Elimination reaction for preparing substituted alkenes

Abstract

The present invention relates to a new process for preparing substituted alkenes of the formula (A), in particular isoxazoline-5,5-vinylcarboxylic acid derivatives of the formula (I).

Description

[0001] Elimination reaction for the production of substituted alkenes

[0002] The present invention relates to a process for preparing substituted alkenes of formula (A), in particular to a process for preparing isoxazoline-5,5-vinylcarboxylic acid derivatives of formula (I) and (V).

[0003] The production of substituted alkenes is an essential process step in a wide variety of synthesis processes in the agrochemical and pharmaceutical industries. Substituted alkenes can usually only be produced cost-intensively and under harsh conditions.

[0004] In particular, isoxazoline-5,5-vinylcarboxylic acid derivatives of the general formula (I) are important precursors of agrochemical active ingredients (cf. WO 2018 / 228985). WO 2018 / 228985 already describes a process for the preparation of isoxazoline-5,5-vinylcarboxylic acid derivatives of the general formula (I). However, the process described therein is only partially suitable for large-scale synthesis due to the use of reagents that are difficult to obtain on an industrial scale, such as trifluoromethanesulfonic anhydride or diazabicycloundecene (DBU).

[0005] The invention was therefore based on the object of providing an elimination reaction for the preparation of substituted alkenes of the formula (A), in particular for the preparation of isoxazoline-5,5-vinylcarboxylic acid derivatives of the formula (I), which is suitable for large-scale synthesis and yet has a high yield and selectivity, so that complex purification methods can be omitted.

[0006] In a first aspect, this object is achieved according to the invention by a process for the preparation of substituted alkenes of the formula (A) wherein

[0007] R 2 H or alkyl,

[0008] R 3 H or alkyl,

[0009] Y CO2R', CN, CHO, CF3, with R 1 Ci-Cs-alkyl, cycloalkyl, unsubstituted benzyl, unsubstituted phenyl, or benzyl or phenyl substituted once or twice by C1-C3 alkyl;

[0010] R 4 , R 5are independently alkyl, cycloalkyl, aryl, heteroaryl, each unsubstituted or substituted, or a heteroatom; or R 4 and R 5 form together with the R 4 and R 5 connecting carbon atom in the compounds of formula (A) is a cycloalkyl, aryl, or heterocyclyl, each unsubstituted or substituted, preferably a substituted isoxazoline, particularly preferably a phenyl-substituted isoxazoline, characterized in that compounds of general formula (B)

[0011] (B), where R 2 , R 3 , R 4 , R 5 and Y have the meanings given above, with a compound of the formula R F SC>2F in the presence of a base and a Lewis acid, where R F is selected from F, CF3, C2F5, C3F7, C4F9, CF2C1, CeF5, alkoxy-CF2, R 6 OCOCF2SO2F with R 6 defined as Ci-Cs-alkyl or cycloalkyl (step 1).

[0012] The process according to the invention provides compounds of formula (A) with high selectivity and yield. Likewise, it is not necessary to use reagents that are difficult to obtain on an industrial scale. Surprisingly, it was found that by using R F SC>2F in combination with a Lewis acid reduced the formation of undesired fluorinated secondary components. Due to the chemical selectivity of the process according to the invention, no complex purification of the product of formula (A) is required, and downstream reactions can be carried out without complex intermediate purification or directly in the reaction mixture. This is particularly important when the undesired secondary components are difficult or impossible to separate from the desired compounds.

[0013] R is preferred F SC>2F represented by SO2F2

[0014] The gas SO2F2 can be produced inexpensively and is therefore well suited for large-scale synthesis according to the present invention. Suitable bases according to the invention are preferably selected from trimethylamine, triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, N,N-dimethylcyclohexylamine, 2-methyl-5-ethylpyridine, pyridine, 3,5-dimethylpyridine, 2,4,6-trimethylpyridine, 2-methylpyridine, 3-methylpyridine, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dibutylformamide, N-methylimidazole (NMI), N-butylimidazole (NBI), 1,3-dimethyl-2-imidazolidinone (DMEU), tetramethylurea (TMU), more preferably from triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine or N,N-dimethylcyclohexylamine.

[0015] Triethylamine, N,N-dimethylcyclohexylamine, or N,N-diisopropylethylamine are particularly preferred as bases. The use of these bases, in particular, leads to high conversions of the compounds of formula (B).

[0016] N,N-dimethylcyclohexylamine is particularly preferred.

[0017] The base is preferably used in amounts of at least 1.8 equivalents, more preferably 2.0 equivalents, particularly preferably at least 2.5 equivalents, based on one equivalent of the compounds of formula (B).

[0018] The base can preferably also be used as a solvent for the process according to the invention. If, alternatively, another solvent is used in addition to the base, the base can be used in amounts of at most 10.0 equivalents, more preferably at most 5.0 equivalents, based on one equivalent of the compounds of formula (B).

[0019] The base is preferably used in amounts between 1.8 and 10, preferably 2.0 and 5.0 equivalents, based on one equivalent of the compounds of formula (B).

[0020] Suitable Lewis acids according to the invention are preferably selected from BF, PF5, and SbR.

[0021] In particular, BF3 is a suitable Lewis acid which can be present as a free gas or as a solution, preferably in acetonitrile, in aliphatic or cyclic ether compounds, as an etherate complex or as a complex with an amine base, more preferably with triethylamine.

[0022] Preferably, BF3 is introduced as a gas, which allows for a simple process, or alternatively preferably as a solution in acetonitrile.

[0023] It is particularly preferred to select SO2F2 for i SCLF and BF3 for the Lewis acid. This combination proves to be cost-effective and allows for high conversion while significantly suppressing the formation of undesirable fluorinated byproducts.

[0024] The Lewis acid is preferably used in amounts of at least 0.8 equivalents, more preferably at least 1.0 equivalents, based on one equivalent of the compounds of formula (B). The Lewis acid is further preferably used in amounts of at most 3.0 equivalents, more preferably at most 1.5 equivalents, based on one equivalent of the compounds of formula (B).

[0025] The Lewis acid is further preferably used in amounts of 0.8 equivalents to 3.0 equivalents, more preferably 1.0 to 1.5 equivalents, based on one equivalent of the compounds of formula (B).

[0026] According to the invention, the compounds of formula (B) are reacted with i SCLF.

