterized in that in step

(2) an organic solvent is used and this is selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, THF, 2-methyl-THF, cyclopentyl methyl ether or acetonitrile.

7. The method according to any one of the preceding claims, characterized in that the same organic solvent is used in step (1) and step (2).

8. The method according to claim 7, characterized in that the solvent is selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, THF, methyl THF and acetonitrile.

9. The method according to any one of claims 1 to 8, characterized in that R ^{2 stands} for fluorine-substituted Ci-C4-alkyl.

10. The method according to any one of claims 1 to 8, characterized in that R ^{2 is} perfluoro-Ci-C3-alkyl.

11. The method according to any one of the preceding claims, characterized in that R ³ for CI,

Br, Ci-C3-alkyl or Ci-C3-alkyl substituted with fluorine, Ci-C3-alkoxy or Ci-C3-alkoxy substituted with fluorine and R ³ for hydrogen, CI, Br, Ci-C3-alkyl or substituted with fluorine Ci-C3-alkyl, Ci-C3-alkoxy or Ci-C3-alkoxy substituted with fluorine.

12. The method according to any one of the preceding claims, characterized in that

R ¹ for chlorine or bromine,

R ² for heptafluoroisopropyl,

R ³ for chlorine, trifluoromethyl, trifluoromethoxy or difluoromethoxy and

R ^{3 represents} hydrogen, chlorine, trifluoromethyl, trifluoromethoxy or difluoromethoxy.