Method for producing isoxazolinecarboxylic acid derivatives

Abstract

The present invention relates to a novel process for preparing isoxazolinecarboxylic acid derivatives of formula (I).

Description

[Technical Field]

[0001] The present invention relates to a novel process for preparing isoxazolinecarboxylic acid derivatives of formula (I). [Background technology]

[0002] Isoxazolinecarboxylic acid derivatives of general formula (I) are important precursors of active pesticide ingredients (e.g., herbicides described in WO2014 / 048882 and WO2018 / 228985).

[0003] The prior art describes numerous cyclization methods for preparing isoxazoline carboxylic acid derivatives, e.g., Tetrahedron Letters, 1991, 6367-6370; Eur. J. Org. Chem. 2008, 5446-5460; Bull. Chem. Soc. Jpn. 1993, 2685. Possible transition states for the cycloaddition are discussed. Also disclosed are yields and isomer ratios depending on the reaction conditions. High levels of stereocontrol could be achieved by chelation in the presence of a suitable metal, e.g., magnesium. However, a drawback of the previously described methods is the need to use dichloromethane (DCM) as a solvent, which is not a preferred solvent for industrial-scale synthesis. Furthermore, the allylic alcohol used as the substrate had to be converted in excess (2 equivalents). The use of DCM as a solvent has also been described for the preparation of other isoxazoline derivatives, for example, in the cyclization of aliphatic nitrile oxides with cyclic and acyclic allylic alcohols in the presence of 3.3 to 3.9 equivalents of 2-propanol and 3 equivalents of a Grignard reagent (e.g., Carreira et al., Angew. Chem. Int. Ed. 2001, 40, 2082; J. Am. Chem. Soc. 2001, 123, 3611; Org. Lett. 2007, 9, 3857). If the compounds of the present invention are prepared by one of the methods known from the literature in a solvent more suitable for industrial scale use, for example, tetrahydrofuran (THF) instead of DCM as the solvent, this results in an isomeric purity insufficient for industrial scale synthesis. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2014 / 048882 [Patent Document 2] International Publication No. 2018 / 228985 [Non-patent literature]

[0005] [Non-Patent Document 1] Tetrahedron Letters, 1991, 6367-6370 [Non-patent document 2] Eur.J.Org.Chem.2008, 5446-5460 [Non-patent document 3] Bull.Chem.Soc.Jpn.1993,2685 [Non-patent document 4] Carreira et al., Angew.Chem.Int.Ed.2001, 40, 2082 [Non-Patent Document 5] J.Am.Chem.Soc.2001, 123, 3611 [Non-patent document 6] Org.Lett.2007, 9, 3857 Summary of the Invention [Problem to be solved by the invention]

[0006] Therefore, the object of the present invention was to provide a process for preparing isoxazolinecarboxylic acid derivatives of general formula (I), which is suitable for synthesis on an industrial scale, has high yields and high isomeric purity, and can avoid tedious purification procedures. [Means for solving the problem]

[0007] The object of the present invention is to provide a compound of general 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 4is 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 H, C1-C 12 -alkyl, unsubstituted benzyl or mono- or di-C1-C4-alkyl-substituted benzyl, R 2 is C1-C4-alkyl] A method for producing an isoxazolinecarboxylic acid derivative of the formula: General formula (II) [ka] [During the ceremony, X 2 ~X 6 has the above definition, X 7 , X 8 , X 10 , X 11 are independently H or C1-C4-alkyl, X 9 is H, C1-C4-alkyl or N(C1-C4-alkyl)2] with a compound of formula (III) [ka] [During the ceremony, R 1 and R 2 is R 1 has the above definition except that is not H. and 1.0 to 2.0 equivalents of a reactive species "R 3OMgHal” (IV) [wherein, R 3 is alkyl, or unsubstituted or alkyl-substituted benzyl, and Hal is halogen, This has been achieved according to the invention by a process which is characterized in that it gives a compound of general formula (I):

[0008] The groups in the compounds of general formulae (I), (II) and (III) preferable The definition is 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, X 7 , X 8 , X 10 , X 11 are independently H, methyl or ethyl; X 9 is H, methyl, ethyl or N(methyl)2, R 1 is H or C1-C4-alkyl, R 2 is methyl or ethyl, R in formula (III) 1 Except =H.

