Process for the preparation of isoxazolinecarboxylic acid derivatives

Description

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

[0002] Isoxazolinecarboxylic acid derivatives of the general formula ( I ) are important precursors of agrochemical active ingredients (cf. WO 2018 / 228985).

[0003] Numerous cyclization methods for the preparation of isoxazolinecarboxylic acid derivatives have been 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.

[0004] If the compounds of the present invention are prepared according to one of the processes known from the literature, yields and isomer purities result which are not sufficient for large-scale synthesis.

[0005] The invention was therefore based on the object of providing a process for the preparation of isoxazolinecarboxylic acid derivatives of the general formula ( I ) which is suitable for large-scale synthesis and has a high yield and isomer purity, so that complex purification methods can be omitted.

[0006] The object was achieved according to the invention by a process for the preparation of isoxazolinecarboxylic acid derivatives of the formula (I) wherein X 2< H, C 1 -C 4 -Alkyl, C 1 -C 4 -Fluoralkyl, C 1 -C 4 -Fluoralkoxy, C 1 -C 4 -Alkoxy, Fluor, CN ist, X 3< H, C 1 -C 4 -Alkyl, C 1 -C 4 -Fluoralkyl, C 1 -C 4 -Fluoralkoxy, C 1 -C 4 -Alkoxy, fluorine, chlorine, CN is, -fluoroalkoxy, C 1 -C 4 -alkoxy, fluorine, chlorine, CN, X 6< H, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 fluoroalkoxy, C 1 -C 4 alkoxy, fluorine, CN, R 1< H, C 1 -C 4 alkyl, R 2< C 1 -C 4 alkyl, characterized in that the compounds of the general formula ( II ) wherein X 2< to X 6< has the meanings given above, X 7< , X 8< , X 10< , X 11< independently of one another are H or C 1 -C 4 -alkyl, X 9< is H, C 1 -C 4 -alkyl or N(C 1 -C 4 -alkyl) 2, with compounds of the formula ( III ) wherein R 1< and R 2< have the meanings given above, with the addition of a reagent combination which enables - based on compounds of the general formula ( II ) - 2.0 to 4.5 equivalents of a reactive species "R 3< OMgHal" ( IV ), where R 3< is C 2 -C 6 -alkyl, unsubstituted or C 1 -C 6 -alkyl-substituted benzyl and Hal is halogen, to give compounds of the general formula ( I ) are implemented.

[0007] Preferred Residue definitions for the compounds of the general formulas ( I ), ( II ) and ( III ) are the following: X 2< is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN, Methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, CN, N(Methyl) 2 R 1< is H, methyl, Ethyl, i-propyl, i-butyl, R 2< is methyl, ethyl.

[0008] Preferred the compound of the general formulas (IV) is generated with one of the following reagent combinations: 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 6 alkyl, benzyl, methylbenzyl, Hal is halogen, M is alkali metal, R 4< is C 1 -C 6 alkyl, aryl, benzyl, allyl, vinyl.

[0009] Alternatively the compound of general formula (IV) is generated with the following reagent combination: R 5< MgHal and R 6< R 7< CO, where R 5< C 1 -C 6 alkyl, aryl, benzyl, R 6< , R 7< H, C 1 -C 6 alkyl, aryl, and the resulting radical definition is R 3< R 5< R 6< R 7< C.

[0010] Preferred Residue definitions for the compounds of the general formulas ( IV ), prepared using the alternative reagent combination: R 5< MgHal and R 6< R 7< CO, are the following: R 5< means C 1 -C 4 alkyl, phenyl, benzyl, p-tolyl, R 6< , R 7< means H, C 1 -C 4 alkyl, phenyl.

[0011] Particularly preferredThe radical definitions for the compounds of general formulas (I), (II) and (III) are as follows: X 2< is H, X 3< is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, CN, X 4< is fluorine, H, X 5< is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, CN, X 6< is H, X 7< , X 8< , X 11< are independently H, methyl, ethyl, X 9< is H, N(methyl) 2 X 10< is H, R 1< is H, methyl, i-propyl, i-butyl. R 2< is methyl.

