Method for producing isoxazolinecarboxylic acid derivatives

Abstract

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

Description

[0001] BCS221035 Ausland NR / ed 15.11.2023 1 Process for the preparation of isoxazolinecarboxylic acid derivatives The present invention relates to a novel process for the preparation of isoxazolinecarboxylic acid derivatives of the formula (I). Isoxazolinecarboxylic acid derivatives of the general formula (I) are important precursors of agrochemical active ingredients (e.g. for herbicides, which are described in WO2014 / 048882 and WO2018 / 228985). Numerous cyclization methods for the preparation of isoxazolinecarboxylic acid derivatives are described in the prior art, for example 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. Yields and isomer ratios are also shown as a function of the reaction conditions. High stereocontrol could be achieved by chelation in the presence of appropriate metals, such as magnesium.A disadvantage of the processes described so far, however, is the necessity of using dichloromethane (DCM) as a solvent, which is not a preferred solvent for large-scale synthesis. Furthermore, the allylic alcohols used as substrates had to be reacted 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., by 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 processes known from the literature in solvents more advantageous for industrial use, for example tetrahydrofuran (THF), instead of DCM as the solvent, the resulting isomeric purities are insufficient for industrial-scale synthesis. The object of the invention was therefore to provide a process for the preparation of isoxazolinecarboxylic acid derivatives of the general formula (I), which is suitable for industrial-scale synthesis and has a high yield and isomeric purity, thus eliminating the need for complex purification methods. This object was achieved according to the invention by a process for the preparation of isoxazolinecarboxylic acid derivatives of the formula (I) BCS221035 Ausland NR / ed 15.11.2023 2. where C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 alkoxy, fluorine, CN is, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4-alkoxy, fluorine, CN, R1 is H, C1-C12-alkyl, unsubstituted benzyl or benzyl substituted once or twice with C1-C4-alkyl, R2 is C1-C4-alkyl, characterized in that the compounds of the general formula (II) wherein X2 to X6 have the meanings given above, X7, X8, X10, X11 independently of one another are H or C1-C4-alkyl, X9 is H, C1-C4-alkyl or N(C1-C4-alkyl)2, BCS221035 Ausland NR / ed 15.11.2023 3 with compounds of the formula (III) (III), wherein R1 and R2 have the meanings given above - with the exception that R1 is not H, with the addition of a reagent combination which enables - based on compounds of the general formula (II) - 1.0 to 2.0 equivalents of a reactive species "R3OMgHal" (IV) to be formed, where R3 is alkyl, unsubstituted or alkyl-substituted benzyl and Hal is halogen, to be converted into compounds of the general formula (I).Preferred radical definitions for the compounds of the general formulas (I), (II) and (III) are the following: X2 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN, X3 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, CN, X4 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN, X5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, CN, X6 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN, X7, X8, X10, X11 are independently H, methyl, ethyl, X9 is H, methyl, ethyl or N(methyl)2, R1 is H, C1-C4-alkyl, BCS221035 Foreign countries NR / ed 15.11.2023 4 R2 is methyl, ethyl, where R1 = H is excluded in formula (III).Preferably, the compounds of the general formula (IV) are generated using one of the following reagent combinations: - R4MgHal and R3OH or - MgHal3 2 and R OM or - MgHal(OR3 2 and Mg) 2, where R3 is C2-C12 alkyl, unsubstituted or C1-C4 alkyl-substituted benzyl, and Hal is halogen, M is alkali metal, R4 is alkyl, unsubstituted aryl, substituted aryl, unsubstituted benzyl, substituted benzyl, allyl, or vinyl. Alternatively, the compounds of the general formula (IV) are generated using the following reagent combination: - R5MgHal and R6R7CO, where R5 is C1-C6 alkyl, aryl, or benzyl, R6, R7 is H, C1-C6 alkyl, or aryl, and the resulting radical definition R3 corresponds to R5R6R7C. Preferred radical definitions for the reagents for preparing compounds of the general formulas (IV), represented by the alternative, are the following: R5 means C1-C4 alkyl, phenyl, benzyl, p-tolyl, R6, R7 means H, C1-C4 alkyl, phenyl.Particularly preferred radical definitions for the compounds of the general formulas (I), (II) and (III) are the following: X2 is H, X3 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, CN, BCS221035 