[0009] Preferably, Compounds of general formula (IV) are produced by one of the following combinations of reagents: -R 4 MgHal and R 3 OH or - MgHal2 and R 3 OM or - MgHal2 and Mg(OR 3 )2, where: R 3 is C2-C 12 -alkyl, or unsubstituted or C1-C4-alkyl-substituted benzyl, and Hal is a halogen, M is an alkali metal; R 4 is alkyl, unsubstituted aryl, substituted aryl, unsubstituted benzyl, substituted benzyl, allyl, or vinyl.

[0010] or The compound of general formula (IV) is produced by the combination of the following reagents: -R 5 MgHal and R 6 R 7 CO, where R 5 is C1-C6-alkyl, aryl or benzyl, R 6 , R 7 is H, C1-C6-alkyl or aryl, and the resulting group definitions R 3 is R 5 R 6 R 7 Corresponds to C.

[0011] For reagents for preparing compounds of general formula (IV) preferable The group definitions are alternatively shown as follows: R 5 is C1-C4-alkyl, phenyl, benzyl or p-tolyl, R6 , R 7 is H, C1-C4-alkyl or phenyl.

[0012] The groups in the compounds of general formulae (I), (II) and (III) Particularly preferred The definition is as follows: X 2 is H, X 3 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN, X 4 is fluorine or H, X 5 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN, X 6 is H, X 7 , X 8 , X 11 are independently H, methyl or ethyl; X 9 is H or N(methyl)2, X 10 is H, R 1 is H, methyl, ethyl, i-propyl or i-butyl, R 2 is methyl, R in formula (III) 1 Except =H.

[0013] More preferably The compounds of general formula (IV) are produced by one of the following combinations of reagents: -R 4 MgHal and R 3 OH or - MgHal2 and R 3 OM or - MgHal2 and Mg(OR 3 )2, where: R 3 is C2-C8-alkyl, Hal is bromine or chlorine, M is an alkali metal; R 4 is C1-C8-alkyl, phenyl, benzyl, p-tolyl or vinyl.

[0014] The groups in the compounds of general formulae (I), (II) and (III) Very particularly preferred The definition is as follows: X 2 is H, X 3 is H or fluorine, X 4 is H, X 5 is H or fluorine, X 6 is H, X 8 is H, methyl or ethyl, X 7 , X 11 are independently H or methyl, and X 9 , X 10 is H, R 1 is H, methyl, i-propyl or i-butyl, R 2 is methyl, R in formula (III) 1 Except =H.

[0015] Even more preferably, Compounds of general formula (IV) are produced by one of the following combinations of reagents: -R 4 MgHal and R 3 OH or - MgHal2 and R 3 OM or - MgHal2 and Mg(OR 3 )2, where: R 3 is i-propyl, i-butyl or 2-butyl, Hal is bromine or chlorine, M is sodium, R 4 is methyl, ethyl, n-butyl or i-propyl.

[0016] The groups in the compounds of general formulae (I), (II) and (III) Most preferred The definition is as follows: X 2 is H, X 3 is fluorine, X 4 is H, X 5 is fluorine, X 6 is H, X 7 , X 8 , X 11 are independently H or methyl; X 9 , X 10 is H, R 1 is H, methyl or i-butyl, R 2 is methyl, R in formula (III) 1 Except =H.

[0017] definition Alkyl means a linear or branched hydrocarbyl group having the number of carbon atoms specified in each case, for example C-C 12-Alkyl, for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

[0018] Hal means halogen and is fluorine, chlorine, bromine or iodine. When this term is used in a group, Hal means a fluorine, chlorine, bromine or iodine atom.

[0019] Alkali metal means lithium, sodium or potassium.

[0020] Aryl means phenyl or naphthyl.

[0021] The compound of formula (I) may be in the form of an isomeric mixture. The desired diastereomeric excess is increased by optimizing the reaction conditions compared to the prior art. 1.7 to 2.0 equivalents of the reactive species "R 3 OMgHal" (IV) is particularly advantageous.

[0022] When the (S)-alcohol is used, the major product is the (S,S)-diastereomer, and the (R,S)-diastereomer is the secondary diastereomer.

[0023] When an (R)-alcohol is used, the major product is the (R,R)-diastereomer, with the (S,R)-diastereomer being the secondary diastereomer. When a (rac)-alcohol is used, the major product is the (S,S / R,R)-rac-diastereomer, with the (S,R / R,S)-rac-diastereomer being the secondary diastereomer.

[0024] Compounds of formula (I) can be isolated as the corresponding ester or as the carboxylic acid after hydrolytic workup.

[0025] Up to 100:0 Diastereomers The ratio can be achieved in the compound of formula (I) through enrichment by crystallization.

[0026] Elucidation of processes and intermediates [ka] The present invention relates to a method for preparing a compound of general formula (II) by reacting a compound of general formula (III) with 1.0 to 2.0 equivalents of a reactive species "R 3 This was achieved by a method for preparing an isoxazoline carboxylic acid derivative of formula (I), which comprises adding a combination of reagents that allows the formation of "OMgHal" (IV) to react with the resulting compound of general formula (I) (Scheme 1).

[0027] Based on the compound of general formula (II), 1.5 to 2.0 equivalents of the reactive species "R 3 The use of "OMgHal" (IV) preferable .

[0028] Based on the compound of general formula (II), 1.7 to 2.0 equivalents of the reactive species "R 3 The use of "OMgHal" (IV) Particularly preferred .

[0029] The addition of water may also be advantageous and may result in further improvement of the diastereomeric ratio (dr). The use of up to 1.0 equivalents of water (based on the compound of general formula (II)) may preferableThe use of 0.1 to 0.6 equivalents of water (based on the compound of general formula (II)) Particularly preferred .

[0030] Cyclization is usually carried out at temperatures between -25°C and 70°C. Preferably The temperature range is 10℃ to 30℃.

[0031] Furthermore, the cyclization can optionally be carried out in the presence of a solvent or diluent or a mixture of solvents. Preferably Toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (i-PrOAc), acetonitrile, methyl tert-butyl ether (MTBE), methyl-THF, ethyl acetate (EtOAc) or a mixture thereof in any ratio.

[0032] Compounds of general formula (III) are prepared by a two-step process, which is known from the literature. The first step is the Baylis-Hillman reaction. A relevant reference is Drewes, SE; Hoole, RFA [Synthetic Communications, 1985, Vol. 15, 12, pp. 1067-1074]. For the second step, a relevant reference is Nascimento et al. (2003, Tetrahedron Asymmetry 14, 311-311).

[0033] Compounds of general formula (II) and (III) are also known from WO2018 / 228985. The preparation of compounds of formula (IIa) from compounds of formula (II) is known from Binenfeld, Zlatko et al.; Glasnik Hemijskog Drustva Beograd (1966), 31 (4-6), 243-50 and Daroszewski, J. et al.; Pharmazie (1986), 41 (10), 699-702. [Example]

[0034] Example The invention is explained in more detail by the following examples, without limiting the invention thereto (Table 1).

[0035] Analysis method The product 1 Characterized by 1 H NMR spectroscopy and / or LC-MS (liquid chromatography mass spectrometry).

[0036] NMR spectra were determined using a Bruker Avance 400 equipped with a flow probe head (volume 60 μl). In individual cases, NMR spectra were measured using a Bruker Avance II 600. In quantitative NMR (qNMR) measurements, methyl 3,5-dinitrobenzoate was used as an internal standard.

