Process for the preparation of substituted anilines

Abstract

The present invention relates to a process for the preparation of a compound of formula (I) starting from a compound of formula (II), wherein R 1 , R 2 , R 3 and R 3 have the meanings described in the present invention.

Description

[0001] This invention relates to a method for preparing compounds of formula (I) starting from compounds of formula (II).

[0002]

[0003] Where R 1 R 2 R 3 and R 3' It has the meaning described below.

[0004] One possible method for preparing compounds of formula (I) or their precursors is described, for example, in EP1380568 and WO2016 / 174052. This preparation is achieved by para-perfluoroalkylation of aniline with substituted ortho and meta positions. A disadvantage of this method is that the product is obtained in only moderately varying yields in some cases (depending on the substitution), or only in good yields by Fenton oxidation, which is extremely wasteful. Furthermore, compounds of formula (I) must be prepared using a multi-stage process. Other possible methods for preparing compounds of formula (I) are also described in WO2016 / 174052, US2010 / 0204504, EP2319830, and EP2325165. In a two-step method, aniline, first perfluoroalkylated at the para position and optionally substituted at the ortho position, is prepared and isolated. It can then be halogenated at the meta position or simultaneously at the meta and ortho positions in another step to obtain compounds of formula (I). A particular drawback of the methods described is the need to separate the perfluoroalkylation intermediates. Firstly, this requires a complex two-step process with higher energy consumption, time requirements, and waste generation. Furthermore, due to the structure of the intermediates, they tend to decompose easily through polymerization, thus exhibiting only limited stability in concentrated forms. Additionally, an extra disadvantage of all the methods described in the prior art is that they are carried out in solvents (e.g., dimethylformamide, dichloromethane, or chloroform) undesirable for industrial-scale methods.

[0005] The substituted aniline of formula (I) is of great significance as a structural unit for the synthesis of novel active agricultural chemical components. Therefore, the problem addressed by this invention is to provide a method for preparing compounds of general formula (I) that can be used inexpensively on an industrial scale and avoids the aforementioned disadvantages. It is also desirable to obtain compounds of formula (I) in high yield and high purity, thereby preferably eliminating the need for any further potentially complex purification of the target compound.

[0006] According to the present invention, this problem is solved by a method for preparing a compound of formula (I).

[0007]

[0008] in

[0009] R 1 It is chlorine or bromine.

[0010] R 2 It is a C1-C4-haloalkyl group, and

[0011] R 3 It is a C1-C4-alkyl group that is cyano, halogenated, optionally halogenated, or CN-substituted, or optionally halogenated.

[0012] This method begins with the compound of formula (II).

[0013]

[0014] Where R 3' It is a C1-C4-alkyl or C1-C4-alkoxy group that is hydrogen-, cyano-, halogen-, optionally halogen-substituted or CN-substituted, and optionally halogen-substituted.

[0015] The method includes the following steps (1) and (2):

[0016] (1) Make the compound of formula (II) and formula R 2 The reaction of a compound with Y, where Y is iodine or bromine, yields a compound of formula (III).

[0017]

[0018] Where R 2 and R 3' Having the definition given above, and

[0019] (2) Chlorinate or bromine a compound of formula (III) with a chlorinating or brominating agent to obtain a compound of formula (I).

[0020] The characteristic feature is that the compound of formula (III) is not separated from the reaction mixture of step (1) before step (2).

[0021] The method of the present invention has the following advantages over the methods described above: it obtains the desired compound of formula (I) in high yield and high purity, while reducing waste streams and process steps, thus allowing the entire process to be carried out in a simpler, more efficient, and therefore cheaper manner. Furthermore, the method of the present invention completely avoids the use of undesirable solvents in industrial-scale methods throughout all steps.

[0022] The preferred embodiments described below relate to—if appropriate—all the structures described herein.

[0023] In the context of this invention, the term halogen preferably means chlorine, fluorine, bromine or iodine, more preferably chlorine, fluorine or bromine.

[0024] In a preferred embodiment of the present invention

[0025] R 2 It is a fluorine-substituted C1-C4-alkyl group.

[0026] More preferably,

[0027] R 2 It is a perfluoro-C1-C3-alkyl (CF3, C2F5 or C3F7 (n-propyl or isopropyl)).

[0028] Most preferably,

[0029] R 2 It is heptafluoroisopropyl.

[0030] In another preferred embodiment,

[0031] R 3 The substituent is selected from Cl, Br, F, C1-C3-alkyl, halogen-substituted C1-C3-alkyl, C1-C3-alkoxy or halogen-substituted C1-C3-alkoxy.

[0032] In a particularly preferred embodiment

[0033] R 3 It is a C1-C3-alkyl, C1-C3-alkoxy, or fluorine-substituted C1-C3-alkoxy group, which is Cl, Br, C1-C3-alkyl, or fluorine-substituted C1-C3-alkoxy group.

[0034] Most preferably,

[0035] R 3 It can be Cl, trifluoromethyl, trifluoromethoxy, or difluoromethoxy.

[0036] In a particularly advantageous configuration of the invention, R 1 and R 3 Both are chlorine or bromine, with chlorine being particularly preferred.

[0037] In another particularly advantageous configuration of the invention,

[0038] R 1 It is chlorine or bromine.

[0039] R 2 It is a perfluoro-C1-C3-alkyl group, and

[0040] R 3 It is a halogen, a C1-C3-alkyl, or a fluorine-substituted C1-C3-alkyl, C1-C3-alkoxy, or a fluorine-substituted C1-C3-alkoxy.

[0041] In a very particularly advantageous configuration of the invention,

[0042] R 1 It is chlorine or bromine.

[0043] R 2 It is heptafluoroisopropyl, and

[0044] R 3 It can be Cl, trifluoromethyl, trifluoromethoxy, or difluoromethoxy.

[0045] In another preferred embodiment,

[0046] R 3' It is a substituent selected from hydrogen, Cl, Br, F, C1-C3-alkyl, halogen-substituted C1-C3-alkyl, C1-C3-alkoxy or halogen-substituted C1-C3-alkoxy.

[0047] In a particularly preferred embodiment

[0048] R 3 It is a C1-C3-alkyl, C1-C3-alkoxy or fluorine-substituted C1-C3-alkoxy group, which is hydrogen, Cl, Br, C1-C3-alkyl or fluorine-substituted C1-C3-alkoxy group.

[0049] Most preferably,

[0050] R 3' It can be hydrogen, Cl, trifluoromethyl, trifluoromethoxy, or difluoromethoxy.

[0051] Aniline of formula (II) used as a starting material is commercially available.

[0052] In this paper, aniline of the following formula (II) is preferred:

[0053] aniline,

[0054] 2-Methylaniline,

[0055] 2-Chloroaniline,

[0056] 2-Trifluoromethylaniline,

[0057] 2-Trifluoromethoxyaniline, and

[0058] 2-Difluoromethoxyaniline.

[0059] The following compounds are particularly preferred in this study:

[0060] aniline,

[0061] 2-Chloroaniline,

[0062] 2-Trifluoromethylaniline,

[0063] 2-Trifluoromethoxyaniline, and

[0064] 2-Difluoromethoxyaniline.

[0065] These compounds preferably produce compounds of the following formula (I):

[0066] 2,6-Dichloro-4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)aniline,

[0067] 2-Chloro-6-methyl-4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)aniline,

[0068] 2-Bromo-6-methyl-4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)aniline,

[0069] 2-Chloro-4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)-6-(trifluoromethyl)aniline,

[0070] 2-Chloro-4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)-6-(trifluoromethoxy)aniline,

[0071] 2-Chloro-6-(difluoromethoxy)-4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)aniline,

[0072] 2-Bromo-4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)-6-(trifluoromethyl)aniline, and

[0073] 2-Bromo-4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)-6-(trifluoromethoxy)aniline.

