Elimination reactions for the preparation of substituted alkenes

Abstract

The present invention relates to a novel process for preparing substituted alkenes of formula (A), in particular isoxazoline-5,5-vinylcarboxylic acid derivatives of formula (I). TIFF2025526902000031.tif82170

Description

[Technical Field]

[0001] The present invention relates to a process for the preparation of substituted alkenes of formula (A), in particular to a process for the preparation of isoxazoline-5,5-vinylcarboxylic acid derivatives of formulae (I) and (V). [Background technology]

[0002] The preparation of substituted alkenes is an essential process step in a wide variety of synthetic processes in the agrochemical and pharmaceutical industries. Substituted alkenes can usually only be prepared using harsh conditions at high cost.

[0003] In particular, isoxazoline-5,5-vinylcarboxylic acid derivatives of the general formula (I) are important precursors of active pesticide ingredients (see WO 2018 / 228985). WO 2018 / 228985 already describes a method for preparing isoxazoline-5,5-vinylcarboxylic acid derivatives of the general formula (I). However, the method described therein is only suitable for industrial-scale synthesis to a limited extent due to the use of reactants that are difficult to obtain on an industrial scale, such as trifluoromethanesulfonic anhydride or diazabicycloundecene (DBU). [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2018 / 228985 Brochure Summary of the Invention [Problem to be solved by the invention]

[0005] It is therefore an object of the present invention to provide an elimination reaction for preparing substituted alkenes of formula (A), in particular for preparing isoxazoline-5,5-vinylcarboxylic acid derivatives of formula (I), which is suitable for synthesis on an industrial scale, nevertheless with high yields and selectivities, so that laborious purification procedures can be dispensed with. [Means for solving the problem]

[0006] In a first aspect, this object according to the invention is to provide a compound of formula (A) [ka] [During the ceremony, R 2 is H or alkyl, R 3 is H or alkyl, Y is CO2R 1 , CN, CHO, CF3, where R 1 is C1-C8-alkyl, cycloalkyl, unsubstituted benzyl, unsubstituted phenyl or mono- or di-C1-C3-alkyl-substituted benzyl or phenyl; R 4 , R 5 are each independently alkyl, cycloalkyl, aryl, heteroaryl (in each case unsubstituted or substituted), or a heteroatom; or R 4 and R 5 is R in the compound of formula (A) 4 and R 5 together with the carbon atom to which it is attached to form a cycloalkyl, aryl, or heterocyclyl (in each case unsubstituted or substituted), preferably a substituted isoxazoline, particularly preferably a phenyl-substituted isoxazoline. 1. A process for preparing a substituted alkene of formula: General formula (B) [ka] [In the formula, R 2 , R 3 , R 4 , R 5 and Y has the above definition. in the presence of a base and a Lewis acid to form a compound of formula R F SO2F (where R F is F, CF3, C2F5, C3F7, C4F9, CF2Cl, C6F5, alkoxy-CF2, R 6 OCOCF2SO2F (where R 6 is achieved by a process characterized in that (step 1) the compound of formula (I) is reacted with a compound of formula (I) selected from the group consisting of C1-C8-alkyl or cycloalkyl.

[0007] The process according to the invention allows compounds of formula (A) to be obtained with high selectivity and yield. Likewise, it is not necessary to use reagents that are difficult to obtain on an industrial scale. Surprisingly, the Lewis acid R F It has been found that the use of SO2F can reduce the formation of undesired fluorinated secondary compounds. Due to the chemical selectivity of the process according to the present invention, laborious purification of the product of formula (A) is not 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 compounds are difficult or impossible to separate from the desired compound.

[0008] R F The SO2F is preferably SO2F2.

[0009] Gaseous SO2F2 can be prepared cost-effectively and is therefore well suited for industrial-scale synthesis according to the present invention.

[0010] Suitable bases according to the present 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.

[0011] As the base, triethylamine, N,N-dimethylcyclohexylamine, or N,N-diisopropylethylamine is particularly preferred, in particular, the use of these bases leads to a high conversion rate of the compound of formula (B).

[0012] N,N-dimethylcyclohexylamine is particularly preferred.

[0013] The base is preferably used in an amount of at least 1.8 equivalents, more preferably 2.0 equivalents, particularly preferably at least 2.5 equivalents relative to 1 equivalent of the compound of formula (B).

[0014] Preferably, the base can also be used as a solvent for the process according to the invention. Alternatively, if another solvent is used in addition to the base, the base can be used in an amount of at most 10.0 equivalents, more preferably at most 5.0 equivalents, relative to 1 equivalent of the compound of formula (B).

[0015] The base is used in an amount of preferably 1.8 to 10 equivalents, more preferably 2.0 to 5.0 equivalents, relative to 1 equivalent of the compound of formula (B).

[0016] Suitable Lewis acids according to the present invention are preferably selected from BF3, PF5, and SbF5.

[0017] In particular, BF3 is a suitable Lewis acid and can be present as a free gas or in solution, preferably in acetonitrile, in aliphatic or cyclic ether compounds, as an ether complex, or as a complex with an amine base, more preferably as a complex with triethylamine.

[0018] Preferably, the BF3 is introduced as a gas, which allows for easy process control, or preferably reacted as a solution in acetonitrile.