[0037] Table 1 [Table 1] TIFF2026500555000006.tif52125a) The reaction was carried out with 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride. b) Product yield after hydrolysis and acidification with sodium hydroxide solution. c) (S)-Methyl 3-hydroxy-2-methylenebutanoate (0.524 g, 95.5 wt%) was used. d) The reaction was carried out with 0.524 mol of 3,5-difluoro-N-hydroxybenzenecarboximidyl chloride. The corresponding carboxylic acid was isolated. [Table 2]

[0038] Example 1 Under an argon atmosphere, 2 equivalents (eq) of 2-propylmagnesium chloride (4.0 ml, 2 mol / l in THF) are initially charged at 20°C, and 2 eq of 2-propanol (0.61 ml) are added dropwise over 10 minutes while cooling (ice bath). Propane escapes (only slight effervescence occurs), and a white solid precipitates. After the addition is complete and gas evolution has ceased, the resulting suspension is stirred for 20 minutes at 20°C. Subsequently, 1 eq of methyl 3-hydroxy-2-methylenebutanoate (0.52 g, 99.8% by weight) is added dropwise at room temperature (RT). The mixture becomes more fluid. The suspension is stirred for another 15 minutes at RT and then cooled to approximately 15°C. Subsequently, a THF solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride (2.55 g, 30.0% by weight) is added dropwise at approximately 15°C via a syringe pump. The addition time is 1 hour (h). The reaction mixture is then warmed to RT and stirred for another hour. An HCl solution is then added to the reaction mixture and extracted with ethyl acetate. The aqueous phase is extracted again with ethyl acetate. The combined organic phases are concentrated under reduced pressure. Toluene (1 ml) and excess aqueous sodium hydroxide are added to the residue, which is stirred at 65 °C. Upon completion of the hydrolysis, the reaction mixture is cooled to RT, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases are concentrated under reduced pressure. After determining the content (qNMR), 0.90 g of product is present in the residue (83%). Diastereomeric ratio = 88:12.

[0039] Example 2 Under an argon atmosphere, 2 equivalents (eq) of 2-propylmagnesium chloride (4.23 ml, 1.87 mol / l in THF) are initially charged at 20°C, and 2 eq of 2-propanol (0.61 ml) are added dropwise over 10 min with cooling (ice bath). Propane escapes (only slight effervescence) and a white solid precipitates. After the addition is complete and gas evolution has ceased, the resulting suspension is stirred for 20 min at 20°C. Subsequently, 1 eq of (S)-methyl 3-hydroxy-2-methylenebutanoate (0.545 g, 95.5% by weight) is added dropwise at room temperature (RT). The mixture becomes more fluid. The suspension is stirred for a further 15 min at RT and then cooled to approximately 15°C. Subsequently, a solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride (4.23 g, 18.1% by weight) in a solvent mixture of toluene / THF is added dropwise via syringe pump at approximately 15 °C together with an additional 0.3 eq of water (22 μl). The addition time is 1 h. The reaction mixture is then warmed to RT and stirred for another 1 h. HCl solution is then added to the reaction mixture and extracted with ethyl acetate. The aqueous phase is extracted again with ethyl acetate. The combined organic phases are concentrated under reduced pressure. Toluene (1 ml) and excess aqueous sodium hydroxide are added to the residue, which is stirred at 65 °C. Upon completion of the hydrolysis, the reaction mixture is cooled to RT, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases are concentrated under reduced pressure. After determining the content (qNMR), 0.93 g of product is present in the residue (86%). Diastereomeric ratio = 92:8.

[0040] Example 13 Under an argon atmosphere, 1.7 equivalents (eq) of 2-propylmagnesium chloride (3.41 ml, 2 mol / l in THF) are initially charged at 20°C. 1.7 eq of 2-propanol (0.52 ml) are added dropwise over 10 minutes while cooling (ice bath). Propane escapes (only slight effervescence occurs) and a white solid precipitates. After the addition is complete and gas evolution has ceased, the resulting suspension is stirred for 20 minutes at 20°C. 1 eq of 2-propyl 3-hydroxy-2-methylenebutanoate (0.79 g, 80.0 wt%) is then added dropwise at room temperature (RT). The mixture becomes more fluid. The suspension is stirred for another 15 minutes at RT and then cooled to approximately 15°C. A THF solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride (2.54 g, 30.1 wt%) is then added dropwise at approximately 15°C via a syringe pump. The addition time is 1 hour (h). The reaction mixture is then warmed to RT and stirred for another 1 h. HCl solution is then added to the reaction mixture and extracted with ethyl acetate. The aqueous phase is extracted again with ethyl acetate. The combined organic phases are concentrated under reduced pressure. Toluene (1 ml) and excess aqueous sodium hydroxide are added to the residue, which is stirred at 65 °C. Upon completion of the hydrolysis, the reaction mixture is cooled to RT, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases are concentrated under reduced pressure. After determining the content (qNMR), 0.90 g of product is present in the residue (83%). Diastereomeric ratio = 89:11.

[0041] Example 14 Under an argon atmosphere, 1.7 equivalents (eq) of 2-propylmagnesium chloride (3.42 ml, 2 mol / l in THF) are initially charged at 20°C. 1.7 eq of 2-propanol (0.52 ml) are added dropwise over 10 minutes while cooling (ice bath). Propane escapes (only slight effervescence) and a white solid precipitates. After the addition is complete and gas evolution has ceased, the resulting suspension is stirred for 20 minutes at 20°C. Subsequently, 1 eq of 2-propyl 3-hydroxy-2-methylenebutanoate (0.79 g, 80.0% by weight) is added dropwise at room temperature (RT). The mixture becomes more fluid. The suspension is stirred for a further 15 minutes at RT and then cooled to approximately 15°C. Subsequently, a solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride (2.59 g, 29.7% by weight) in a solvent mixture of toluene / THF is added dropwise via syringe pump at approximately 15 °C together with an additional 0.3 eq of water (22 μl). The addition time is 1 h. The reaction mixture is then warmed to RT and stirred for another 1 h. HCl solution is then added to the reaction mixture and extracted with ethyl acetate. The aqueous phase is extracted again with ethyl acetate. The combined organic phases are concentrated under reduced pressure. Toluene (1 ml) and excess aqueous sodium hydroxide are added to the residue, which is stirred at 65 °C. Upon completion of the hydrolysis, the reaction mixture is cooled to RT, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases are concentrated under reduced pressure. After determining the content (qNMR), 0.93 g of product is present in the residue (86%). Diastereomeric ratio = 89:11.

[0042] Example 21 Under an argon atmosphere, 1.8 equivalents (eq) of 2-propylmagnesium chloride (552 ml, 1.71 mol / l in THF) are initially charged at 20°C. 1.8 eq of 2-propanol (73 ml) are added dropwise over 90 minutes while cooling (ice bath). The temperature is maintained between 15 and 30°C. Propane escapes (only slight effervescence occurs) and a white solid precipitates. After the addition is complete and gas evolution has ceased, the resulting suspension is stirred for 40 minutes until an internal temperature of 20°C is reached. Subsequently, 1 eq of isobutyl 3-hydroxy-2-methylenebutanoate (93.90 g, 96.1% by weight) is added dropwise over 35 minutes at a temperature between 20 and 25°C. The mixture becomes more fluid. The suspension is stirred for a further 75 minutes at room temperature and then cooled to approximately 15°C. Subsequently, a solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride (233.0 g, 43.1 wt%) in a solvent mixture of toluene and THF was added dropwise via a dropping funnel at approximately 15 °C (ice bath) along with an additional 0.3 eq. of water (2.83 ml). The addition time was 1 hour (h) 45 min. The internal temperature was maintained at 15-20 °C. After the addition was complete, the reaction mixture was warmed to RT and stirred for at least another 2.5 h. The reaction mixture was then mixed with HCl solution (16.9 wt%, 140.4 g) while cooling in a water bath (20 °C), and the organic phase was removed. The aqueous phase was then washed with toluene, and the combined organic phases were concentrated under reduced pressure. Toluene (100 g), water (58 g), and excess aqueous sodium hydroxide (32 wt%, 85.1 g) were added to the residue and vigorously stirred at 65 °C. After completion of hydrolysis (2.5 h), the reaction mixture is cooled to RT and concentrated under reduced pressure to a thick suspension (60 °C bath, 240 mbar to 85 mbar). This is followed by acidification with sulfuric acid (20 wt%, 100 ml) under vigorous stirring. The product precipitates, then is filtered off and dried. An additional 35 ml of 20 wt% sulfuric acid is added to the mother liquor (pH 1-2), and the mother liquor is extracted with isopropyl acetate (iPrOAc) (2 x 200 ml). The combined organic phases are concentrated under reduced pressure. The residue is combined with the solid, suspended in isopropyl acetate (iPrOAc) (500 ml), and stirred at 60 °C for 6 h. The suspension is then concentrated (50 °C, 200 mbar to 150 mbar) until it is still stirrable.300 ml of toluene are added to the thick suspension. Distillation is continued at 50 °C / 150 mbar to 120 mbar until the suspension thickens again. The suspension is cooled to RT and left overnight until crystallization is complete. The suspension is then filtered and washed with 290 ml of toluene to obtain the solid product, which is then dried. After determining the content of the filtered solid (119.20 g, 96.5 wt%) (qNMR), the product yield is 81% with a diastereomeric ratio of 98:2. 8% of the product is present in the concentrated mother liquor (43.13 g, 25.2 wt%). The diastereomeric ratio of the mother liquor corresponds to 41:59.

[0043] 1 H NMR (401MHz, DMSO-d6): δ (ppm) = 1.11 (d, J = 6.5 Hz, 3H), 3.61 (d, J = 17.8, 1H), 3.67 (d, J = 17.8, 1H), 4.10 (q, J = 6.4 Hz, 1H), 5.20 (bs, 1H), 7.34-7.45 (m, 3H), 13.28 (bs, 1H). 19 F-NMR (376MHz, DMSO-d6): δ (ppm) = -108.7 (m, 2F). Example 22 Under an argon atmosphere, 1.7 equivalents (eq) of 2-propylmagnesium chloride (3.64 ml, 1.87 mol / l in THF) are initially charged at 20°C. 1.7 equivalents of 2-propanol (0.52 ml) are added dropwise over 10 minutes while cooling (ice bath). Propane escapes (only slight effervescence) and a white solid precipitates. After the addition is complete and gas evolution has ceased, the resulting suspension is stirred for 20 minutes at 20°C. Subsequently, 1 eq of isobutyl 3-hydroxy-2-methylenebutanoate (0.70 g, 98.2% by weight) is added dropwise at room temperature (RT). The mixture becomes more fluid. The suspension is stirred for a further 15 minutes at RT and then cooled to approximately 15°C. Subsequently, a solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride in THF (2.54 g, 30.2% by weight) is added dropwise via syringe pump at approximately 15 °C. The addition time is 1 hour (h). The reaction mixture is then warmed to RT and stirred for another 1 h. HCl solution is then added to the reaction mixture and extracted with ethyl acetate. The aqueous phase is extracted again with ethyl acetate. The combined organic phases are concentrated under reduced pressure. Toluene (1 ml) and excess aqueous sodium hydroxide are added to the residue, which is stirred at 65 °C. Upon completion of the hydrolysis, the reaction mixture is cooled to RT, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases are concentrated under reduced pressure. After determining the content (qNMR), 0.93 g of product is present in the residue (86%). Diastereomeric ratio = 93:7.

[0044] Example 23 Under an argon atmosphere, 1.7 equivalents (eq) of 2-propylmagnesium chloride (3.87 ml, 1.76 mol / l in THF) are initially charged at 20°C. 1.7 eq of 2-propanol (0.52 ml) are added dropwise over 10 minutes while cooling (ice bath). Propane escapes (only slight effervescence) and a white solid precipitates. After the addition is complete and gas evolution has ceased, the resulting suspension is stirred for 20 minutes at 20°C. Subsequently, 1 eq of isobutyl 3-hydroxy-2-methylenebutanoate (0.70 g, 98.2% by weight) is added dropwise at room temperature (RT). The mixture becomes more fluid. The suspension is stirred for a further 15 minutes at RT and then cooled to approximately 15°C. Subsequently, a solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride (4.24 g, 18.1 wt%) in a solvent mixture of toluene / THF is added dropwise via syringe pump at approximately 15 °C together with an additional 0.3 eq of water (22 μl). The addition time is 1 h. The reaction mixture is then warmed to RT and stirred for another 1 h. HCl solution is then added to the reaction mixture and extracted with ethyl acetate. The aqueous phase is extracted again with ethyl acetate. The combined organic phases are concentrated under reduced pressure. Toluene (1 ml) and excess aqueous sodium hydroxide are added to the residue, which is stirred at 65 °C. Upon completion of the hydrolysis, the reaction mixture is cooled to RT, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases are concentrated under reduced pressure. After determining the content (qNMR), 0.95 g of product is present in the residue (88%). Diastereomeric ratio = 93:7.

[0045] Example 30 2 ml of dry THF is first charged under an argon atmosphere. 2 eq. of (S)-methyl 3-hydroxy-2-methylenebutanoate (1.09 g, 95.5 wt.%) is then added at RT, and the solution is cooled to -78 °C in a cooling bath (acetone / dry ice). 2 eq. of 2-propylmagnesium chloride (4.55 ml, 1.76 mol / l in THF) is then carefully added dropwise at -78 °C while stirring. The reaction mixture is stirred for another 40 minutes at -78 °C and then warmed. The clear solution is then cooled to approximately 15 °C (water bath). 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride in THF (2.54 g, 30.1 wt.%) is then added dropwise at approximately 15 °C via syringe pump. The addition time is 1 hour (h). The reaction mixture is then warmed to RT and stirred for another hour. HCl solution is then added to the reaction mixture, which is then extracted with ethyl acetate. The aqueous phase is extracted again with ethyl acetate. The combined organic phases are concentrated under reduced pressure. Toluene (1 ml) and excess aqueous sodium hydroxide are added to the residue, which is stirred at 65 °C. Upon completion of the hydrolysis, the reaction mixture is cooled to RT, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases are concentrated under reduced pressure. After determining the content (qNMR), 0.95 g of product is present in the residue (88%). Diastereomeric ratio = 81:19.

[0046] Table 1: [Table 3] TIFF2026500555000009.tif86125

[0047] From Table 1, the resulting yield of the compound of formula (I) is determined by the variable R 1 It is clear that the choice of

Claims

1. Formula (I) 【Chemistry 1】 [During the ceremony, 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, R １ is H, C １ -C １２ -alkyl, unsubstituted benzyl or mono- or di-C １ -C ４ -alkyl-substituted benzyl; R ２ is C １ -C ４ -alkyl] A method for producing an isoxazolinecarboxylic acid derivative of the formula: General formula (II) 【Chemistry 2】 [During the ceremony, X ２ ~X ６ has the above definition, X ７ , X ８ , X １０ , X １１ are independently H or C １ -C ４ - alkyl, X ９ is H, C １ -C ４ - alkyl or N(C １ -C ４ -alkyl) ２ is] The compound Formula (III) 【Transformation 3】 [During the ceremony, R １ and R ２ is R １ has the above definition except that is not H. and 1.0 to 2.0 equivalents of a reactive species "R ３ OMgHal' (IV) [wherein, R ３ is alkyl, unsubstituted or alkyl-substituted benzyl, and Hal is halogen; A process which provides a compound of general formula (I):

2. The method according to claim 1, wherein the definitions of the groups in the compounds of general formulae (I), (II) and (III) 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, X ７ , X ８ , X １０ , X １１ are independently H, methyl or ethyl; X ９ is H, methyl, ethyl or N(methyl) ２ and R １ is H or C １ -C ４ - alkyl, R ２ is methyl or ethyl, R in formula (III) １ =Excluding H.

3. The method according to any one of claims 1 and 2, wherein the definitions of the groups in the compounds of general formulae (I), (II) and (III) are as follows: X ２ is H, X ３ is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN, X ４ is fluorine or H, X ５ is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy or CN, X ６ is H, X ７ , X ８ , X １１ are independently H, methyl or ethyl; X ９ is H or N(methyl) ２ and X １０ is H, R １ is H, methyl, ethyl, i-propyl or i-butyl, R ２ is methyl, R in formula (III) １ =Excluding H.

4. The method according to any one of claims 1 to 3, wherein the definitions of the groups in the compounds of general formulae (I), (II) and (III) are as follows: X ２ is H, X ３ is H or fluorine, X ４ is H, X ５ is H or fluorine, X ６ is H, X ８ is H, methyl or ethyl, X ７ , X １１ are independently H or methyl; X ９ , X １０ is H, R １ is H, methyl, i-propyl or i-butyl, R ２ is methyl, R in formula (III) １ =Excluding H.

5. The method according to any one of claims 1 to 4, wherein the definitions of the groups in the compounds of general formulae (I), (II) and (III) are as follows: X ２ is H, X ３ is fluorine, X ４ is H, X ５ is fluorine, X ６ is H, X ７ , X ８ , X １１ are independently H or methyl; X ９ , X １０ is H, R １ is H, methyl or i-butyl, R ２ is methyl, R in formula (III) １ =Excluding H.

6. The method according to any one of claims 1 to 5, wherein the definitions of the groups in the compound of general formula (IIa) are as follows: X ７ , X ８ , X １０ , X １１ are independently H, methyl or ethyl; X ９ is H, methyl, ethyl or N(methyl) ２ is.

7. The method according to any one of claims 1 to 6, wherein the definitions of the groups in the compound of general formula (IIa) are as follows: X ７ , X １１ is H, X ８ , X １０ are independently H, methyl or ethyl; X ９ is H, methyl, ethyl or N(methyl) ２ is.

8. The method according to any one of claims 1 to 7, wherein the compound of general formula (IV) is produced by one of the following combinations of reagents: -R ４ MgHal and R ３ OH or - MgHal ２ and R ３ OM or - MgHal ２ and magnesium (OR ３ ) ２ , where: R ３ is C ２ -C １２ - alkyl, unsubstituted or C １ -C ４ -alkyl-substituted benzyl, and Hal is a halogen; M is an alkali metal; R ４ is alkyl, unsubstituted aryl, substituted aryl, unsubstituted benzyl, substituted benzyl, allyl, or vinyl.

9. The method according to any one of claims 1 to 8, wherein the compound of general formula (IV) is produced by one of the following combinations of reagents: -R ４ MgHal and R ３ OH or - MgHal ２ and R ３ OM or - MgHal ２ and Mg(OR ３ ) ２ , where: -R ３ is C ２ -C ８ - alkyl, Hal is bromine or chlorine, M is an alkali metal, -R ４ is C １ -C ８ -alkyl, phenyl, benzyl, p-tolyl or vinyl.

10. The method according to any one of claims 1 to 8, wherein the compound of general formula (IV) is produced by one of the following combinations of reagents: -R ４ MgHal and R ３ OH or - MgHal ２ and R ３ OM or - MgHal ２ and Mg(OR ３ ) ２ , where: -R ３ is C ２ -C ８ - alkyl, Hal is bromine or chlorine, M is an alkali metal, -R ４ is C １ -C ４ -alkyl, phenyl, benzyl, p-tolyl or vinyl.

11. Based on the compound of general formula (II), 1.3 to 2.0 equivalents of reactive species "R ３ 11. The method according to claim 1, wherein "OMgHal" (IV) is used.

12. Based on the compound of general formula (II), 1.7 to 2.0 equivalents of reactive species "R ３ 11. The method according to claim 1, wherein "OMgHal" (IV) is used.

13. 11. The process according to any one of claims 1 to 10, characterized in that 0.1 to 0.6 equivalents of additional water, based on formula (II), are used.

14. 14. The process according to any one of claims 1 to 13, characterized in that the solvent is toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (i-PrOAc), acetonitrile, methyl tert-butyl ether (MTBE), methyl-THF, ethyl acetate (EtOAc) or a mixture thereof in any ratio.

15. The method according to any one of claims 1 to 14, characterized in that the reaction is carried out at a temperature of from -25°C to 70°C.

16. The method according to any one of claims 1 to 14, characterized in that the reaction is carried out at 10°C to 30°C.

17. 17. The method according to any one of claims 1 to 16, characterized in that the diastereomeric ratio is increased by an additional crystallization step.

18. The method according to any one of claims 1 to 8, characterized in that the compound of general formula (IV) is produced via Grignard reaction using the following combination of reagents: -R ５ MgHal and R ６ R ７ CO, where R ５ is C １ -C ６ - alkyl, aryl or benzyl, R ６ , R ７ is H, C １ -C ６ - alkyl or aryl, and the resulting group definition is R ３ R ５ R ６ R ７ Corresponds to C.

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