Ausland NR / ed 15.11.2023 5 X4 is fluorine, H, X5 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, CN, X6 is H, X7, X8, X11 are independently H, methyl, ethyl, X9 is H, N(methyl)2X10 is H, R1 is H, methyl, ethyl, i-propyl, i-butyl, R2 is methyl, where R1 = H is excepted in the formula (III). The compounds of the general formula (IV) are particularly preferably generated with one of the following reagent combinations: - R4MgHal and R3OH or - MgHal 3 2 and R OM or - MgHal 3 2 and Mg(OR ) 2, where R3 is C2-C8 alkyl, Hal is bromine, chlorine, M is alkali metal, R4 is C1-C8 alkyl, phenyl, benzyl, p-tolyl, vinyl.Very particularly preferred radical definitions for the compounds of the general formulas (I), (II) and (III) are the following: X2 is H, X3 is H, fluorine, X4 is H, X5 is H, fluorine, X6 is H, BCS221035 Ausland NR / ed 15.11.2023 6 X8 is H, methyl, ethyl X7, X11 are independently H, methyl, X9, X10 are H R1 is H, methyl, i-propyl, i-butyl, R2 is methyl, where R1 = H is excepted in the formula (III). The compounds of the general formula (IV) are very particularly preferably generated with one of the following reagent combinations: - R4MgHal and R3OH or - MgHal2 and R3OM or - MgHal2 and Mg(OR3)2, where R3 is i-propyl, i-butyl, 2-butyl, Hal is bromine, chlorine, M is sodium, R4 is methyl, ethyl, n-butyl, i-propyl.The most preferred radical definitions for the compounds of general formulas (I), (II) and (III) are the following: X2 is H, X3 is fluorine, X4 is H, X5 is fluorine, X6 is H, X7, X8, X11 are independently H, methyl, X9, X10 are H, R1 is H, methyl, i-butyl, R2 is methyl, where R1 = H is excluded in formula (III). Definitions BCS221035 Ausland NR / ed 15.11.2023 7 Alkyl means saturated, straight-chain or branched hydrocarbon radicals with the specified number of carbon atoms, e.g. C. 1 -C 12-Alkyl such as methyl, ethyl, propyl, 1-5 methylethyl, butyl, 1-methyl-propyl, 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. Hal means halogen and stands for fluorine, chlorine, bromine, or iodine. When used for a radical, Hal means a fluorine, chlorine, bromine, or iodine atom. Alkali metal means lithium, sodium, or potassium. Aryl means phenyl or naphthyl. The compounds of formula (I) can exist as mixtures of isomers.The desired diastereomeric excess is increased compared to the state of the art thanks to the optimized reaction conditions. 1.7 to 2.0 equivalents of a reactive species "R3OMgHal" (IV) are particularly advantageous. When using an (S)-alcohol, the major product is the (S,S)-diastereomer, and the (R,S)-diastereomer is the minor diastereomer. When using an (R)-alcohol, the major product is the (R,R)-diastereomer, and the (S,R)-diastereomer is the minor diastereomer. When using a rac-alcohol, the major product is the (S,S / R,R)-rac-diastereomer, and the (S,R / R,S)-rac-diastereomer is the minor diastereomer. The compounds of formula (I) can be isolated as the corresponding esters or as carboxylic acids after hydrolytic workup. The diastereomer ratio of up to 100:0 can be achieved for the compounds of formula (I) by enrichment by crystallization.Explanation of the processes and intermediates BCS221035 Ausland NR / ed 15.11.2023 8 Scheme 1 The object was achieved by a process for the preparation of isoxazolinecarboxylic acid derivatives of the formula (I), characterized in that the compounds of the general formula (II) are reacted with compounds of the formula (III) with the addition of a reagent combination which enables 1.0 to 2.0 equivalents of a reactive species “R3OMgHal” (IV), based on compounds of the general formula (II), to be formed, to give compounds of the general formula (I) (Scheme 1). Preference is given to using 1.5 to 2.0 equivalents of the reactive species “R3OMgHal” (IV), based on compounds of the general formula (II). Particular preference is given to using 1.7 to 2.0 equivalents of the reactive species “R3OMgHal” (IV), based on compounds of the general formula (II).In addition, the addition of water can be advantageous and lead to a further improvement in the diastereomer ratio (dr). Preference is given to using up to 1.0 equivalent of water (based on compounds of the general formula (II)). Particular preference is given to using 0.1 to 0.6 equivalents of water (based on compounds of the general formula (II)). The cyclization is usually carried out in a temperature range from -25°C to 70°C, preferably 10°C to 30°C. Furthermore, the cyclization is optionally carried out in the presence of a solvent or diluent or a solvent mixture. Preferred solvents are toluene, xylene, tetrahydrofuran (THF), isopropyl acetate (i-PrOAc), acetonitrile, methyl tert-butyl ether (MTBE), methyl THF, ethyl acetate (EtOAc) or mixtures in any ratios thereof. BCS221035 Ausland NR / ed 15.11.2023 9 The compounds of