[0019] R F Particularly preferred is the selection of SO2F2 as the SO2F and BF3 as the Lewis acid, as this combination has proven to be cost-effective and allows high conversion rates while significantly suppressing the formation of undesired fluorinated secondary components.

[0020] The Lewis acid is preferably used in an amount of at least 0.8 equivalents, more preferably at least 1.0 equivalent, relative to 1 equivalent of the compound of formula (B).

[0021] The Lewis acid is more preferably used in an amount of at most 3.0 equivalents, more preferably at most 1.5 equivalents, relative to 1 equivalent of the compound of formula (B).

[0022] The Lewis acid is more preferably used in an amount of 0.8 to 3.0 equivalents, and even more preferably 1.0 to 1.5 equivalents, relative to 1 equivalent of the compound of formula (B).

[0023] Compounds of formula (B) can be prepared according to the present invention by reacting F React with SO2F.

[0024] where R FSO2F is preferably used in an amount of at least 0.8 equivalents, more preferably at least 1.0 equivalent, particularly preferably at least 1.2 equivalents relative to 1 equivalent of the compound of formula (B).

[0025] R F SO2F is further preferably used in an amount of at most 4.0 equivalents, more preferably at most 3.0 equivalents, and particularly preferably at most 1.5 equivalents relative to 1 equivalent of the compound of formula (B).

[0026] R F SO2F is more preferably used in an amount of 0.8 to 4.0 equivalents, more preferably 1.0 to 3.0 equivalents, and even more preferably 1.2 to 1.5 equivalents relative to 1 equivalent of the compound of formula (B).

[0027] Alternatively, R F SO2F can be used in significant excess. F The SO2F can be reacted again in further processes, this is especially true for SO2F2 introduced as a gas.

[0028] 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.

[0029] More preferably, step 1 is carried out at least in part at a temperature in the range of 60° C. to 100° C. Higher temperatures can further improve the conversion rate of the reaction.

[0030] In particular, it is preferable to carry out step 1 at an initial temperature of 10°C to 30°C and a final temperature of 60°C to 100°C.

[0031] The reaction time in step 1 is preferably in the range of 6 to 40 hours, particularly preferably in the range of 10 to 30 hours.

[0032] More preferably, step 1 is carried out at a temperature in the range of 60°C to 100°C for at least 5 hours, more preferably at least 10 hours, and particularly preferably at least 15 hours.More preferably, step 1 is carried out at a temperature in the range of 60°C to 100°C for 10 to 30 hours.

[0033] The reaction of step 1 is preferably carried out in the region of standard pressure (1013 hPa). Optionally, the reaction can alternatively be carried out under elevated or reduced pressure.

[0034] For example, the reaction can be carried out preferably in the range of 300 hPa to 5000 hPa or 500 hPa to 2000 hPa, preferably in the range of 1013 hPa±200 hPa.

[0035] The reaction of step 1 is preferably carried out in a solvent, where 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 (iPrOAc), 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 (silene), N,N-dimethylcyclohexylamine or a mixture thereof in any ratio.

[0036] In addition to the aforementioned bases N,N-dimethylacetamide, N,N-dimethylformamide or N,N-dimethylcyclohexylamine, other nitrogen-containing solvents or organic bases can be used.

[0037] Particularly preferred are acetonitrile, toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (i-PrOAc), or N,N-dimethylcyclohexylamine.

[0038] Alternatively, step 1 can be carried out in an excess of (liquid) base without the use of an additional solvent, in which case step 1 is in particular carried out with an excess of one of the above bases.

[0039] In a second aspect, the object according to the invention is to provide a compound of formula (I) [ka] [During the ceremony, X 2 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine or CN, X 3 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine, chlorine or CN, X 4 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine or CN, X 5 is H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 alkoxy, fluorine, chlorine or CN; X 6 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine or CN, R 1 is C1-C8-alkyl, cycloalkyl, unsubstituted benzyl, unsubstituted phenyl or mono- or di-C1-C3-alkyl-substituted benzyl or phenyl; R 2 is H or alkyl. 1. A process for preparing an isoxazoline-5,5-vinylcarboxylic acid derivative of the formula General formula (IV) [ka] [In the formula, R 1 , R 2 , X 2 ~X 6 has the definition above] in the presence of a base and a Lewis acid to form a compound of formula R F SO2F (where R F is F, CF3, C2F5, C3F7, C4F9, CF2Cl, C6F5, alkoxy-CF2, R 6 OCOCF2SO2F (where R 6 is achieved by a process characterized in that (step 1) the compound of formula (I) is reacted with a compound of formula (I) selected from the group consisting of C1-C8-alkyl or cycloalkyl.

[0040] Compounds of formula (I) are also obtained in high yields and industrial scale syntheses can be designed cost-effectively.

[0041] The process features described above and their technical effects on the conversion of compounds of formula (B) to compounds of formula (A) apply equally to the conversion of compound (IV) to compound (I): R F The SO2F is preferably SO2F2.

[0042] Suitable bases according to the present 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 triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine or N,N-dimethylcyclohexylamine.

[0043] As base, triethylamine, N,N-dimethylcyclohexylamine or N,N-diisopropylethylamine are particularly preferred.

[0044] The base is preferably used in an amount of at least 1.8 equivalents, more preferably at least 2.0 equivalents, particularly preferably at least 2.5 equivalents relative to 1 equivalent of the compound of formula (IV).