[0027] R F SC>2F is preferably used in amounts of at least 0.8 equivalents, more preferably at least 1.0 equivalents, particularly preferably at least 1.2 equivalents, based on one equivalent of the compounds of formula (B).

[0028] R F SC>2F is further preferably used in amounts of at most 4.0 equivalents, more preferably at most 3.0 equivalents, particularly preferably at most 1.5 equivalents, based on one equivalent of the compounds of formula (B).

[0029] R F SC>2F is further preferably used in amounts of 0.8 equivalents to 4.0 equivalents, more preferably in amounts of 1.0 to 3.0 equivalents, even more preferably in amounts of 1.2 to 1.5 equivalents, based on one equivalent of the compounds of formula (B).

[0030] Alternatively, R F SC>2F can also be used in significant excesses. Unconverted R F SC2F can be recycled in subsequent processes. This applies particularly to SO2F2, which is introduced as a gas.

[0031] Step 1 is preferably carried out at a reaction temperature in the range of -20 °C to 120 °C, more preferably in the range of 20 °C to 100 °C.

[0032] More preferably, step 1 is carried out at least partially at a temperature in the range between 60 °C and 100 °C. The elevated temperature can further increase the conversion of the reaction.

[0033] Particularly preferably, step 1 is carried out at an initial temperature of 10 °C to 30 °C and at a connection temperature of 60 °C to 100 °C.

[0034] The reaction time of step 1 is preferably in the range of 6 to 40 h, particularly preferably in the range of 10 to 30 h.

[0035] Further preferably, step 1 is carried out at a temperature in the range between 60°C and 100°C for a period of at least 5 hours, further preferably at least 10 hours, particularly preferably at least 15 hours. Further preferably, step 1 is carried out at a temperature in the range between 60°C and 100°C for a period of 10 to 30 hours. The reaction of step 1 is preferably carried out at atmospheric pressure (1013 hPa). Optionally, however, the reaction can also be carried out under elevated or reduced pressure.

[0036] For example, the reaction can be carried out in the range from 300 hPa to 5000 hPa or from 500 hPa to 2000 hPa, preferably in the range of 1013 hPa ± 200 hPa.

[0037] The reaction of step 1 is preferably carried out in a solvent. Suitable solvents include, in particular, acetonitrile, propionitrile, butyronitrile, acetone, N,N-dimethylacetamide, N-methylpyrrolidinone (NMP), N,N-dimethylformamide (DMF), dimethylpropyleneurea (DMPU), toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (i-PrOAc), dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate (4-methyl-1,3-dioxolan-2-one), ethyl acetate (EtOAc), methyl tert-butyl ether (MTBE), cyclopropyl methyl ether (CPME), methyl THF, 4-methyltetrahydropyran (methyl THP), tert-amyl methyl ether (TAME), dihydrolevoglucosenone (Cyrene), N,N-dimethylcyclohexylamine, or mixtures thereof in any ratios.

[0038] Other nitrogen-containing solvents or organic bases besides the above-mentioned bases N,N-dimethylacetamide, N,N-dimethylformamide or N,N-dimethylcyclohexylamine can also be used.

[0039] Particularly preferred are acetonitrile, toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (i-PrOAc), or N,N-dimethylcyclohexylamine.

[0040] Alternatively, step 1 can be carried out in an excess of the (liquid) base without the use of an additional solvent. In this case, step 1 is carried out in an excess of one of the above-mentioned bases.

[0041] In a second aspect, the object is achieved according to the invention by a process for the preparation of isoxazoline-5,5-vinylcarboxylic acid derivatives of the formula (I), where X 2 H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine or CN,

[0042] X 3 H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, chlorine or CN,

[0043] X 4 H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine or CN,

[0044] X 5H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, chlorine or CN,

[0045] X 6 H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine or CN,

[0046] R 1 Ci-Cs-alkyl, cycloalkyl, unsubstituted benzyl, unsubstituted phenyl or benzyl or phenyl substituted one or more times by C1-C3 alkyl,

[0047] R 2 H or alkyl, characterized in that compounds of the general formula (IV) where R 1 , R 2 , X 2 to X 6 have the meanings given above, with a compound of the formula R F SC>2F in the presence of a base and a Lewis acid, where R F is selected from F, CF3, C2F5, C3F7, C4F9, CF2CI, CeFs, alkoxy-CF2, R 6 OCOCF2SC>2F with R 6 defined as Ci-Cs-alkyl or cycloalkyl (step 1).

[0048] The compounds of formula (I) are also obtained in high yields; large-scale synthesis can be carried out cost-effectively.

[0049] The process features and their technical effects described above for the conversion of compounds of formula (B) into (A) apply equally to the conversion of compounds (IV) into (I):

[0050] R is preferred F SC>2F represented by SO2F2

[0051] According to the invention, suitable bases are preferably selected from trimethylamine, triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, N,N-dimethylcyclohexylamine, 2-methyl-5-ethylpyridine, pyridine, 3,5-dimethylpyridine, 2,4,6-trimethylpyridine, 2-methylpyridine, 3-methylpyridine, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dibutylformamide, N-methylimidazole (NMI), N-butylimidazole (NBI), 1,3-dimethyl-2-imidazolidinone (DMEU), tetramethylurea (TMU), more preferably from triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine or N,N-dimethylcyclohexylamine.

[0052] Particularly preferred bases are triethylamine, N,N-dimethylcyclohexylamine or N,N-diisopropylethylamine.

[0053] The base is preferably used in amounts of at least 1.8 equivalents, more preferably at least 2.0 equivalents, particularly preferably at least 2.5 equivalents, based on one equivalent of the compounds of formula (IV).

[0054] The base can preferably also be used as a solvent for the process according to the invention. If another solvent is used in addition to the base, the base can be used in amounts of at most 10.0 equivalents, more preferably at most 5.0 equivalents, based on one equivalent of the compound of formula (IV). The base can in particular be used in amounts between 1.8 and 10, preferably 2.0 and 5.0 equivalents, based on one equivalent of the compound of formula (IV).

[0055] Suitable Lewis acids according to the invention are preferably selected from BF3, PF5, and SbF5.

[0056] In particular, BF3 is a suitable Lewis acid, which can be present as a free gas or as a solution, preferably in acetonitrile, in aliphatic or cyclic ether compounds, as an etherate complex or as a complex with an amine base, more preferably with triethylamine.

