Elimination reactions for preparation of substituted olefins

Abstract

The present invention relates to a novel process for the preparation of substituted olefins of formula (A), in particular isoxazoline-5, 5-vinyl carboxylic acid derivatives of formula (I). # imgabs0 #

Description

[0001] The present invention relates to a process for preparing substituted olefins of formula (A), in particular a process for preparing isoxazoline-5,5-vinylcarboxylic acid derivatives of formula (I) and (V).

[0002] The preparation of substituted olefins is an essential process step in various synthesis processes in the agrochemical and pharmaceutical industries. Substituted olefins can usually only be prepared under severe conditions and at high cost.

[0003] In particular, isoxazoline-5,5-vinyl carboxylic acid derivatives of the general formula (I) are important precursors of active agricultural chemical ingredients (see WO2018 / 228985). WO2018 / 228985 has described a method for preparing isoxazoline-5,5-vinyl carboxylic 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).

[0004] It is therefore an object of the present invention to provide an elimination reaction for preparing substituted olefins of the formula (A), in particular for preparing isoxazoline-5,5-vinylcarboxylic acid derivatives of the formula (I), which is suitable for industrial-scale synthesis and has high yields and selectivities, thereby making it possible to dispense with laborious purification processes.

[0005] In a first aspect, the objects of the present invention are achieved by a process for preparing substituted olefins of formula (A),

[0006]

[0007] in

[0008] R 2 is H or alkyl,

[0009] R 3 is H or alkyl,

[0010] Y is CO2R 1 、CN、CHO、CF3,

[0011] Where R 1 is C1-C8 alkyl, cycloalkyl, unsubstituted benzyl, unsubstituted phenyl, or mono- or di-C1-C3-alkyl-substituted benzyl or phenyl;

[0012] R 4 , R 5 each independently is alkyl, cycloalkyl, aryl, heteroaryl (in each case unsubstituted or substituted) or a heteroatom;

[0013] or R4 and R 5 Connected to R in the compound of formula (A) 4 and R 5 The carbon atoms of the isoxazoline radicals are taken together to form a cycloalkyl radical, an aryl radical or a heterocyclyl radical, which are in each case unsubstituted or substituted, preferably substituted isoxazoline radicals, particularly preferably phenyl-substituted isoxazoline radicals,

[0014] It is characterized in that the compound of general formula (B) and formula R F SO2F compounds react in the presence of a base and a Lewis acid, where R F Selected from F, CF3, C2F5, C3F7, C4F9, CF2Cl, C6F5, alkoxy-CF2, R 6 OCOCF2SO2F, where R 6 is defined as C1-C8-alkyl or cycloalkyl (step 1),

[0015]

[0016] Where R 2 , R 3 , R 4 , R 5 and Y have the above definitions.

[0017] By the process of the present invention, the compound of formula (A) can be obtained with high selectivity and high yield. Likewise, there is no need to use any reagents that are difficult to obtain on an industrial scale. Surprisingly, it has been found that R F SO2F is used together with Lewis acid to reduce the formation of undesirable fluorinated secondary components. Due to the chemoselectivity of the inventive method, the time-consuming and laborious purification of the product of formula (A) is not needed, and subsequent reactions can be carried out without complicated intermediate purification or directly carried out in the reaction mixture. When undesirable secondary components are difficult or impossible to separate with desired compounds, this aspect is particularly important.

[0018] R F SO2F is preferably SO2F2.

[0019] According to the present invention, gaseous SO2F2 can be prepared economically and efficiently and is therefore very suitable for industrial-scale synthesis.

[0020] According to the present invention, the suitable base is preferably selected from trimethylamine, triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, N,N-dimethylcyclohexylamine, 2-methyl-5-ethylpyridine, pyridine, 3,5-lutidine, 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 selected from triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine or N,N-dimethylcyclohexylamine.

[0021] As the base, triethylamine, N,N-dimethylcyclohexylamine or N,N-diisopropylethylamine is particularly preferred. In particular, the use of these bases enables a high conversion rate of the compound of formula (B) to be achieved.

[0022] N,N-dimethylcyclohexylamine is particularly preferred.

[0023] The amount of the base used is preferably at least 1.8 equivalents, more preferably 2.0 equivalents, particularly preferably at least 2.5 equivalents, based on 1 equivalent of the compound of the formula (B).

[0024] Preferably, the base can also be used as a solvent in the process of the present invention. Alternatively, if another solvent is used in addition to the base, the base may be used in an amount of up to 10.0 equivalents, more preferably up to 5.0 equivalents, based on 1 equivalent of the compound of formula (B).

[0025] The amount of the base to be used is preferably 1.8 to 10 equivalents, preferably 2.0 to 5.0 equivalents, based on 1 equivalent of the compound of the formula (B).

[0026] According to the invention, suitable Lewis acids are preferably selected from BF3, PF5 and SbF5.

[0027] In particular, BF3 is a suitable Lewis acid, which can be present in the form of free gas or solution, preferably in acetonitrile, aliphatic or cyclic ether compounds; as an ether complex or as a complex with an amine base, more preferably a complex with triethylamine.

[0028] Preferably, BF3 is introduced as a gas, which allows simple process control, or preferably the reaction is carried out as an acetonitrile solution.