[0012] Particularly preferred the connection of the general formulas ( IV ) using one of the following reagent combinations: 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< C 2 -C 4 -alkyl, halo means bromine, chlorine, mal means alkali metal, R 4< C 1 -C 4 -alkyl, phenyl, benzyl, p-tolyl, vinyl.

[0013] Particularly preferred Residue definitions for the compounds of the general formulas (I ), ( II ) and ( III ) are the following: X 2< is H, X 3< is H, fluorine, X 4< is H, fluorine, X 5< is H, fluorine, X 6< is H, X 8< is H, methyl, ethyl X 7< , X 11< is independently H, methyl, X 9< , X 10< is HR 1< is H, methyl, i -Butyl. R 2< is methyl.

[0014] Particularly preferred the connection of the general formulas ( IV ) using one of the following reagent combinations: R 4< MgHal and R 3< OH or MgHal 2 and R 3< OM or MgHal 2 and Mg(OR 3< ) 2 , where R3< i -propyl, i -Butyl means, Halbrom, Chlor means, M sodium means, R 4< Methyl, Ethyl, n -Butyl, i -Propyl means.

[0015] Most preferred Residue definitions for the compounds of the general formulas ( I ), ( II ) and ( III ) are the following: X 2< is H, X 3< is fluorine, X 4< is H, X 5< is fluorine, X 6< is H, X 7< , X 3< , X 11< is independently H, methyl, X 9< , X 10< is H, R 1< is H, methyl, R 2< is methyl.

[0016] Compounds of the formula ( I ), where the radicals correspond to the above-mentioned general, preferred, particularly preferred, very particularly preferred and most preferred definitions and are present as isomer mixtures:

[0017] The isomer ratio between ( Ia ) and ( Ib ) varies, in general ( Ia ) in excess. This desired excess is increased by the optimized reaction conditions compared to the state of the art. To achieve a high diastereomeric excess, it is particularly advantageous if 2.0 to 4.5 equivalents of a reactive species "R 3< OMgHal" ( IV) are present in the reaction mixture.

[0018] The compounds of the formula (I) can be isolated as the corresponding esters or as carboxylic acids after hydrolytic workup.

[0019] The ratio up to 100:0 can be used for compounds of the formula (I) can be achieved through enrichment by crystallization.

[0020] The present invention further relates to compounds of the formula ( Ia ) and ( Ib ), in any mixing ratio, except 1: 1, where the radicals are the following: X 2< is H, X 3< is fluorine, X 4< is H, X 5< is fluorine, X 6< is H, R 1< is H, methyl and R 2< is methyl; except 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylic acid methyl ester.

[0021] Preferred is the mixing ratio ( Ia ): ( Ib ) of at least 90:1, particularly preferred of at least 95:5, particularly preferredof at least 99:1.

[0022] The starting material used is enantiomerically pure ( S )-( III ), the compounds of the formula ( Yaaa ) and ( Iba ) produce.

[0023] The present invention further relates to compounds of the formula ( Yaaa ) and (b), in any mixing ratio, except 1:1, where the radicals are the following: X 2< is H, X 3< is fluorine, X 4< is H, X 5< is fluorine, X 6< is H, R 1< is H, methyl and R 2< is methyl; except 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylic acid methyl ester.

[0024] The preferred mixing ratio is ( Yaaa ): ( Iba ) of at least 90:1, particularly preferred of at least 95:5, particularly preferred of at least 99:1.

[0025] The starting material used is enantiomerically pure ( R )-( III ), the compounds of the formula ( Iab) and ( Ibb ) produce.

[0026] The present invention further relates to compounds of the formula ( Iab ) and ( Ibb ), in any mixing ratio, except 1: 1, where the radicals are the following: X 2< is H, X 3< is fluorine, X 4< is H, X 5< is fluorine, X 6< is H, R 1< is H, methyl and R 2< is methyl; except 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylic acid methyl ester and 3-phenyl-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylic acid methyl ester.

