Process for preparation of isoxazoline carboxylic acid derivatives

Abstract

The present invention relates to a novel process for the preparation of isoxazoline carboxylic acid derivatives of formula (I).

Description

[0001] The present invention relates to a novel method for preparing isoxazoline carboxylic acid derivatives of formula (I).

[0002] The isoxazoline carboxylic acid derivatives of the general formula (I) are important precursors of agrochemical active ingredients (for example, the herbicides described in WO2014 / 048882 and WO2018 / 228985).

[0003] The prior art describes a variety of cyclization methods for preparing isoxazoline carboxylic acid derivatives, for example, Tetrahedron Letters, 1991, 6367-6370; Eur. J. Org. Chem. 2008, 5446-5460; Bull. Chem. Soc. Jpn. 1993, 2685. Possible transition states of the cycloaddition reaction are also discussed. In addition, the yield and isomer ratio under different reaction conditions are disclosed. In the presence of a suitable metal (e.g., magnesium), a high level of stereocontrol can be achieved through chelate formation. However, a disadvantage of the methods described so far is the need to use dichloromethane (DCM) as a solvent, which is not a preferred solvent for industrial-scale synthesis. In addition, it is necessary to convert an excess (2 equivalents) of allyl alcohol used as a substrate. The use of DCM as a solvent has also been described for the preparation of other isoxazoline derivatives, such as the cyclization of aliphatic nitrile oxides with cyclic and acyclic allyl 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 using one of the methods known in the literature in a solvent more favorable for industrial scale application (e.g., tetrahydrofuran (THF)) rather than DCM, the resulting isomer purity is insufficient for industrial scale synthesis.

[0004] It was therefore an object of the present invention to provide a process for preparing isoxazolinecarboxylic acid derivatives of the general formula (I) which is suitable for industrial-scale synthesis and has high yields and isomeric purity, thus obviating the need for laborious purification processes.

[0005] According to the present invention, the object is achieved by a method for preparing an isoxazoline carboxylic acid derivative of general formula (I)

[0006]

[0007] in

[0008] X 2is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy,

[0009] C1-C4-alkoxy, fluorine, CN,

[0010] X 3 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy,

[0011] C1-C4-alkoxy, fluorine, chlorine, CN,

[0012] X 4 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy,

[0013] C1-C4-alkoxy, fluorine, CN,

[0014] X 5 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy,

[0015] C1-C4-alkoxy, fluorine, chlorine, CN,

[0016] X 6 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy,

[0017] C1-C4-alkoxy, fluorine, CN,

[0018] R 1 is H, C1-C12-alkyl, unsubstituted benzyl, or mono- or di-C1-C4-

[0019] Alkyl-substituted benzyl,

[0020] R 2 is a C1-C4-alkyl group,

[0021] It is characterized in that the compound of general formula (II) is reacted with the compound of formula (III) to obtain the compound of general formula (I),

[0022]

[0023] in

[0024] X 2 To X 6 With the above definition,

[0025] X 7 、X 8 、X 10 、X 11 are independently H or C1-C4-alkyl,

[0026] X 9 is H, C1-C4-alkyl or N(C1-C4-alkyl)2,

[0027]

[0028] in

[0029] R 1 and R 2 With the above definition - but R 1 Not for H,

[0030] Add the active substance "R 3 OMgHal" (IV) reagent combination - based on the compound of general formula (II),

[0031] R 3 is alkyl, unsubstituted or alkyl-substituted benzyl, and

[0032] Hal is a halogen.

[0033] The groups in the compounds of general formula (I), (II) and (III) Preferred The definition is as follows:

[0034] X 2 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN,

[0035] X 3 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, CN,

[0036] X 4 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN,

[0037] X 5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, CN,

[0038] X 6 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN,

[0039] X 7 、X 8 、X 10 、X 11 are independently H, methyl, ethyl,

[0040] X 9 is H, methyl, ethyl or N(methyl)2,

[0041] R 1 is H, C1-C4 alkyl,

[0042] R 2 Methyl, ethyl,

[0043] In formula (III), R is not included. 1 =H.