[0029] SO2F2 is particularly preferred as R F SO2F and BF3 as Lewis acid. This combination has proven to be cost-effective and enables high conversions while significantly suppressing the formation of undesirable fluorinated secondary components.

[0030] The amount of the Lewis acid to be used is preferably at least 0.8 equivalent, more preferably at least 1.0 equivalent, based on 1 equivalent of the compound of formula (B).

[0031] The amount of the Lewis acid to be used is further preferably at most 3.0 equivalents, more preferably at most 1.5 equivalents, based on 1 equivalent of the compound of formula (B).

[0032] The amount of the Lewis acid to be used is further preferably 0.8 to 3.0 equivalents, more preferably 1.0 to 1.5 equivalents, based on 1 equivalent of the compound of formula (B).

[0033] According to the present invention, the compound of formula (B) and R F SO2F reaction.

[0034] In this paper, R F The amount of SO2F used is preferably at least 0.8 equivalent, more preferably at least 1.0 equivalent, particularly preferably at least 1.2 equivalent, based on 1 equivalent of the compound of formula (B).

[0035] R F The amount of SO2F used is further preferably at most 4.0 equivalents, more preferably at most 3.0 equivalents, particularly preferably at most 1.5 equivalents, based on 1 equivalent of the compound of formula (B).

[0036] R F The amount of SO2F used is further preferably 0.8 to 4.0 equivalents, more preferably 1.0 to 3.0 equivalents, even more preferably 1.2 to 1.5 equivalents, based on 1 equivalent of the compound of formula (B).

[0037] Alternatively, an excess of R F SO2F. Unreacted R F SO2F2 can be reacted again in a subsequent process. This applies in particular to SO2F2 introduced in gaseous form.

[0038] 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.

[0039] More preferably, step 1 is at least partially carried out at a temperature of 60° C. to 100° C. An elevated temperature can further increase the conversion rate of the reaction.

[0040] Specifically, step 1 is preferably performed at an initial temperature of 10°C to 30°C and a final temperature of 60°C to 100°C.

[0041] The reaction time of step 1 is preferably 6 to 40 hours, particularly preferably 10 to 30 hours.

[0042] More preferably, step 1 is performed at a temperature of 60°C to 100°C for at least 5 hours, more preferably at least 10 hours, particularly preferably at least 15 hours. More preferably, step 1 is performed at a temperature of 60°C to 100°C for 10 to 30 hours.

[0043] The reaction of step 1 is preferably carried out under standard pressure (1013 hPa). Optionally, the reaction can also be carried out under increased or reduced pressure.

[0044] For example, the reaction is preferably carried out at 300 hPa to 5000 hPa or 500 hPa to 2000 hPa, preferably at 1013 hPa±200 hPa.

[0045] The reaction of step 1 is preferably carried out in a solvent. Suitable solvents here are in particular acetonitrile, propionitrile, butyronitrile, acetone, N, N-dimethylacetamide, N-methylpyrrolidone (NMP), N, N-dimethylformamide (DMF), dimethylpropylene urea (DMPU), toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (iPrOAc), dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate (4-methyl-1,3-dioxolane-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), dihydro-levorotatory glucose ketone (cyrene), N, N-dimethylcyclohexylamine or a mixture thereof in any ratio.

[0046] Besides the above-mentioned bases N,N-dimethylacetamide, N,N-dimethylformamide or N,N-dimethylcyclohexylamine, other nitrogen-containing solvents or organic bases can also be used.

[0047] Particularly preferred are acetonitrile, toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (i-PrOAc) or N,N-dimethylcyclohexylamine.

[0048] Alternatively, step 1 can be carried out in an excess of a (liquid) base, without using an additional solvent. In this case, step 1 is in particular carried out in an excess of one of the above-mentioned bases.

[0049] In a second aspect, the object of the present invention is achieved by a process for preparing isoxazoline-5,5-vinylcarboxylic acid derivatives of formula (I),

[0050]

[0051] in

[0052] X 2is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine or CN,

[0053] X 3 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine, chlorine or CN,

[0054] X 4 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine or CN,

[0055] X 5 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine, chlorine or CN,

[0056] X 6 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine or CN,

[0057] R 1 is C1-C8-alkyl, cycloalkyl, unsubstituted benzyl, unsubstituted phenyl, or mono- or di-C1-C3-alkyl-substituted benzyl or phenyl;

[0058] R 2 is H or alkyl,

[0059] It is characterized in that the compound of general formula (IV) and formula R F SO2F compounds react in the presence of base and Lewis acid, where R F Selected from F, CF3, C2F5, C3F7, C4F9, CF2Cl, C6F5, alkoxy-CF2, R 6 OCOCF2SO2F, where R 6 is defined as C1-C8-alkyl or cycloalkyl (step 1),

[0060]

[0061] Where R 1 , R 2 , X 2 To X 6 With the above definition.

[0062] Compounds of formula (I) can also be obtained in high yields; the synthesis on an industrial scale can be designed economically and efficiently.

[0063] The above method features and the technical effects of converting the compound of formula (B) into (A) are also applicable to the conversion of compound (IV) into (I):

[0064] R F SO2F is preferably SO2F 2。

[0065] According to the present invention, the suitable base is preferably selected from trimethylamine, triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, N,N-dimethylcyclohexylamine, 2-methyl-5-ethylpyridine, pyridine, 3,5-lutidine, 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 selected from triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine or N,N-dimethylcyclohexylamine.