[0045] Preferably, the base can also be used as a solvent for the process according to the present invention. When using another solvent in addition to the base, the base can be used in an amount of at most 10.0 equivalents, more preferably at most 5.0 equivalents, relative to 1 equivalent of the compound of formula (IV). The base can be used in an amount of 1.8 to 10 equivalents, preferably 2.0 to 5.0 equivalents, relative to 1 equivalent of the compound of formula (IV).

[0046] Suitable Lewis acids according to the present invention are preferably selected from BF3, PF5, and SbF5.

[0047] In particular, BF3 is a suitable Lewis acid and can be present as a free gas or in solution, preferably in acetonitrile, in aliphatic or cyclic ether compounds, as an ether complex, or as a complex with an amine base, more preferably as a complex with triethylamine.

[0048] Preferably, the BF3 is introduced as a gas, which allows for easy process control, or preferably reacted as a solution in acetonitrile.

[0049] R F It is particularly preferred to select SO2F2 as the SO2F and BF3 as the Lewis acid.

[0050] The Lewis acid is preferably used in an amount of at least 0.8 equivalents, more preferably at least 1.0 equivalent, relative to 1 equivalent of the compound of formula (IV).

[0051] The Lewis acid is more preferably used in an amount of at most 3.0 equivalents, more preferably at most 1.5 equivalents, relative to 1 equivalent of the compound of formula (IV).

[0052] The Lewis acid is used in an amount of preferably 0.8 to 3.0 equivalents, more preferably 1.0 to 1.5 equivalents, relative to 1 equivalent of the compound of formula (IV).

[0053] Compounds of formula (IV) can be prepared according to the present invention by reacting F React with SO2F.

[0054] where R F SO2F is preferably used in an amount of at least 0.8 equivalents, more preferably at least 1.0 equivalent, particularly preferably at least 1.2 equivalents relative to 1 equivalent of the compound of formula (IV).

[0055] R F SO2F is further preferably used in an amount of at most 4.0 equivalents, more preferably at most 3.0 equivalents, and particularly preferably at most 1.5 equivalents relative to 1 equivalent of the compound of formula (IV).

[0056] R F SO2F is used in an amount of more preferably 0.8 to 4.0 equivalents, more preferably 1.0 to 3.0 equivalents, and even more preferably 1.2 to 1.5 equivalents relative to 1 equivalent of the compound of formula (IV).

[0057] Alternatively, R F SO2F can be used in significant excess. F The SO2F can be reacted again in further processes, this is especially true for SO2F2 introduced as a gas.

[0058] 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.

[0059] More preferably, step 1 is carried out at least in part at a temperature in the range of 60° C. to 100° C. Higher temperatures can further improve the conversion rate of the reaction.

[0060] In particular, it is preferable to carry out step 1 at an initial temperature of 10°C to 30°C and a final temperature of 60°C to 100°C.

[0061] The reaction time in step 1 is preferably in the range of 6 to 40 hours, particularly preferably in the range of 10 to 30 hours.

[0062] More preferably, step 1 is carried out at a temperature in the range of 60°C to 100°C for at least 5 hours, more preferably at least 10 hours, and particularly preferably at least 15 hours.More preferably, step 1 is carried out at a temperature in the range of 60°C to 100°C for 10 to 30 hours.

[0063] The reaction of step 1 is preferably carried out in the region of standard pressure (1013 hPa). Optionally, the reaction can alternatively be carried out under elevated or reduced pressure.

[0064] For example, the reaction can be carried out preferably in the range of 300 hPa to 5000 hPa or 500 hPa to 2000 hPa, preferably in the range of 1013 hPa±200 hPa.

[0065] The reaction of step 1 is preferably carried out in a solvent, in particular acetonitrile, propionitrile, butyronitrile, acetone, N,N-dimethylacetamide, N-methylpyrrolidinone (NMP), N,N-dimethylformamide (DMF), dimethylpropyleneurea (DMPU), toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (iPrOAc), 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 (silene), N,N-dimethylcyclohexylamine or a mixture thereof in any ratio.

[0066] In addition to the aforementioned bases N,N-dimethylacetamide, N,N-dimethylformamide or N,N-dimethylcyclohexylamine, other nitrogen-containing solvents or organic bases can be used.

[0067] Particularly preferred are acetonitrile, toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (i-PrOAc), or N,N-dimethylcyclohexylamine.

[0068] Alternatively, step 1 can be carried out in an excess of (liquid) base without the use of an additional solvent, in which case step 1 is in particular carried out with an excess of one of the above bases.

[0069] The preferred embodiments described below refer, where appropriate, to all formulae described herein.

[0070] X 2 ~X 6 About preferable The group definitions are as follows: X 2 is H, 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.

[0071] X 2 ~X 6 About Particularly preferred The group definitions are as follows: X 2 is H, X 3 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN, X 4 is fluorine, H, X 5 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN, X 6 is H.

[0072] X 2 ~X 6 About Very particularly preferred The group definitions are as follows: X 2 is H, X 3 is H or fluorine, X 4 is H or fluorine, X 5 is H or fluorine, X 6 is H.

[0073] X 2 ~X 6 About Most preferred The group definitions are as follows: X 2 is H, X 3 is fluorine, X 4 is H, X 5 is fluorine, X 6 is H.