general formula (III) are prepared via a two-step process and are known from the literature. The first step is a Baylis-Hillman reaction. A relevant reference is: Drewes, SE; Hoole, RFA [Synthetic Communications, 1985, vol. 15, 12, pp. 1067-1074]. A relevant reference for the second step is: Nascimento et al. (2003, Tetrahedron Asymmetry 14, 311-311). The compounds of general formula (II) and (III) are also known from WO 2018 / 228985. The preparation of compounds of formula (IIa) from (II) is described in 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. Examples The present invention is explained in more detail with reference to the following examples, without limiting the invention to them (Table 1).Measurement Method: The products were characterized by 1H-NMR spectroscopy and / or LC / MS (Liquid Chromatography Mass Spectrometry). The NMR spectra were determined using a Bruker Avance 400 equipped with a flow-through probe head (60 µl volume). In individual cases, the 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. Table 1: Additional qNMR Diastereomeric ratio, Example a) Water / i-PrOMgCl, Equivalent Yield b), dr R. 1Water in No. (Eq.) % (NMR) (II), Eq. 1 2 OMe <0.05 83 88 : 12 2 c) 2 OMe 0.3 86 92 : 8 BCS221035 Foreign NR / ed November 15, 2023 10 3c) 1.9 OMe <0.05 86 87 : 13 4c) 1.9 OMe 0.3 86 91 : 9 5c) 1.8 OMe 0.3 87 89: 11 6 c) 1.7 OMe 0.3 86 85: 15 7 2 i-PrO <0.05 85 93: 7 8 2 i-PrO 0.3 89 93: 7 9 1.9 i-PrO <0.05 85 91: 9 10 1.9 i-PrO 0.3 88 92 : 8 11 1.8 i-PrO <0.05 86 92 : 8 12 1.8 i-PrO 0.3 88 92 : 8 13 1.7 i-PrO <0.05 83 89 : 11 14 1.7 i-PrO 0.3 86 89 : 11 15 2 i-BuO <0.05 87 94 : 6 16 2 i-BuO 0.3 91 95 : 5 17 1.9 i-BuO <0.05 81 94 : 6 18 1.9 i-BuO 0.3 88 95 : 5 19 1.8 i-BuO <0.05 85 93: 7 20 1.8 i-BuO 0.3 90 94: 6 21 d) 1.8 i-BuO 0.3 81 (solid) 98: 2 8 (mother liquor) 41: 59 22 1.7 i-BuO <0.05 86 93: 7 23 1.7 i-BuO 0.3 88 93: 7 24 1.5 i-BuO <0.05 85 91: 9 25 1.5 i-BuO 0.3 83 92: 8 26 1.4 i-BuO <0.05 87 90: 10 27 1.4 i-BuO 0.3 87 90: 10 28 1,3 i-BuO <0,05 88 87 : 13 29 1,3 i-BuO 0,3 85 87 : 13 a) Reactions were carried out with 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride.b) The yield of the product after hydrolysis with sodium hydroxide solution and acidification. 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-hydroxybenzenecarboximidoyl chloride. The corresponding carboxylic acid was isolated. BCS221035 Ausland NR / ed 15.11.2023 11 State of the Art (X. 2-6=H) R1, Eq. Yield, Diastereomeric Base, Eq Conditions Educt % ratio, dr CH2Cl2, -78 to -30 °C Methyl, 2 EtMgBr, 2 100 92:8 / 89:11 / to RT Bull. Chem. Soc. Jpn. Methyl, 1 NEt3, 1 CH2Cl2, -30 °C 90 30:70 1993, THF / CH2Cl2, -78 to 2685-2689 Methyl, 1 EtMgBr, 1 93 / 86 63:37 / 81:19 -30 °C Conditions from the state of the art, THF or THF / DCM as solvent (X2,4,6=H, X3,5=F) THF, -78 to Example 30 Methyl, 2 2-PrMgCl, 2 88 81 : 19 15 °C THF / DCM, -78 to Example 31 Methyl, 2 2-PrMgCl, 2 87 85 : 15 15 °C Example 1 Under an argon atmosphere, 2 equivalents (eq) 2-Propylmagnesium chloride (4.0 mL, 2 mol / L in THF) is placed at 20°C. 2 eq of 2-propanol (0.61 mL) is added dropwise over 10 minutes (min) while cooling (in an ice bath). Propane escapes (foams only slightly) 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 wt%) is added at room temperature (RT). The mixture becomes more liquid. The suspension is stirred for a further 15 min at RT and then cooled to approximately 15 °C. A solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride in THF (2.55 g, 30.0 wt%) is then added dropwise at approximately 15 °C via a syringe pump. The addition time is 1 hour (hr). The reaction mixture is then warmed to RT and stirred for a further 1 h. The reaction mixture is then treated with HCl solution and extracted with ethyl acetate. The aqueous phase is extracted again with ethyl acetate. The combined organic phases are concentrated under vacuum. Toluene (1 mL) and an excess of aqueous sodium hydroxide solution are added to the residue, and the mixture is stirred at 65 °C. After complete hydrolysis, the BCS221035 Ausland NR / ed 15.11.2023 12 The reaction mixture was cooled to RT, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases were concentrated under vacuum. According to assay (qNMR), the residue contained 0.90 g of product (83%). Diastereomer ratio = 88:12. Example 2: Under an argon atmosphere, 2 equivalents (eq) of 2-propylmagnesium chloride (4.23 mL, 1.87 mol / L in THF) were initially charged at 20 °C. 2 eq of 2-propanol (0.61 mL) were added dropwise over 10 minutes (min) while cooling (in an ice bath). Propane escaped (foamed only slightly), and a white solid precipitated. After the addition was complete and gas evolution had ceased, the resulting suspension was stirred at 20 °C for 20 minutes. Subsequently, 1 eq of (S)-methyl 