[0066] As the base, triethylamine, N,N-dimethylcyclohexylamine or N,N-diisopropylethylamine is particularly preferred.

[0067] The amount of the base used is preferably at least 1.8 equivalents, more preferably at least 2.0 equivalents, particularly preferably at least 2.5 equivalents, based on 1 equivalent of the compound of the formula (IV).

[0068] Preferably, a base can also be used as a solvent for the process of the present invention. If another solvent is used in addition to the base, the amount of the base is up to 10.0 equivalents, more preferably up to 5.0 equivalents, based on 1 equivalent of the compound of formula (IV). The amount of the base is particularly preferably 1.8 to 10 equivalents, preferably 2.0 to 5.0 equivalents, based on 1 equivalent of the compound of formula (IV).

[0069] According to the invention, suitable Lewis acids are preferably selected from BF3, PF5 and SbF5.

[0070] In particular, BF3 is a suitable Lewis acid, which can be present in the form of free gas or in solution, preferably in acetonitrile, aliphatic or cyclic ether compounds, as an ether complex or as a complex with an amine base, more preferably with triethylamine.

[0071] Preferably, BF3 is introduced in gaseous form, which allows simple process control, or alternatively, the reaction is preferably carried out in the form of a solution in acetonitrile.

[0072] SO2F2 is particularly preferred as R F SO2F and BF3 were selected as Lewis acid.

[0073] The Lewis acid is preferably used in an amount of at least 0.8 equivalent, more preferably at least 1.0 equivalent, based on 1 equivalent of the compound of formula (IV).

[0074] The amount of the Lewis acid to be used is further preferably up to 3.0 equivalents, more preferably up to 1.5 equivalents, based on 1 equivalent of the compound of the formula (IV).

[0075] The amount of the Lewis acid to be used is further preferably 0.8 to 3.0 equivalents, more preferably 1.0 to 1.5 equivalents, based on 1 equivalent of the compound of formula (IV).

[0076] According to the present invention, the compound of formula (IV) and R F SO2F reaction.

[0077] Here, R F The amount of SO2F used is preferably at least 0.8 equivalent, more preferably at least 1.0 equivalent, particularly preferably at least 1.2 equivalent, based on 1 equivalent of the compound of formula (IV).

[0078] R F SO2F is further preferably at most 4.0 equivalents, more preferably at most 3.0 equivalents, particularly preferably at most 1.5 equivalents, based on 1 equivalent of the compound of the formula (IV).

[0079] R F The amount of SO2F used is further preferably 0.8 to 4.0 equivalents, more preferably 1.0 to 3.0 equivalents, even more preferably 1.2 to 1.5 equivalents, based on 1 equivalent of the compound of formula (IV).

[0080] Alternatively, excess R F SO2F. Unreacted R F SO2F2 can be reacted again in a subsequent process. This applies in particular to SO2F2 introduced in gaseous form.

[0081] Step 1 is preferably carried out at a reaction temperature of -20°C to 120°C, more preferably 20°C to 100°C.

[0082] More preferably, step 1 is at least partially carried out at a temperature of 60° C. to 100° C. An elevated temperature can further increase the conversion rate of the reaction.

[0083] Specifically, step 1 is preferably performed at an initial temperature of 10°C to 30°C and a final temperature of 60°C to 100°C.

[0084] The reaction time of step 1 is preferably 6 to 40 hours, particularly preferably 10 to 30 hours.

[0085] More preferably, step 1 is carried out at a temperature of 60°C to 100°C for at least 5 hours, more preferably at least 10 hours, particularly preferably at least 15 hours. More preferably, step 1 is carried out at a temperature of 60°C to 100°C for 10 to 30 hours.

[0086] The reaction of step 1 is preferably carried out under standard pressure (1013 hPa). Optionally, the reaction can be carried out under increased or reduced pressure.

[0087] For example, the reaction can be preferably carried out at 300 hPa to 5000 hPa or 500 hPa to 2000 hPa, preferably at 1013 hPa±200 hPa.

[0088] The reaction of step 1 is preferably carried out in a solvent. Suitable solvents here are particularly acetonitrile, propionitrile, butyronitrile, acetone, N, N-dimethylacetamide, N-methylpyrrolidone (NMP), N, N-dimethylformamide (DMF), dimethylpropylene urea (DMPU), toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (iPrOAc), dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate (4-methyl-1,3-dioxolane-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), dihydro-levorotatory glucose ketone (cyrene), N, N-dimethylcyclohexylamine or a mixture thereof in any proportion.

[0089] Besides the above-mentioned bases N,N-dimethylacetamide, N,N-dimethylformamide or N,N-dimethylcyclohexylamine, other nitrogen-containing solvents or organic bases can also be used.

[0090] Particularly preferred are acetonitrile, toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (i-PrOAc) or N,N-dimethylcyclohexylamine.

[0091] Alternatively, step 1 can be carried out in an excess of a (liquid) base, without using an additional solvent. In this case, step 1 is in particular carried out in an excess of one of the above-mentioned bases.