[0074] Regarding further configurations of the present invention: R 1 is preferably 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, particularly preferably isopropyl, 2-methyl-1-propyl, 1-methyl-1-propyl, cyclohexyl, 3-methyl-1-butyl and most preferably 2-methyl-1-propyl.

[0075] R 2 is preferably H, methyl or ethyl.

[0076] Other preferred The group definitions are as follows: R 1is 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, R 2 is H, methyl or ethyl.

[0077] other Particularly preferred The group definitions are as follows: R 1 is methyl, ethyl, isopropyl, n-propyl, 2-methyl-1-propyl, 1-methyl-1-propyl, cyclohexyl, 3-methyl-1-butyl, 1-butyl or 1-pentyl, R 2 is H, methyl or ethyl.

[0078] Other very particularly preferred The group definitions are as follows: R 1 is methyl, ethyl, isopropyl, n-propyl, 2-methyl-1-propyl, 1-methyl-1-propyl, 3-methyl-1-butyl or 1-butyl, R 2 is H or methyl.

[0079] Other most preferred The group definitions are as follows: R 1 is methyl, ethyl, isopropyl, n-propyl, 2-methyl-1-propyl or 1-butyl, R 2 is H.

[0080] For compounds of formula (I), (III), (IV) and (V) Other preferred The group definitions are as follows: X 2 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN, X 3is 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, R 1 is 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, R 2 is H, methyl or ethyl.

[0081] Other particularly preferred The group definitions are as follows: X 2 is H, X 3 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN, X 4 is fluorine, H, X 5 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN, X 6 is H, R 1 is methyl, ethyl, isopropyl, n-propyl, 2-methyl-1-propyl, 1-methyl-1-propyl, cyclohexyl, 3-methyl-1-butyl, 1-butyl or 1-pentyl, R 2 is H, methyl or ethyl.

[0082] Other very particularly preferred The group definitions are as follows: X 2 is H, X 3 is H or fluorine, X 4 is H or fluorine, X 5 is H or fluorine, X 6 is H, R 1 is methyl, ethyl, isopropyl, n-propyl, 2-methyl-1-propyl, 1-methyl-1-propyl, 3-methyl-1-butyl or 1-butyl, R 2 is H or methyl.

[0083] Other most preferred The group definitions are as follows: X 2 is H, X 3 is fluorine, X 4 is H, X 5 is fluorine, X 6 is H, R 1 is methyl, ethyl, isopropyl, n-propyl, 2-methyl-1-propyl or 1-butyl, R 2 is H.

[0084] In a further particular configuration of the present invention, the method according to the invention according to the second aspect further comprises the step of: [ka] [In the formula, R 2 and X 2 ~X 6 have the definitions given above. The compound of formula R 1-OH (where R 1 involves the preparation of a compound of formula (IV) by reacting a compound of formula (IV) with a compound of formula (IV) having the definition given above (Step 0-1).

[0085] In a further particular configuration of the present invention, the compound of formula (I) [ka] [In the formula, R 1 , R 2 and X 2 ~X 6 has the definition above] can also be hydrolyzed in the presence of a base and then protonated in the presence of an acid, or hydrolyzed in the presence of an acid to give the compound of formula (V) [ka] [In the formula, R 2 and X 2 ~X 6 has the above meaning. (Step 2) The compounds of formulae (I), (III), (IV) and (V) can be in the form of isomeric mixtures: Here, the isomer ratios between (Ia) and (Ib), (IIIa) and (IIIb), (IVa) and (IVb), and (Va) and (Vb) are different. The same applies to compounds of formula (A) and (B). [ka] [ka] [ka] [ka] The terms used herein are known to those skilled in the art. Otherwise, the following definitions apply: CC double bond [ka] represents the cis or trans configuration of the respective group.

[0086] This can be achieved, for example, by the formula (A) [ka] The compound has the configuration [ka] is understood to mean

[0087] The expression "equivalents to 1 equivalent" refers to the ratio of the molar amounts of the respective compounds. For example, if a base is used in an amount of 1.8 equivalents to 1 equivalent of the compound of formula (B), this corresponds to a ratio of 1.8 mol to 1 mol.

[0088] In the context of the present invention, unless otherwise defined elsewhere, the term "alkyl" according to the present invention, by itself or in combination with further terms (e.g., haloalkyl), is understood to mean the radical of a saturated aliphatic hydrocarbon group, which can be branched (isoalkyl, containing 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 groups.

[0089] The term "alkoxy", by itself or in combination with further terms (e.g., haloalkoxy), is understood in the present invention to mean an O-alkyl group, wherein the term "alkyl" is defined as above.

[0090] According to the present invention, unless defined differently elsewhere, the term "cycloalkyl", by itself or in combination with further terms, is understood to mean a C3-C8-cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. "Cycloalkyl" is understood to mean both unsubstituted and substituted cycloalkyl groups.

[0091] Halogen-substituted groups, such as fluoroalkyl, may be monohalogenated or, up to the maximum number of possible substituents, polyhalogenated.

[0092] According to the present invention, unless otherwise defined, the term "aryl" by itself or in combination with other terms is understood to mean a monocyclic or polycyclic, preferably monocyclic or bicyclic, aromatic hydrocarbon group, preferably having 6, 10 or 14 carbon atoms. The aryl group may be unsubstituted or may be mono- or polysubstituted by the same or different substituents. Examples of suitable aryl groups are phenyl, 1-naphthyl, 2-naphthyl and anthracenyl.