[0027] The preferred mixing ratio is ( Iab ): ( Ibb ) of at least 90:1, particularly preferred of at least 95:5, particularly preferred of at least 99:1. Explanation of the processes and intermediate product

[0028]

[0029] The problem was solved by a process for the preparation of isoxazolinecarboxylic acid derivatives of the formula ( I) characterized in that the compounds of the general formula ( II ) with compounds of the formula ( III ) with the addition of a reagent combination that allows 2.0 to 4.5 equivalents of a reactive species "R 3< OMgHal" ( IV ) based on compounds of the general formula ( II ) can be formed to form compounds of the general formula ( I ) (Scheme 1).

[0030] Various possible reagent combinations can be found in Table 1, although this selection is not exhaustive.

[0031] Preferred are 2.8 to 3.2 equivalents of the reactive species "R 3< OMgHal" ( IV ) based on compounds of the general formula ( II ).

[0032] Particularly preferred are 3 equivalents of the reactive species "R 3< OMgHal" ( IV ) based on compounds of the general formula ( II ).

[0033] The cycling is usually carried out in a temperature range of -25°C to 70°C, preferably 10°C to 30 °C.

[0034] Furthermore, the cyclization is optionally carried out in the presence of a solvent or diluent or a solvent mixture. Preferred The solvents are 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.

[0035] The compounds of the 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]. For the second step, a relevant reference is: Nascimento et al. (2003, Tetrahedron Asymmetry 14, 311-311).

[0036] The compounds of the general formula ( II ) and ( III ) are also known from WO 2018 / 228985. The preparation of the compounds of the formula ( IIa ) out of ( 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. Examples

[0037] The present invention is explained in more detail with reference to the following examples, without limiting the invention to them. Measurement method

[0038] The products were characterized by 1< H-NMR spectroscopy and / or LC / MS (Liquid Chromatography Mass Spectrometry).

[0039] The NMR spectra were determined using a Bruker Avance 400 equipped with a flow-through probe (60 µl volume). In individual cases, the NMR spectra were measured using a Bruker Avance II 600. Example 1

[0040] 2-Propanol (48 mL) and THF (61 mL) are placed in a 1 L reaction vessel at 24°C under an argon atmosphere. The mixture is cooled to 0°C. Then, 204 mL of a methylmagnesium chloride solution (3M in THF) is added over two hours, maintaining the reaction temperature at 10 to 25°C (cooling with an ice bath). Methane escapes and a white solid precipitates. The resulting suspension is further stirred and warmed to 20°C after gas evolution has ceased. Then, 27.46 g of methyl 3-hydroxy-2-methylene-butanoate is added to the reaction mixture at 20°C over 30 minutes. The reaction temperature is maintained at 18 to 22°C using a water bath. After the addition, the reaction mixture is stirred for a further 10 minutes before 240 g of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride in a solvent mixture of toluene / THF / i-PrOAc / DBF (16.3 wt.-%) are added, cooling the reaction vessel with an ice bath. After the addition is complete, the reaction mixture is worked up by adding it to 40.25 g of HCl (37 wt%) in 83.85 g of water at room temperature. The organic phase is separated. It is rinsed with toluene (25 mL) and distilled (head temperature 48-58 °C, 580 to 160 mbar).

[0041] Hydrolysis is carried out with 69.4 g of NaOH (20 wt%, 1.7 equivalents). The solution is stirred at 60°C for 1 hour until complete.

