Preparation method for isoxazoline compound containing sulfone five-membered heterocyclic group

Abstract

The present invention paticluarly relates to a preparation method for an isoxazoline compound containing a sulfone five-membered heterocyclic group. The preparation method comprises: taking a substituted benzoic acid and a five-membered sulfone amine as initial raw materials, and performing a three-step reaction of amidation, a condensation-dehydration one-pot method and ring closing, so as to obtain a target object. The process has mild reaction conditions, high safety, a low amount of three wastes, low pollution, and cheap and readily available raw materials, and is beneficial for large-scale industrial production.

Description

Preparation method of isoxazoline compounds containing sulfone five-membered heterocyclic group

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of Chinese patent application No. 202410385365.4 filed on April 1, 2024, the contents of which are incorporated herein by reference. Technical Field

[0003] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing an isoxazoline compound containing a sulfone five-membered heterocycle. Background Art

[0004] Traditional chemical pesticides are restricted or banned due to issues such as high residue levels, increased resistance, and high toxicity. Developing highly active, highly selective, low-risk, and low-residue pesticides has become a key development direction for green pesticides. In recent years, new non-competitive GABA receptor antagonists—isoxazoline insecticides such as Fluralaner, Afoxalaner, Sarolaner, and Fluxametamide—have been reported, potentially targeting the TM1 and TM3 regions of the GABA receptor (Vet Parasitol, 2014, 201, 179; Insect Biochem Mol Biol, 2014, 45, 111).

[0005] Isoxazoline derivatives and their substituted compounds have agricultural bactericidal, insecticidal, antiviral and herbicidal activities, and are therefore widely used in green pesticides. For example, the 3,5-disubstituted isoxazoline derivative synthesized by Ning Guohui in 2014 is a highly effective and broad-spectrum agricultural fungicide (Ning Guohui et al., Organic Chemistry, 2014, 34(09):1800). The target compound has a good control effect on eight fungi, including cucumber gray mold, tomato early blight, peanut brown spot, rapeseed sclerotium, apple ring spot, wheat fusarium, pepper phytophthora, and rice sheath blight, showing broad-spectrum antibacterial activity. Several fungicides have been developed, such as the antibacterial drugs sulfamethoxazole and benzyl oxacillin. Due to the advantages of high efficiency, low toxicity and environmental friendliness of isoxazoline compounds, isoxazoline compounds remain a hot topic in the creation of green pesticides today. However, the existing preparation methods of isoxazoline compounds are complex and costly, and it is necessary to develop new preparation methods of isoxazoline compounds so that these compounds can be better applied in the prevention and treatment of agricultural pests. Summary of the Invention

[0006] In view of the deficiencies of the prior art, the present invention provides a method for preparing an isoxazoline compound containing a sulfone five-membered heterocyclic group.

[0007] The technical solutions of the present invention are as follows:

[0008] The first aspect of the present invention provides a compound represented by formula II,

[0009] wherein X1, X2 and X3 are each independently selected from H, F, Cl or CF3; and n is selected from 0, 1 or 2.

[0010] The second aspect of the present invention provides the use of a compound of formula II for preparing a compound of formula I.

[0011] wherein X1, X2 and X3 are each independently selected from H, F, Cl or CF3; and n is selected from 0, 1 or 2.

[0012] The compound of formula I of the present invention can be selected from the pure compound of formula IA, the pure compound of formula IB, or a mixture of the compound of formula IA and the compound of formula IB in any proportion.

[0013] A third aspect of the present invention provides a method for preparing a compound of formula I from a compound of formula II, comprising the following steps: subjecting the compound of formula II to a ring-closing reaction in a suitable solvent in the presence of a base and hydroxylamine, with or without a catalyst, at a temperature ranging from -10°C to the boiling point of the solvent, to obtain a compound of formula I; the reaction formula is as follows:

[0014] Where n is 0, 1 or 2;

[0015] X1, X2 and X3 are each independently selected from H, F, Cl or CF3.