[0093] The term "heteroaryl" refers to a monocyclic or polycyclic, preferably monocyclic, bicyclic, or tricyclic, aromatic hydrocarbon radical, preferably having 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, and especially preferably having 5 or 6 carbon atoms, in each case in which one or more carbon atoms are replaced by heteroatoms independently selected from the group consisting of oxygen, sulfur, and nitrogen (NH). Heteroaryl groups may have, as ring members, preferably 1, 2, 3, 4, or 5, particularly preferably 1, 2, or 3, heteroatoms, each independently selected from the group consisting of oxygen, sulfur, and nitrogen (NH). Heteroaryl groups may be unsubstituted, monosubstituted, or polysubstituted by the same or different substituents. Examples of suitable heteroaryl groups include indolizinyl, benzimidazolyl, tetrazolyl, triazinyl, isoxazolyl, phthalazinyl, carbazolyl, carbolinyl, diazanaphthyl, 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, quinoxalinyl, quinazolinyl, quinolinyl, naphthridinyl and isoquinolinyl.

[0094] In the context of the present invention, aryl or heteroaryl groups may be fused to a monocyclic or bicyclic ring system. Examples of aryl groups fused to a monocyclic or bicyclic ring system include (2,3)-dihydrobenzo[b]thiophenyl, (2,3)-dihydro-1H-indenyl, indolinyl, (2,3)-dihydrobenzofuranyl, (2,3)-dihydrobenzo[d]oxazolyl, benzo[d][1,3]dioxolyl, benzo[d][1,3]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)-dihydrobenzo[b][1,4]dioxinyl, (2,3)-dihydrobenzo[b][1,4]oxathiinyl, (6,7,8,9)-tetrahydro-5H-benzo[7]annulenyl, (2,3,4,5)-tetrahydro-1H-benzo[b]azepinyl and (2,3,4,5)-tetrahydro-1H-benzo[c]azepinyl.

[0095] The term "heterocyclyl" generally refers to a ring system having at least two different elements, particularly N or O, or N and O, in combination with the ring-forming carbon atoms. The heterocyclic system may be saturated or aromatic and may be mono- or polysubstituted. An example is isoxazoline, which is preferably substituted.

[0096] If one of the aforementioned groups is mono- or polysubstituted, suitable substituents are those familiar to those skilled in the art, preferably each independently F, Cl, Br, I, -NO, -CN, -OH, -SH, -NH, C-C-alkyl, C-C-fluoroalkyl, C-C-fluoroalkoxy, C-C-alkoxy, fluoroalkoxy, -N(C 1-5 -alkyl)2, -N(C1-5 -alkyl)(phenyl), -N(C 1-5 -alkyl)(CH2-phenyl), -N(C 1-5 -alkyl)(CH2-CH2-phenyl), -NH-C(=O)-OC 1-5 -Alkyl, -C(=O)-H, -C(=O)-C 1-5 -Alkyl, -C(=O)-phenyl, -C(=S)-C 1-5 -Alkyl, -C(=S)-phenyl, -C(=O)-OH, -C(=O)-OC 1-5 -Alkyl, -C(=O)-O-phenyl, -C(=O)-NH2, -C(=O)-NH-C 1-5 -Alkyl, -C(=O)-N(C 1-5 -alkyl)2, -S(=O)-C 1-5 -Alkyl, -S(=O)-phenyl, -S(=O)2-C 1-5 -alkyl, -S(=O)2-phenyl, -S(=O)2-NH2 and -SO3H.

[0097] The ranges specified above apply generally or as preferred ranges correspondingly throughout the method. These definitions can be combined with each other as desired, i.e., including combinations between the respective preferred ranges.

[0098] According to the present invention, it is preferred to use methods in which there are combinations of the meanings and ranges specified above as preferred.

[0099] According to the present invention, it is particularly preferred to use methods in which there are combinations of the meanings and ranges specified above as being particularly preferred.

[0100] According to the invention, it is very particularly preferred to use methods in which there are combinations of the meanings and ranges specified above as being very particularly preferred.

[0101] According to the present invention, it is most preferred to use a method in which there is a combination of the meanings and ranges specified above as most preferred.

[0102] Elucidation of methods and intermediates Process 0-1 The process according to the present invention comprises reacting a compound of formula (IV) [ka] [In the formula, R 1 , R 2 and X 2 ~X 6 has the definition above] The compound of formula (III) [ka] [In the formula, R 2 , and X 2 ~X 6 have the definitions given above. The compound of formula R 1 -OH (where R 1 may comprise step 0-1, in which the compound of formula (I) is prepared by reacting the compound of formula (I) with the compound of formula (II) having the definition given above.

[0103] Scheme 1 [ka] The preparation of compounds of formula (III) is described, for example, in WO2018 / 228985.

[0104] Compound (III) of formula R 1 The esterification of the compound of formula (III) with an alcohol of -OH to obtain compound (IV) can be carried out, for example, in the presence of 1.0 to 1.3 equivalents of thionyl chloride or a catalytic amount of sulfuric acid per equivalent of the compound of formula (III) at 0 to 80°C (standard pressure) for 1.5 to 3 hours. 1 It is preferred here to use the compound of --OH as reactant and solvent in a clear excess, for example of 4 to 8 equivalents.