[0044] Preferably , the compound of formula (IV) is generated by one of the following reagent combinations:

[0045] -R 4 MgHal and R 3 OH, or

[0046] -MgHal2 and R 3 OM, or

[0047] -MgHal2 and Mg(OR 3 )2, where

[0048] R 3 C2-C 12 -alkyl, unsubstituted or C1-C4-alkyl-substituted benzyl, and

[0049] Hal is halogen,

[0050] M is an alkali metal,

[0051] R 4 is an alkyl group, an unsubstituted aryl group, a substituted aryl group, an unsubstituted benzyl group, a substituted benzyl group, an allyl group, or a vinyl group.

[0052] or , the compound of general formula (IV) is generated by combining the following reagents:

[0053] -R 5 MgHal and R 6 R 7 CO, of which

[0054] R 5 is C1-C6-alkyl, aryl, benzyl,

[0055] R 6 、R 7 is H, C1-C6-alkyl, aryl,

[0056] And the resulting group definition

[0057] R 3 Corresponding to R 5 R 6 R 7C.

[0058] Reagents for preparing compounds of general formula (IV) Preferred The group definitions (presented in an optional manner) are as follows:

[0059] R 5 is C1-C4-alkyl, phenyl, benzyl, p-tolyl,

[0060] R 6 、R 7 It is H, C1-C4-alkyl, or phenyl.

[0061] The groups in the compounds of general formula (I), (II) and (III) Particularly preferred The definition is as follows:

[0062] X 2 For H,

[0063] X 3 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy,

[0064] CN,

[0065] X 4 For fluorine, H,

[0066] X 5 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy,

[0067] CN,

[0068] X 6 For H,

[0069] X 7 、X 8 、X 11 are independently H, methyl, ethyl,

[0070] X 9 For H, N (methyl) 2,

[0071] X 10 For H,

[0072] R 1 is H, methyl, ethyl, isopropyl, isobutyl,

[0073] R 2 is methyl,

[0074] In formula (III), R is not included. 1 =H.

[0075] More preferably , the compound of formula (IV) is generated by one of the following reagent combinations:

[0076] -R 4 MgHal and R 3 OH, or

[0077] -MgHal2 and R 3 OM, or

[0078] -MgHal2 and Mg(OR 3 )2, where R 3 is a C2-C8-alkyl group,

[0079] Hal is bromine or chlorine,

[0080] M is an alkali metal,

[0081] R 4 It is C1-C8-alkyl, phenyl, benzyl, p-tolyl, or vinyl.

[0082] The groups in the compounds of general formula (I), (II) and (III) Very particularly preferred The definition is as follows: X 2 For H,

[0083] X 3 For H, fluorine,

[0084] X 4 For H,

[0085] X 5 For H, fluorine,

[0086] X 6 For H,

[0087] X 8 is H, methyl, ethyl,

[0088] X 7 、X 11 are independently H, methyl,

[0089] X 9 、X 10 For H,

[0090] R 1 is H, methyl, isopropyl, isobutyl,

[0091] R 2 is methyl,

[0092] In formula (III), R is not included. 1 =H.

[0093] Even more preferably , the compound of formula (IV) is generated by one of the following reagent combinations:

[0094] -R 4 MgHal and R 3 OH, or

[0095] -MgHal2 and R 3 OM, or

[0096] -MgHal2 and Mg(OR 3 )2, where R 3 isopropyl, isobutyl, 2-butyl,

[0097] Hal is bromine or chlorine,

[0098] M is sodium,

[0099] R 4 It is methyl, ethyl, n-butyl, and isopropyl.

[0100] The groups in the compounds of general formula (I), (II) and (III) Best The definition is as follows:

[0101] X 2 For H,

[0102] X 3 For fluorine,

[0103] X 4 For H,

[0104] X 5 For fluorine,

[0105] X 6 For H,

[0106] X 7 、X 8 、X 11 are independently H, methyl,

[0107] X 9 、X 10 For H,

[0108] R 1 is H, methyl, isobutyl,

[0109] R 2 is methyl,

[0110] In formula (III), R is not included. 1 =H.