[0074] Special Selection

[0075] 2,6-Dichloro-4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)aniline,

[0076] 2-Chloro-4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)-6-(trifluoromethyl)aniline,

[0077] 2-Chloro-4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)-6-(trifluoromethoxy)aniline,

[0078] 2-Chloro-6-(difluoromethoxy)-4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)aniline, and

[0079] 2-Bromo-4-(1,1,1,2,3,3,3-heptafluoroprop-2-yl)-6-(trifluoromethoxy)aniline.

[0080] In the context of this invention, unless otherwise defined elsewhere, the term "alkyl"—alone or in combination with other terms (e.g., haloalkyl)—is to be understood as referring to a group of saturated aliphatic hydrocarbons having 1 to 12, preferably 1 to 6, and more preferably 1 to 4 carbon atoms, and may be branched or unbranched. C1-C 12 Examples of -alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 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.

[0081] The term “alkoxy”—alone or in combination with other terms (e.g., haloalkoxy)—is to be understood in this application as referring to an O-alkyl group, wherein the term “alkyl” is as defined above.

[0082] According to the present invention, unless otherwise defined elsewhere, the term "aryl" shall be understood to mean an aromatic group having 6 to 14 carbon atoms, preferably phenyl, naphthyl, anthracene or phenanthryl, more preferably phenyl.

[0083] Halogen-substituted groups (e.g., haloalkyl groups) are monohalogenated or polyhalogenated up to the maximum possible number of substituents. In the case of polyhalogenation, the halogen atoms can be the same or different. Unless otherwise stated, the optionally substituted groups can be mono- or poly-substituted, wherein in the case of polyhalogenation, the substituents can be the same or different.

[0084] The broadly specified or preferred ranges mentioned above apply accordingly to the entire method. These definitions can be combined with each other as needed, i.e., combinations between their respective preferred ranges.

[0085] According to the present invention, it is preferred to use a method having a combination of the meanings and scopes specified above as preferred.

[0086] According to the present invention, it is particularly preferred to use a method having a combination of the meanings and scope specified above as particularly preferred.

[0087] According to the present invention, it is highly preferred to use a method having a combination of the meanings and scope specified above as highly preferred.

[0088] The present invention particularly utilizes methods having combinations of meanings and scopes specified above by the term "particularly".

[0089] The present invention specifically uses a method having a combination of meanings and scopes specified above by the term "specifically".

[0090] Method Description

[0091] Step (1):

[0092] According to the present invention, a compound of formula (II) is reacted with a compound of formula R wherein Y is iodine or bromine. 2 The reaction of compound -Y yields compound (III).

[0093]

[0094] Where R 2 and R 3' It has the definition given above.

[0095] According to the present invention, it is preferred to use 0.9 to 2.0 equivalents, more preferably 1.0 to 1.8 equivalents, and most preferably 1.0 to 1.5 equivalents of formula R herein. 2 -Y compounds, based on the total molar amount of compounds of formula (II) used. Although using a larger excess is chemically possible, it is not an economically feasible option.

[0096] In this article, the Chinese formula R 2 The compound of -Y is used in pure form, or in solution form in a preferred solvent for reaction at a concentration of 40-95% by weight, more preferably in pure form or in solution form in any preferred organic solvent at a concentration of 60-90% by weight, and most preferably in pure form or in solution form in a preferred solvent at a concentration of 60-85% by weight.

[0097] In a preferred embodiment of the present invention

[0098] Y represents iodine.

[0099] Preferred formula R 2 The compounds of -Y are particularly pentafluoroiodoethane, heptafluoro-1-iodopropane, heptafluoro-2-iodopropane and heptafluoro-2-bromopropane, with heptafluoro-2-iodopropane and heptafluoro-2-bromopropane being especially preferred, and heptafluoro-2-iodopropane being very particularly preferred.

[0100] The compound of formula (III) can be prepared in step (1) from the corresponding aniline, for example, similar to the methods described in JP 2012 / 153635 A and CN 106748807 A.

[0101] In step (1), a suitable organic solvent is preferably used. Suitable solvents include, for example: aromatic or aliphatic halogenated hydrocarbons, especially aromatic or aliphatic chlorinated hydrocarbons, such as tetrachloroethane, dichloropropane, dichloromethane, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, chlorotoluene, and trichlorobenzene; esters, especially methyl acetate, ethyl acetate, n-propyl acetate, and isopropyl acetate or butyl acetate; ethers, especially tetrahydrofuran (THF), 2-methyl-THF, cyclopentylmethyl ether, tert-butylmethyl ether, or diethyl ether; optionally substituted aliphatic, alicyclic, or aromatic hydrocarbons, especially pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, ligroin, benzene, toluene, anisole, xylene, mesitylene, or nitrobenzene; and nitriles, especially acetonitrile or propionitrile.

[0102] 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 particularly preferred.

[0103] Solvents can be used alone or in combination of two or more.

[0104] Step (1) is preferably carried out in a two-phase system consisting of one of the above-mentioned organic solvents of the present invention and water, for example, in a ratio of 5:1 to 1:5 (organic solvent: water), more preferably in a ratio of 5:1 to 1:2, and most preferably in a ratio of 2:1 to 1:2.

[0105] Step (1) is preferably carried out in the presence of a phase transfer catalyst, which is preferably selected from quaternary ammonium salts (especially tetra-n-butylammonium bisulfate, chlorides or bromides) and tetraalkylphosphonium salts (especially tri-n-butyl(tetradecyl)butylphosphonium chloride or trihexyltetradecylphosphonium chloride). The phase transfer catalyst is more preferably selected from tetra-n-butylammonium bisulfate and trihexyltetradecylphosphonium chloride.

[0106] According to the invention, the phase transfer catalyst is preferably used in a proportion of 0.005 to 0.06 equivalents, more preferably in a proportion of 0.01 to 0.05 equivalents, based on the total molar amount of compound (II) used. The catalyst is preferably used in pure form herein.

[0107] Step (1) is preferably carried out in the presence of a reducing agent, such as sodium dithionite or potassium dithionite, more preferably sodium dithionite. According to the invention, 0.9 to 2.0 equivalents, more preferably 1.0 to 1.8 equivalents, and most preferably 1.0 to 1.5 equivalents, are preferably used herein based on the total molar amount of compound (II) used. The reducing agent is preferably used herein in its pure form.

[0108] Step (1) is preferably carried out in the range of -10°C to 80°C, more preferably in the range of 0°C to 60°C, and most preferably in the range of 5°C to 40°C.

[0109] Step (1) is preferably performed within the standard pressure range (1013 hPa), for example, within the range of 300 hPa to 5000 hPa or 500 hPa to 2000 hPa, preferably within the range of 1013 hPa ± 200 hPa.

[0110] The reaction time for perfluoroalkylation in step (1) is preferably 3 to 48 hours, more preferably 3 to 24 hours, and most preferably 6 to 24 hours.

[0111] Compound R 2 -Y is preferably added by continuous metering over a period of 2 to 10 hours, more preferably 3 to 6 hours.

[0112] Step (1) is preferably performed under pH monitoring. The pH of the reaction solution is preferably maintained in the range of 3 to 7, more preferably in the range of 4 to 7. It is preferred to add compound R... 2 During the -Y period and throughout the subsequent reaction time, pH is monitored by adding a suitable base known to those skilled in the art, such as a pure substance or aqueous solution of an alkali metal / alkaline earth metal carbonate, alkali metal / alkaline earth metal bicarbonate, or alkali metal / alkaline earth metal hydroxide. In some cases, compound R is added at the beginning of metering. 2 Prior to Y, it may be advantageous to adjust the pH of the reaction mixture to a preferred pH (especially pH 4 to 5) by adding a suitable acid known to those skilled in the art, such as a carboxylic acid (e.g., acetic acid or propionic acid), an inorganic acid (e.g., hydrochloric acid or sulfuric acid), or a sulfonic acid (e.g., methanesulfonic acid).

[0113] Step (2), chlorination / bromination:

[0114] According to the present invention, the compound of formula (III) is reacted with a chlorinating agent or a brominating agent to obtain the compound of formula (I).