[0105] Compound (III) of formula R 1 The esterification of -OH with an alcohol to give compound (IV) can generally be carried out under any conditions known in the prior art for such reactions.

[0106] The compound of formula (IV) can be isolated by suitable work-up steps commonly known to those skilled in the art and further characterized, and then used in step 1.

[0107] Process 1 A preferred method according to the present invention is to prepare a compound of formula (I) [ka] [In the formula, R 1 , R 2 , and X 2 ~X 6 has the definition above] The compound of formula (IV) [ka] [In the formula, R 1 , R 2 and X 2 ~X 6 has the definition above] in the presence of a base and a Lewis acid (e.g., BF3) to form a compound of R F SO2F (where R F wherein R 1 is a methyl group having the same meaning as defined above.

[0108] Scheme 2 [ka] In this process, a compound of formula (II) is formed as an intermediate, which is gradually converted to a compound of formula (I) during the reaction.

[0109] Process 2 The process according to the present invention comprises hydrolyzing a compound of formula (I) in the presence of a base, followed by protonation in the presence of an acid, or hydrolysis in the presence of an acid, to give (V): [ka] [In the formula, R 2 and X 2 ~X 6 has the definition above] The method can further include obtaining a compound of formula (I).

[0110] Scheme 3: [ka] Suitable bases are especially inorganic bases, such as carbonates (e.g., (NH4)2CO3, Li2CO3, Na2CO3, K2CO3, CaCO3, MgCO3), bicarbonates (e.g., NH4HCO3, LiHCO3, NaHCO3, KHCO3) or hydroxides (e.g., LiOH, NaOH, KOH, Ca(OH)2); alkali metal or alkaline earth metal hydroxides are particularly preferred here, and KOH or NaOH are especially preferred.

[0111] The base is used in the form of an aqueous solution having a concentration of preferably 1 to 50% by weight, more preferably 5 to 45% by weight, and most preferably 5 to 35% by weight.

[0112] 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 especially preferably in the range of 15°C to 60°C.

[0113] The reaction is preferably carried out in the region of standard pressure (1013 hPa), for example in the range of 300 hPa to 5000 hPa or 500 hPa to 2000 hPa, preferably in the range of 1013 hPa±200 hPa.

[0114] The hydrolysis reaction time is preferably in the range of 0.5 to 10 hours.

[0115] The hydrolysis of the compound of formula (I) to give compound (V) can generally be carried out under any of the conditions known in the prior art for such reactions.

[0116] The compounds of formula (I) can be isolated and further characterized by suitable work-up steps generally known to those skilled in the art, for example by extraction and optionally distillation.

[0117] Usually, after step 1, R 1 It is also possible to carry out transesterification of the compound of formula (I) at position.

[0118] Alternatively, step 2 can be carried out in the presence of an acid.

[0119] Overall Method In an advantageous configuration, the method according to the invention comprises steps 0-1 and 1, particularly advantageously 0-1, 1 and 2.

[0120] Scheme 4 [ka] Scheme 4 provides a schematic overview of the process according to the present invention, including all optional and mandatory steps. The reaction conditions and reactants are selected here according to the preferred configurations of the present invention described above. All substituents in the formula are defined as above.

[0121] The compounds of formula (IV) and (I) can be isolated and optionally purified before being used in the respective next synthetic step. However, it is also possible to use the compounds directly in the next step without isolation and purification. In this case, the solvent and excess reagents from the previous step are removed by standard methods before the compounds are used in the next synthetic step. [Example]

[0122] The present invention will be described in more detail by the following examples, but the present invention is not limited to these examples.

[0123] Measurement method The product 1 H-NMR and 19 It was characterized by F-NMR spectroscopy and HPLC (high performance liquid chromatography).

[0124] NMR spectra were determined using a Bruker Avance 400 equipped with a flow probe head (volume 60 μl). The NMR data in the examples are listed in conventional form (δ values, multiplet splitting, number of hydrogen or fluorine atoms).

[0125] The solvent and frequency at which the NMR spectrum was recorded are stated in each case.

[0126] HPLC (High Performance Liquid Chromatography) was performed on an Agilent 1100 LC system with the following parameters: a) For reaction monitoring (HPLC area %) Column: 150 × 4.6 mm, stainless steel; Stationary phase: Phenomenex, Luna 5 μm C18 100 Å; Mobile phase: Acetonitrile / water (containing 0.25 mL / L trifluoroacetic acid) 63 / 37 (v / v), isocratic elution; Oven temperature: 40 °C; Flow rate: 2.0 mL / min; Run time: 6 min, Injection volume: 1 μl.

[0127] b) For the determination of (V) Column: 100 × 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 equipped with UV detection and external standard quantification was used.

[0128] Example I: Preparation of 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid according to the present invention Step 0-1: Isopropyl 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylate A suspension of 500 g of 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylic acid (1808 mmol, purity 98.1 wt%) 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 via a metering pump within 3 hours. The solution was then reacted at 50 °C for another 3 hours. At the end of the reaction, a solid precipitated from the solution, especially after the suspension had cooled to room temperature. The conversion of 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylic acid or the formation of isopropyl 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylate could be analyzed by HPLC. The yield of the desired isopropyl 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylate was >98%.