[0057] Preferably, BF3 is introduced as a gas, which allows a simple process, or alternatively preferably reacted as a solution in acetonitrile.

[0058] It is particularly preferred to select SO2F2 for i SCLF and BF3 for the Lewis acid.

[0059] The Lewis acid is preferably used in amounts of at least 0.8 equivalents, more preferably at least 1.0 equivalents, based on one equivalent of the compounds of formula (IV).

[0060] The Lewis acid is further preferably used in amounts of at most 3.0 equivalents, more preferably at most 1.5 equivalents, based on one equivalent of the compounds of formula (IV).

[0061] The Lewis acid is further preferably used in amounts of 0.8 equivalents to 3.0 equivalents, more preferably 1.0 to 1.5 equivalents, based on one equivalent of the compounds of formula (IV). The compounds of formula (IV) are preferably substituted according to the invention with RF SO2F implemented.

[0062] R F SC>2F is preferably used in amounts of at least 0.8 equivalents, more preferably at least 1.0 equivalents, particularly preferably at least 1.2 equivalents, based on one equivalent of the compounds of formula (IV).

[0063] R F SC>2F is further preferably used in amounts of at most 4.0 equivalents, more preferably at most 3.0 equivalents, particularly preferably at most 1.5 equivalents, based on one equivalent of the compounds of formula (IV).

[0064] R F SC>2F is further preferably used in amounts of 0.8 equivalents to 4.0 equivalents, more preferably in amounts of 1.0 to 3.0 equivalents, even more preferably in amounts of 1.2 to 1.5 equivalents, based on one equivalent of the compounds of formula (IV).

[0065] Alternatively, R FSC>2F can also be used in significant excesses. Unconverted R F SC2F can be recycled in subsequent processes. This applies particularly to SO2F2, which is introduced as a gas.

[0066] Step 1 is preferably carried out at a reaction temperature in the range of -20 °C to 120 °C, more preferably in the range of 20 °C to 100 °C.

[0067] More preferably, step 1 is carried out at least partially at a temperature in the range between 60 °C and 100 °C. The elevated temperature can further increase the conversion of the reaction.

[0068] Particularly preferably, step 1 is carried out at an initial temperature of 10 °C to 30 °C and at a connection temperature of 60 °C to 100 °C.

[0069] The reaction time of step 1 is preferably in the range of 6 to 40 h, particularly preferably in the range of 10 to 30 h.

[0070] Further preferably, step 1 is carried out at a temperature in the range between 60°C and 100°C for a period of at least 5 hours, further preferably at least 10 hours, particularly preferably at least 15 hours. Further preferably, step 1 is carried out at a temperature in the range between 60°C and 100°C for a period of 10 to 30 hours.

[0071] The reaction in step 1 is preferably carried out at atmospheric pressure (1013 hPa). Optionally, however, the reaction can also be carried out under elevated or reduced pressure.

[0072] For example, the reaction can be carried out in the range of 300 hPa to 5000 hPa or 500 hPa to 2000 hPa, preferably in the range of 1013 hPa ± 200 hPa. The reaction of step 1 is preferably carried out in a solvent. Suitable solvents are in particular acetonitrile, propionitrile, butyronitrile, acetone, N,N-dimethylacetamide, N-methylpyrrolidinone (NMP), N,N-dimethylformamide (DMF), dimethylpropyleneurea (DMPU), toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (i-PrOAc), dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate (4-methyl-1,3-dioxolan-2-one), ethyl acetate (EtOAc), methyl tert-butyl ether (MTBE), cyclopropyl methyl ether (CPME), methyl THF, 4-methyltetrahydropyran (methyl THP), tert-amyl ethyl ether (TAME), dihydrolevoglucosenone (Cyrene), N,N-dimethylcyclohexyl amine or mixtures in any ratios thereof.

[0073] Other nitrogen-containing solvents or organic bases besides the above-mentioned bases N,N-dimethylacetamide, N,N-dimethylformamide or N,N-dimethylcyclohexylamine can also be used.

[0074] Particularly preferred are acetonitrile, toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (i-PrOAc), or N,N-dimethylcyclohexylamine.

[0075] Alternatively, step 1 can be carried out in an excess of the (liquid) base without the use of an additional solvent. In this case, step 1 is carried out in an excess of one of the above-mentioned bases.

[0076] The preferred embodiments described below refer, where applicable, to all formulas described herein.

[0077] Preferred residual definitions for X 2 to X 6 are the following:

[0078] X 2is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN,

[0079] X 3 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy or CN,

[0080] X 4 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN,

[0081] X 5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy or CN,

[0082] X 6 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN.

[0083] Particularly preferred residual definitions for X 2 to X 6 are the following: X 2 is H,

[0084] X 3 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN,

[0085] X 4 is fluorine, H,

[0086] X 5 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN,

[0087] X 6 is H.

[0088] Particularly preferred residue definitions for X 2 to X 6 are the following:

[0089] X 2 is H,

[0090] X 3 is H or fluorine,

[0091] X 4 is H or fluorine,

[0092] X 5 is H or fluorine,

[0093] X 6 is H.

[0094] Most preferred residue definitions for X 2 to X 6 are the following:

[0095] X 2 is H,

[0096] X 3 is fluorine,

[0097] X 4 is H,

[0098] X 5 is fluorine,

[0099] X 6 is H.

[0100] For further embodiments of the invention:

[0101] R 1 preferably represents methyl, ethyl, isopropyl, n-propyl, 2-methyl-1-propyl, 1-methyl-1-propyl, cyclohexyl, 3-methyl-1-butyl, 1-butyl, 1-pentyl, benzyl or tert-butyl, particularly preferably isopropyl, 2-methyl-1-propyl, 1-methyl-1-propyl, cyclohexyl, 3-methyl-1-butyl, 1-butyl or 1-pentyl, very particularly preferably isopropyl, 2-methyl-1-propyl, 1-methyl-1-propyl, cyclohexyl, 3-methyl-1-butyl and most preferably isopropyl or 2-methyl-1-propyl.

[0102] R 2 preferably represents H, methyl or ethyl.