[0092] The preferred embodiments described below apply, where appropriate, to all formulae described herein.

[0093] X 2 To X 6 of Preferred group definition as follows:

[0094] X 2 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN,

[0095] X 3 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy or CN,

[0096] X 4 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN,

[0097] X 5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy or CN,

[0098] X 6 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN.

[0099] X 2 To X 6 Particularly preferred The groups are defined as follows:

[0100] X 2 For H,

[0101] X 3 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN,

[0102] X4 is fluorine or H,

[0103] X 5 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN,

[0104] X 6 For H.

[0105] X 2 To X 6 Very particularly preferred The groups are defined as follows:

[0106] X 2 For H,

[0107] X 3 is H or fluorine,

[0108] X 4 is H or fluorine,

[0109] X 5 is H or fluorine,

[0110] X 6 For H.

[0111] X 2 To X 6 The most preferredThe groups are defined as follows:

[0112] X 2 For H,

[0113] X 3 For fluorine,

[0114] X 4 For H,

[0115] X 5 For fluorine,

[0116] X 6 For H.

[0117] Regarding the further configuration of the present invention:

[0118] R 1 Preferred 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, particularly preferably isopropyl, 2-methyl-1-propyl, 1-methyl-1-propyl, cyclohexyl, 3-methyl-1-butyl, 1-butyl or 1-pentyl, especially preferably isopropyl, 2-methyl-1-propyl, 1-methyl-1-propyl, cyclohexyl, 3-methyl-1-butyl, and most preferably isopropyl or 2-methyl-1-propyl.

[0119] R 2 Preferred is H, methyl or ethyl.

[0120] Other preferred The groups are defined as follows:

[0121] 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,

[0122] R 2 is H, methyl or ethyl,

[0123] Other particularly preferred The groups are defined as follows:

[0124] 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,

[0125] R 2 is H, methyl or ethyl,

[0126] Other very particularly preferred The groups are defined as follows:

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

[0128] R 2 is H or methyl,

[0129] Other most preferred The groups are defined as follows:

[0130] R 1 is methyl, ethyl, isopropyl, n-propyl, 2-methyl-1-propyl or 1-butyl,

[0131] R 2 For H,

[0132] The compounds of formula (I), (III), (IV) and (IV) Other preferred The groups are defined as follows:

[0133] X 2 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN,

[0134] X 3 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy or CN,

[0135] X 4 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN,

[0136] X 5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy or CN,

[0137] X 6 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy or CN,

[0138] 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,

[0139] R 2 is H, methyl or ethyl,

[0140] Other particularly preferred The groups are defined as follows:

[0141] X 2 For H,

[0142] X 3 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN,

[0143] X 4 For fluorine, H,

[0144] X 5 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN,

[0145] X 6 For H,

[0146] 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,

[0147] R 2 is H, methyl or ethyl,

[0148] Other very particularly preferred The groups are defined as follows:

[0149] X 2 For H,

[0150] X 3 is H or fluorine,

[0151] X 4 is H or fluorine,

[0152] X 5 is H or fluorine,

[0153] X 6 For H,

[0154] R 1 is methyl, ethyl, isopropyl, n-propyl, 2-methyl-1-propyl, 1-methyl-1-propyl, 3-methyl-1-butyl or 1-butyl,

[0155] R 2 is H or methyl,

[0156] Other most preferred The groups are defined as follows:

[0157] X 2 For H,

[0158] X 3 For fluorine,

[0159] X 4 For H,

[0160] X 5 For fluorine,

[0161] X 6 For H,

[0162] R 1 is methyl, ethyl, isopropyl, n-propyl, 2-methyl-1-propyl or 1-butyl,

[0163] R 2 For H,

[0164] In another specific configuration of the present invention, the method according to the second aspect of the present invention further comprises reacting a compound of formula (III) with a compound of formula R 1 -OH compound (where R 1 having the above definition) to prepare the compound of formula (IV) (step 0-1),

[0165]

[0166] in

[0167] R 2 and X 2 To X 6 Having the definitions given above.

[0168] In another specific configuration of the present invention, the compound of formula (I)

[0169]

[0170] Where R 1 , R 2 and X 2 To X 6 With the above definition

[0171] It can also be 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 a compound of formula (V)

[0172]

[0173] Where R 2 and X 2 To X 6 has the meaning given above. (Step 2)

[0174] The compounds of formula (I), (III), (IV) and (V) may be in the form of isomeric mixtures:

[0175] The isomer ratios between (Ia) and (Ib), (IIIa) and (IIIb), (IVa) and (IVb) and (Va) and (Vb) here may vary. The same applies to the compounds of the formulae (A) and (B).

[0176]

[0177]

[0178] The terms used herein are known to those skilled in the art. Otherwise, the following definitions apply:

[0179] CC double bond represents the cis or trans configuration of the corresponding group. This means, for example, that a compound of formula (A)

[0180]

[0181] It should be understood as referring to the configuration

[0182]

[0183] The expression "equivalent, based on 1 equivalent" refers to the ratio of the molar amounts of the corresponding compounds. For example, based on 1 equivalent of the compound of formula (B), if the amount of the base used is 1.8 equivalents, this corresponds to a ratio of 1.8 moles to 1 mole.