[0129] Process 1 Example 1.a: A 250 ml four-neck flask equipped with a reflux condenser was initially charged with 50 g of isopropyl 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylate as a suspension in 66 ml of acetonitrile at 20 °C. The mixture was purged with nitrogen. A total of 12.86 g of BF gas (4.5 L; 1.2 equivalents) was then introduced above the liquid surface. The pressure was equalized via an air balloon. The gas rapidly dissolved in the mixture, and after approximately 4 g had been added, a solution was formed. The gas was added over 30 min. The solution was then stirred for 35 min, and 60.92 g of N,N-dimethylcyclohexylamine (3 equivalents) was slowly added. The temperature was maintained at 20 °C. After 1 h, 17.75 g of SO2F2 (4.1 L; 1.09 equivalents) was added, and the mixture was heated to 80 °C. The mixture was held at 80° C. for a total of 19 hours.

[0130] A sample was analyzed by HPLC and found to be 98% isopropyl 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylate.

[0131] Example 1.b: A 250 mL reactor equipped with a reflux condenser was initially charged under nitrogen with 124.9 g of a suspension of isopropyl 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylate in xylene (38.4 wt %), followed by 10 g of acetonitrile. Then, at 20° C., 82.5 g of a BF3 acetonitrile solution (15.2% in acetonitrile) was added dropwise over 20 minutes. After the addition was complete, the resulting solution was further stirred at 20° C. for 10 minutes, followed by the dropwise addition of 78.0 g of N,N-dimethylcyclohexylamine (4 equivalents) over 2 hours, ensuring that the temperature did not exceed 25° C. Finally, 20.0 g of SO2F2 (1.2 equivalents) were metered in below the surface at 20-25°C over 4 hours and, after complete addition, stirred for 10 minutes at 20°C, then heated to 80°C over 6 hours and stirred for a further 15 hours at this temperature.

[0132] A sample was analyzed by HPLC and found to be >99% isopropyl 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylate.

[0133] Process 2 Example 2.a: The mixture from Example 1.a was distilled at an internal temperature of 75° C. up to 90 mbar. Hydrolysis was carried out with 126.4 g of NaOH (20 wt %, 4 eq.). The solution was stirred at 65° C. for 25 min until hydrolysis was complete. HPLC analysis of a sample of the reaction mixture after acidification gave 98% 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid.

[0134] Example 2.b: 86 g of acetonitrile was removed from the mixture of Example 1.b by distillation at 80 °C up to 300 mbar, and the reaction mixture was diluted with 80 g of xylene. After the addition of 156 g of water, the phases were separated, and the aqueous phase was extracted again with 25 g of xylene. The combined organic phase was treated with 156 g of water, 9.2 g of isopropanol, and 61.4 g of NaOH (20 wt%, 2.0 equivalents). The reaction mixture was stirred at 50 °C for 8 hours, and completion of the hydrolysis was confirmed by HPLC analysis, yielding 98% of 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid after acidification of a sample of the reaction mixture. The separated aqueous phase can be further processed for disposal. For this purpose, potassium hydroxide or another potassium base can be added until the pH is >9. The resulting potassium tetrafluoroborate (KBF4) is separated by filtration; fluoride can be further removed, if necessary, using agents commonly used by those skilled in the art.

[0135] Post-processing Example 3.a Upon completion of hydrolysis of the mixture of Example 2.a, the mixture was distilled under reduced pressure at 53-56°C to remove N,N-dimethylcyclohexylamine by azeotropic distillation, and the aqueous phase from the distillate was repeatedly fed to the reaction mixture.

[0136] The distilled reaction mixture was added to 2.5 equivalents of hydrochloric acid in 100 mL of water and cooled in an ice bath. The product initially separated as an oil and crystallized overnight at room temperature to give a solid. The solid was filtered under suction, washed with 250 mL of water, and then air-dried. 40.95 g of the desired 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid was isolated. The purity was determined by quantitative HPLC to be 95% (corresponding to a 97% yield).

[0137] Example 3.b After completion of hydrolysis of the mixture of Example 2.b and cooling to 20°C, the phases were first separated and the organic phase was discarded. The aqueous phase was then adjusted to pH 1-2 by adding 32% by weight 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 under reduced pressure 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 was isolated. The purity, as determined by quantitative HPLC, was 96.1% (corresponding to a 96% yield).

[0138] NMR data for the isolated and purified products and intermediates were determined as follows: Isopropyl 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylate (after step 0-1) 1 H-NMR (400 MHz, CDCl3): δ (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). 19 F-NMR (376 MHz, CDCl3): δ (ppm) = -108.4 (m, 2F). Isopropyl 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylate (after step 1) 1H-NMR (401 MHz, CDCl3): δ (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). 19 F-NMR (376 MHz, CDCl3): δ (ppm) = -108.4 (m, 2F). 3-(3,5-Difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid (after step 2) 1 H-NMR (400 MHz, CDCl3): δ (ppm) = 3.40 (d, J = 17.1 Hz, 1H), 3.92 (d, J = 17.1 Hz, 1H), 5.44 (d, J = 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 (m, 2H), 9.61 (bs, 1H). 19 F-NMR (376 MHz, CDCl3): δ (ppm) = -108.0 (m, 2F). Example II: Preparation of 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid with and without Lewis acid To carry out the comparison, the methods described in Examples 1.a, 2.a and 3.a were used, but no Lewis acid was used in reaction mixtures 2 and 3. Acetonitrile was used as the solvent.