[0103] Further preferred residue definitions are the following: R 1 is methyl, ethyl, iso-propyl, n-propyl, 2-methyl-1-propyl, 1-methyl-1-propyl, cyclohexyl, 3-methyl-1-butyl, 1-butyl, 1-pentyl, benzyl or tert-butyl,

[0104] R 2 is H, methyl or ethyl,

[0105] Other particularly preferred residue definitions are the following:

[0106] R 1 is methyl, ethyl, iso-propyl, n-propyl, 2-methyl-1-propyl, 1-methyl-1-propyl, cyclohexyl, 3-methyl-1-butyl, 1-butyl or 1-pentyl,

[0107] R 2 is H, methyl or ethyl,

[0108] Other particularly preferred residue definitions are the following:

[0109] R 1 is methyl, ethyl, iso-propyl, n-propyl, 2-methyl-l-propyl, 1-methyl-1-propyl, 3-methyl-1-butyl or 1-butyl,

[0110] R 2 is H or methyl,

[0111] The most preferred residue definitions are the following:

[0112] R 1 is methyl, ethyl, iso-propyl, n-propyl, 2-methyl-l-propyl or 1-butyl,

[0113] R 2 is H,

[0114] Further preferred radical definitions for the compounds of formulas (I), (III), (IV) and (V) are the following:

[0115] X 2 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN,

[0116] X 3 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy or CN,

[0117] X 4 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN,

[0118] X 5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy or CN,

[0119] X 6 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN, R 1is methyl, ethyl, iso-propyl, n-propyl, 2-methyl-1-propyl, 1-methyl-1-propyl, cyclohexyl, 3-methyl-1-butyl, 1-butyl, 1-pentyl, benzyl or tert-butyl,

[0120] R 2 is H, methyl or ethyl,

[0121] Other particularly preferred residue definitions are the following:

[0122] X 2 is H,

[0123] X 3 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN,

[0124] X 4 is fluorine, H,

[0125] X 5 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN,

[0126] X 6 is H,

[0127] R 1 is methyl, ethyl, iso-propyl, n-propyl, 2-methyl-1-propyl, 1-methyl-1-propyl, cyclohexyl, 3-methyl-1-butyl, 1-butyl or 1-pentyl,

[0128] R 2 is H, methyl or ethyl,

[0129] Other particularly preferred residue definitions are the following:

[0130] X 2 is H,

[0131] X 3 is H or fluorine,

[0132] X 4 is H or fluorine,

[0133] X 5 is H or fluorine,

[0134] X 6 is H,

[0135] R 1 is methyl, ethyl, iso-propyl, n-propyl, 2-methyl-l-propyl, 1-methyl-1-propyl, 3-methyl-1-butyl or 1-butyl,

[0136] R 2 is H or methyl,

[0137] The most preferred residual definitions are the following:

[0138] X 2 is H,

[0139] X 3 is fluorine,

[0140] X 4 is H, X 5 is fluorine,

[0141] X 6 is H,

[0142] R 1 is methyl, ethyl, iso-propyl, n-propyl, 2-methyl-1-propyl or 1-butyl,

[0143] R 2 is H, In a further particular embodiment of the invention, the process according to the invention according to the second aspect further comprises the preparation of the compounds of formula (IV) by reacting compounds of formula (III) wherein

[0144] R 2 and X 2 to X 6 have the meanings given above, with compounds of the formula R'-OH, wherein R 1 has the meaning mentioned above. (Steps 0-1)

[0145] In a further particular embodiment of the invention, the compounds of formula (I) where R 1 , R 2 and X 2 to X 6 have the meanings given above, further hydrolyzed in the presence of a base and then protonated in the presence of an acid or alternatively hydrolyzed in the presence of an acid to give compounds of the formula (V)

[0146] (V), where R 2 and X 2 to X6 have the meanings mentioned above. (Step 2)

[0147] The compounds of formulas (I), (III), (IV), and (V) can exist as isomer mixtures: the isomer ratio between (Ia) and (Ib), (IIIa) and (IIIb), (IVa) and (IVb), and (Va) and (Vb) varies. The same applies to the compounds of formulas (A) and (B).

[0148] (IVa) (IVb)

[0149]

[0150] The terms used here are familiar to those skilled in the art. The following definitions apply:

[0151] The CC double bond represents a cis or a trans configuration of the respective

[0152] residues. This means, for example, for compounds of formula (A) that the configurations understand.

[0153] The term "...equivalents relative to one equivalent" refers to the ratios of the amounts of the respective compounds. For example, if the base is used in an amount of 1.8 equivalents relative to one equivalent of a compound of formula (B), this corresponds to a ratio of 1.8 mol to 1 mol.

[0154] Unless defined otherwise elsewhere, the term “alkyl”, according to the invention either on its own or in combination with other terms, such as, for example, haloalkyl, is understood in the context of the present invention to mean a radical of a saturated, aliphatic hydrocarbon group which can be branched (iso-alkyl, contains at least one secondary, tertiary, or quaternary carbon atom in the alkyl chain) or unbranched (n-alkyl). “Alkyl” is understood to mean both unsubstituted and substituted alkyl radicals. The term “alkoxy”, either on its own or in combination with other terms, such as, for example, haloalkoxy, is understood here to mean an O-alkyl radical, where the term “alkyl” has the meaning given above.

[0155] Unless defined otherwise elsewhere, the term "cycloalkyl," either alone or in combination with other terms, is understood according to the invention to mean a C's-Cs cycloalkyl radical, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. "Cycloalkyl" includes both unsubstituted and substituted cycloalkyl radicals.

[0156] Halogen-substituted radicals, e.g. fluoroalkyl, are singly or polyhalogenated up to the maximum possible number of substituents.

[0157] Unless defined otherwise elsewhere, the term "aryl," either alone or in combination with other terms, is understood according to the invention to mean a mono- or polycyclic, preferably a mono- or bicyclic, aromatic hydrocarbon radical having preferably 6, 10, or 14 carbon atoms. An aryl radical may be unsubstituted or monosubstituted or polysubstituted by identical or different substituents. Suitable aryl radicals include, for example, phenyl, 1-naphthyl, 2-naphthyl, and anthracenyl.