[0184] In the context of the present invention, unless otherwise defined, the term "alkyl", whether alone or in combination with other terms (such as haloalkyl), is understood according to the present invention to mean a group of saturated aliphatic hydrocarbon radicals, which may 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 alkyl and substituted alkyl.

[0185] The term "alkoxy", whether alone or in combination with other terms, such as haloalkoxy, is understood in the present case to mean an O-alkyl group, wherein the term "alkyl" is as defined above.

[0186] According to the present invention, unless otherwise defined, the term "cycloalkyl", whether alone or in combination with other terms, is understood to mean a C3-C8-cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. "Cycloalkyl" is understood to mean unsubstituted and substituted cycloalkyl groups.

[0187] Halogen-substituted radicals, such as fluoroalkyl, are mono- or polyhalogenated up to the maximum number of possible substituents.

[0188] According to the present invention, unless otherwise defined, the term "aryl", whether alone or in combination with other terms, is understood to mean a monocyclic or polycyclic, preferably monocyclic or bicyclic aromatic hydrocarbon radical, preferably having 6, 10 or 14 carbon atoms. The aryl group may be unsubstituted or monosubstituted or polysubstituted, the substituents being identical or different. Examples of suitable aryl groups are phenyl, 1-naphthyl, 2-naphthyl and anthracenyl.

[0189] The term "heteroaryl" denotes a monocyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic aromatic hydrocarbon radical, which preferably has 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, particularly preferably has 5, 6, 9, 10, 13 or 14 carbon atoms, especially preferably has 5 or 6 carbon atoms, wherein one or more carbon atoms in each case have been replaced by heteroatoms independently selected from oxygen, sulfur and nitrogen (NH). Heteroaryl may have preferably 1, 2, 3, 4 or 5 heteroatoms, particularly preferably 1, 2 or 3 heteroatoms as ring members, each heteroatom being independently selected from oxygen, sulfur and nitrogen (NH). Heteroaryl may be unsubstituted or monosubstituted or polysubstituted, the substituents being identical or different. Examples of suitable heteroaryl groups include indolizinyl, benzimidazolyl, tetrazolyl, triazinyl, isoxazolyl, phthalazinyl, carbazolyl, carbolyl, naphthyridinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thienyl, benzo[d]thiazolyl, benzodiazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl, indazolyl, quinoxalinyl, quinazolinyl, quinolinyl, naphthyridinyl and isoquinolinyl.

[0190] In the context of the present invention, an aryl or heteroaryl group 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]thienyl, (2,3)-dihydro-1H-indenyl, indolyl, (2,3)-dihydrobenzofuranyl, (2,3)-dihydrobenzo[d]oxazolyl, benzo[d][1,3]dioxolyl, benzo[d][1,3]oxathiolanyl, isoindolyl, (1,3)-dihydroisobenzofuranyl, (1,3)-dihydrobenzo[c]thienyl, (1,2,3,4)-tetrahydronaphthyl, (1,2,3,4)-tetrahydroquinolinyl, chromanyl, thiochroman ...thiochromanyl, (1,2,3,4)-tetrahydroquinolinyl, thiochromanyl, (1,2 4]oxazinyl, (2,3,4)-tetrahydroisoquinolyl, (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]dioxanyl, (2,3)-dihydrobenzo[b][1,4]oxathiazinyl, (6,7,8,9)-tetrahydro-5H-benzo[7]annulyl, (2,3,4,5)-tetrahydro-1H-benzo[b]azepinyl and (2,3,4,5)-tetrahydro-1H-benzo[c]azepinyl.

[0191] The term "heterocyclyl" generally refers to a ring system having at least two different elements, in particular N or O, or a combination of N and O with ring-forming carbon atoms. The heterocyclic ring system may be saturated or aromatic and mono- or polysubstituted. Examples are isoxazolines, preferably substituted.

[0192] If one of the abovementioned radicals is monosubstituted or polysubstituted, suitable substituents are all substituents familiar to the person skilled in the art, preferably those which are each independently selected from the group consisting of the following radicals: F, Cl, Br, I, -NO2, -CN, -OH, -SH, -NH2, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluoroalkoxy, -N(C 1-5 -alkyl)2, -N(C 1-5 -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.

[0193] The above-specified ranges (general ranges or preferred ranges) also apply to the entire method. These definitions can be combined with each other as required, that is, including combinations between various preferred ranges.

[0194] According to the invention, preference is given to using methods in which combinations of the above-mentioned preferred meanings and ranges are present.

[0195] According to the invention, particular preference is given to using methods in which combinations have the meanings and ranges specified above as being particularly preferred.

[0196] According to the invention, very particular preference is given to using processes in which a combination of the meanings and ranges specified above is very particularly preferred.

[0197] According to the present invention, it is most preferred to use a method in which a combination having the above-mentioned most preferred meanings and ranges is used.

[0198] Elucidation of methods and intermediates

[0199] Step 0-1

[0200] The method of the present invention may comprise step 0-1, wherein the compound of formula (IV) is reacted with a compound of formula (III) and a compound of formula R 1 -OH (where R 1 The compounds having the definitions given above) are prepared by reacting

[0201]

[0202] Where R 1 , R 2 and X 2 To X 6 With the definitions given above,

[0203]

[0204] Where R 2 and X 2 To X 6 has the definitions given above.