[0115] In the context of this specification, the term halogenating agent is used to refer to a chlorinating agent or a brominating agent.

[0116] In the following explanatory section relating to step (2), the term halogen means chlorine or bromine.

[0117] Suitable halogenating agents are those known to those skilled in the art, such as chlorine, bromine, chlorine- or bromine-containing inorganic salts, or chlorine- or bromine-containing organic molecules, wherein the bond between the organic group and the halogen atom is polarized, such that the chlorine or bromine atom is a carrier of a partially positive charge, for example, N-halosuccinimide, 1,3-dihalo-5,5-dimethylhydantoin, or halocyanuric acid (organohalogenated compounds).

[0118] Suitable halogenating agents in this article are chlorine, bromine, or organic halogenating agents, more preferably selected from N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (TCCA), 1,3,5-tribromo-1,3,5-triazine-2,4,6-trione, or 1,3-dibromo-1,3,5-triazine-2,4,6-trione. Most preferably, the halogenated compound is selected from chlorine, bromine, 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), 1,3-dibromo-5,5-dimethylhydantoin (DBDMH), 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione, 1,3,5-tribromo-1,3,5-triazine-2,4,6-trione, or 1,3-dibromo-1,3,5-triazine-2,4,6-trione, and particularly preferably chlorine, bromine, 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) or 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (TCCA).

[0119] Halogenating agents can be used alone or in combination of two or more, provided that the compounds used contain the same halogen.

[0120] According to the present invention, the proportion of the halogenating agent used can be 1.0 to 3.0 equivalents (monohalogenated compounds), 0.5 to 1.5 equivalents (dihalogenated compounds), or 0.3 to 1.0 equivalents (trihalogenated compounds), and preferably 1.0 to 2.5 equivalents (monohalogenated compounds), 0.5 to 0.8 equivalents (dihalogenated compounds), or 0.33 to 0.75 equivalents (trihalogenated compounds), based on the total molar amount of compound (III) used. If suitable, this can be achieved by adding a reducing agent known to those skilled in the art, followed by analysis by HPLC. a The excess halogenating agent is neutralized after complete conversion, and the reducing agent is, for example, an alkali metal / alkaline earth metal sulfite, an alkali metal / alkaline earth metal dithionite, or an alkali metal / alkaline earth metal thiosulfate. The reducing agent may preferably be used in the form of a pure substance or an aqueous solution (e.g., a saturated aqueous solution).

[0121] According to the invention, the halogenating agent may be in pure form as a solid or in pure form as a suspension or solution in a suitable organic solvent that is inert under the reaction conditions, particularly in the selection of the solvent used for the reaction, preferably at a concentration of 40-90% by weight, more preferably at a concentration of 60-95% by weight. Suitable organic solvents are particularly the preferred solvents mentioned below for step (2).

[0122] Step (2) does not require a special catalyst. In some cases, activation with a catalytic amount of acid may be advantageous, but this is by no means necessary in the reaction claimed herein. More particularly, this is advantageous when using organic chlorinating agents such as N-chlorosuccinimide (NCS) and 1,3-dichloro-5,5-dimethylhydantoin (DCDMH)

[0123] Suitable acids may preferably be selected from inorganic acids (e.g., sulfuric acid, hydrochloric acid and hydrofluoric acid), sulfonic acids (e.g., methanesulfonic acid, trifluoromethanesulfonic acid and 4-toluenesulfonic acid), carboxylic acids (e.g., trifluoroacetic acid and trichloroacetic acid) and Lewis acids (e.g. ferric trifluoromethanesulfonate and scandium trifluoromethanesulfonate (III)).

[0124] The reaction is preferably carried out in a temperature range of -78°C to 200°C, more preferably in a temperature range of -20°C to 100°C, and most preferably in a temperature range of 0°C to 50°C.

[0125] The reaction can be carried out at either increased or decreased pressure. However, it is preferred to carry out the reaction at standard pressure, for example, in the range of 1013 hPa ± 300 hPa, or in the range of 1013 hPa ± 100 hPa, or in the range of 1013 hPa ± 50 hPa.

[0126] Step (2) is preferably carried out in a suitable organic solvent. Useful diluents or solvents for carrying out step (2) generally include organic solvents that are inert under specific reaction conditions.

[0127] Examples include: aromatic or aliphatic halogenated hydrocarbons, especially aromatic or aliphatic chlorinated hydrocarbons, such as tetrachloroethane, dichloropropane, dichloromethane, dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, chlorotoluene, and trichlorobenzene; nitriles, especially acetonitrile, propionitrile, butyronitrile, isobutyronitrile, benzyl nitrile, or m-chlorobenzyl nitrile; optionally substituted aliphatic, alicyclic, or aromatic hydrocarbons, especially pentane, hexane, heptane, octane, nonane, cyclohexane, methylcyclohexane, petroleum ether, light petroleum, or nitrobenzene; esters, especially methyl acetate, ethyl acetate, isopropyl acetate, acetic acid... Butyl acetate, isobutyl acetate, dimethyl carbonate, dibutyl carbonate, or ethylene carbonate; amides, especially N,N-dimethylformamide (DMF), N,N-dipropylformamide, N,N-dibutylformamide (DBF), N,N-dimethylacetamide (DMAC), or N-methylpyrrolidine (NMP); aliphatic or alicyclic ethers, especially 1,2-dimethoxyethane (DME), diethylene glycol dimethyl ether, tetrahydrofuran (THF), 2-methyl-THF, 1,4-dioxane, tert-butyl methyl ether, or cyclopentyl methyl ether; and carboxylic acids, especially acetic acid, propionic acid, or butyric acid.

[0128] Preferred diluents or solvents are aromatic or aliphatic halogenated hydrocarbons, especially 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-propionic acid.

[0129] In a very particularly preferred embodiment, the solvent is selected from ethyl acetate, isopropyl acetate, tert-butyl methyl ether, cyclopentyl methyl ether, THF, 2-methyl-THF, and acetonitrile. Acetonitrile, tert-butyl methyl ether, ethyl acetate, and isopropyl acetate are very particularly preferred.

[0130] Solvents can be used alone or in combination of two or more.

[0131] The halogenation duration of the compound of formula (III) is preferably in the range of 0.5 hours to 10 hours, more preferably in the range of 0.25 hours to 5 hours. Longer reaction times are possible, but are not economically feasible.

[0132] The halogenating agent can be added to the other reactants either in a single step or through metered addition over a prolonged period. In some cases, it may also be advantageous to meteredly add a solution of compound (III) in one of the solvents mentioned in step (2) to a solution or suspension of the halogenating agent in one of the preferred solvents in step (2). The duration of metered addition herein is preferably in the range of 0.5 to 6 hours, more preferably 1 to 4 hours. Longer metering times are possible from a technical standpoint, but are not economically feasible.

[0133] The metering addition is preferably carried out in a temperature range of -78°C to 200°C, more preferably in a temperature range of -20°C to 100°C, and most preferably in a temperature range of 0°C to 50°C. In an advantageous configuration, the temperature at which the metering addition is carried out corresponds to the reaction temperature.

[0134] In a particularly advantageous configuration of the invention, the same organic solvent is used in steps (1) and (2).

[0135] In the context of this configuration of the invention, the solvents in both steps are preferably selected from esters, ethers, or nitriles; more preferably, they are 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 particularly preferred.

[0136] The solvents mentioned may be used alone or in combination of two or more.

[0137] A feature of the method of the present invention is that the compound of formula (III) is not isolated from the reaction mixture of step (1) before step (2).

[0138] In the context of this invention, the term "separation" means the complete separation of the compound of formula (III) from the reaction mixture, i.e., from all solvents and salts, by a separation method known to those skilled in the art. Furthermore, in the context of this invention, "separation" means that all organic solvents from step (1) were never removed after step (1) and before step (2).

[0139] Preferably, the compound of formula (III) in step (1) is used directly in step (2) in the form of a solution in the organic solvent of step (1).