[0158] The term "heteroaryl" means a monocyclic or polycyclic, preferably a mono-, bi-, or tricyclic, aromatic hydrocarbon radical having preferably 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms, particularly preferably having 5, 6, 9, 10, 13, or 14 carbon atoms, most preferably having 5 or 6 carbon atoms, in which one or more carbon atoms have each been replaced by a heteroatom independently selected from the group consisting of oxygen, sulfur, and nitrogen (NH). Heteroaryl radicals can preferably have 1, 2, 3, 4, or 5, particularly preferably 1, 2, or 3, heteroatom(s) independently selected from the group consisting of oxygen, sulfur, and nitrogen (NH) as ring member(s). A heteroaryl residue can be unsubstituted or monosubstituted or polysubstituted by identical or different substituents.Als geeignete Heteroaryl-Reste seien beispielsweise Indolizinyl, Benzimidazolyl, Tetrazolyl, Triazinyl, Isoxazolyl, Phthalazinyl, Carbazolyl, Carbolinyl, Diaza-naphthyl, Thienyl, Furyl, Pyrrolyl, Pyrazolyl, Pyrazinyl, Pyranyl, Triazolyl, Pyridinyl, Imidazolyl, Indolyl, Isoindolyl, Benzo[b]furanyl, Benzo [b]thiophenyl, Benzo [d]thiazolyl, Benzodiazolyl, Benzotriazolyl, Benzoxazolyl, Benzisoxazolyl, Thiazolyl, Thiadiazolyl, Oxazolyl, Oxadiazolyl, Pyridazinyl, Pyrimidinyl, Indazolyl, Chinoxalinyl, Chinazolinyl, Chinolinyl, Naphthridinyl und Isochinolinyl genannt.

[0159] In the context of the present invention, aryl or heteroaryl residues can be condensed (annelated) with a mono- or bicyclic ring system. Examples of aryl residues that are condensed with a mono- or bicyclic ring system are (2,3)-dihydrobenzo[b]thiophenyl, (2,3)-dihydro- IH-indenyl, indolinyl, (2,3)-dihydrobenzofuranyl, (2,3)-dihydrobenzo[d]oxazolyl, benzo[d][l,3]dioxolyl, benzo[d][l,3]oxathiolyl, isoindolinyl, (1,3)-dihydroisobenzofuranyl, (1,3)-dihydrobenzo[c]thiophenyl, (1,2,3,4)-tetrahydronaphthyl, (1,2,3,4)-tetrahydroquinolinyl, chromanyl, thiochromanyl, (1,2,3,4)-tetrahydroisoquinolinyl, (1,2,3,4)-Tetrahydroquinoxalinyl, (3,4)-Dihydro-2H-benzo [b] [1,4]oxazinyl, (3,4)-Dihydro-2H-benzo [b] [1,4]thiazinyl, (2,3)-Dihydro-benzo [b] [1,4] dioxinyl, (2,3)-Dihydrobenzo[b][l,4]oxathiynyl, (6,7,8,9)-Tetrahydro-5H-benzo[7]annulenyl, (2, 3,4,5)-

[0160] Tetrahydro-1H-benzo[b]azepinyl and (2,3,4,5)-tetrahydro-1H-benzo[c]azepinyl are called.

[0161] The term "heterocyclyl" generally refers to cyclic systems containing at least two different elements, especially N or O, or N and O in combination with ring-forming carbon atoms. These heterocyclic systems can be saturated or aromatic, as well as mono- or polysubstituted. An example is isoxazoline, preferably substituted.

[0162] If one of the above-mentioned radicals is mono- or polysubstituted, suitable substituents are all those familiar to the person skilled in the art, preferably those which are independently selected from the group consisting of F, Cl, Br, I, -NO2, -CN, -OH, -SH, -NH2, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluoroalkoxy, -N(C1-5-alkyl)2, -N(C1-5-alkyl)(phenyl), -N(C1-5-alkyl)(CH2-phenyl), -N(C1-5-alkyl)(CH2-CH2-phenyl), -NH-C(=O)-O-C1-5-alkyl, -C(=O)-H, -C(=O)-C1-5-alkyl, -C(=O)-phenyl, -C(=S)-C1-5-alkyl, -C(=S)-Phenyl, -C(=O)-OH, -C(=O)-O-Ci.5-Alkyl, -C(=O)-O-Phenyl, -C(=O)-NH2, -C(=O)-NH-Ci.5-Alkyl, -C(=O)-N(Ci.5-Alkyl)2, -S(=O)-Ci.5-Alkyl, - S(=O)- phenyl, -S(=O)2- Ci.5-alkyl, -S(=O)2-phenyl, -S(=O)2-NH2 and -SO3H.

[0163] The general areas listed above, or those listed in priority areas, apply accordingly to the entire procedure. These definitions can be combined with each other, including between the respective priority areas.

[0164] According to the invention, processes are preferably used in which a combination of the meanings and ranges listed above as preferred is present.

[0165] According to the invention, processes in which a combination of the meanings and ranges listed above as being particularly preferred are particularly preferred are used.

[0166] According to the invention, very particular preference is given to using processes in which a combination of the meanings and ranges listed above as being very particularly preferred is present.

[0167] According to the invention, methods are most preferably used in which a combination of the meanings and ranges listed above as being particularly preferred is present.

[0168] Explanation of the processes and intermediates

[0169] Step 0-1 The process according to the invention may comprise a step 0-1 in which the production of the

[0170] Compounds of formula (IV) where R 1 , R 2 andX 2 to X 6 have the meanings given above, by reacting compounds of formula (III) where R 2 , and X 2 to X 6 have the meanings given above, with compounds of the formula R'-OH, wherein R 1 has the meaning given above.

[0171] The preparation of compounds of formula (III) is described, for example, in WO 2018 / 228985.

[0172] The esterification of compound (III) with alcohols of the formula R'-OH to compound (IV) can be carried out, for example, in the presence of 1.0 to 1.3 equivalents of thionyl chloride or catalytic amounts

[0173] Sulphuric acid, based on one equivalent of the compounds of formula (III), at 0 to 80 °C (at

[0174] Normal pressure) for 1.5 to 3 hours. Compounds of the formula R'-OH are preferably used as reactant and solvent in a significant excess of, for example, 4 to 8 equivalents.

[0175] The esterification of compound (III) with alcohols of formula R 1 -OH to compound (IV) can generally be carried out under all conditions known in the art for such reactions. The compounds of formula (IV) can be isolated and further characterized by suitable workup steps generally known to those skilled in the art and subsequently used in step 1.