[0205] Solution 1

[0206]

[0207] The preparation of compound (III) is described in, for example, WO2018 / 228985.

[0208] To obtain compound (IV), compound (III) and formula R 1 The esterification reaction of the alcohol of formula R-OH 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 (based on 1 equivalent of the compound of formula (III)) at 0 to 80° C. (under standard pressure) for 1.5 to 3 hours. It is preferred to use a significant excess (e.g. 4 to 8 equivalents) of the compound of formula R 1 -OH compounds serve as reactants and solvents.

[0209] To obtain compound (IV), compound (III) and formula R 1 The alcohol with -OH is subjected to an esterification reaction which can generally be carried out under any conditions known in the art for such reactions.

[0210] The compound of formula (IV) can be isolated and further characterized by suitable work-up steps generally known to those skilled in the art and can subsequently be used in step 1 .

[0211] Step 1

[0212] A preferred method of the present invention comprises step 1, wherein the compound of formula (I) is reacted with a compound of formula (IV) by reacting R F SO2F (where R F having the definitions given above) in the presence of a base and a Lewis acid (e.g. BF3),

[0213]

[0214] Where R 1 , R 2 and X 2 To X 6 With the definitions given above,

[0215]

[0216] Where R 1 , R 2 and X 2 To X 6 has the definitions given above.

[0217] Solution 2

[0218]

[0219] In this step, a compound of formula (II) is formed as an intermediate, which is gradually converted into a compound of formula (I) during the reaction.

[0220] Step 2

[0221] The method according to the present invention may further comprise the following steps to obtain the compound of formula (V): the compound of formula (I) is 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,

[0222]

[0223] Where R 2 and X 2 To X 6 has the definitions given above.

[0224] Scenario 3:

[0225]

[0226] Suitable bases are especially inorganic bases, such as carbonates (e.g. (NH 4)2 CO3, Li2CO3, Na2CO3, K2CO3, CaCO3, MgCO 3) , 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, with KOH or NaOH being particularly preferred.

[0227] The base is preferably used in the form of an aqueous solution having a concentration of 1 to 50% by weight, more preferably in the form of an aqueous solution having a concentration of 5 to 45% by weight, and most preferably in the form of an aqueous solution having a concentration of 5 to 35% by weight.

[0228] 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, especially preferably in the range of 15°C to 60°C.

[0229] The reaction is preferably carried out in the standard pressure range (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.

[0230] The hydrolysis reaction time is preferably 0.5 hour to 10 hours.

[0231] The hydrolysis of the compound of formula (I) to give compound (V) can generally be carried out under any conditions known in the prior art for such reactions.

[0232] The compounds of formula (I) can be isolated by suitable work-up steps generally known to the person skilled in the art (for example by extraction and optionally distillation) and further characterized.

[0233] Usually, after step 1, the compound of formula (I) can also be treated with 1 The esterification reaction at the position is not hydrolyzed (step 2).

[0234] Alternatively, step 2 can also be carried out in the presence of an acid.

[0235] Overall approach

[0236] In an advantageous embodiment, the method according to the invention comprises steps 0-1 and 1, and particularly advantageously comprises steps 0-1, 1 and 2.

[0237] Solution 4

[0238]

[0239] Scheme 4 gives an overall schematic diagram of the method of the present invention, including all optional steps and required steps. Here, the reaction conditions and reactants are selected according to the present invention and preferred embodiments described above. All variables in the chemical formula are as defined above.

[0240] Formula (IV) and (I) compounds can also be separated and optionally purified before being used in the next synthesis step. However, the compound can also be used directly in the next step without separation and purification. In this case, before the compound is used in the next synthesis step, the solvent and excess reagent of the previous stage are removed by standard methods. Example

[0241] The present invention is explained in more detail by the following examples, but the present invention is not limited thereto.

[0242] Measurement method

[0243] Product by 1 H-NMR, 19 The products were characterized by F-NMR spectroscopy and HPLC (high performance liquid chromatography).

[0244] NMR spectra were measured using a Bruker Avance 400 equipped with a flow probe (volume 60 μl). The NMR data of the examples are listed in the conventional form (δ value, multiplicity of splitting, number of hydrogen or fluorine atoms).

[0245] The solvent and the frequency at which the NMR spectra were recorded are listed in each case.

[0246] HPLC (high performance liquid chromatography) was performed using an Agilent 1100LC system with the following parameters:

[0247] a) For monitoring the reaction (HPLC area %)

[0248] Column: 150x 4.6mm, stainless steel; Stationary phase: Phenomenex, Luna 5μm C18 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; running time 6 minutes, injection volume 1 μl.

[0249] b) For quantitative (V)

[0250] Chromatographic column: 100x 4.6mm, stainless steel; stationary phase: Daicel, Chiracel OZ-3; mobile phase: heptane / ethanol 90 / 10 (v / v), isocratic elution; oven temperature 40°C; flow rate: 1.0mL / min; run time 10 minutes, injection volume 5μl. Use an instrument with UV detection and external standard quantification.