[0140] In the method of the present invention, the reaction volume may be increased in the form of a solid, liquid, or suspension during the reaction sequence, for example, in the form of a solid, a dissolved or suspended halogenating agent, or a solvent (the same solvent as in the first step or another solvent). More specifically, an acid or base may be added between reaction steps (1) and (2), and the aqueous components of the reaction mixture may be partially or completely removed.

[0141] According to the present invention, it is further preferred to remove less than 30% by volume, more preferably less than 20% by volume and most preferably less than 10% by volume of organic solvent in step (1) before the start of step (2), based on the volume of organic solvent used.

[0142] It is particularly advantageous when the organic solvent is not actively removed after step (1). Active removal of the organic solvent should generally be understood to mean the removal of the organic solvent by distillation under standard pressure or reduced pressure, optionally by heat treatment of the reaction mixture.

[0143] In another preferred configuration of the invention, steps (1) and (2) are performed in the same reaction vessel. In this case, those skilled in the art will select a reaction vessel from the outset that can accommodate all volumes of reactions (1) and (2).

[0144] In other words, the preferred reaction sequence is a telescoped reaction in one or more containers, preferably one container.

[0145] The method of the present invention preferably consists of steps (1) and (2).

[0146] Optionally, steps (1) and / or (2) can also be repeated in the same reaction vessel, for example, two or three times, without further post-processing. The reaction mixture in step (1) can, for example, be reacted according to HPLC. a After complete conversion, it is mixed again with the compound of formula (II) of the present invention and the reducing agent, and compound R is added in a metered manner under pH monitoring. 2 -Y is converted to a compound of formula (III). This operation can be repeated, or the reaction mixture can be further processed according to the invention. The reaction mixture in step (2) can be similarly processed according to HPLC. a After complete conversion, it is mixed again with the compound of formula (III), and then further converted into the compound of formula (I) by adding the halogenating agent of the present invention.

[0147] Compound (I) can be post-processed and separated after complete reaction, for example by removing the solvent, washing with water and extracting and separating the organic phase with a suitable organic solvent, and removing the solvent under reduced pressure. The residue can also be vacuum distilled using a concentric column at 0.05–1 bar and crystallized in solvents known to those skilled in the art.

[0148] Option 1:

[0149]

[0150] Scheme 1 provides a general schematic diagram of the method of the present invention having two steps. The reaction conditions and reactants are selected according to the above-described inventive configuration and preferred configuration. Formulas (I), (II), (III) and R... 2 All variables in -Y are defined as described above.

[0151] A preferred embodiment of the method of the present invention is as follows:

[0152] First, the compound of formula (II) is added to a mixture of an organic solvent and water. After adding the phase-transfer catalyst of the present invention (e.g., tetra-n-butylammonium bisulfate or tri-n-hexyl(tetradecyl)phosphonium chloride) and the reducing agent of the present invention (e.g., sodium dithionite), the perfluoroalkylating agent of the present invention (e.g., heptafluoro-2-iodopropane) is added over 2 to 10 hours at a preferably -10°C to 80°C, more preferably 0°C to 60°C, optionally after the pH has been adjusted to 4 to 5 with a suitable acid (e.g., acetic acid) before the start of metered addition. Preferably, the pH of the reaction mixture is maintained in the range of 3 to 7 throughout the reaction time by adding a suitable base in solid form or in aqueous solution (e.g., 40% by weight of potassium carbonate aqueous solution). Preferably, after 3 to 48 hours, the aqueous phase is removed, and the organic phase is optionally washed with water or aqueous hydrochloric acid (e.g., 5% or 25% by weight). Preferably, at -20°C to 100°C, more preferably at 0°C to 50°C, the organic phase containing the compound of formula (III) is mixed with a halogenating agent (e.g., in solid form or in solution form in the organic solvent of the present invention) for preferably 0.5 to 6 hours. Conversion complete (HPLC) a After that, any excess halogenating agent present is neutralized by adding a reducing agent (e.g., in the form of a pure substance or an aqueous solution) and the compound of formula (I) is isolated. (Steps (1) and (2)).

[0153] In another advantageous embodiment, the compound of formula (II) is first added to a mixture of an organic solvent and water, and after the addition of the phase transfer catalyst of the present invention (e.g., tetra-n-butylammonium bisulfate or tri-n-hexyl(tetradecyl)phosphonium chloride) and the reducing agent of the present invention (e.g., sodium dithionite), the perfluoroalkylating agent of the present invention (e.g., heptafluoro-2-iodopropane) is added, preferably at -10°C to 80°C, more preferably 0°C to 60°C, over 2 to 10 hours, optionally after the pH has been adjusted to 4 to 5 with a suitable acid (e.g., acetic acid) before the start of metered addition. Preferably, the pH of the reaction mixture is maintained in the range of 3 to 7 throughout the reaction time by adding a suitable base in solid form or in aqueous solution (e.g., 40% by weight of an aqueous solution of potassium carbonate). Preferably, after 3 to 48 hours, following the addition of another portion of the compound of formula (II) and the reducing agent of the present invention (e.g., sodium dithionite), the perfluoroalkylating agent of the present invention (e.g., heptafluoro-2-iodopropane) is added over 2 to 10 hours at a preferably -10°C to 80°C, more preferably 0°C to 60°C. The pH of the reaction mixture is preferably maintained in the range of 3 to 7 throughout the reaction time by adding a suitable base, either in solid form or in aqueous solution (e.g., aqueous potassium carbonate solution). Preferably, after 3 to 48 hours, the process may optionally be repeated or the aqueous phase may be removed, optionally by washing the organic phase with water or aqueous hydrochloric acid (e.g., 5% or 25% by weight), and preferably at a -20°C to 100°C, more preferably 0°C to 50°C, preferably over 0.5 to 6 hours, the organic phase containing the compound of formula (III) is mixed with a halogenating agent (e.g., in solid form or in solution form in the organic solvent of the present invention). Conversion complete (HPLC) a After that, any excess halogenating agent present is neutralized by adding a reducing agent (e.g., in the form of a pure substance or an aqueous solution) and the compound of formula (I) is separated. (Steps (1) (twice) and (2)).

[0154] A particularly preferred embodiment of the method of the present invention is as follows:

[0155] First, the compound of formula (II) is added to a mixture of ethyl acetate and water, and after the addition of tetrabutylammonium bisulfate and sodium dithionite, heptafluoro-2-iodopropane is added at 0°C to 60°C over 3 to 6 hours, optionally after the pH has been adjusted to 4 to 5 with acetic acid before the start of metered addition. The pH of the reaction mixture is maintained in the range of 4 to 7 throughout the metered addition and reaction time by adding 40% by weight of an aqueous solution of potassium carbonate. Preferably, after 3 to 24 hours, the aqueous phase is removed, optionally by washing the organic phase with water or aqueous hydrochloric acid (e.g., 5% by weight or 25% by weight), and preferably at 0 to 50°C over 1 to 4 hours, the organic phase containing the compound of formula (III) is mixed with chlorine or 1,3,5-trichloro-1,3,5-triazine-2,4,6-dione (TCCA) (chlorination), or with bromine or 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) (bromination). Conversion complete (HPLC) a Afterward, any excess halogenating agent present is neutralized by adding sodium sulfite (in the form of pure substance or aqueous solution) and the compound of formula (I) is isolated. (Steps (1) and (2)). Example

[0156] The following examples illustrate the method of the present invention in detail, but do not limit the invention.

[0157] method:

[0158] The NMR data for the examples are presented in the conventional form (δ value, multiplet splitting, number of hydrogen atoms).

[0159] The solvent and frequency used to record the NMR spectrum are described in each case.

[0160] a) HPLC (High Performance Liquid Chromatography) on a reversed-phase column (C18), Agilent 1100LC system; Phenomenex Prodigy 100 x 4 mm ODS3; eluent A: acetonitrile (0.25 ml / L); eluent B: water (0.25 ml TFA / L); linear gradient from 5% acetonitrile to 95% acetonitrile over 7.00 min, followed by 95% acetonitrile for another 1.00 min; oven temperature 40°C; flow rate:

[0161] 2.0 ml / min.