3-hydroxy-2-methylenebutanoate (0.545 g, 95.5 wt%) is added dropwise at room temperature (RT). The mixture becomes more liquid. The suspension is stirred for a further 15 min at RT and then cooled to approximately 15 °C.A solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride in a solvent mixture of toluene / THF (4.23 g, 18.1 wt%) with an additional 0.3 eq of water (22 µL) was then added dropwise at approximately 15°C via a syringe pump. The addition time was 1 hour (hr). The reaction mixture was then warmed to RT and stirred for 1 h. HCl solution was then added to the reaction mixture and extracted with ethyl acetate. The aqueous phase was extracted again with ethyl acetate. The combined organic phases were concentrated under vacuum. Toluene (1 mL) and an excess of aqueous sodium hydroxide solution were added to the residue, and the mixture was stirred at 65°C. After complete hydrolysis, the reaction mixture was cooled to RT, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases were concentrated under vacuum. According to assay (qNMR), the residue contains 0.93 g of product (86%).Diastereomeric ratio = 92:8. 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 (min) while cooling (in an ice bath). Propane escapes (foams only slightly) 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 at room temperature (RT). The mixture becomes more liquid. 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 in THF (2.54 g, 30.1 wt%) is added dropwise via a syringe pump at approximately 15 °C. The addition time is 1 hour (hr).The reaction mixture is then warmed to RT and stirred for 1 h. 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 vacuum. Toluene (1 mL) and an excess of aqueous sodium hydroxide solution are added to the residue and stirred at 65 °C. After complete 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 vacuum. According to assay (qNMR), the residue contains 0.90 g of product (83%). Diastereomer ratio = 89:11. Example 14: 1.7 equivalents (eq) of 2-propylmagnesium chloride (3.42 mL, 2 mol / L in THF) are initially charged at 20 °C under an argon atmosphere. 1.7 eq of 2-propanol (0.52 mL) are added dropwise over 10 minutes (min) while cooling (ice bath).Propane escapes (foams only slightly) 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 at room temperature (RT). The mixture becomes more liquid. The suspension is stirred for a further 15 min at RT and then cooled to approximately 15°C. A solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride in a solvent mixture of toluene / THF (2.59 g, 29.7 wt%) with an additional 0.3 eq of water (22 µL) is then added dropwise via a syringe pump at approximately 15°C. The addition time is 1 hour (hr). The reaction mixture is then warmed to RT and stirred for a further 1 hr. The reaction mixture is then treated with HCl solution and extracted with ethyl acetate. The aqueous phase is extracted again with ethyl acetate.The combined organic phases are concentrated under vacuum. Toluene (1 mL) and an excess of aqueous sodium hydroxide solution are added to the residue and stirred at 65 °C. After complete 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 vacuum. According to assay (qNMR), the residue contains 0.93 g of product (86%). Diastereomer ratio = 89:11. 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 (min) while cooling (ice bath). The temperature was maintained between 15-30 °C. Propane escaped (foamed only slightly) and a white solid precipitated.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 wt%) is added dropwise at a temperature between 20 and 25 °C over 35 minutes. The mixture becomes more liquid. 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 in a solvent mixture of toluene / THF (233.0 g, 43.1 wt%) with an additional 0.3 eq of water (2.83 mL) was added dropwise via a dropping funnel at approximately 15 °C (ice bath). The addition time was 1 hour (hr) and 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 2.5 h. The reaction mixture was then acidified with HCl solution (16.9 wt%).-%, 140.4 g) while cooling in a water bath (20 °C), and the organic phase is separated. The aqueous phase is washed with toluene, and the combined organic phases are concentrated under vacuum. Toluene (100 g), water (58 g), and an excess of aqueous sodium hydroxide solution (32 wt%, 85.1 g) are added to the residue, and the mixture is stirred vigorously at 65 °C. After complete hydrolysis (2.5 hrs), the reaction mixture is cooled to RT and concentrated under vacuum to a thick suspension (60 °C bath, 240 mbar to 85 mbar). The mixture is then acidified with sulfuric acid (20 wt%, 100 mL) while stirring vigorously. The product precipitates, is then filtered off, and dried. An additional 35 mL of 20 wt% sulfuric acid (pH mother liquor 1-2) is added to the mother liquor and extracted with isopropyl acetate (iPrOAc) (2 x 200 mL). The combined organic phases are concentrated under vacuum.The residue is combined with the solid and suspended in isopropyl acetate (iPrOAc) (500 mL) and stirred at 60 °C for 6 h. The suspension is then concentrated until it is still stirrable (50 °C, 200 mbar to 150 mbar). 