[0111] definition

[0112] Alkyl means a saturated, straight-chain or branched hydrocarbon radical having the number of carbon atoms specified in each case, for example C1-C 12-alkyl groups such as 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.

[0113] Hal means halogen, which is fluorine, chlorine, bromine or iodine. If the term is applied to a radical, Hal means a fluorine, chlorine, bromine or iodine atom.

[0114] Alkali metal means lithium, sodium or potassium.

[0115] Aryl means phenyl or naphthyl.

[0116] The compound of formula (I) may exist in the form of a mixture of isomers. Compared with the prior art, the optimized reaction conditions increase the desired diastereomeric excess. 1.7 to 2.0 equivalents of the active substance "R 3 OMgHal" (IV) is particularly advantageous.

[0117] When the (S)-alcohol is used, the major product is the (S,S)-diastereomer, while the (R,S)-diastereomer is the minor diastereomer.

[0118] When (R)-alcohol is used, the major product is the (R,R)-diastereomer, while the (S,R)-diastereomer is the minor diastereomer. When (rac)-alcohol is used, the major product is the (S,S / R,R)-rac-diastereomer, while the (S,R / R,S)-rac-diastereomer is the minor diastereomer.

[0119] The compound of formula (I) can be isolated as the corresponding ester or, after a hydrolysis workup, as the carboxylic acid.

[0120] By crystallization enrichment, the compound of formula (I) can be Diastereomers The ratio reaches up to 100:0.

[0121] Description of methods and intermediates

[0122]

[0123] The object is achieved by a method for preparing an isoxazoline carboxylic acid derivative of formula (I), characterized in that a compound of formula (II) is reacted with a compound of formula (III), and an active substance "R 3 OMgHal" (IV) to obtain compounds of general formula (I) (Scheme 1).

[0124] Preferred Using 1.5 to 2.0 equivalents of the active substance "R 3 OMgHal”(IV).

[0125] Especially preferred Using 1.7 to 2.0 equivalents of the active substance "R 3 OMgHal”(IV).

[0126] Addition of water may also be advantageous and may further improve the diastereomeric ratio (dr). Preferred Up to 1.0 equivalent of water (based on the compound of formula (II)) is used. Especially preferred 0.1 to 0.6 equivalents of water (based on the compound of the general formula (II)) are used.

[0127] The cyclization reaction is usually carried out at -25°C to 70°C. Preferred The temperature range is 10°C to 30°C.

[0128] In addition, the cyclization reaction is optionally carried out in the presence of a solvent, a diluent or a solvent mixture. Preferred It 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 proportion.

[0129] Compounds of formula (III) are prepared by a two-stage process known from the literature. The first stage is the Baylis-Hillman reaction. References include: Drewes, SE; Hoole, RFA [Synthetic Communications, 1985, Vol. 15, 12, pp. 1067-1074]. References include: Nascimento et al. (2003, Tetrahedron Asymmetry 14, 311-311).

[0130] Compounds of the general formula (II) and (III) are also known from WO 2018 / 228985. The preparation of compounds of the formula (IIa) from (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

[0131] The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto (Table 1).

[0132] Analytical methods

[0133] Product passed 1 The samples were characterized by H NMR spectroscopy and / or LC-MS (liquid chromatography coupled with mass spectrometry).

[0134] NMR spectra were measured using a Bruker Avance 400 equipped with a flow probe (volume 60 μl). In some 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.

[0135] Table 1

[0136]

[0137] a) reacting with 3,5-difluoro-N-hydroxybenzenecarboximidoyl chloride.

[0138] b) The yield of the product after hydrolysis with sodium hydroxide solution and acidification.

[0139] c) (S)-Methyl 3-hydroxy-2-methylenebutanoate (0.524 g, 95.5% by weight) was used.