[0162] Step 1: Preparation of the compound of formula (III)

[0163] 4-[1,2,2,2-Tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-1a)

[0164] 4.5 g (13.0 mmol, 0.02 equivalence) of tetra-n-butylammonium bisulfate and 144.0 g (0.70 mol, 1.1 equivalence, 85 wt%) of sodium dithionite were sequentially added to an initial feed of 60.0 g (0.64 mol, 1.0 equivalence) of aniline in 450 ml each of water and ethyl acetate. 214.0 g (0.70 mol, 1.1 equivalence) of heptafluoro-2-iodopropane was added metered over 3 hours at room temperature, maintaining the pH at 6.0–7.0 by adding 40 wt% K₂CO₃ aqueous solution during the metered addition. After the addition was complete, stirring was continued for another 3 hours at approximately 21 °C and the same pH. The phases were then separated, and the organic phase was washed with 40 ml each of 20 wt% NaCl and 2.5 wt% HCl. The analysis was performed by HPLC. a) It was detected that 98% was converted to the desired product. The organic phase was then used in step (2) without further processing.

[0165] An analytical sample containing pure compounds was obtained after separation by removing the solvent through distillation.

[0166] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.35 (d, J = 8.9 Hz, 2H), 6.72 (d, J = 7.7 Hz, 2H), 3.91 (br s, 2H).

[0167] 4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-1b)

[0168] 0.1 g (0.4 mmol, 0.005 wt%) of tetra-n-butylammonium bisulfate and 17.9 g (87.8 mol, 1.1 wt%, 85 wt%) of sodium dithionite were sequentially added to an initial feed of 7.5 g (79.8 mmol, 1.0 wt%) of aniline in 60 ml each of water and ethyl acetate. 26.8 g (87.8 mmol, 1.1 wt%) of heptafluoro-2-iodopropane diluted in 8 ml of ethyl acetate was added metered over 4 hours at 20–22 °C, maintaining the pH at 6.0–7.0 by adding 40 wt% K₂CO₃ aqueous solution during the metered addition. After the addition was complete, the mixture was stirred for another 1.5 hours at approximately 20–22 °C and the same pH. The analysis was performed by HPLC. a) The conversion rate was 98% to the desired product. The phases were separated, and the organic phase was washed with 75 ml of 10% wt% HCl. The organic phase was then used in step (2) without further treatment.

[0169] An analytical sample containing pure compounds was obtained after separation by removing the solvent through distillation.

[0170] 1H-NMR (CDCl3, 400MHz) δ (ppm) = 7.35 (d, J = 8.9 Hz, 2H), 6.72 (d, J = 7.7 Hz, 2H), 3.91 (br s, 2H).

[0171] 4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-1c)

[0172] 1.4 g (1.6 mmol, 0.02 equivalents) of tri-n-butyl(tetradecyl)phosphonium chloride and 17.9 g (87.8 mol, 1.1 equivalents, 85 wt%) of sodium dithionite were sequentially added to an initial feed of 7.5 g (79.8 mmol, 1.0 equivalents) of aniline in 60 ml each of water and ethyl acetate. 26.8 g (87.8 mmol, 1.1 equivalents) of heptafluoro-2-iodopropane diluted in 8 ml of ethyl acetate was added metered over 3 hours at 20–22 °C, maintaining the pH at 6.0–7.0 by adding 40 wt% K₂CO₃ aqueous solution during the metered addition. After the addition was complete, the mixture was stirred for another 4 hours at approximately 20–22 °C and the same pH. The analysis was performed by HPLC. a) 96% was detected to have converted to the desired product. The phases were separated, and the organic phase was washed with 75 ml of 10% wt% HCl. The organic phase was then used in step (2) without further treatment.

[0173] An analytical sample containing pure compounds was obtained after separation by removing the solvent through distillation.

[0174] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.35 (d, J = 8.9 Hz, 2H), 6.72 (d, J = 7.7 Hz, 2H), 3.91 (br s, 2H).

[0175] 4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-1d)

[0176] 3.3 g (9.7 mmol, 0.06 equivalent) of tetra-n-butylammonium bisulfate and 35.9 g (170.0 mol, 1.1 equivalent, 85 wt%) of sodium dithionite were sequentially added to an initial feed of 15.0 g (150.0 mmol, 1.0 equivalent) of aniline in 120 ml each of water and isopropyl acetate. 53.51 g (170.0 mmol, 1.1 equivalent) of heptafluoro-2-iodopropane was metered over 3 hours at 20–22 °C, maintaining the pH at 6.0–7.0 by adding 40 wt% K₂CO₃ aqueous solution during the metered addition. After the addition was complete, the mixture was stirred for another 5 hours at approximately 20–22 °C and the same pH. The analysis was performed by HPLC. a)94% was detected to have been converted to the desired product. The phases were separated, and the organic phase was then used in step (2) without further processing.

[0177] An analytical sample containing pure compounds was obtained after separation by removing the solvent through distillation.

[0178] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.35 (d, J = 8.9 Hz, 2H), 6.72 (d, J = 7.7 Hz, 2H), 3.91 (br s, 2H).

[0179] 4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-1e)

[0180] 2.2 g (6.2 mmol, 0.02 equivalence) of tetra-n-butylammonium bisulfate and 71.9 g (0.35 mol, 1.1 equivalence, 85 wt%) of sodium dithionite were sequentially added to an initial feed of 30.0 g (0.31 mol, 1.0 equivalence) of aniline in 240 ml each of water and isopropyl acetate. 90.0 g (0.35 mol, 1.1 equivalence) of heptafluoro-2-bromopropane was metered over 3 hours at -5°C via a gas inlet tube, maintaining the pH at 6.0–7.0 by adding 40 wt% K₂CO₃ aqueous solution during the metered addition. After the addition was complete, the mixture was stirred at approximately -5°C and the same pH for another 3 hours, then warmed to 20°C overnight. The analysis was performed by HPLC. a) 96% was detected to have converted to the desired product. The phases were separated, and the organic phase was washed with 40 ml each of 20 wt% NaCl and 2.5 wt% HCl. The organic phase was then used in step (2) without further treatment.

[0181] An analytical sample containing pure compounds was obtained after separation by removing the solvent through distillation.

[0182] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.35 (d, J = 8.9 Hz, 2H), 6.72 (d, J = 7.7 Hz, 2H), 3.91 (br s, 2H).

[0183] 2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-2a)

[0184] 0.5 g (1.6 mmol, 0.02 equivalent) of tetra-n-butylammonium bisulfate and 19.3 g (94.0 mmol, 1.2 equivalent, 85 wt%) of sodium dithionite were added sequentially to an initial feed of 10.0 g (78.3 mol, 1.0 equivalent) of 2-chloroaniline in 100 ml each of water and ethyl acetate. The pH was adjusted to 5 by adding 1.25 g (20.8 mmol, 0.3 equivalent) of acetic acid. 26.3 g (86.2 mmol, 1.1 equivalent) of heptafluoro-2-iodopropane diluted in 6 ml of ethyl acetate was metered over 3 hours at 20–22 °C, maintaining the pH at 4.0–5.0 by adding 40 wt% K₂CO₃ aqueous solution during the metered addition. After the addition was complete, the mixture was stirred for another 4 hours at approximately 20–22 °C and the same pH. The analysis was performed by HPLC. a) 94% was detected to have converted to the desired product. The phases were separated, and the organic phase was washed with 75 ml of 10% wt% HCl. The organic phase was then used in step (2) without further treatment.

[0185] An analytical sample containing pure compounds was obtained after separation by removing the solvent through distillation.

[0186] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.47 (s, 1H), 7.28 (d, J = 8.0Hz, 1H), 6.81 (d, J = 8.0Hz, 1H), 4.13 (br s, 2H).