[0176] Step 1

[0177] The preferred process according to the invention comprises a step 1 in which the preparation of the compounds of formula (I) where R 1 , R 2 , and X 2 to X 6 have the meanings given above, by reacting compounds of formula (IV) where R 1 , R 2 and X 2 to X 6 have the meanings given above, with R F SO2F, where R F has the meaning given above, in the presence of a base and a Lewis acid such as BF.

[0178] Scheme 2

[0179] In this step, compounds of formula (II) are formed as intermediates, which are increasingly converted into compounds of formula (I) during the reaction.

[0180] Step 2 The process according to the invention can further comprise the hydrolysis of compounds of formula (I) to compounds of formula (V)

[0181] (V), where R 2 and X 2 to X 6 have the meanings given above, in the presence of a base followed by protonation in the presence of an acid, or alternatively hydrolysis in the presence of an acid.

[0182] Scheme 3:

[0183] (I) (V) Suitable bases are, in particular, inorganic bases, such as, for example, carbonates (such as, for example, (NH4)2CO3, Li2CO3, Na2CO3, K2CO3, CaCO3, MgCO3), bicarbonates (such as, for example, NF UHCO3, LiHCO3, NaHCO3, KHCO3) or hydroxides (such as, for example, LiOH, NaOH, KOH, Ca(OH)2). Particular preference is given to alkali metal or alkaline earth metal hydroxides, very particular preference being given to KOH or NaOH. The base is preferably used as an aqueous solution in concentrations of 1-50% by weight, more preferably as an aqueous solution in concentrations of 5-45% by weight, most preferably as an aqueous solution in concentrations of 5-35% by weight.

[0184] The reaction with the base is preferably carried out at a reaction temperature in the range of 0 °C to 90 °C, particularly preferably in the range of 10 °C to 80 °C and most preferably in the range of 15 °C to 60 °C.

[0185] The reaction is preferably carried out in the range of normal pressure (1013 hPa), e.g. in the range from 300 hPa to 5000 hPa or from 500 hPa to 2000 hPa, preferably in the range of 1013 hPa ± 200 hPa.

[0186] The reaction time of the hydrolysis is preferably in the range of 0.5 h to 10 h.

[0187] The hydrolysis of the compounds of formula (I) to compound (V) can generally be carried out under all conditions known in the art for such reactions.

[0188] The compounds of formula (I) can be isolated and further characterized by suitable work-up steps generally known to the person skilled in the art, such as extraction and, if appropriate, distillation.

[0189] In general, following step 1, instead of hydrolysis (step 2), a transesterification of the compound of formula (I) at position R 1 take place.

[0190] Alternatively, step 2 can also be carried out in the presence of an acid.

[0191] Overall procedure

[0192] In an advantageous embodiment, the method according to the invention comprises steps 0-1 and 1, particularly advantageously 0-1, 1 and 2.

[0193] Scheme 4

[0194]

[0195] Scheme 4 provides a schematic representation of the process according to the invention, including all optional and mandatory steps. Reaction conditions and reactants are selected according to the inventive and preferred embodiments described above. All variables in the formulas are defined as described above.

[0196] The compounds of formula (IV) and (I) can be isolated and, if necessary, purified before being used in the next synthesis step. However, it is also possible for the compounds to be used directly in the next step without isolation and purification. If necessary, the solvent and excess reagents from the precursor are removed using standard methods before the compounds are used in the next synthesis step.

[0197] Examples

[0198] The present invention is explained in more detail with reference to the following examples, without limiting the invention to them.

[0199] Measurement method

[0200] The products were analyzed by 'H-NMR and 19 F-NMR spectroscopy and HPLC (High Performance Liquid Chromatography).

[0201] The NMR spectra were determined using a Bruker Avance 400 equipped with a flow-through probe (60 μl volume). The NMR data for the examples are presented in classical form (5-values, multiplet splitting, number of H or F atoms).

[0202] The solvent and frequency in which the NMR spectrum was recorded are indicated.

[0203] HPLC (High Performance Liquid Chromatography) was performed on an Agilent 1100 LC system with the following parameters: a) for reaction control (HPLC area%) column: 150 x 4.6 mm, stainless steel; stationary phase: Phenomenex, Luna 5pm C18 100 Å; mobile phase: acetonitrile / water (with 0.25 mL / L trifluoroacetic acid) 63 / 37 (v / v), isocratic elution; oven temperature: 40 °C; flow: 2.0 mL / min; run time: 6 min, injection volume: 1 μL. b) for the quantification of (V)

[0204] Column: 100 x 4.6 mm, stainless steel; stationary phase: Daicel, Chiracel OZ-3; mobile phase: heptane / ethanol 90 / 10 (v / v), isocratic elution; oven temperature: 40 °C; flow rate: 1.0 mL / min; run time: 10 min, injection volume: 5 μL. An instrument with UV detection and external standard quantification was used.

[0205] Example I: Preparation of 3-(3,5-dichlorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid according to the invention

[0206] Step 0-1: Isopropyl 3-(3,5-difluorophenyl)-5-(l-hydroxyethyl)-4H-isoxazole-5-carboxylate

[0207] A suspension of 500 g of 3-(3,5-difluorophenyl)-5-(l-hydroxyethyl)-4H-isoxazole-5-carboxylic acid (1808 mmol, 98.1 wt% purity) in 1100 g of 2-propanol (99.0%) at 20 °C was heated to an internal temperature of 50 °C. 260.1 g of thionyl chloride (2176 mmol, 99.5%) was added over 3 h using a metering pump. The solution was then allowed to react for another 3 h at 50 °C. At the end of the reaction, a solid precipitated from the solution, especially after the suspension cooled to room temperature. The conversion of 3-(3,5-difluorophenyl)-5-(l-hydroxyethyl)-4H-isoxazole-5-carboxylic acid or the formation of isopropyl 3-(3,5-difluorophenyl)-5-(l-hydroxyethyl)-4H-isoxazole-5-carboxylate can be analyzed by HPLC. The yield of the desired isopropyl 3-(3,5-difluorophenyl)-5-(l-hydroxyethyl)-4H-isoxazole-5-carboxylate was > 98%.