[0140] d) reacting with 0.524 mol of 3,5-difluoro-N-hydroxybenzoimidoyl chloride to isolate the corresponding carboxylic acid.

[0141]

[0142] Example 1

[0143] Under an argon atmosphere, 2 equivalents (eq) of 2-propylmagnesium chloride (4.0 ml, 2 mol / l in THF) were first added at 20 ° C. Then, under cooling (ice bath), 2 equivalents of 2-propanol (0.61 ml) were added dropwise over 10 minutes. Propane escaped (only a small amount of foam) and a white solid precipitated. After the addition was complete and the gas no longer escaped, the resulting suspension was stirred at 20 ° C for 20 minutes. Subsequently, 1 equivalent of 3-hydroxy-2-methylenebutyric acid methyl ester (0.52 g, 99.8 wt %) was added dropwise at room temperature (RT). The mixture became more fluid. The suspension was continued to stir at room temperature for 15 minutes and then cooled to about 15 ° C. Subsequently, a solution of 3,5-difluoro-N-hydroxybenzoimidoyl chloride in THF (2.55 g, 30.0 wt %) was added dropwise with a syringe pump at about 15 ° C. The addition time was 1 hour (h). Subsequently, the reaction mixture was warmed to room temperature and continued to stir 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 reduced pressure. Toluene (1 ml) and an excess of aqueous sodium hydroxide solution were added to the residue and stirred at 65 ° C. After the hydrolysis was completed, the reaction mixture was cooled to room temperature, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases were concentrated under reduced pressure. Assay (qNMR) showed, the residue contained 0.90 g of product (83%). Diastereoisomer ratio = 88:12.

[0144] Example 2

[0145] Under an argon atmosphere, 2 equivalents (eq) of 2-propylmagnesium chloride (4.23 ml, 1.87 mol / l in THF) were first added at 20°C. Then, under cooling (ice bath), 2 equivalents of 2-propanol (0.61 ml) were added dropwise over 10 minutes. Propane evolved (only a small amount of foam) and a white solid precipitated. After the addition was complete and gas evolution ceased, the resulting suspension was stirred at 20°C for 20 minutes. Subsequently, 1 equivalent of (S)-methyl 3-hydroxy-2-methylenebutanoate (0.545 g, 95.5 wt %) was added dropwise at room temperature (RT). The mixture became more fluid. The suspension was further stirred at room temperature for 15 minutes and then cooled to approximately 15°C. Subsequently, at about 15 ° C, a solution of 3,5-difluoro-N-hydroxybenzimidoyl chloride in a toluene / THF solvent mixture (4.23 g, 18.1 wt %) was added dropwise through a syringe pump together with an additional 0.3 equivalents of water (22 μl). The addition time was 1 hour (h). Subsequently, the reaction mixture was warmed to room temperature and continued to stir for 1 hour. 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 reduced pressure. Toluene (1 ml) and excess sodium hydroxide aqueous solution were added to the residue and stirred at 65 ° C. After the hydrolysis was completed, the reaction mixture was cooled to room temperature, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases were concentrated under reduced pressure. The residue contained 0.93 g of product (86%) by content determination (qNMR). Diastereoisomer ratio = 92:8.

[0146] Example 13

[0147] Under an argon atmosphere, 1.7 equivalents (eq) of 2-propylmagnesium chloride (3.41 ml, 2 mol / l in THF) were first added at 20 ° C. Then, under cooling (ice bath), 1.7 equivalents of 2-propanol (0.52 ml) were added dropwise over 10 minutes. Propane escaped (only a small amount of foam) and a white solid precipitated. After the addition was complete and the gas no longer escaped, the resulting suspension was stirred at 20 ° C for 20 minutes. Subsequently, 1 equivalent of 2-propyl 3-hydroxy-2-methylenebutanoate (0.79 g, 80.0 wt %) was added dropwise at room temperature (RT). The mixture became more fluid. The suspension was continued to stir at room temperature for 15 minutes and then cooled to about 15 ° C. Subsequently, a solution of 3,5-difluoro-N-hydroxybenzoimidoyl chloride in THF (2.54 g, 30.1 wt %) was added dropwise with a syringe pump at about 15 ° C. The addition time was 1 hour (h). Subsequently, the reaction mixture was warmed to room temperature and continued to stir 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 reduced pressure. Toluene (1 ml) and an excess of aqueous sodium hydroxide solution were added to the residue and stirred at 65 ° C. After the hydrolysis was completed, the reaction mixture was cooled to room temperature, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases were concentrated under reduced pressure. Assay (qNMR) showed, the residue contained 0.90 g of product (83%). Diastereoisomer ratio = 89:11.