[0042] For workup, 100 mL of toluene, 100 mL of water, and 3.00 g of H 2 SO 4 (20 wt%) were added to the reaction mixture, resulting in two phases. The organic phase was separated, and the aqueous phase (pH ~7) was washed with 50 mL of toluene to extract residual DBF. 200 mL of i-PrOAc was added to the resulting aqueous phase, which contained the sodium salt of the product, followed by 65.09 g of H 2 SO 4 (20 wt%) at room temperature and with vigorous stirring, resulting in a two-phase mixture with the aqueous phase at pH 1. The organic phase was separated, and the aqueous phase was extracted with 50 mL of i-PrOAc to remove the remaining product. The i-PrOAc phases were combined and distilled with stirring under reduced pressure (210 to 200 mbar) at 50 °C, resulting in a thick but still easily stirrable suspension (after distillation of approximately 150 mL i-PrOAc).Then, 100 mL of toluene was added, and distillation continued with stirring at reduced pressure (200 to 150 mbar) at 50°C (approximately 100 mL of i-PrOAc / toluene mixture was distilled off). The mixture was cooled to room temperature and left to stand overnight to complete crystallization. The suspension was then filtered and washed on the filter with another 50 mL of toluene, resulting in a solid, which was dried in a vacuum oven (40°C, 20 mbar), yielding 45.54 g (98.0% purity, 80.6% yield) of the product. The product (5S)-3-(3,5-difluorophenyl)-5-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid was analyzed by HPLC and showed a dr of 97.6:2.4. The mother liquor showed a dr of (31.3:68.7).

[0043] 1< H-NMR (400MHz, DMSO- d 6 ): δ (ppm) = 1.12 (d, J = 6.5 Hz, 3H), 3.62 (d, J = 17.8, 1H), 3.68 (d, J = 17.8, 1H), 4.10 (q, J= 6.4 Hz, 1H), 5.30 (bs, 1H), 7.33-7.48 (m, 3H), 13.24 (bs, 1H).

[0044] 19< F-NMR (376MHz, DMSO- d 6 ): δ (ppm) = -108.7 (m, 2F). Example 2

[0045] In a 2 L double-jacketed vessel, 74.74 g of magnesium (3.075 equivalents) in THF (1 L) are placed under a nitrogen atmosphere and at a jacket temperature of 20°C. 2.5 mL of 2-propylmagnesium chloride solution (2M in THF, 0.005 equivalents) are then added and stirred for 10 min. Then, 248.00 g of 2-chloropropane (99%, 3.126 equivalents) are slowly added dropwise. The internal temperature rises to 35°C, and the jacket temperature is adjusted to 10°C. All of the 2-chloropropane is added dropwise over a period of 2 hours. The internal temperature is maintained at approximately 30 to 34°C by cooling. The magnesium reacts slowly. After the addition is complete, the temperature drops slowly, and the jacket temperature is slowly increased to 30°C. Stirring is continued for a total of two hours at an internal temperature of 29 to 33°C, until only a few magnesium flakes remain. 185.17 g of 2-propanol (3.075 equivalents) are added dropwise at a jacket temperature of 15°C.The internal temperature is maintained at 30 to 35°C. Continuous gas evolution (propane) is observed. A solid slowly precipitates. A thick, still stirrable suspension forms. After the addition over 1 hour and 30 minutes, a thick, gray suspension is obtained. The mixture is cooled to 20°C, and 130.40 g of methyl (3S)-3-hydroxy-2-methylenebutanoate (1 equivalent) is added. The mixture is stirred for a further 10 minutes, and the jacket temperature is adjusted to 10°C. A solution of 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride (15.2%, 1260.30 g) is then added dropwise over 1.5 hours at an internal temperature of 18 to 20°C and a jacket temperature of 10°C. After the addition is complete, the mixture is stirred for a further 1 hour at 20°C.

[0046] For workup, the reaction mixture is poured onto 403 g of ice and 200 g of HCl solution (37 wt%). The organic phase is separated and concentrated at a bath temperature of 50°C and a pressure of 350 mbar. 314.40 g of sodium hydroxide solution (20 wt%, 1.57 equivalents) are added to the resulting residue, and the mixture is stirred at 60°C for two hours until hydrolysis is complete. The solvent is distilled off at a bath temperature of 325 mbar and a pressure of 60°C. 450 g of water and 372 g of toluene are added to the residue. After extraction, the toluene phase is separated.

[0047] The aqueous phase was then acidified with sulfuric acid (500 g, 20 wt%) and extracted with i-propyl acetate. The solvent of the organic phase was removed (40 to 61 °C internal temperature, 200 mbar). The resulting suspension was filtered at 20 °C and washed on the filter with another 280 mL of toluene, yielding a solid that was air-dried.