[0187] 2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-2b)

[0188] 2.2 g (6.3 mmol, 0.02 equivalent) of tetra-n-butylammonium bisulfate and 77.1 g (0.38 mmol, 1.2 equivalent, 85 wt%) of sodium dithionite were sequentially added to an initial feed of 40.0 g (0.31 mol, 1.0 equivalent) of 2-chloroaniline in 400 ml each of water and ethyl acetate. The pH was adjusted to 5 by adding 4.8 g (79.9 mmol, 0.25 equivalent) of acetic acid. 114.8 g (0.38 mol, 1.2 equivalent) of heptafluoro-2-iodopropane diluted in 26 ml of ethyl acetate was metered over 3 hours at 20–22 °C, maintaining the pH at 4.0–5.0 by adding 40 wt% K₂CO₃ aqueous solution during the metered addition. After the addition was complete, the mixture was stirred for another 4 hours at approximately 20–22 °C and the same pH. The analysis was performed by HPLC. a) The conversion rate was 99% to the desired product. The phases were separated, and the organic phase was washed with 300 ml of 10% wt% HCl. The organic phase was then used in step (2) without further treatment.

[0189] An analytical sample containing pure compounds was obtained after separation by removing the solvent through distillation.

[0190] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.47 (s, 1H), 7.28 (d, J = 8.0Hz, 1H), 6.81 (d, J = 8.0Hz, 1H), 4.13 (br s, 2H).

[0191] 2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-2c)

[0192] 0.5 g (1.6 mmol, 0.02 equivalent) of tetra-n-butylammonium bisulfate and 19.3 g (94.0 mmol, 1.2 equivalent, 85 wt%) of sodium dithionite were sequentially added to an initial feed of 10.0 g (78.3 mmol, 1.0 equivalent) of 2-chloroaniline in 100 ml each of water and tert-butyl methyl ether. The pH was adjusted to 5 by adding 1.0 g (16.6 mmol, 0.2 equivalent) of acetic acid. 26.3 g (86.2 mmol, 1.1 equivalent) of heptafluoro-2-iodopropane diluted in 6 ml of ethyl acetate was metered over 3 hours at 20–22 °C, maintaining the pH at 4.0–5.0 by adding 40 wt% K₂CO₃ aqueous solution during the metered addition. After the addition was complete, the mixture was stirred for another 4 hours at approximately 20–22 °C and the same pH. The analysis was performed by HPLC. a) 82% was detected to have converted to the desired product. The phases were separated, and the organic phase was washed with 75 ml of 10% wt% HCl. The organic phase was then used in step (2) without further treatment.

[0193] An analytical sample containing pure compounds was obtained after separation by removing the solvent through distillation.

[0194] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.47 (s, 1H), 7.28 (d, J = 8.0Hz, 1H), 6.81 (d, J = 8.0Hz, 1H), 4.13 (br s, 2H).

[0195] 2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-2d)

[0196] 0.8 g (2.4 mmol, 0.02 equivalence) of tetra-n-butylammonium bisulfate and 28.9 g (0.14 mmol, 1.2 equivalence, 85 wt%) of sodium dithionite were sequentially added to an initial feed of 15.0 g (0.12 mol, 1.0 equivalence) of 2-chloroaniline in 120 mL of water and 90 mL of ethyl acetate. The pH was adjusted to 5 by adding 1.9 g (31.6 mmol, 0.3 equivalence) of acetic acid. 40.1 g (0.13 mmol, 1.1 equivalence) of heptafluoro-2-iodopropane diluted in 7 mL of ethyl acetate was metered over 3 hours at 20–22 °C, maintaining the pH at 4.0–5.0 by adding 40 wt% K₂CO₃ aqueous solution during the metered addition. After the addition was complete, the mixture was stirred for another 4 hours at approximately 20–22 °C and the same pH. The analysis was performed by HPLC. a) 94% was detected to have converted to the desired product. The phases were separated, and the organic phase was washed with 75 ml of 10% wt% HCl. The organic phase was then used in step (2) without further treatment.

[0197] An analytical sample containing pure compounds was obtained after separation by removing the solvent through distillation.

[0198] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.47 (s, 1H), 7.28 (d, J = 8.0Hz, 1H), 6.81 (d, J = 8.0Hz, 1H), 4.13 (br s, 2H).

[0199] 4-[1,2,2,2-Tetrafluoro-1-(trifluoromethyl)ethyl]-2-(trifluoromethoxy)aniline (III-3a)

[0200] 1.55 g (4.4 mmol, 0.02 equivalent) of tetra-n-butylammonium bisulfate and 68.0 g (0.33 mol, 1.5 equivalent) of sodium dithionite were added sequentially to an initial feed of 40.0 g (0.22 mol, 1.0 equivalent) of 2-trifluoromethoxyaniline in 400 ml of water and 250 ml of ethyl acetate. 100.2 g (0.33 mol, 1.5 equivalent) of heptafluoro-2-iodopropane was added metered over 2.5 hours at room temperature, maintaining the pH at 4.0–5.0 by adding 40% by weight of K₂CO₃ aqueous solution during the metered addition. After the addition was complete, the mixture was stirred for another 1 hour at approximately 21°C, and then the phases were separated. The organic phase was diluted with 100 ml of n-heptane and then washed 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.

[0201] An analytical sample containing pure compounds was obtained after separation by removing the solvent through distillation.

[0202] 1 H-NMR (DMSO-d6, 400MHz) δ (ppm) = 7.51 (d, J = 9.0 Hz, 1H), 7.44 (s, 1H), 7.43 (d, J = 9.0 Hz, 1H), 6.38 (br s, 2H).

[0203] 4-[1,2,2,2-Tetrafluoro-1-(trifluoromethyl)ethyl]-2-(trifluoromethoxy)aniline (III-3b)

[0204] 4.6 g (13.5 mmol, 0.06 equivalence) of tetra-n-butylammonium bisulfate and 59.0 g (0.29 mol, 0.4 equivalence, 85 wt%) of sodium dithionite were sequentially added to an initial feed of 40.0 g (0.22 mol, 1.0 equivalence) of 2-trifluoromethoxyaniline in 600 mL of water and 360 mL of ethyl acetate. 100.2 g (0.34 mol, 1.5 equivalence) of heptafluoro-2-iodopropane dissolved in 20 g of ethyl acetate was added metered over 1.5 hours at 25 °C, maintaining the pH between 4.0 and 4.9 by adding 40 wt% K₂CO₃ aqueous solution during the metered addition. After the addition was complete, the mixture was stirred for another 2 hours at approximately 21 °C and the same pH. The analysis was performed by HPLC. a) >95% conversion to the desired product was detected. Subsequently, another 40.0 g (0.22 mol, 1.0 equivalent) of 2-trifluoromethoxyaniline and 59.0 g (0.29 mol, 0.4 equivalent, 85 wt%) of sodium dithionite were added, followed by the metered addition of 100.2 g (0.34 mol, 1.5 equivalent) of heptafluoro-2-iodopropane dissolved in 20 g of ethyl acetate over 1.5 hours at 25 °C. The pH was maintained at 4.0–4.9 during the metered addition by adding 40 wt% K₂CO₃ aqueous solution, and the mixture was stirred at the same pH for another 2 hours at 21 °C. The reaction was analyzed by HPLC. a) The conversion rate was >97% to the desired product. This process was repeated once over 1.5 hours at pH 4.0–4.9 using 40.0 g (0.22 mol, 1.0 equivalence) of 2-trifluoromethoxyaniline, 59.0 g (0.29 mol, 0.4 equivalence, 85 wt%) of sodium dithionite, and 100.2 g (0.34 mol, 1.5 equivalence) of heptafluoro-2-iodopropane dissolved in 20 g of ethyl acetate, followed by stirring at pH 4.0–4.9 for another 3 hours. The product was analyzed by HPLC. a)The conversion rate was >97% to the desired product. The phases were separated, and after adding 400 ml of n-heptane, the organic phase was washed twice with 300 ml of 20% HCl each time, and once with 300 ml of saturated NaCl aqueous solution. The organic phase was then used in step (2) without further treatment.

[0205] An analytical sample containing pure compounds was obtained after separation by removing the solvent through distillation.