[0148] Example 14

[0149] Under an argon atmosphere, 1.7 equivalents (eq) of 2-propylmagnesium chloride (3.42 ml, 2 mol / l in THF) were first added at 20°C. Then, under cooling (ice bath), 1.7 equivalents of 2-propanol (0.52 ml) were added dropwise over 10 minutes. Propane evolved (only a small amount of foam) and a white solid precipitated. After the addition was complete and gas evolution ceased, the resulting suspension was stirred at 20°C for 20 minutes. Subsequently, 1 equivalent of 2-propyl 3-hydroxy-2-methylenebutanoate (0.79 g, 80.0 wt %) was added dropwise at room temperature (RT). The mixture became more fluid. The suspension was further stirred at room temperature for 15 minutes and then cooled to approximately 15°C. Subsequently, at about 15 ° C, a solution of 3,5-difluoro-N-hydroxybenzimidoyl chloride in a toluene / THF solvent mixture (2.59 g, 29.7 wt %) was added dropwise via a syringe pump together with an additional 0.3 equivalents of water (22 μl). The addition time was 1 hour (h). Subsequently, the reaction mixture was warmed to room temperature and continued to stir 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 reduced pressure. Toluene (1 ml) and excess sodium hydroxide aqueous solution were added to the residue and stirred at 65 ° C. After the hydrolysis was complete, the reaction mixture was cooled to room temperature, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases were concentrated under reduced pressure. The residue contained 0.93 g of product (86%) by content determination (qNMR). Diastereoisomer ratio = 89:11.

[0150] Example 21

[0151] Under an argon atmosphere, 1.8 equivalents (eq) of 2-propylmagnesium chloride (552 ml, 1.71 mol / l in THF) were first added at 20°C. Then, under cooling (ice bath), 1.8 equivalents of 2-propanol (73 ml) were added dropwise over 90 minutes. The temperature was maintained between 15-30°C. Propane evolved (only a small amount of foam) and a white solid precipitated. After the addition was complete and gas no longer evolved, the resulting suspension was stirred for 40 minutes until the internal temperature reached 20°C. Subsequently, at a temperature of 20-25°C, 1 equivalent of isobutyl 3-hydroxy-2-methylenebutyrate (93.90 g, 96.1 wt %) was added dropwise over 35 minutes. The mixture became more fluid. The suspension was continued to stir at room temperature for 75 minutes and then cooled to about 15°C. Subsequently, at about 15 ° C (ice bath), a solution of 3,5-difluoro-N-hydroxybenzamide chloride in a toluene / THF solvent mixture (233.0 g, 43.1 wt %) was added dropwise through a dropping funnel together with an additional 0.3 equivalents of water (2.83 ml). The addition time was 1 hour and 45 minutes. The internal temperature was maintained between 15-20 ° C. After the addition was completed, the reaction mixture was warmed to room temperature and continued to stir for at least 2.5 hours. Then, under cooling in a water bath (20 ° C), the reaction mixture was mixed with HCl solution (16.9 wt %, 140.4 g), 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 an excess of sodium hydroxide aqueous solution (32 wt %, 85.1 g) were added to the residue and vigorously stirred at 65 ° C. After the hydrolysis was complete (2.5 h), the reaction mixture was cooled to room temperature and concentrated under reduced pressure to a thick suspension (60° C. bath temperature, 240 mbar to 85 mbar). It was then acidified with sulfuric acid (20% by weight, 100 ml) under vigorous stirring. The product precipitated, then filtered and dried. Furthermore, 35 ml of 20% by weight sulfuric acid was added to the mother liquor (mother liquor pH value was 1-2), and the mother liquor was extracted with isopropyl acetate (iPrOAc) (2 x 200 ml). The combined organic phases were concentrated under reduced pressure. The residue was combined with the solid and suspended in isopropyl acetate (iPrOAc) (500 ml) and stirred at 60° C. for 6 h. The suspension was then concentrated to a level that was still stirrable (50° C., 200 mbar to 150 mbar). 300 ml of toluene was added to the thick suspension. Distillation was continued at 50° C. / 150 mbar to 120 mbar until the suspension thickened again. The suspension was cooled to room temperature and allowed to stand overnight until crystallization was complete. The suspension was then filtered and rinsed with 290 ml of toluene to obtain a solid product, which was then dried. The filtered solid (119.20 g, 96.5 wt %) was assayed (qNMR) to give an 81% yield of the product with a diastereoisomer ratio of 98:2.The concentrated mother liquor (43.13 g, 25.2 wt%) contained 8% of the product. The diastereoisomer ratio of the mother liquor was 41:59.

[0152] 1 H NMR (401MHz, DMSO-d6): δ (ppm) = 1.11 (d, J = 6.5Hz, 3H), 3.61 (d, J = 17.8, 1H), 3.67 (d, J=17.8,1H),4.10(q,J=6.4Hz,1H),5.20(bs,1H),7.34-7.45(m,3H),13.28(bs,1H).

[0153] 19 F-NMR (376MHz, DMSO-d6): δ (ppm) = -108.7 (m, 2F).

[0154] Example 22

[0155] Under an argon atmosphere, 1.7 equivalents (eq) of 2-propylmagnesium chloride (3.64 ml, 1.87 mol / l in THF) were first added at 20 ° C. Then, under cooling (ice bath), 1.7 equivalents of 2-propanol (0.52 ml) were added dropwise over 10 minutes. Propane escaped (only a small amount of foam) and a white solid precipitated. After the addition was complete and gas no longer escaped, the resulting suspension was stirred at 20 ° C for 20 minutes. Subsequently, 1 equivalent of 3-hydroxy-2-methylenebutyric acid isobutyl ester (0.70 g, 98.2 wt %) was added dropwise at room temperature (RT). The mixture became more fluid. The suspension was continued to stir at room temperature for 15 minutes and then cooled to about 15 ° C. Subsequently, at about 15 ° C, a solution of 3,5-difluoro-N-hydroxybenzoimidoyl chloride in THF (2.54 g, 30.2 wt %) was added dropwise using a syringe pump. The addition time is 1 hour (h). Subsequently, the reaction mixture is warmed to room temperature and continued to stir for 1h. HCl solution is then added to the reaction mixture and extracted with ethyl acetate. The aqueous phase is extracted with ethyl acetate again. The combined organic phases are concentrated under reduced pressure. Toluene (1ml) and excess sodium hydroxide aqueous solution are added to the residue and stirred at 65°C. After the hydrolysis is complete, 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 reduced pressure. Assay (qNMR) showed, the residue contained 0.93g of product (86%). Diastereoisomer ratio = 93:7.

[0156] Example 23

[0157] Under an argon atmosphere, 1.7 equivalents (eq) of 2-propylmagnesium chloride (3.87 ml, 1.76 mol / l in THF) were first added at 20°C. Then, under cooling (ice bath), 1.7 equivalents of 2-propanol (0.52 ml) were added dropwise over 10 minutes. Propane evolved (only a small amount of foam) and a white solid precipitated. After the addition was complete and gas evolution ceased, the resulting suspension was stirred at 20°C for 20 minutes. Subsequently, 1 equivalent of isobutyl 3-hydroxy-2-methylenebutyrate (0.70 g, 98.2 wt %) was added dropwise at room temperature (RT). The mixture became more fluid. The suspension was further stirred at room temperature for 15 minutes and then cooled to approximately 15°C. Subsequently, at about 15 ° C, a solution of 3,5-difluoro-N-hydroxybenzimidoyl chloride in a toluene / THF solvent mixture (4.23 g, 18.1 wt %) was added dropwise via a syringe pump together with an additional 0.3 equivalents of water (22 μl). The addition time was 1 hour (h). Subsequently, the reaction mixture was warmed to room temperature and continued to stir 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 reduced pressure. Toluene (1 ml) and excess sodium hydroxide aqueous solution were added to the residue and stirred at 65 ° C. After the hydrolysis was complete, the reaction mixture was cooled to room temperature, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases were concentrated under reduced pressure. The residue contained 0.95 g of product (88%) by content determination (qNMR). Diastereoisomer ratio = 93:7.

[0158] Example 30

[0159] Under an argon atmosphere, 2 ml of anhydrous THF was first added. Then at room temperature, 2 equivalents of (S)-3-hydroxy-2-methylenebutanoic acid methyl ester (1.09 g, 95.5 wt %) were added, and the solution was cooled to -78 ° C with a cooling bath (acetone / dry ice). Subsequently, at -78 ° C, under stirring, 2 equivalents of 2-propylmagnesium chloride (4.55 ml, 1.76 mol / l in THF) were carefully added dropwise. The reaction mixture was continued to stir at -78 ° C for 40 minutes and then heated. The clear solution was then cooled to about 15 ° C (water bath). Subsequently, at about 15 ° C, a solution of 3,5-difluoro-N-hydroxybenzamide chloride in THF (2.54 g, 30.1 wt %) was added dropwise with a syringe pump. The addition time was 1 hour (h). Subsequently, the reaction mixture was warmed to room temperature and continued to stir for 1 h. The 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 reduced pressure. Toluene (1 ml) and excess aqueous sodium hydroxide solution were added to the residue and stirred at 65° C. After the hydrolysis was complete, the reaction mixture was cooled to room temperature, acidified (pH 1-2), and extracted twice with ethyl acetate. The combined organic phases were concentrated under reduced pressure. Assay (qNMR) revealed 0.95 g of product (88%) in the residue. Diastereoisomer ratio = 81:19.

[0160] Table 1:

[0161]

[0162] *The reaction was completed when almost complete conversion of the reactant compound of formula (II) was observed by HPLC.

[0163] **After hydrolysis according to step 2 of the above example

[0164] It is clear from Table 1 that the yield of the compound of formula (I) is highly dependent on the variable R 1 choice.

Claims

1. Method for preparing isoxazoline carboxylic acid derivatives of formula (I) in X 2 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine, CN, X 3 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine, chlorine, CN, X 4 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine, CN, X 5 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine, chlorine, CN, X 6 is H, C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-fluoroalkoxy, C1-C4-alkoxy, fluorine, CN, R 1 is H, C1-C12-alkyl, unsubstituted benzyl, or mono- or di-C1-C4-alkyl-substituted benzyl, R 2 is a C1-C4-alkyl group, It is characterized by: The compound of formula (II) is reacted with the compound of formula (III) to obtain the compound of formula (I), in X 2 To X 6 With 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, in R 1 and R 2 With the above definition - but R 1 Not H, Adding can form 1.0 to 2.0 equivalents of active substance "R 3 OMgHal" (IV) reagent combination - based on the compound of general formula (II), in R 3 is alkyl, unsubstituted or alkyl-substituted benzyl, and Hal is a halogen.

2. The method according to claim 1, wherein the groups in the compounds of general formula (I), (II) and (III) are defined as follows: X 2 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN, X 3 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, CN, X 4 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN, X 5 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, chlorine, methoxy, CN, X 6 is H, methyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, fluorine, methoxy, CN, X 7 、X 8 、X 10 、X 11 are independently H, methyl, ethyl, X 9 is H, methyl, ethyl or N(methyl)2, R 1 is H, C1-C4 alkyl, R 2 Methyl, ethyl, In formula (III), R is not included. 1 =H.