[0139] The yields of the desired isopropyl 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylate (I) and the desired 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid (V) after hydrolysis are shown in the table below under "Yield I, %." In Examples 4 to 6, the reaction temperature was continuously increased during the reaction (room temperature (RT), 80°C, 100°C, held for the time indicated in the "Time" column in each case) at key points during the reaction, according to the reaction time and temperature indicated in each row, and the yields were measured. [Table 1] The presence of Lewis acid in reaction mixtures 1, and 4-6 according to the present invention leads to high HPLC yields and up to 97% isolated yields of the desired product (V), 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid, whereas the yield without Lewis acid in HPLC (reaction mixtures 2 and 3) is up to 70% with a large amount of the undesired by-product VI.

Claims

1. Formula (I) 【Chemical Formula 1】 [During the ceremony, R １ is C １ -C ８ -alkyl, cycloalkyl, unsubstituted benzyl, unsubstituted phenyl or mono- or di-C １ -C ３ -alkyl-substituted benzyl or phenyl, R ２ is H or alkyl, X ２ is H, C １ -C ４ -Alkyl, C １ -C ４ -fluoroalkyl, C １ -C ４ -fluoroalkoxy, C １ -C ４ -alkoxy, fluorine or CN, X ３ is H, C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, C １ -C ４ alkoxy, fluorine, chlorine or CN; X ４ is H, C １ -C ４ -Alkyl, C １ -C ４ -fluoroalkyl, C １ -C ４ -fluoroalkoxy, C １ -C ４ -alkoxy, fluorine or CN, X ５ is H, C １ -C ４ Alkyl, C １ -C ４ Fluoroalkyl, C １ -C ４ Fluoroalkoxy, C １ -C ４ alkoxy, fluorine, chlorine or CN; X ６ is H, C １ -C ４ -Alkyl, C １ -C ４ -fluoroalkyl, C １ -C ４ -fluoroalkoxy, C １ -C ４ -alkoxy, fluorine or CN. A method for preparing a compound of the formula General formula (IV) 【Chemistry 2】 [In the formula, R １ , R ２ , X ２ , X ３ , X ４ , X ５ and X ６ has the definition above] in the presence of a base and a Lewis acid to form a compound of formula R Ｆ SO ２ F (where R Ｆ , F, CF ３ , C ２ F ５ , C ３ F ７ , C ４ F ９ , C.F. ２ Cl, C ６ F ５ , alkoxy-CF ２ , and R ６ OCOCF ２ SO ２ F, and R ６ is C １ -C ８ -alkyl or cycloalkyl) with a compound of formula (I).

2. 2. The 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), 1,3-dimethyl-2-imidazolidinone (DMEU) or tetramethylurea (TMU).

3. 2. The process according to claim 1, characterized in that the base is selected from triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine or N,N-dimethylcyclohexylamine.

4. 4. The process according to any one of claims 1 to 3, characterized in that the base is used in an amount of 1.8 to 10.0 equivalents, preferably 2.0 to 5.0 equivalents, relative to 1 equivalent of the compound of formula (IV).

5. The Lewis acid is BF ３ , P.F. ５ or SbF ５ The method according to any one of claims 1 to 4, characterized in that the compound is selected from the group consisting of:

6. The Lewis acid is BF ３ and preferably BF ３ is introduced as a gas or BF ３ 6. The method according to claim 1, wherein the compound is introduced as a solution in acetonitrile.

7. 7. The process according to any one of claims 1 to 6, characterized in that the Lewis acid is used in an amount of 0.8 to 3.0 equivalents, preferably 1.0 to 1.5 equivalents, relative to 1 equivalent of the compound of formula (IV).

8. R Ｆ The method according to any one of claims 1 to 7, wherein is F.

9. R Ｆ SO ２ 9. The process according to any one of claims 1 to 8, characterized in that F is used in an amount of 0.8 to 4.0 equivalents, preferably 1.0 to 3.0 equivalents, relative to 1 equivalent of the compound of formula (IV).

10. 10. The process according to any 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 (iPrOAc), 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 (silene), N,N-dimethylcyclohexylamine or mixtures thereof in any ratio.

11. 11. The method according to any one of claims 1 to 10, characterized in that the method is carried out at least partly at a temperature in the range of 60°C to 100°C.

12. Formula (III) 【Chemistry 3】 The compound of formula R １ with a compound of —OH to prepare a compound of formula (IV), In the formula, R １ , R ２ and X ２ ~X ６ has the definition set forth in claim 1 The method according to any one of claims 1 to 11, characterized in that

13. Formula (V) 【Chemistry 4】 to obtain a compound of formula (I) 【Chemistry 5】 in the presence of a base or an acid, In the formula, R １ , R ２ and X ２ ~X ６ has the definition set forth in claim 1 The method according to any one of claims 1 to 12, characterized in that

14. X ２ is H, 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 The method according to any one of claims 1 to 13, characterized in that

15. X ２ is H, X ３ is H or fluorine, X ４ is H or fluorine, X ５ is H or fluorine, and X ６ But it is H 15. The method according to any one of claims 1 to 14.

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