[0206] 1 H-NMR (DMSO-d6, 400MHz) δ (ppm) = 7.51 (d, J = 9.0 Hz, 1H), 7.44 (s, 1H), 7.43 (d, J = 9.0 Hz, 1H), 6.38 (br s, 2H).

[0207] The following general formula (III) 4-perfluoroalkylaniline can be prepared in a manner similar to Examples (III-1a) and (III-1b):

[0208] 4-[1,2,2,2-Tetrafluoro-1-(trifluoromethyl)ethyl]-2-(trifluoromethyl)aniline (III-4)

[0209] 1 H-NMR (DMSO-d6, 400MHz) δ (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).

[0210] 2-Ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-5)

[0211] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.63 (d, J = 8.3Hz, 1H), 7.53 (br s, 1H), 7.43 (d, J = 8.3Hz, 1H), 2.92 (q, J = 7.6Hz, 2H), 1.35 (t, J = 7.6Hz, 3H).

[0212] Step (2): Preparation of the compound of formula (I)

[0213] 2,6-Dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (I-1a)

[0214] 180.0 g (0.64 mol, 1.0 equivalent) of 4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-1) (Example (III-1a)) in solution in 450 mL of ethyl acetate from step (1) was diluted with another 150 mL of ethyl acetate, and after the addition of 100 mL of water, 96.0 g (128.0 mmol, 2.0 equivalent) of chlorine gas was added over 5 hours at 0–5 °C. The phases were then separated, and the aqueous phase was extracted sequentially with a mixture of 100 mL of ethyl acetate and 50 mL of n-heptane, and then with a mixture of 50 mL of ethyl acetate and 25 mL of n-heptane. The combined organic phases were washed twice with 100 mL of 20% NaCl solution each time, and after solvent removal, a reddish-brown oily product was obtained: yield 200.0 g (95% of theoretical value).

[0215] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.41 (s, 2H), 4.76 (br s, 2H).

[0216] 2,6-Dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (I-1b)

[0217] 27.0 g (0.38 mol, 2.5 equivalents) of chlorine gas was added over 4 hours at 0–5 °C to 41.5 g (0.15 mol, 1.0 equivalents) of 4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-1) (Example (III-1d)) in solution in 120 ml of isopropyl acetate from step (1). Subsequently, 40 ml of ice water was gradually added to separate the phases, and the aqueous phase was extracted with 40 ml of isopropyl acetate. The combined organic phases were washed twice with 40 ml of 20 wt% NaCl solution, and after solvent removal, a reddish-brown oily product was obtained: yield 42.5 g (86% of theoretical value).

[0218] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.41 (s, 2H), 4.76 (br s, 2H).

[0219] 2,6-Dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (I-1c)

[0220] A solution of 13.1 g (55.7 mmol, 0.7 equivalent) of 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (TCCA) in 40 mL of ethyl acetate was added to 20.8 g (79.7 mmol, 1.0 equivalent) of 4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-1) (Example (III-1c)) in 50 mL of ethyl acetate from step (1) over 2 hours at 0–5 °C. The reaction was heated to 20–25 °C over 2.5 hours and stirred at this temperature for 1 hour. The resulting solid was filtered off, and the clear solution was mixed with 10 mL of saturated Na₂SO₃ aqueous solution and 30 mL of water. After separating the phases, the organic phase was washed with 20 ml of water and 20 ml of saturated NaCl solution, and the solvent was removed under reduced pressure to obtain a light brownish-red oily product, which solidified upon cooling: yield 26.1 g (89.9% of the theoretical value).

[0221] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.41 (s, 2H), 4.76 (br s, 2H).

[0222] 2,6-Dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (I-1d)

[0223] A solution of 12.9 g (54.8 mmol, 0.35 equivalent) of 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (TCCA) in 50 mL of ethyl acetate was added to 46.3 g (0.16 mol, 1.0 equivalent) of 2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-2) (Example (III-2a)) in 100 mL of ethyl acetate from step (1) over 2 hours at 0–5 °C. The reaction was heated to 20–25 °C over 2.5 hours and stirred at this temperature for 1 hour. The resulting solid was filtered off, and the clear solution was mixed with 40 mL of saturated Na₂SO₃ aqueous solution and 120 mL of water. After separating the phases, the organic phase was washed with 80 ml of water and 80 ml of saturated NaCl solution, and the solvent was removed under reduced pressure to obtain a light brownish-red oily product, which solidified upon cooling: yield 50.7 g (88.6% of the theoretical value).

[0224] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.41 (s, 2H), 4.76 (br s, 2H).

[0225] 2,6-Dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (I-1e)

[0226] 23.1 g (78.3 mol, 1.0 equivalent) of 2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-2) (Example (III-2c)) in solution in 100 ml tert-butyl methyl ether from step (1) was metered into a suspension of 6.4 g (27.4 mmol, 0.35 equivalent) of 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (TCCA) in 50 ml tert-butyl methyl ether over 2 hours at 0-5 °C. The reaction was heated to 20-25 °C over 2.5 hours and stirred at this temperature for 1 hour. The resulting solid was filtered off, and the clear solution was mixed with 20 ml of saturated Na₂SO₃ aqueous solution and 60 ml of water. After separating the phases, the organic phase was washed with 40 ml of water and 40 ml of saturated NaCl solution, and the solvent was removed under reduced pressure to obtain a product in the form of a light reddish-brown oil: yield 20.9 g (67.7% of the theoretical value).

[0227] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.41 (s, 2H), 4.76 (br s, 2H).

[0228] 2,6-Dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (I-1f)

[0229] 0.15 g (1.5 mmol, 0.05 equivalent) of 96% by weight H₂SO₄ was added to 8.8 g (29.9 mmol, 1.0 equivalent) of 2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-2) (Example (III-2b)) in solution in 30 mL of ethyl acetate from step (1) at 0–5 °C, followed by the addition of 3.16 g (15.7 mmol, 0.53 equivalent) of 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) in portions over 1 hour. The ice bath was removed and the reaction was stirred at room temperature for 2 hours. The slightly turbid solution was then mixed with 10 mL of saturated aqueous Na₂SO₃ solution and 30 mL of water. After separating the phases, the organic phase was diluted with 50 ml of ethyl acetate and then washed with 30 ml of water. The solvent was removed under reduced pressure to obtain the product in the form of a light orange solid: yield 9.7 g (98% of the theoretical value).

[0230] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.41 (s, 2H), 4.76 (br s, 2H).

[0231] 2,6-Dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (I-1g)

[0232] 4.86 g (35.6 mmol, 1.05 equivalent) of N-chlorosuccinimide (NCS) was added at room temperature to 20.0 g (33.9 mmol, 1.0 equivalent) of 2-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (III-2) (Example (III-2a)) in solution in 40 mL of ethyl acetate from step (1). The solution was then heated to 50 °C and stirred at that temperature for 3 hours. Subsequently, the slightly turbid solution was mixed with 10 mL of saturated Na₂SO₃ aqueous solution and 30 mL of water. After diluting the organic phase with 40 mL of ethyl acetate, the phases were separated and the solvent was removed under reduced pressure to give the product in the form of a beige solid: yield 10.4 g (93% of theoretical value).

[0233] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.41 (s, 2H), 4.76 (br s, 2H).

[0234] 2-Bromo-4-[1,2,2,2-Tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)aniline (I-2)

[0235] 234.6 g (0.68 mol, 1.0 equivalent) of 4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2-(trifluoromethoxy)aniline (III-3) (Example (III-3b)) in the form of a solution of 40 ml ethyl acetate in 360 ml of ethyl acetate and 400 ml of n-heptane from step (1) was added, followed by the addition of 200 ml of water, and then 119.0 g (0.75 mol, 1.1 equivalent) of bromine in 40 ml of ethyl acetate was added over 1 hour at 25-30°C. The pH was adjusted to 6-8 by adding 53% by weight of an aqueous solution of K₂CO₃ throughout the metering time. The results were obtained by HPLC. a) Complete conversion to the desired product was detected. The phases were separated, and the organic phase was washed with 400 ml of 10% (w / w) sodium thiosulfate aqueous solution and dried. The solvent was removed under reduced pressure at 40°C. A deep red oily product was obtained. Yield: 248.0 g (86% of theoretical value).