3. The method according to claim 1 or 2, wherein the groups in the compounds of general formula (I), (II) and (III) are defined as follows: X 2 For H, X 3 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, CN, X 4 For fluorine, H, X 5 is H, methyl, trifluoromethyl, difluoromethyl, fluorine, chlorine, methoxy, CN, X 6 For H, X 7 、X 8 、X 11 are independently H, methyl, ethyl, X 9 For H, N (methyl) 2, X 10 For H, R 1 is H, methyl, ethyl, isopropyl, isobutyl, R 2 is methyl, In formula (III), R is not included. 1 =H.

4. The process according to any one of claims 1 to 3, wherein the groups in the compounds of the general formulae (I), (II) and (III) are defined as follows: X 2 For H, X 3 For H, fluorine, X 4 For H, X 5 For H, fluorine, X 6 For H, X 8 is H, methyl, ethyl, X 7 、X 11 are independently H, methyl, X 9 、X 10 For H, R 1 is H, methyl, isopropyl, isobutyl, R 2 is methyl, In formula (III), R is not included. 1 =H.

5. The process according to any one of claims 1 to 4, wherein the groups in the compounds of the general formulae (I), (II) and (III) are defined as follows: X 2 For H, X 3 For fluorine, X 4 For H, X 5 For fluorine, X 6 For H, X 7 、X 8 、X 11 are independently H, methyl, X 9 、X 10 For H, R 1 is H, methyl, isobutyl, R 2 is methyl, In formula (III), R is not included. 1 =H.

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

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

8. The method according to any one of claims 1 to 7, wherein the compound of formula (IV) is generated by one of the following reagent combinations: -R 4 MgHal and R 3 OH, or -MgHal2 and R 3 OM, or -MgHal2 and Mg(OR 3 )2, where R 3 C2-C 12 alkyl, unsubstituted or C1-C4-alkyl-substituted benzyl, and Hal is halogen, M is an alkali metal, R 4 is alkyl, unsubstituted aryl, substituted aryl, unsubstituted benzyl, Substituted benzyl, allyl, vinyl.

9. The method according to any one of claims 1 to 8, wherein the compound of formula (IV) is generated by one of the following reagent combinations: -R 4 MgHal and R 3 OH, or -MgHal2 and R 3 OM, or -MgHal2 and Mg(OR 3 )2, where R 3 is a C2-C8-alkyl group, Hal is bromine or chlorine, M is an alkali metal, R 4 It is C1-C8-alkyl, phenyl, benzyl, p-tolyl, or vinyl.

10. The method according to any one of claims 1 to 8, wherein the compound of formula (IV) is generated by one of the following reagent combinations: -R 4 MgHal and R 3 OH, or -MgHal2 and R 3 OM, or -MgHal2 and Mg(OR 3 )2, where R 3 is a C2-C8-alkyl group, Hal is bromine or chlorine, M is an alkali metal, R 4 It is C1-C4-alkyl, phenyl, benzyl, p-tolyl, or vinyl.

11. The method according to any one of claims 1 to 10, characterized in that Using 1.3 to 2.0 equivalents of active substance "R 3 OMgHal" (IV), based on the compound of general formula (II).

12. The method according to any one of claims 1 to 10, characterized in that Using 1.7 to 2.0 equivalents of active substance "R 3 OMgHal" (IV), based on the compound of general formula (II).

13. The method 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 method 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 proportion.

15. The method 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 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. The method according to any one of claims 1 to 16, characterized in that The diastereomeric ratio was increased by further crystallization steps.

18. The method according to any one of claims 1 to 8, characterized in that The compound of formula (IV) is generated by Grignard reaction in combination with the following reagents: -R 5 MgHal and R 6 R 7 CO, of which R 5 is C1-C6-alkyl, aryl, benzyl, R 6 、R 7 is H, C1-C6-alkyl, aryl, and the resulting radical definition corresponds to R 3 R 5 R 6 R 7 C.

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