[0048] The product obtained is (5S)-3-(3,5-difluorophenyl)-5-[(1S)-1-hydroxyethyl]-4,5-dihydro-1,2-oxazole-5-carboxylic acid: 208.5 g (98.1%, dr >99.9:0.1, 75.4% yield).

[0049] 1< H-NMR (401MHz, DMSO- d 6 ): 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).

[0050] 19< F-NMR (376MHz, DMSO- d 6 ): δ (ppm) = -108.7 (m, 2F). Example 10

[0051] 6.79 g (51.2 mmol) of methyl (3S)-3-hydroxy-2-methylenebutanoate were dissolved in 650 ml of dichloromethane at room temperature under an argon atmosphere, and isopropanol was added. The clear solution was cooled to 0°C. Subsequently, 156 ml (156 mmol) of EtMgBr (1M) in THF were slowly added dropwise (exothermally). The solution became cloudy. A solution of 10.00 g (52.2 mmol) of 3,5-difluoro-N-hydroxybenzimidoyl chloride in 100 ml of DCM was then slowly added dropwise with stirring (15 min) and slowly warmed to room temperature. A distinct yellow color appeared. TLC in EA / nHeptane 1:1 showed complete conversion after 30 min.

[0052] Processing: The solution was added to 1 l of a 1:1 mixture of 2N HCl and saturated NaCl solution and extracted twice with 400 ml of methylene chloride each time, dried over Na 2 SO 4 , filtered, and concentrated. LCMS analysis of the crude product showed a diastereomeric ratio of 86% to 14%. Chromatography on silica gel (nHep / ethyl acetate) yielded 1 mL = 600 mg (4.0%) lipophilic diastereomer.

[0053] 1< H NMR (CDCl 3 ): 1.10 (d, 3H, CHCH 3 ), 2.3 (s br., 1H, OH), 3.53 (d, 1H, CHH isoxazoline), 3.72 (d, 1H, CHH isoxazoline), 3.84b(s, 3H, OCH 3 ), 4.34 (q, 1H, CHCH 3 ), 6.88 (tt, 1H, aromatic H), 7.22 (m, 2H, aromatic H).