300 mL of toluene is added to the viscous suspension. Distillation is continued at 50 °C / 150 mbar to 120 mbar until a viscous suspension is formed again. The suspension is cooled to room temperature and left overnight for complete crystallization. The suspension is then filtered and washed with 290 mL of toluene, yielding a solid, which is subsequently dried. According to qNMR determination of the filtered solid (119.20 g, 96.5 wt%), the product yield is 81%, diastereomeric ratio = 98:2. The concentrated mother liquor (43.13 g, 25.2 wt%) contains 8% product. The diastereomeric ratio of the mother liquor is 41:59. 1H NMR (401 MHz, 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). 19F-NMR (376MHz, DMSO-d6): δ (ppm) = -108.7 (m, 2F). BCS221035 Ausland NR / ed 15.11.2023 15 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 eq of 2-propanol (0.52 mL) are added dropwise over 10 minutes (min) while cooling (ice bath). Propane escapes (foams only slightly) 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 isobutyl 3-hydroxy-2-methylenebutanoate (0.70 g, 98.2 wt%) is then added at room temperature (RT). The mixture becomes more liquid. The suspension is stirred for a further 15 min at RT and then cooled to approximately 15 °C.A solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride in THF (2.54 g, 30.2 wt%) was then added dropwise at approximately 15°C via a syringe pump. The addition time was 1 hour (hr). The reaction mixture was then warmed to RT and stirred for 1 h. HCl solution was then added to the reaction mixture and extracted with ethyl acetate. The aqueous phase was extracted again with ethyl acetate. The combined organic phases were concentrated under vacuum. Toluene (1 mL) and an excess of aqueous sodium hydroxide solution were added to the residue, and the mixture was stirred at 65°C. After complete hydrolysis, the reaction mixture was cooled to RT, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases were concentrated under vacuum. According to assay (qNMR), the residue contained 0.93 g of product (86%). Diastereomer ratio = 93:7.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 (min) while cooling (in an ice bath). Propane escapes (foams only slightly) 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 isobutyl 3-hydroxy-2-methylenebutanoate (0.70 g, 98.2 wt%) is then added at room temperature (RT). The mixture becomes more liquid. 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 in a solvent mixture of toluene / THF (4.24 g, 18.1 wt%) with an additional 0.3 eq of water (22 µL) is added dropwise via a syringe pump at approximately 15 °C. The addition time is 1 hour (hr).The reaction mixture is then warmed to RT and stirred for 1 h. 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 vacuum. Toluene (1 mL) and an excess of aqueous sodium hydroxide solution are added to the residue and stirred at 65 °C. After complete 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 vacuum. According to assay (qNMR), the residue contains 0.95 g of product (88%). Diastereomer ratio = 93:7. Example 30: 2 mL of dry THF are placed under an argon atmosphere. For this purpose, 2 eq of (S)-methyl 3-hydroxy-2-methylenebutanoate (1.09 g, 95.5 wt.-%) and the solution is cooled to -78°C using a cold bath (acetone / dry ice). Then, 2 eq. of 2-propylmagnesium chloride (4.55 mL, 1.76 mol / L in THF) is carefully added dropwise over a period of 15 min at -78°C while stirring. The reaction mixture is stirred for a further 40 min at -78°C and then warmed up. The clear solution is then cooled to approximately 15°C (water bath). A solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride in THF (2.54 g, 30.1 wt%) is then added dropwise at approximately 15°C via a syringe pump. The addition time is 1 hour (hr). The reaction mixture is then warmed to RT and stirred for a further 1 h. HCl solution is then added to the reaction mixture, and the mixture is extracted with ethyl acetate. The aqueous phase is extracted again with ethyl acetate. The combined organic phases are concentrated under vacuum.Toluene (1 mL) and an excess of aqueous sodium hydroxide solution are added to the residue and stirred at 65°C. After complete hydrolysis, the reaction mixture is cooled to room temperature, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases are concentrated under vacuum. According to assay (qNMR), the residue contains 0.95 g of product (88%). Diastereomer ratio = 81:19.