[0208] Step 1

[0209] Example La:

[0210] In a 250 ml four-necked flask equipped with a reflux condenser, 50 g of isopropyl 3-(3,5-difluorophenyl)-5-(l-hydroxyethyl)-4H-isoxazole-5-carboxylate was placed as a suspension in 66 ml of acetonitrile at 20 °C. The mixture was purged with nitrogen. A total of 12.86 g of BR gas (4.5 L; 1.2 eq) was then introduced over the liquid surface. Pressure equalization was achieved using a balloon. The gas quickly dissolved in the mixture; a solution formed after approximately 4 g of addition. The gas was added over a period of 30 minutes. The solution was then stirred for 35 minutes, and 60.92 g of N,N-dimethylcyclohexylamine (3 eq) was slowly added. The temperature was maintained at 20 °C. After 1 h, 17.75 g of SO2F2 (4.1 L; 1.09 eq) were added, and the mixture was heated to 80 °C. The mixture was then kept at 80 °C for a total of 19 h.

[0211] The sample was analyzed by HPLC and found to be 98% isopropyl 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylate.

[0212] Example 1b: In a 250 mL reactor equipped with a reflux condenser, 124.9 g of a suspension of isopropyl 3-(3,5-difluorophenyl)-5-(l-hydroxyethyl)-4H-isoxazole-5-carboxylate in xylene (38.4 wt%) were placed under nitrogen, and 10 g of acetonitrile were added. At 20 °C, 82.5 g of BR-acetonitrile solution (15.2% in acetonitrile) were then added dropwise over 20 min. After the addition was complete, the resulting solution was stirred for a further 10 min at 20 °C, and then 78.0 g of N,N-dimethylcyclohexylamine (4 eq) was added dropwise over a period of 2 h, ensuring that a temperature of 25 °C was not exceeded. Finally, 20.0 g SO2F2 (1.2 eq) were added below the liquid level at 20-25 °C over 4 h. After complete addition, the reaction was stirred at 20 °C for 10 min and then heated to 80 °C over 6 h and stirred at this temperature for a further 15 h.

[0213] A sample was analyzed by HPLC and found to be >99% isopropyl 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylate.

[0214] Step 2

[0215] Example 2.a:

[0216] The mixture from Example La was distilled at an internal temperature of 75 °C and up to 90 mbar. Hydrolysis was carried out with 126.4 g of NaOH (20 wt. %, 4 equivalents). The solution was stirred at 65 °C for 25 minutes until saponification was complete. HLPC analysis after acidification of a reaction mixture sample yielded 98% 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid.

[0217] Example 2.b:

[0218] At 80 °C, 86 g of acetonitrile were removed by distillation from the batch of Example 1b up to 300 mbar, and the reaction mixture was diluted with 80 g of xylene. After adding 156 g of water, the phases were separated, and the aqueous phase was extracted again with 25 g of xylene. The combined organic phases were treated with 156 g of water, 9.2 g of isopropanol, and 61.4 g of NaOH (20 wt.%, 2.0 eq). The reaction mixture was stirred for 8 h at 50 °C, so that the completeness of the saponification was determined by HLPC analysis. After acidification of a reaction mixture sample, 98% of 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid was obtained. The separated aqueous phase can be further processed for disposal. For this purpose, it is mixed with potassium hydroxide or another potassium base up to a pH value > 9.The resulting potassium tetrafluoroborate salt (KBF4) is separated by filtration; additional removal of fluoride can also be carried out as required using agents commonly known to the expert.

[0219] Reprocessing

[0220] Example 3.a After complete saponification of the batch from Example 2.a, the mixture was distilled at 53-56 °C under vacuum to remove N,N-dimethylcyclohexyl amine by azeotropic distillation, and the lower water phase of the distillate was repeatedly added to the reaction mixture.

[0221] After distillation, the reaction mixture was added to 2.5 eq of hydrochloric acid in 100 mL of water, cooled in an ice bath. The product initially precipitated as an oil and crystallized overnight at room temperature to form a solid. The solid was filtered off with suction, washed with 250 mL of water, and then dried in air. 40.95 g of the desired 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid were isolated. The purity was determined by quantitative HPLC and was found to be 95% (corresponding to a yield of 97%).

[0222] Example 3.b

[0223] After complete saponification and cooling of the mixture from Example 2.b to 20 °C, the phases were separated and the organic phase discarded. The aqueous phase was then adjusted to pH 1-2 by adding 32 wt.% hydrochloric acid, and the product was extracted three times with a total of 130 g of tert-butyl methyl ether. The combined organic extracts were completely concentrated in vacuo at 40 °C, and the product was isolated as a solid. 38.6 g of the desired 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid were isolated. The purity was determined by quantitative HPLC and was 96.1% (corresponding to a yield of 96%).

[0224] The NMR data of the isolated and purified products and intermediates were determined as follows:

[0225] Isopropyl 3-(3,5-difluorophenyl)-5-(l-hydroxyethyl)-4H-isoxazole-5-carboxylate (after step 0-1)

[0226] ’H-NMR (400MHz, CDC13): 5 (ppm) = 1.28-1.32 (m, 9H), 2,18 (s, 1H), 3.53 (d, J= 17.4 Hz, 1H), 3.67 (d, J= 17.4 Hz, 1H), 4.22 (q, J= 6.5 Hz, 1H), 5.13 (hept, J= 6.3 Hz, 1H), 6.84-6.91 (m, 1H), 7.15-7.22 (m, 2H).

[0227] 19 F-NMR (376MHZ, CDCh): 5 (ppm) = -108.4 (m, 2F).

[0228] Isopropyl-3-(3,5-difluorphenyl)-5-vinyl-4H-isoxazol-5-carboxylat (nach Schritt 1)

[0229] ’H-NMR (401MHz, CDCh): 5 (ppm) = 1.31 (dd, J= 6.3, 1.0 Hz, 6H), 3.31 (d, J= 17.0 Hz, 1H), 3.89 (d, J= 17.0 Hz, 1H), 5.11 (hept, J= 6.3 Hz, 1H), 5.36 (d, J= 10.7 Hz, 1H), 5.54 (d, J= 17.2 Hz, 1H), 6.13 (dd, J= 17.2, 10.7 Hz, 1H), 6.84-6.90 (m, 1H), 7.15-7.22 (m, 2H).

[0230] 19 F-NMR (376MHZ, CDCh): 5 (ppm) = -108.4 (m, 2F).