[0251] Example I: Preparation of 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid of the present invention

[0252] Step 0-1: 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylic acid isopropyl ester

[0253] A suspension of 500 g of 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylic acid (1808 mmol, purity 98.1% by weight) in 1100 g of 2-propanol (99.0%) at 20° C. is heated to an internal temperature of 50° C. 260.1 g of thionyl chloride (2176 mmol, 99.5%) are added over 3 hours using a metering pump. The solution is then reacted at 50° C. for a further 3 hours. At the end of the reaction, a solid precipitates out of the solution, especially after the suspension has 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 can be analyzed by HPLC. The yield of the desired isopropyl 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylate was >98%.

[0254] Step 1

[0255] Example 1.a:

[0256] At 20°C, in a 250 ml four-necked flask equipped with a reflux condenser, a suspension of 50 g of isopropyl 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylate in 66 ml of acetonitrile was initially added. The mixture was purged with nitrogen. Subsequently, a total of 12.86 g of BF3 gas (4.5 L; 1.2 eq.) was introduced above the liquid surface. The pressure was balanced by a balloon. The gas quickly dissolved in the mixture; after adding about 4 g, a solution was formed. The gas was added within 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 hour, 17.75 g of SO2F2 (4.1 L; 1.09 eq.) was added, and the mixture was heated to 80°C. The mixture was maintained at 80°C for a total of 19 hours.

[0257] A sample was analyzed by HPLC; 98% of isopropyl 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylate was found.

[0258] Example 1.b:

[0259] In a 250 mL reactor equipped with a reflux condenser, 124.9 g of a suspension of isopropyl 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylate in xylene (38.4% by weight) were initially added under nitrogen, followed by 10 g of acetonitrile. 82.5 g of a BF3 solution in acetonitrile (15.2% in acetonitrile) were then added dropwise at 20° C. over the course of 20 minutes. After the addition was complete, the resulting solution was stirred for a further 10 minutes at 20° C., and then 78.0 g of N,N-dimethylcyclohexylamine (4 equivalents) were added dropwise over the course of 2 hours, without the temperature exceeding 25° C. Finally, 20.0 g of SO2F2 (1.2 equivalents) were metered in below the liquid surface at 20-25° C. over the course of 4 hours, and after the addition was complete, the reaction mixture was stirred for a further 10 minutes at 20° C., then heated to 80° C. over the course of 6 hours and stirred at this temperature for a further 15 hours.

[0260] A sample was analyzed by HPLC; >99% isopropyl 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylate was found.

[0261] Step 2

[0262] Example 2.a:

[0263] The mixture from Example 1.a 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% by weight, 4 equivalents). The solution was stirred at 65° C. for 25 minutes until the hydrolysis was complete. A sample of the reaction mixture was acidified and subjected to HLPC analysis, which showed 98% of 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid.

[0264] Example 2.b:

[0265] 86 g of acetonitrile were removed from the mixture of Example 1.b by distillation at 80° C. at a pressure of up to 300 mbar, and the reaction mixture was diluted with 80 g of xylene. After 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 phases were treated with 156 g of water, 9.2 g of isopropanol and 61.4 g of NaOH (20% by weight, 2.0 equivalents). The reaction mixture was stirred at 50° C. for 8 hours in order to determine by HLPC analysis that the hydrolysis was complete and, after acidification of a sample of the reaction mixture, 98% of 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid was obtained. With regard to its workup, the separated aqueous phase can be further processed. For this purpose, potassium hydroxide or another potassium base can be added thereto until the pH is >9. The resulting potassium tetrafluoroborate salt (KBF4) was isolated by filtration; fluoride can also be removed as required using reagents conventionally used by those skilled in the art.

[0266] Post-processing

[0267] Example 3.a

[0268] When the hydrolysis of the mixture of Example 2.a was completed, the mixture was distilled under reduced pressure at 53-56° C. to remove N,N-dimethylcyclohexylamine by azeotropic distillation, and the lower aqueous phase of the distillate was repeatedly fed to the reaction mixture.

[0269] 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 was initially isolated as an oil and crystallized overnight at room temperature to give a solid. The solid was filtered and 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% (equivalent to a yield of 97%).

[0270] Example 3.b

[0271] After the hydrolysis was completed, the mixture of Example 2.b was cooled 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 of hydrochloric acid, and the product was extracted three times with a total of 130g of tert-butyl methyl ether. The combined organic extracts were fully concentrated under reduced pressure at 40°C, and the product was separated as a solid. 38.6g of the desired 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid was isolated. The purity was 96.1% (equivalent to a yield of 96%) by quantitative HPLC.

[0272] The NMR data of the separated and purified products and intermediates were determined as follows:

[0273] 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylic acid isopropyl ester (after step 0-1)

[0274] 1 H-NMR (400MHz, CDCl3): δ (ppm) = 1.28-1.32 (m, 9H), 2.18 (s, 1H), 3.53 (d, J = 17.4Hz, 1H), 3.67 (d, J = 17.4Hz, 1H), 4.22 (q, J = 6.5Hz, 1H), 5.13 (hept, J = 6.3Hz, 1H), 6.84-6.91 (m, 1H), 7.15-7.22 (m, 2H).

[0275] 19 F-NMR (376MHz, CDCl3): δ (ppm) = -108.4 (m, 2F).