[0002] BCS221035 Foreign NR / ed 10.11.2023 - 17 - Table 1: R1 Base Temperature Reaction time Conversion Yield Yield (equivalents) (°C) (h)* (%) Compound Compound Formula (I), Formula HPLC area% (IV)**, HPLC area% Iso-Propyl N,N- 155-160 20.5 98 85 86 Dimethylcyclo-hexylamine (3) Iso-Propyl N,N- 155-160 20.5 98 87 84 Dimethylcyclo-hexylamine (5) 2- N,N- 160 17 99 86 Not determined Methylpropa Dimethylcyclo n-1-yl-hexylamine (5) n-Butyl N,N- 160 14 98 83 Not determined Dimethylcyclo-hexylamine (5) Cyclohexyl N,N- 155 19 99 90 Not determined as dimethylcyclo-hexylamine (5) Propyl N,N- 152 13 98 75 Not determined as dimethylcyclo-hexylamine (5) Ethyl N,N- 160 7 98 58 Not determined as dimethylcyclo-hexylamine (comparison) BCS221035 Foreign countries NR / ed 10.11.2023 - 18 - Methyl N,N- 130-138 1.33 99 1.7 Not determined Dimethylcyclo (comparison) -hexylamine (5) * The reaction was terminated when almost complete conversion of the starting compound of the formula (II) could be observed by HPLC ** after hydrolysis according to step 2 described above as an example It can be seen from Table 1 that the yield of compounds of the formula (I) obtained depends strongly on the selection of the variable R1.

Claims

BCS221035 Ausland NR / ed 10.11.2023 - 19 - Patent claims:

1. Process for the preparation of isoxazolinecarboxylic acid derivatives of the formula (I) a) where H, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4 alkoxy, fluorine, CN is, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 fluoroalkoxy, C1-C4-alkoxy, fluorine, CN, R1 is H, C1-C12-alkyl, unsubstituted benzyl or benzyl substituted once or twice with C1-C4-alkyl, R2 is C1-C4-alkyl, characterized in that the compounds of the general formula (II) , BCS221035 Ausland NR / ed 10.11.2023 - 20 - wherein X2 to X6 have the meanings given above, X7, X8, X10, X11 independently of one another are H or C1-C4-alkyl, X9 is H, C1-C4-alkyl or N(C1-C4-alkyl)2, with compounds of the formula (III) (III), wherein R1 and R2 have the meanings given above, - with the exception that R1 is not H, 'with the addition of a reagent combination which makes it possible - based on compounds of the general formula (II) - to form 1.0 to 2.0 equivalents of a reactive species "R3OMgHal" (IV), where R3 is alkyl, unsubstituted or alkyl-substituted benzyl and Hal is halogen, to give compounds of the general formula (I).

2. The process according to claim 1, wherein the radical definitions for the compounds of the general formulas (I), (II) and (III) are as follows: X2 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN, X3 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, CN, X4 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN, BCS221035 Foreign NR / ed 10.11.2023 - 21 - X5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, CN, X6 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN, X7, X8, X10, X11 are independently H, methyl, ethyl, X9 is H, methyl, ethyl or N(methyl) 2, R1 is H, C1-C4-alkyl, R2 is methyl, ethyl, where R1 = H in formula (III) is excluded.

3. The process according to any one of claims 1 to 2, wherein the radical definitions for the compounds of the general formulas (I), (II) and (III) are as follows: X2 is H, X3 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, CN, X4 is fluorine, H, X5 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, CN, X6 is H, X7, X8, X11 are each independently H, methyl, ethyl, X9 is H, N(methyl) 2,X10 is H, R1 is H, methyl, ethyl, i-propyl, i-butyl, R2 is methyl, where R1 = H in formula (III) is excluded.