[0016] In some embodiments, the solvent is selected from one or more of methanol, ethanol, isopropanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile, tetrahydrofuran, acetone, N,N-dimethylformamide, N-methylpyrrolidone, dioxane, water and water.

[0017] In some embodiments, the base is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, morpholine and pyridine.

[0018] In some embodiments, the hydroxylamine is selected from hydroxylamine hydrochloride and / or an aqueous solution of hydroxylamine.

[0019] In some embodiments, the catalyst is selected from an achiral phase transfer catalyst and / or a chiral phase transfer catalyst.

[0020] In some embodiments, n is selected from 2.

[0021] In some embodiments, X1, X2, and X3 are each independently selected from F, Cl, or CF3.

[0022] In some embodiments, the solvent is selected from one or more of methanol, ethanol, dichloromethane, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile and tetrahydrofuran.

[0023] In some embodiments, the base is selected from one or more of potassium carbonate, sodium hydroxide and potassium hydroxide.

[0024] In some embodiments, the hydroxylamine is selected from hydroxylamine hydrochloride and / or an aqueous solution of hydroxylamine.

[0025] In some embodiments, the catalyst is tetrabutylammonium bromide.

[0026] In some typical embodiments, the solvent is selected from dichloroethane and / or toluene.

[0027] In some embodiments, the base is selected from sodium hydroxide and / or potassium hydroxide.

[0028] In some embodiments, the hydroxylamine is selected from hydroxylamine hydrochloride and / or an aqueous solution of hydroxylamine.

[0029] In some embodiments, the catalyst is tetrabutylammonium bromide.

[0030] The present invention also provides a method for preparing a compound of formula IA from a compound of formula II, comprising the following steps: adding a chiral phase transfer catalyst to the compound of formula II in a suitable solvent in the presence of a base and hydroxylamine, and performing a ring-closing reaction at a temperature ranging from -10°C to the boiling point of the solvent to obtain a compound of formula IA; the reaction formula is as follows:

[0031] Where n is 0, 1 or 2;

[0032] X1, X2 and X3 are each independently selected from H, F, Cl or CF3.

[0033] In some embodiments, the solvent is selected from one or more of methanol, ethanol, isopropanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile, tetrahydrofuran, acetone, N,N-dimethylformamide, N-methylpyrrolidone, dioxane and water.

[0034] In some embodiments, the base is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, morpholine and pyridine.

[0035] In some embodiments, the hydroxylamine is selected from hydroxylamine hydrochloride and / or an aqueous solution of hydroxylamine.

[0036] In some embodiments, the chiral phase transfer catalyst is selected from one or more of the following structures:

[0037] wherein X is a halogen.

[0038] The present invention also provides a method for preparing a mixture of a compound of formula IA and a compound of formula IB from a compound of formula II. The compound of formula II is added to a suitable solvent in the presence of a base and hydroxylamine, and a chiral phase transfer catalyst is added. The temperature is within the range of -10°C to the boiling point of the solvent, and a ring-closing reaction is carried out to obtain a mixture of a compound of formula IA and a compound of formula IB. The reaction formula is as follows:

[0039] Where n is 0, 1 or 2;

[0040] X1, X2 and X3 are each independently selected from H, F, Cl or CF3.

[0041] In some embodiments, the solvent is selected from one or more of methanol, ethanol, isopropanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile, tetrahydrofuran, acetone, N,N-dimethylformamide, N-methylpyrrolidone, dioxane and water.

[0042] In some embodiments, the base is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, morpholine and pyridine.

[0043] In some embodiments, the hydroxylamine is selected from hydroxylamine hydrochloride and / or an aqueous solution of hydroxylamine.

[0044] In some embodiments, the chiral phase transfer catalyst is selected from one or more of the following structures:

[0045] wherein X is a halogen.

[0046] The present invention also provides a method for preparing a compound of formula I from a compound of formula IIA, comprising the following steps: adding a chiral phase transfer catalyst to a compound of formula II in a suitable solvent in the presence of a base and hydroxylamine, and performing a ring-closing reaction at a temperature ranging from -10°C to the boiling point of the solvent to obtain a compound of formula I; the reaction formula is as follows:

[0047] Where n is 0, 1 or 2;

[0048] X1, X2 and X3 are each independently selected from H, F, Cl or CF3.