[0276] 3-(3,5-Difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid isopropyl ester (after step 1)

[0277] 1 H-NMR (401MHz, CDCl3): δ (ppm) = 1.31 (dd, J = 6.3, 1.0Hz, 6H), 3.31 (d, J = 17.0Hz, 1H), 3.89 (d, J = 17.0Hz, 1H), 5.11 (hept, J = 6. 3Hz, 1H), 5.36 (d, J = 10.7Hz, 1H), 5.54 (d, J = 17.2Hz, 1H), 6.13 (dd, J = 17.2, 10.7Hz, 1H), 6.84-6.90 (m, 1H), 7.15-7.22 (m, 2H).

[0278] 19 F-NMR (376MHz, CDCl3): δ (ppm) = -108.4 (m, 2F).

[0279] 3-(3,5-Difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid (after step 2)

[0280] 1 H-NMR (400MHz, CDCl3): δ (ppm) = 3.40 (d, J = 17.1Hz, 1H), 3.92 (d, J = 17.1Hz, 1H), 5.44 (d, J = 10.7Hz, 1H), 5 .63(d,J=17.2Hz,1H),6.16(dd,J=17.2,10.7Hz,1H),6.86-6.92(m,1H),7.14-7.21(m,2H),9.61(bs,1H).

[0281] 19 F-NMR (376MHz, CDCl3): δ (ppm) = -108.0 (m, 2F).

[0282] Example II: Preparation of 3-(3,5-difluorophenyl)-5-vinyl- 4H-isoxazole-5-carboxylic acid

[0283] For comparison, the method described in Examples 1.a, 2.a and 3.a was used, but no Lewis acid was added to the reaction mixtures 2 and 3. Acetonitrile was used as solvent.

[0284] The corresponding 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 given in the table below in the column Yield I (%). The yields were measured in Examples 4 to 6, wherein the reaction temperature was successively increased during the reaction (room temperature (RT), 80° C., 100° C., in each case for the time stated in the “Time” column), and were measured at key points in the course of the reaction according to the reaction time and temperature stated in the respective row.

[0285]

[0286]

[0287] *The numbers in brackets are the isolated yields of the acid (V).

[0288] ** Yield of (V) instead of (I) after hydrolysis according to step 2 of the above example, HPLC area %

[0289] ***Reactions were performed in a glass autoclave at 3.5 bar.

[0290] Among them, in the reaction mixtures 1 and 4 to 6 of the present invention, the presence of Lewis acid leads to high HPLC yield, and the isolated yield of the desired product (V) 3-(3,5-difluorophenyl)-5-vinyl-4H-isoxazole-5-carboxylic acid is up to 97%, while the HPLC yield without using Lewis acid (reaction mixtures 2 and 3) is up to 70%, and contains a large amount of undesirable by-product VI.

Claims

1. A process for preparing a compound of formula (I), in R 1 is C1-C8 alkyl, cycloalkyl, unsubstituted benzyl, unsubstituted phenyl, or benzyl or phenyl substituted by mono- or di-C1-C3 alkyl; R 2 is H or alkyl, 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, It is characterized in that The compound of general formula (IV) and formula R F SO2F compounds react in the presence of base and Lewis acid. Where R F Selected from F, CF3, C2F5, C3F7, C4F9, CF2Cl, C6F5, alkoxy-CF2 and R 6 OCOCF2SO2F, where R 6 is defined as C1-C8-alkyl or cycloalkyl, Where R 1 , R 2 , X 2 , X 3 , X 4 , X 5 and X 6 With the above definition.

2. The method 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-lutidine, 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), and tetramethylurea (TMU).

3. The method according to claim 1, characterized in that The base is selected from triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine and N,N-dimethylcyclohexylamine.

4. The method 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, based on 1 equivalent of the compound of formula (IV).

5. The method according to any one of claims 1 to 4, characterized in that The Lewis acid is selected from BF3, PF5 and SbF5.

6. The method according to any one of claims 1 to 5, characterized in that The Lewis acid is BF3, which is preferably introduced in gaseous form or in solution in acetonitrile.

7. The method 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, based on 1 equivalent of the compound of formula (IV).

8. The method according to any one of claims 1 to 7, characterized in that R F For F.

9. The method according to any one of claims 1 to 8, characterized in that R F The amount of SO2F used is 0.8 to 4.0 equivalents, preferably 1.0 to 3.0 equivalents, based on 1 equivalent of the compound of formula (IV).

10. The method according to any one of claims 1 to 9, characterized in that The method is carried out in a solvent selected from the following: acetonitrile, propionitrile, butyronitrile, acetone, N,N-dimethylacetamide, N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), dimethylpropylene urea (DMPU), toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (iPrOAc), dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate (4-methyl-1,3-dioxolane-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), dihydro-levorotatory glucosone (cyrene), N,N-dimethylcyclohexylamine or a mixture thereof in any proportion.

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

12. The method according to any one of claims 1 to 11, characterized in that It also includes the step of reacting a compound of formula (III) with a compound of formula R 1 -OH to prepare a compound of formula (IV), Where R 1 , R 2 and X 2 To X 6 Having the meaning given in claim 1.

13. The method according to any one of claims 1 to 12, characterized in that The method also includes the reaction of the compound of formula (I) in the presence of a base or an acid to generate a compound of formula (V), Where R 1 , R 2 and X 2 To X 6 As defined in claim 1.

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

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

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