[0231] 3-(3,5-Difluorphenyl)-5-vinyl-4H-isoxazol-5-carbonsäure (nach Schritt 2) ’H-NMR (400MHz, CDC13): 5 (ppm) = 3.40 (d, J= 17.1 Hz, 1H), 3.92 (d, J= 17.1 Hz, 1H), 5.44 (d, J =

[0232] 10.7 Hz, 1H), 5.63 (d, J= 17.2 Hz, 1H), 6.16 (dd, J = 17.2, 10.7 Hz, 1H), 6.86-6.92 (m, 1H), 7.14-7.21

[0233] (m, 2H), 9.61 (bs, 1H).

[0234] 19 F-NMR (376MHZ, CDCI3): 5 (ppm) = -108.0 (m, 2F).

[0235] Example II: Preparation of 3-(3,5-Difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid with and without Lewis acid

[0236] In a comparative experiment, the procedure described in Examples 1a, 2.a, and 3.a was used, but without Lewis acid in reaction batches 2 and 3. Acetonitrile was used as the solvent.

[0237] The respective yields of the desired isopropyl 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylate (I) or, after hydrolysis, the desired 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid (V) are listed in the "Yield I, %" column of the table below. Yields were measured in Examples 4 to 6, in which the reaction temperature was successively increased during the reaction (room temperature (RT), 80 °C, 100 °C, each maintained for the times specified in the "Time" column), at random during the reaction according to the reaction times and temperatures specified in the respective rows.

[0238] * The number in parentheses represents the isolated yield of the acid (V).

[0239] ** Yield of (V) instead of (I), HPLC area%, after hydrolysis according to the procedure described above

[0240] Step 2

[0241] *** The reaction was carried out under 3.5 bar in a glass autoclave. While the presence of the Lewis acid in reaction mixtures 1 and 4 to 6 according to the present invention leads to a high HPLC yield and up to 97% isolated yield of the desired product (V), 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid, the yields without Lewis acid (reaction mixtures 2 and 3) in the HPLC are a maximum of 70% with high amounts of undesirable byproduct VI.

Claims

Patent claims:

1. Process for the preparation of compounds of formula (I) (I), wherein R 1 Ci-Cs-alkyl, cycloalkyl, unsubstituted benzyl, unsubstituted phenyl or benzyl or phenyl substituted one or more times by C1-C3 alkyl, R 2 H or alkyl, X 2 H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine or CN, X 3 H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, chlorine or CN, X 4 H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine or CN, X 5 H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine, chlorine or CN, X 6 H, Ci-C4-alkyl, Ci-C4-fluoroalkyl, Ci-C4-fluoroalkoxy, Ci-C4-alkoxy, fluorine or CN, characterized in that compounds of the general formula (IV) where R 1 , R 2 , X 2 , X 3 , X 4 , X 5 and X 6 have the meanings given above, with a compound of the formula R F SC>2F in the presence of a base and a Lewis acid, where R F is selected from F, CF3, C2F5, C3F7, C4F9, CF2C1, CeF5, alkoxy-CF2, and R 6 OCOCF2SO2F with R 6 defined as Ci-Cs-alkyl or cycloalkyl.

2. Process according to claim 1, characterized in that the base is selected from Trimethylamine, triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, N,N-dimethylcyclohexylamine, 2-methyl-5-ethylpyridine, pyridine, 3, 5-dimethylpyridine, 2,4,6- Trimethylpyridine, 2-methylpyridine, 3-methylpyridine, N,N-dimethylacetamide, N,N-dimethylformamide, N,N-dibutylformamide, N-methylimidazole (NMI), N-butylimidazole (NBI), l,3-dimethyl-2-imidazolidinone (DMEU), tetramethyl urea (TMU).

3. Process according to claim 1, characterized in that the base is selected from Triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine and N,N- Dimethylcyclohexylamine .

4. Process according to one of claims 1 to 3, characterized in that the base is used in amounts between 1.8 and 10.0 equivalents, preferably between 2.0 and 5.0 equivalents, based on one equivalent of the compounds of formula (IV).

5. Process according to one of claims 1 to 4, characterized in that the Lewis acid is selected from BF3, PF5, and SbFs.

6. Process according to one of claims 1 to 5, characterized in that the Lewis acid is represented by BF3, preferably BF3 introduced as a gas or BF3 as a solution in acetonitrile.

7. Process according to one of claims 1 to 6, characterized in that the Lewis acid is used in amounts between 0.8 and 3.0 equivalents, preferably 1.0 to 1.5 equivalents, based on one equivalent of the compounds of formula (IV). Method according to one of claims 1 to 7, characterized in that R F F. Method according to one of claims 1 to 8, characterized in that R FS02F is used in amounts between 0.8 and 4.0 equivalents, preferably between 1.0 and 3.0 equivalents, based on one equivalent of the compounds of formula (IV). Process according to one of claims 1 to 9, characterized in that the process is carried out in a solvent selected from acetonitrile, propionitrile, butyronitrile, acetone, N,N-dimethylacetamide, N-methylpyrrolidinone (NMP), N,N-dimethylformamide (DMF), dimethylpropyleneurea (DMPU), toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (i-PrOAc), dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate (4-methyl-1,3-dioxolan-2-one), ethyl acetate (EtOAc), methyl tert-butyl ether (MTBE), cyclopropyl methyl ether (CPME), methyl THF, 4-methyltetrahydropyran (methyl THP), tert-amyl methyl ether (TAME), dihydrolevoglucosenone (Cyrene), N,N-dimethylcyclohexyl amine or mixtures in any ratios thereof is carried out.A process according to any one of claims 1 to 10, characterized in that the process is carried out at least partially at a temperature in the range between 60°C and 100°C. A process according to any one of claims 1 to 11, characterized in that it further comprises the preparation of compounds of formula (IV) by reacting compounds of formula (III). with compounds of the formula R'-OH, wherein R 1 , R 2 andX 2 to X 6 have the meanings given in claim 1. Process according to one of claims 1 to 12, characterized in that it further comprises the reaction of the compounds of formula (I) (I), to compounds of formula (V) (V), where R 1 , R 2 and X 2 to X 6have the meanings given in claim 1, in the presence of a base or acid. Process according to one of claims 1 to 13, characterized in that X 2 H is methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN; X 3 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy or CN, X 4 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN, X 5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy or CN, X 6 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN. Process according to one of claims 1 to 14, characterized in that X 2 H is, X 3 H or fluorine, X 4H or fluorine, X 5 H or fluorine, and X 6 is H.

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