[0054] Fr. 2 m = 7700 mg (51.7%) polar diastereomer 1< H NMR (CDCl 3 ): 1.29 (d, 3H, CHCH 3 ), 2.10 (d, 1H, OH), 3.57 (d, 1H, CHH isoxazoline), 3.69 (d, 1H, CHH isoxazoline), 3.84b(s, 3H, OCH 3 ), 4.24 (q, 1H, CHCH 3 ), 6.88 (tt, 1H, arom.H), 7.18 (m, 2H, arom. H). Table 1: R1, (III) Stereochemistry, Equiv. Reagent combination (IV) Solvent, temperature yield Diastereomeric ratio, dr According to the invention Example 1 Methyl, rac, 1 eq 3.0 eq MeMgCl (22% in THF) 3.05 eq i-PrOH 1. THF, 10-25 °C 2. THF / Toluene / i-PrOAc / DBF, 20 °C 81% (isolated) 98:2 (isolated) 93:7 (reaction mixture) Example 2 Methyl, S, 1 eq 3.075 eq Mg, 3.075 eq i-PrOH, 0.5 mol% i-PrMgCl, 3.126 eq i-PrCl 1. THF, 30–35 °C; 1. 2. THF / Toluene / DBF, 18–20 °C 75% (isolated) 100:0 (isoliert) 93:7 (Reaktions mischung) Baseball 3 Methyl, S, 1 Äq 3.6 Äq MgCl 2 3.5 Äq for ProONa (25% in THF) 2. THF, 20–50 °C 3. THF / Toluene / PrOAc / DBF, 20 °C 85% (HPLC) 92:8 Baseball 4 Methyl, negative, 1 Äq 1.5 Äq MgCl 2 1.5 Äq Mg(OPr-i) 2 1. CH 3 CN, 20–80 °C; 2. Toluene / EtOAc / DBF, − 20–20 °C 84% (HPLC) 94:6 Baseball 5 in Propyl, negative, 1 Äq 3.075 Äq Mg, 3.075 Äq PrOH, 0.5 mol% PrMgCl, 3.126 Äq PrCl 1. THF, 22–40 °C; 2. THF / Toluene / DBF, 20 °C 79% (HPLC) 94:6 Baseball 6 Butyl, negative, 1 Äq 3.0 Äq MeMgCl (22% in THF) 3.075 Äq PrOH 1. THF, 25–35 °C; 2. THF / Toluene / DBF, 20 °C 84% (HPLC) 94:6 Baseball 7 Butyl, negative, 1 Äq 3.0 Äq MeMgCl (22% in THF) 3.075 Äq BuOH 1. THF, 25–35 °C; 2. THF / Toluene / DBF, 20 °C 83% (HPLC) 93:7 Baseball 8 Butyl, negative, 1 Äq 3.075 Äq Mg, 3.075 Äq PrOH, 0.5 mol% PrMgCl, 3.126 Äq PrCl 1. THF, 22–40 °C; 2. THF / Toluene / DBF, 20 °C 83% (HPLC) 95:5 Baseball 9 Butyl, negative, 1 Äq 3.075 Äq Mg, 3.075 Äq BuOH, 0.5 mol% PrMgCl, 3.126 Äq PrCl 1. THF, 22-40°C; 2. THF / Toluene / DBF, 20°C 84% (HPLC) 93:7 Example 10 Methyl, rac, 1 eq 3.0 eq MeMgCl (22% in THF), 3.075 eq CH3CHO 1. THF, -20 °C to RT 2. THF / Toluene, 15-20 °C 75% (HPLC) 91:9 Conditions from the prior art applied to the reaction according to the invention (Example 10) Carreira ACIE 2001, 40, 2082, JACS 2001, 123, 3611, OL 2007, 9, 3857 Cyclic and acyclic allyl alcohols 3.3 eq i-PrOH, 3 eq EtMgBr CH 2 Cl 2 , 0 °C - RT 70% 86:14 State of the art (X 2-6 =H) Bull. Chem. Soc. Jpn. 1993, 2685-2689 Methyl, 2 eq 2 eq EtMgBr CH 2 Cl 2 , -78 to -30 °C / to RT 100 92:8 / 89:11 Methyl, 1 eq 1 eq NEt 3 CH 2 Cl 2 , -30 °C 90 30:70 Methyl, 1 eq 1 eq EtMgBr THF / CH 2 Cl 2 , -78 to -30 °C 93 / 86 63:37 / 81:19

Claims

1. Process for preparing isoxazolinecarboxylic acid derivatives of the formula (I) in which X2 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine, CN, X3 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine, chlorine, CN, X4 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine, CN, X5 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine, chlorine, CN, X6 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine, CN, R1 is H, C1-C4-alkyl, R2 is C1-C4-alkyl, characterized in that the compounds of the general formula (II) in which X2 to X6 have the definitions given above, X7, X8, X10, X11 are independently H or C1-C4-alkyl, X9 is H, C1-C4-alkyl or N(C1-C4-alkyl)2, are reacted with compounds of the formula (III) in which R1 and R2 have the definitions given above, with addition of a combination of reagents that enables formation of 2.0 to 4.5 equivalents of a reactive species "R3OMgHal" (IV) - based on compounds of the general formula (II), where R3 is C2-C6-alkyl, unsubstituted or C1-C6-alkylsubstituted benzyl and Hal is halogen, to give compounds of the general formula (I).

2. Process according to Claim 1, wherein the definitions of the radicals in the compounds of the general formulae (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, X5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, CN, X6 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN, R1 is H, methyl, ethyl, i-propyl, i-butyl, R2 is methyl, ethyl.

3. Process according to either of Claims 1 and 2, wherein the definitions of the radicals in the compounds of the general formulae (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, R1 is H, methyl, i-propyl, i-butyl, R2 is methyl.