[0049] In some embodiments, the solvent is selected from one or more of methanol, ethanol, isopropanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile, tetrahydrofuran, acetone, N,N-dimethylformamide, N-methylpyrrolidone, dioxane and water.

[0050] In some embodiments, the base is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, morpholine and pyridine.

[0051] In some embodiments, the hydroxylamine is selected from hydroxylamine hydrochloride, hydroxylamine aqueous solution or a mixture thereof.

[0052] In some embodiments, the chiral phase transfer catalyst is selected from one or more of the following structures:

[0053] wherein X is a halogen.

[0054] The fourth aspect of the present invention provides a compound represented by formula IV,

[0055] wherein n is selected from 0, 1 or 2.

[0056] The fifth aspect of the present invention provides the use of the compound represented by formula IV for preparing the compound represented by formula II

[0057] wherein X1, X2 and X3 are each independently selected from H, F, Cl or CF3; and n is selected from 0, 1 or 2.

[0058] A sixth aspect of the present invention provides a method for preparing a compound of formula II from a compound of formula IV, comprising the following steps: reacting a compound of formula IV with a compound of formula III in a suitable solvent in the presence of a base, with or without a catalyst, at a temperature ranging from -10°C to the boiling point of the solvent, to obtain a compound of formula II, as shown in the following reaction formula:

[0059] wherein X1, X2 and X3 are each independently selected from H, F, Cl or CF3; and n is selected from 0, 1 or 2.

[0060] In some embodiments, the solvent is selected from one or more of methanol, ethanol, isopropanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile, tetrahydrofuran, acetone, N,N-dimethylformamide, N-methylpyrrolidone, dioxane and water.

[0061] In some embodiments, the base is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, morpholine and pyridine.

[0062] In some embodiments, n is 2.

[0063] In some embodiments, X1, X2, and X3 are each independently selected from F, Cl, or CF3.

[0064] In some embodiments, the solvent is selected from one or more of methanol, ethanol, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone and dioxane.

[0065] In some embodiments, the base is selected from one or more of triethylamine, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, and potassium hydroxide.

[0066] A seventh aspect of the present invention provides a method for preparing a compound of formula IV, wherein a compound of formula VI and a compound of formula V are subjected to an amide reaction in a suitable solvent in the presence of a suitable halogenating agent and a suitable base, with or without a catalyst, at a temperature ranging from -10°C to the boiling point of the solvent, to obtain a compound of formula IV. The reaction formula is as follows:

[0067] Where n is 0, 1 or 2.

[0068] In some embodiments, the solvent is selected from one or more of methanol, ethanol, isopropanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile, tetrahydrofuran, acetone, N,N-dimethylformamide, N-methylpyrrolidone, dioxane and water.

[0069] In some embodiments, the halogenating agent is selected from: thionyl chloride and / or oxalyl chloride.

[0070] In some embodiments, the base is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, morpholine and pyridine.

[0071] In some embodiments, the catalyst is N,N-dimethylformamide.

[0072] In some embodiments, n is 2.

[0073] In some embodiments, the solvent is selected from one or more of dichloroethane, ethyl acetate, toluene, xylene, tetrahydrofuran, and acetone.

[0074] In some embodiments, the halogenating agent is selected from thionyl chloride and oxalyl chloride.

[0075] In some embodiments, the base is selected from one or more of triethylamine, sodium carbonate, potassium carbonate and sodium hydroxide.

[0076] In some embodiments, the catalyst is N,N-dimethylformamide.