[0236] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.59 (s, 1H), 7.34 (s, 1H), 4.65 (br s, 2H).

[0237] 2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)aniline (I-3)

[0238] 0.99 g (4.3 mmol, 0.35 equivalent) of 1,3,5-trichloro-1,3,5-triazine-2,4,6-trione (TCCA) in 5 mL of ethyl acetate was added over 2 hours at 0–5 °C to 4.0 g (12.1 mmol, 1.0 equivalent) of 4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2-(trifluoromethyl)aniline (III-4) in 10 mL of ethyl acetate from step (1). The reaction was heated to 20–25 °C over 2.5 hours and stirred at that temperature for 1 hour. The resulting solid was filtered off, and the clear solution was mixed with 10 mL of saturated Na₂SO₃ aqueous solution and 10 mL of water. After separation of the phases, the organic phase was washed with 15 mL of water and 15 mL of saturated NaCl solution, and the solvent was removed under reduced pressure to give the product as a pale yellow oil: yield 3.16 g (71% of theoretical value).

[0239] 1 H-NMR (DMSO-d6, 400MHz) δ (ppm) = 7.72 (br s, 1H), 7.46 (br s, 1H), 6.56 (br s, 2H).

[0240] 2-Bromo-4-[1,2,2,2-Tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)aniline (I-4a)

[0241] At 20–25 °C for 1 hour, 20.0 g (60.8 mmol, 1.0 equivalent) of 4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2-(trifluoromethyl)aniline (III-4) in solution in 40 mL of ethyl acetate from step (1) was added in metric amounts to a suspension of 9.3 g (31.9 mmol, 0.53 equivalent) of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) and 0.16 g (1.52 mmol, 0.025 equivalent) of 98% by weight of H₂SO₄ in 100 mL of ethyl acetate. The reaction was stirred at this temperature for another 30 minutes. After adding 25 mL of saturated Na₂SO₃ aqueous solution and 75 mL of water, the phases were separated, and the organic phase was diluted with 100 mL of n-heptane and washed with 100 mL of water. The solvent was removed under reduced pressure to obtain a product in the form of a pale red oil: yield 20.4 g (82% of the theoretical value).

[0242] 1H-NMR (DMSO-d6, 400MHz) δ (ppm) = 7.86 (br s, 1H), 7.50 (br s, 1H), 6.43 (br s, 2H).

[0243] 2-Bromo-4-[1,2,2,2-Tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)aniline (I-4b)

[0244] 4.0 g (12.1 mmol, 1.0 equivalent) of 4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2-(trifluoromethyl)aniline (III-4) from step (1) in 10 mL of ethyl acetate was added metrically to a suspension of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in 20 mL of ethyl acetate over 1 hour at 20–25 °C. The reaction was stirred at this temperature for another 30 minutes. After adding 5 mL of saturated Na₂SO₃ aqueous solution, 15 mL of water, and 25 mL of n-heptane, the phases were separated, and the organic phase was diluted with 15 mL of water and 15 mL of saturated NaCl aqueous solution. The solvent was removed under reduced pressure to give the product as an orange oil: yield 4.0 g (80% of theoretical value).

[0245] 1 H-NMR (DMSO-d6, 400MHz) δ (ppm) = 7.86 (br s, 1H), 7.50 (br s, 1H), 6.43 (br s, 2H).

[0246] 2-Bromo-4-[1,2,2,2-Tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)aniline (I-4c)

[0247] 4.0 g (12.1 mmol, 1.0 equivalent) of 4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2-(trifluoromethyl)aniline (III-4) from step (1) in 10 mL of ethyl acetate was added metrically to a suspension of 2.3 g (12.7 mmol, 1.05 equivalent) of N-bromosuccinimide (NBS) in 20 mL of ethyl acetate over 1 hour at 20–25 °C. The reaction was stirred at this temperature for another 60 minutes. After adding 5 mL of saturated Na₂SO₃ aqueous solution, 15 mL of water, and 25 mL of n-heptane, the phases were separated, and the organic phase was diluted with 15 mL of water and 15 mL of saturated NaCl aqueous solution. The solvent was removed under reduced pressure to give the product as an orange oil: yield 4.0 g (81% of theoretical value).

[0248] 1H-NMR (DMSO-d6, 400MHz) δ (ppm) = 7.86 (br s, 1H), 7.50 (br s, 1H), 6.43 (br s, 2H).

[0249] The following general formula (I) of 4-perfluoroalkylaniline can be prepared in a manner similar to that of Examples (I-1d):

[0250] 2-Chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethoxy)aniline (I-5)

[0251] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.45 (s, 1H), 7.30 (s, 1H), 4.59 (s, 2H).

[0252] 2-Chloro-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (I-6)

[0253] 1 H-NMR (CDCl3, 400MHz) δ (ppm) = 7.43s, 1H), 7.17 (s, 1H), 2.54 (q, J = 7.5Hz, 2H), 1.28 (t, J = 7.5Hz, 3H).

Claims

1. Method for preparing compounds of formula (I) in R 1 It is chlorine or bromine. R 2 It is a C1-C4-haloalkyl group, and R 3 It is a C1-C4-alkyl group that is cyano, halogenated, optionally halogenated, or CN-substituted, or optionally halogenated. The method begins with the compound of formula (II). Where R 3' It is a C1-C4-alkyl or C1-C4-alkoxy group that is hydrogen-, cyano-, halogen-, optionally halogen-substituted or CN-substituted, and optionally halogen-substituted. The method includes the following steps (1) and (2): (1) Make 1.0 to 1.5 equivalents of the compound of formula (II) and the compound of formula (II) used, based on the total molar amount. 2 The reaction of a compound with Y, where Y is iodine or bromine, yields a compound of formula (III). Where R 2 and R 3' Having the definition given above, and (2) Chlorinate or bromine a compound of formula (III) with a chlorinating or brominating agent to obtain a compound of formula (I). Its features are, The compound of formula (III) is not isolated from the reaction mixture of step (1) before step (2), and the organic solvent is used in step (1) and is not actively removed after step (1). The same organic solvent is used in steps (1) and (2), and the same organic solvent is selected from ethyl acetate and isopropyl acetate. Step (1) is maintained at a pH of 3 to 7, and Among them, compound R 2 -Y is added in step (1) by continuous metering over a period of 3 to 6 hours.

2. The method according to claim 1, characterized in that... The compound of formula (III) in step (1) is used directly in step (2) in solution form in the organic solvent of step (1).

3. The method according to any one of claims 1 and 2, characterized in that... Steps (1) and (2) are carried out in the same reaction vessel.

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

5. The method according to any one of claims 1 and 2, characterized in that... R 2 It is a fluorine-substituted C1-C4-alkyl group.

6. The method according to claim 5, characterized in that... R 2 It is a perfluoro-C1-C3-alkyl group.

7. The method according to any one of claims 1 and 2, characterized in that... R 3 It is a C1-C3-alkyl, C1-C3-alkoxy, or fluorine-substituted C1-C3-alkoxy group, and R is a C1-C3-alkyl, C1-C3-alkoxy, or fluorine-substituted C1-C3-alkoxy group. 3' It is a C1-C3-alkyl, C1-C3-alkoxy or fluorine-substituted C1-C3-alkoxy group, which is hydrogen, Cl, Br, C1-C3-alkyl or fluorine-substituted C1-C3-alkoxy group.

8. The method according to any one of claims 1 and 2, characterized in that... R 1 It is chlorine or bromine. R 2 It is heptafluoroisopropyl. R 3 It is chlorine, trifluoromethyl, trifluoromethoxy, or difluoromethoxy, and R 3' It can be hydrogen, chlorine, trifluoromethyl, trifluoromethoxy, or difluoromethoxy.

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