4. The process according to any one of claims 1 to 3, wherein the radical definitions for the compounds of general formulas (I), (II) and (III) are as follows: X2 is H, X3 is H, fluorine, X4 is H, X5 is H, fluorine, X6 is H, X8 is H, methyl, ethyl BCS221035 Ausland NR / ed 10.11.2023 - 22 - X7, X11 are independently H, methyl, X9, X10 are H R1 is H, methyl, i-propyl, i-butyl, R2 is methyl, where R1 = H in the formula (III) is excluded.

5. The process according to any one of claims 1 to 4, wherein the radical definitions for the compounds of the general formulas (I), (II) and (III) are as follows: X2 is H, X3 is fluorine, X4 is H, X5 is fluorine, X6 is H, X7, X8, X11 are independently H, methyl, X9, X10 is H, R1 is H, methyl, i-butyl, R2 is methyl, where R1 = H in the formula (III) is excluded.

6. The process according to any one of claims 1 to 5, wherein the radical definitions for the compounds of the general formula (IIa) are as follows: X7, X8, X10, X11 independently of one another are H, methyl, ethyl, X9 is H, methyl, ethyl, or N(methyl) 2.

7. The process according to any one of claims 1 to 6, wherein the radical definitions for the compounds of the general formula (IIa) are as follows: X7, X11 is H, X8, X10 independently of one another are H, methyl, ethyl, X9 is H, methyl, ethyl, N(methyl) 2.

8. The process according to any one of claims 1 to 7, wherein the compound of the general formula (IV) is generated with one of the following reagent combinations BCS221035 Foreign NR / ed 10.11.2023 - 23 - are: - R4MgHal and R3OH or - MgHal2 and R3OM or - MgHal2 and Mg(OR3)2, where R3 is C2-C 12-alkyl, unsubstituted or C1-C4-alkyl-substituted benzyl and Hal is halogen, M is alkali metal, R4 is alkyl, unsubstituted aryl, substituted aryl, unsubstituted benzyl, substituted benzyl, allyl, vinyl.

9. The process according to any one of claims 1 to 8, wherein the compounds of the general formula (IV) are generated using one of the following reagent combinations: - R4MgHal and R3OH or - MgHal2 and R3OM or - MgHal2 and Mg(OR3)2, where - R3 is C2-C8-alkyl, - Hal is bromine or chlorine, - M is alkali metal, - R4 is C1-C8-alkyl, phenyl, benzyl, p-tolyl, vinyl.

10. The process according to any one of claims 1 to 8, wherein the compounds of the general formula (IV) are generated with one of the following reagent combinations: - R4MgHal and R3OH or - MgHal2 and R3OM or - MgHal2 and Mg(OR3)2, where - R3 is C2-C8-alkyl, BCS221035 Ausland NR / ed 10.11.2023 - 24 - - Hal denotes bromine or chlorine - M denotes alkali metal, - R4 denotes C1-C8 alkyl, phenyl, benzyl, p-tolyl, vinyl.

11. The process according to any one of claims 1 to 10, characterized in that 1.3 to 2.0 equivalents of the reactive species "R3OMgHal" (IV) are used, based on compounds of the general formula (II).

12. The process according to any one of claims 1 to 10, characterized in that 1.7 to 2.0 equivalents of the reactive species "R3OMgHal" (IV) are used, based on compounds of the general formula (II).

13. 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.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 mixtures thereof in any ratio.

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

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

17. The process according to any one of claims 1 to 16, characterized in that the dr ratio is increased by a further crystallization step. 18.Process according to one of claims 1 to 8, characterized in that the compounds of the general formula (IV) are generated via a Grignard reaction, namely with the following reagent combinations: - R5MgHal and R6R7CO, where R5 is C1-C6 alkyl, aryl, benzyl, R6, R7 is H, C1-C6 alkyl, aryl, and the resulting radical definition corresponds to R3R5R6R7C.

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