[0077] The present invention has the following beneficial effects: The method uses substituted benzoic acid and pentasulfone amine as starting materials, and obtains the target product through a three-step reaction process of amidation, condensation-dehydration in a one-pot process, and ring closure. This process has mild reaction conditions, high safety, low waste generation, minimal pollution, and uses inexpensive and readily available raw materials. The method of the present invention utilizes a final ring closure approach to prepare isoxazoline compounds, resulting in high yields, easy control of the chiral isomers of the product, and favorable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0078] FIG1 is a chromatogram of chiral liquid chromatography detection of the compound prepared in Example 1;

[0079] FIG2 is a chromatogram of chiral liquid chromatography detection of the compound prepared in Example 3. DETAILED DESCRIPTION

[0080] The following examples may enable those skilled in the art to more fully understand the present invention, but the present invention is not limited to the scope of the examples.

[0081] In the following examples, unless otherwise specified, all raw materials used were commercially available or prepared according to existing techniques and were of analytical grade. The following examples illustrate the preparation of some of the compounds of the present invention. Other compounds can be prepared using known methods by modifying raw materials commonly used in the art.

[0082] The synthetic route of the compound of formula I of the present invention is as follows:

[0083] The chiral phase transfer catalysts of the present invention are prepared by the following method:

[0084] R is selected from

[0085] Chiral liquid chromatography test conditions are as follows:

[0086] Chromatographic column and model: CHIRALPAK IB N-3, 4.6mmI.D*250mmL, filler 3 micron.

[0087] Mobile phase composition: n-hexane (70%), ethanol (30%).

[0088] Detection wavelength: 238nm

[0089] Example 1

[0090] 4-Acetyl-2-methylbenzoic acid (5 g, 28 mmol) was added to 15 ml of toluene, and thionyl chloride (4 g, 36 mmol) and N,N-dimethylformamide (0.1 ml) were added in sequence. The system was heated to reflux for 5 h. After removing thionyl chloride under reduced pressure, the mixture was transferred to a dropping funnel.

[0091] Take another 100ml three-necked flask, add 15ml of toluene, 3-aminocyclopentane hydrochloride (7.2g, 42mmol), and triethylamine (9.92g, 98mmol) in sequence, and add the above-mentioned acyl chloride solution dropwise at a temperature of <60℃. After the addition, keep the temperature at 60℃ and react for 5h. Cool the system to <5℃ for crystallization, filter and dry to obtain 6.7g of light yellow solid. 1H NMR (400MHz, DMSO-d6) δ8.82 (d, J=6.8Hz, 1H), 7.86-7.78 (m, 2H), 7.47 (d, J= 7.8Hz,1H),4.65(h,J=7.2Hz,1H),3.51(dd,J=13.5,7.7Hz,1H),3.38-3.34( m,1H),3.20(dt,J=13.2,8.1Hz,1H),3.06(dd,J=13.4,7.0Hz,1H),2.59(s,3 H), 2.45 (dt, J = 13.2, 6.6 Hz, 1H), 2.39 (s, 3H), 2.17 (dq, J = 13.3, 8.1 Hz, 1H).

[0092] 4-Acetyl-N-(1,1-dioxytetrahydrothiophen-3-yl)-2-methylbenzamide (5 g, 16.9 mmol) was added to 20 ml of dichloroethane, and then 3,5-dichloro-4-fluorotrifluoroacetophenone (7.64 g, 25.35 mmol), triethylamine (1.71 g, 16.9 mmol), and potassium carbonate (1.17 g, 8.45 mmol) were added in sequence. The system was heated to 50 ° C and reacted for 8 h. The temperature was lowered to <10 ° C, filtered and dried to obtain 7 g of off-white solid. 1 H NMR (400MHz, DMSO-d6) δ8.89(dd,J=21.7,6.7Hz,1H),7.95-7.91(m,1H),7.84-7.77(m,2H),7.59(d,J=6.3Hz,2H),7.48(d,J=7.9Hz, 1H), 4.65 (h, J = 7.0Hz, 1H), 3.52 (dt, J = 13.3, 6.1Hz, 1H), 3.26-3.01 (m, 3H), 2.43 (s, 1H), 2.39 (s, 3H), 2.17 (dq, J = 13.2, 8.1Hz, 1H).

[0093] (Z)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4-4-trifluorobut-2-enyl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)-2-methylbenzamide (4.76 g, 8.8 mmol) was added to 20 ml of dichloroethane, and tetrabutylammonium bromide (0.86 g, 2.65 mmol) and hydroxylamine hydrochloride aqueous solution (0.92 g, 13.2 mmol) were added in sequence. The temperature was lowered to 0-5°C, and sodium hydroxide aqueous solution (1.56 g, 39 mmol) was added dropwise with the temperature controlled at <5°C. After the addition was completed and the temperature was kept warm for 8 hours, the system was extracted with water twice, washed with water, and the organic phase was rotary evaporated to dryness to obtain 4.66 g of a light yellow solid.

[0094] 1 H NMR (400MHz, DMSO-d6) δ8.79(d,J=6.8Hz,1H),7.81(d,J=6.2Hz,2H),7.61(d,J=6.8 Hz,2H),7.50-7.43(m,1H),4.65(h,J=7.2Hz,1H),4.35(d,J=8.9Hz,2H),3.51(dd,J= 13.5,7.7Hz,1H),3.39-3.34(m,1H),3.20(dt,J=13.3,8.1Hz,1H),3.06(dd,J=13.5, 7.1Hz, 1H), 2.44 (dt, J=13.2, 6.6Hz, 1H), 2.38 (s, 3H), 2.17 (dq, J=13.4, 8.1Hz, 1H).

[0095] LCMS: M+Na 575.22 / 577.18.

[0096] The chromatogram of the final product prepared in Example 1 detected by chiral liquid chromatography is shown in FIG1 , and the corresponding peak data are shown in Table 1.

[0097] Table 1 Peak data of the final product prepared in Example 1

[0098] It can be seen from Figure 1 and Table 1 that the final product prepared using the achiral catalyst tetrabutylammonium bromide has four configurations, whose liquid phase retention times are 11.34 minutes (5R, 3R), 11.8 minutes (5S, 3R), 18.2 minutes (5R, 3S) and 21.5 minutes (5S, 3S), and their peak area ratios are 25.0:23.3:21.2:26.7.

[0099] Example 2

[0100] 4-Acetyl-N-(1,1-dioxytetrahydrothiophen-3-yl)-2-methylbenzamide (20 g, 67.6 mmol) was added to 80 ml of dichloroethane, and 3,5-bis(trifluoromethyl)trifluoroacetophenone (31.4 g, 101.4 mmol), triethylamine (6.84 g, 67.7 mmol), and potassium carbonate (4.68 g, 33.9 mmol) were added in sequence. The system was heated to 50 ° C and reacted for 8 h. The temperature was cooled to <10 ° C and filtered and dried to obtain 35 g of an off-white solid. 1H NMR (400MHz, DMSO-d6) δ8.88(dd,J=10.6,6.7Hz,1H),8.32(t,J=11.9Hz,1H),8.22(s,1H),8.04(d,J=3.3Hz,2H),7.89-7.74(m,2H),7.47(dd,J=7.1 ,5.1Hz,1H),4.65(q,J=7.1Hz,1H),3.52(dt,J=13.6,7.2Hz,1H),3.26-3. 02(m,3H),2.44(d,J=5.6Hz,1H),2.39(d,J=6.1Hz,3H),2.21-2.14(m,1H).

[0101] (Z)-4-(3-(3,5-bis(trifluoromethyl)phenyl)-4,4-4-trifluorobut-2-enyl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)-2-methylbenzamide (5 g, 8.51 mmol) was added to 20 ml of dichloroethane, and tetrabutylammonium bromide (0.82 g, 2.55 mmol) and hydroxylamine hydrochloride aqueous solution (0.89 g, 12.77 mmol) were added in sequence. The temperature was lowered to 0-5°C, and sodium hydroxide aqueous solution (1.50 g, 37.44 mmol) was added dropwise with the temperature controlled at <5°C. After the addition was completed and the temperature was kept warm for 8 hours, the system was extracted with water twice, washed with water, and the organic phase was rotary evaporated to dryness to obtain 4.48 g of a light yellow solid.

[0102] 1 H NMR(400MHz,DMSO-d6)δ8.80(d,J=6.8Hz,1H),8.36(s,1H),8.22(s,2H),7.66-7.60( m,2H),7.51-7.44(m,1H),4.65(h,J=7.3Hz,1H),4.47(d,J=13.3Hz,2H),3.51(dd,J= 13.5,7.7Hz,1H),3.39-3.34(m,1H),3.20(dt,J=13.3,8.1Hz,1H),3.06(dd,J=13.5, 7.1Hz, 1H), 2.45 (dt, J=13.1, 6.5Hz, 1H), 2.38 (s, 3H), 2.17 (dq, J=13.5, 8.2Hz, 1H).

[0103] LCMS: M+H 603.29.

[0104] Example 3

[0105] (Z)-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4-4-trifluorobut-2-enyl)-N-(1,1-dioxidotetrahydrothiophene-3-yl)-2-methylbenzamide (4g, 7.4mmol) was added to 20ml of dichloroethane, followed by the addition of catalyst (1.2g) and hydroxylamine hydrochloride aqueous solution (0.77g, 11.1mmol). The temperature was lowered to 0-5°C, and sodium hydroxide aqueous solution (1.37g) was added dropwise with the temperature controlled at <5°C. After the addition was completed and the temperature was kept at <5°C for 8h, the system was extracted with water twice, washed with water, and dried. The organic phase was rotary evaporated to dryness to obtain 3.95g of a light yellow solid. The catalyst is

[0106] The chromatogram of the final product prepared in Example 3 detected by chiral liquid chromatography is shown in FIG2 , and the corresponding peak data are shown in Table 2.

[0107] Table 2 Peak data of the final product prepared in Example 3

[0108] Figure 2 and Table 2 show that the isoxazoline ring position of the final product prepared using the chiral catalyst is primarily S-configured, with the R configuration accounting for less than 5%. The liquid phase retention times of the four isomers are 11.7 minutes (5R, 3R), 12.1 minutes (5S, 3R), 18.5 minutes (5R, 3S), and 21.7 minutes (5S, 3S), respectively, with a peak area ratio of 1.6:48.1:2.1:46.6.

[0109] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as the contents disclosed by the present invention and fall within the scope of protection of the present invention.

Claims

1. A compound represented by formula II or a salt thereof, in, X1, X2 and X3 are each independently selected from H, F, Cl or CF3; n is selected from 0, 1 or 2.

2. Use of the compound of formula II according to claim 1 for preparing a compound of formula I, in, X1, X2 and X3 are each independently selected from H, F, Cl or CF3; n is selected from 0, 1 or 2.

3. A method for preparing a compound of formula I, characterized in that: The method comprises the following steps: The compound of formula II is subjected to a ring-closing reaction in a suitable solvent in the presence of a base and hydroxylamine, with or without a catalyst, at a temperature ranging from -10°C to the boiling point of the solvent to obtain a compound of formula I; Where n is 0, 1 or 2; X1, X2 and X3 are each independently selected from H, F, Cl or CF3.

4. The method according to claim 3, characterized in that The solvent is selected from one or more of methanol, ethanol, isopropanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile, tetrahydrofuran, acetone, N,N-dimethylformamide, N-methylpyrrolidone, dioxane and water; and / or, the base is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, morpholine and pyridine; and / or, the hydroxylamine is selected from hydroxylamine hydrochloride and / or a hydroxylamine aqueous solution; And / or, the catalyst is selected from achiral phase transfer catalysts and / or chiral phase transfer catalysts.

5. The method according to claim 4, characterized in that n is selected from 2; and / or, X1, X2 and X3 are each independently selected from F, Cl or CF3; and / or, the solvent is selected from one or more of methanol, ethanol, dichloromethane, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile and tetrahydrofuran; and / or, the base is selected from one or more of potassium carbonate, sodium hydroxide and potassium hydroxide; and / or, the hydroxylamine is selected from hydroxylamine hydrochloride and / or a hydroxylamine aqueous solution; And / or, the catalyst is tetrabutylammonium bromide.

6. The method according to claim 5, characterized in that The solvent is selected from dichloroethane and / or toluene; and / or, the base is selected from sodium hydroxide and / or potassium hydroxide; and / or, the hydroxylamine is selected from hydroxylamine hydrochloride and / or a hydroxylamine aqueous solution; And / or, the catalyst is tetrabutylammonium bromide.

7. A method for preparing a compound of formula IA, characterized in that The method comprises the following steps: Compound II is added to a suitable solvent in the presence of a base and hydroxylamine, and a chiral phase transfer catalyst is added at a temperature ranging from -10°C to the boiling point of the solvent to carry out a ring-closing reaction to obtain compound IA; Where n is 0, 1 or 2; X1, X2 and X3 are each independently selected from H, F, Cl or CF3.

8. The method according to claim 7, characterized in that The solvent is selected from one or more of methanol, ethanol, isopropanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile, tetrahydrofuran, acetone, N,N-dimethylformamide, N-methylpyrrolidone, dioxane and water; and / or, the base is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, morpholine and pyridine; and / or, the hydroxylamine is selected from hydroxylamine hydrochloride and / or a hydroxylamine aqueous solution; And / or, the chiral phase transfer catalyst is selected from one or more substances shown in the following structures, Wherein, X is a halogen.

9. A compound represented by formula IV or a salt thereof, in, n is selected from 0, 1 or 2.

10. Use of the compound of formula IV according to claim 9 for preparing a compound of formula II, in, X1, X2 and X3 are each independently selected from H, F, Cl or CF3; n is selected from 0, 1 or 2.

11. A method for preparing a compound of formula II, characterized in that: The method comprises the following steps: The compound of formula IV and the compound of formula III are reacted in a suitable solvent in the presence of a base with or without a catalyst at a temperature ranging from -10°C to the boiling point of the solvent to obtain a compound of formula II by a one-pot condensation-dehydration reaction; wherein X1, X2 and X3 are each independently selected from H, F, Cl or CF3; and n is selected from 0, 1 or 2.

12. The method according to claim 11, characterized in that The solvent is selected from one or more of methanol, ethanol, isopropanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile, tetrahydrofuran, acetone, N,N-dimethylformamide, N-methylpyrrolidone, dioxane and water; And / or, the base is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, morpholine and pyridine.

13. The method according to claim 12, characterized in that X1, X2 and X3 are each independently selected from F, Cl or CF3; and / or, n is selected from 2; and / or, the solvent is selected from one or more of methanol, ethanol, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone and dioxane; And / or, the base is selected from one or more of triethylamine, potassium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide and potassium hydroxide.

14. A method for preparing a compound of formula IV, characterized in that The method comprises the following steps: a compound of formula VI and a compound of formula V are reacted in a suitable solvent in the presence of a suitable halogenating agent and a suitable base, with or without a catalyst, at a temperature ranging from -10°C to the boiling point of the solvent, to obtain a compound of formula IV. The reaction formula is as follows: Where n is 0, 1 or 2.

15. The method according to claim 14, characterized in that The solvent is selected from one or more of methanol, ethanol, isopropanol, propanol, butanol, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, ethyl acetate, toluene, xylene, acetonitrile, tetrahydrofuran, acetone, N,N-dimethylformamide, N-methylpyrrolidone, dioxane and water; and / or, the halogenating agent is selected from thionyl chloride and / or oxalyl chloride; and / or, the base is selected from one or more of triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, morpholine and pyridine; And / or, the catalyst is N,N-dimethylformamide; Preferably, n is 2; and / or, the solvent is selected from one or more of dichloroethane, ethyl acetate, toluene, xylene, tetrahydrofuran and acetone; and / or, the halogenating agent is selected from thionyl chloride and / or oxalyl chloride; and / or, the base is selected from one or more of triethylamine, sodium carbonate, potassium carbonate and sodium hydroxide; And / or, the catalyst is N,N-dimethylformamide.

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