4. Process according to any of Claims 1 to 3, wherein the definitions of the radicals in the compounds of the general formulae (I), (II) and (III) are as follows: X2 is H, X3 is H, fluorine, X4 is H, fluorine, X5 is H, fluorine, X6 is H, R1 is H, methyl, i-butyl, R2 is methyl.

5. Process according to any of Claims 1 to 4, wherein the definitions of the radicals in the compounds of the general formulae (I), (II) and (III) are as follows: X2 is H, X3 is fluorine, X4 is H, X5 is fluorine, X6 is H, R1 is H, methyl, R2 is methyl.

6. Process according to any of Claims 1 to 5, wherein the definitions of the radicals in the compounds of the general formula (IIa) are as follows: X7, X8, X10, X11 are independently H, methyl, ethyl, X9 is H, methyl, ethyl or N(methyl)2.

7. Process according to any of Claims 1 to 6, wherein the definitions of the radicals in the compounds of the general formula (IIa) are as follows: X7, X11 is H, X8, X10 are independently H, methyl, ethyl, X9 is H, methyl, ethyl, N(methyl)2.

8. Process according to any of Claims 1 to 7, wherein the definitions of the radicals in the compounds of the general formula (IIa) are as follows: X8 is H, methyl, ethyl, X7, X11 is independently H, methyl, X9, X10 is H.

9. Process according to any of Claims 1 to 8, wherein the compound of the general formula (IV) is generated by one of the following combinations of reagents: - R4MgHal and R3OH or - MgHal2 and R3OM or - MgHal2 and Mg(OR3)2, where R3 is C2-C6-alkyl, benzyl, methylbenzyl, Hal is halogen, M is alkali metal, R4 is C1-C6-alkyl, aryl, benzyl, allyl, vinyl.

10. Process according to any of Claims 1 to 9, wherein the compound of the general formula (IV) is generated by one of the following combinations of reagents: - R4MgHal and R3OH or - MgHal2 and R3OM or - MgHal2 and Mg(OR3)2, where - R3 is C2-C4-alkyl, - Hal is bromine or chlorine, - M is alkali metal, - R4 is C1-C4-alkyl, phenyl, benzyl, p-tolyl, vinyl.

11. Process according to any of Claims 1 to 10, wherein the compound of the general formula (IV) is generated by one of the following combinations of reagents: - R4MgHal and R3OH or - MgHal2 and R3OM or - MgHal2 and Mg(OR3)2, where R3 is i-propyl, i-butyl, Hal is bromine, chlorine, M is sodium, R4 is methyl, ethyl, n-butyl, i-propyl.

12. Process according to any of Claims 1 to 11, characterized in that 2.8 to 3.2 equivalents of the reactive species "R3OMgHal" (IV) are used, based on compounds of the general formula (II).

13. Process according to any of Claims 1 to 12, 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 in any ratios thereof.

14. Process according to any of Claims 1 to 13, characterized in that the reaction is conducted at -25°C to 70°C.

15. Process according to any of Claims 1 to 13, characterized in that the reaction is conducted at 10°C to 30°C.

16. Process according to any of Claims 1 to 15, characterized in that the diastereomeric ratio is increased by a further crystallization step.

17. Process according to any of Claims 1 to 8, characterized in that the compounds of the general formula (IV) are generated via a Grignard reaction, with the following combinations of reagents: R5MgHal and R6R7CO, where R5 is C1-C6-alkyl, aryl, benzyl, R6, R7 are H, C1-C6-alkyl, aryl, and the resulting radical definition R3 is R5R6R7C.

18. Compounds of the formula (Ia) and (Ib) in any mixing ratio except 1:1, wherein the radicals have the definitions according to Claim 5, excluding methyl 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylate:

19. Compounds of the formula (Iaa) and (Iba) in any mixing ratio except 1:1, wherein the radicals have the definitions according to Claim 5, excluding methyl 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylate:

20. Compounds of the formula (Iab) and (Ibb) in any mixing ratio except 1:1, wherein the radicals have the definitions according Claim 5, excluding methyl 3-(3,5-difluorophenyl)-5-(1-hydroxyethyl)-4H-isoxazole-5-carboxylate: