CN113582937A

CN113582937A - Green preparation method of water-soluble vitamin E-involved isoxazole compound

Info

Publication number: CN113582937A
Application number: CN202110926237.2A
Authority: CN
Inventors: 王宇光; 周金秋; 刘贝; 陈圆
Original assignee: Zhejiang University of Technology ZJUT
Current assignee: Zhejiang University of Technology ZJUT
Priority date: 2021-08-12
Filing date: 2021-08-12
Publication date: 2021-11-02
Anticipated expiration: 2041-08-12
Also published as: CN113582937B

Abstract

The invention provides a green synthesis method of an isoxazole compound shown in a formula (III), which comprises the following steps: taking an aldoxime compound shown in a formula (I) as a substrate, reacting with an alkyne compound shown in a formula (II) for 6-16h at room temperature under the combined action of N-chlorosuccinimide and an alkaline substance in an aqueous solution of a surfactant with the mass concentration of 1-5 wt%, and carrying out aftertreatment on the obtained reaction liquid to obtain an isoxazole compound shown in a formula (III); the invention takes water as a reaction solvent, reduces the use amount of an organic solvent and realizes zero emission of the solvent.

Description

Green preparation method of water-soluble vitamin E-involved isoxazole compound

Technical Field

The invention relates to a green synthesis method of an isoxazole compound participated by water-soluble vitamin E.

Background

Isoxazoles are a common structural scaffold in many biologically active molecules. Isoxazole derivatives also have a wide range of biological activities, such as neurotoxin (A), antidepressant-like active substance (B), anti-beta-lactamase antibiotic (C), and synthetic androgen danazol (D) with histone deacetylase (HADC) probe (E) which inhibits gonadotropin production. In addition, isoxazole derivatives can also be used as main precursors for synthesizing different organic compounds.

Several methods are currently available for the synthesis of isoxazole scaffolds. In 2005, the Fokin group used sodium ascorbate to treat CuSO₄·5H₂Reducing O into Cu (I) which is used as a catalyst to catalyze N-hydroxyl imidazole chloride and alkyne to generate isoxazole derivatives. The traditional method for synthesizing the isoxazole skeleton by using the metal-free catalyst can be summarized as follows: 2-alkyl-1-keto-o-methyloximes with ICl, I₂，Br₂Reactions, the reaction of N-hydroxy-4-toluenesulfonamide with α, β -unsaturated carbonyl compounds, the cycloaddition of alkynyl compounds with nitrile oxides, the dehydration of nitroalkanes with dipolar molecules in the presence of DABCO, and the cascade reaction of α -hydroxy-4-toluenesulfonamide with α, β -unsaturated carbonyl compounds. However, homogeneous metal-catalyzed synthesis of isoxazole derivatives involves Pd-catalyzed four-component coupling of terminal alkynes, hydrazines (hydroxylamines), carbon monoxide and aryl iodides, Pd-catalyzed Sonogashira coupling of acidic chlorides with terminal alkynes, followed by 1, 3-dipolar cycloaddition, AuCl₃Catalyzing the cycloisomerization of alpha, beta-acetylene oxime, sequentially catalyzing four-step reaction of propiolic alcohol by Fe and Pd, and reacting terminal alkyne with n-BuLi. In 2013, Huang topic group studied Cu₂And (3) taking ethanol as a solvent to react for 2 hours to synthesize the 3, 5-disubstituted isoxazole in a regioselective manner. Recently, Ram Lou n subject group synthesized 3, 5-disubstituted isoxazoles in deep eutectic solvents.

However, these reactions have disadvantages of low yield, many synthesis steps, severe reaction conditions, use of expensive Pd or Au catalysts, use of toxic reagents, and difficulty in operation. Therefore, it is desired to establish a simple method for synthesizing 1, 3-dipolar addition isoxazole in an aqueous phase with TPGS-750-M. Compared with the prior method, the method has the main advantages that water is used as an environment-friendly solvent with the participation of TPGS-750-M, the reaction condition is simple, the yield is high, the purity is high, and the method is environment-friendly.

Disclosure of Invention

In order to solve the problems of large pollution, more wastes and the like in the prior art, the invention provides a green and simple synthesis method of an isoxazole compound shown in a formula (III), which completes the synthesis of the isoxazole compound in a water phase under the participation of a micro micelle formed by TPGS-750-M.

In order to achieve the purpose, the invention adopts the following technical scheme:

the invention provides a green synthesis method of an isoxazole compound shown in a formula (III), which comprises the following steps:

taking an aldoxime compound shown in the formula (I) as a substrate, reacting with an alkyne compound shown in the formula (II) in an aqueous solution of a surfactant with the mass concentration of 1 wt% -5 wt% (preferably 2 wt%) under the combined action of N-chlorosuccinimide (NCS) and an alkaline substance at room temperature for 6-16h (preferably 8h), and carrying out aftertreatment on the obtained reaction liquid to obtain an isoxazole compound shown in the formula (III); the mass ratio of the alkyne compound shown in the formula (II), the aldoxime compound shown in the formula (I), the N-chlorosuccinimide and the alkaline substance is 1:1-1.5:1-1.8:0.5-2 (preferably 1:1.5:1.8: 1.3);

in the formulae (I) and (III), R₁Is one of the following groups: cyclohexyl, 3-pentyl, phenyl substituted with methyl, isopropyl, halogen or methoxy;

in the formulae (II) and (III), R₂Selected from one of the following groups: phenyl, p-methylphenyl, halogen-substituted phenyl, C₁～C₆Alkyl-substituted phenyl of (1), C₁～C₃Alkoxy-substituted phenyl, benzyl, thienyl, 4-dimethylaminophenyl, C₁～C₈Alkyl group of (A) or (B),

The alkaline substance is one of the following substances: sodium hydroxide (NaOH), potassium carbonate (K)₂CO₃) Triethylamine (Et)₃N), piperidine (preferably triethylamine and piperidine, most preferably triethylamine); the surfactant in the surfactant aqueous solution is tocopherol methoxypolyethylene glycol succinate (TPGS-750-M). (when cesium carbonate is used as the basic substance, almost no product is produced)

The reaction formula is as follows:

the invention recommends that the reaction be carried out under stirring conditions.

Further, the volume of the aqueous solution of the surfactant is 5 to 20mL/mmol (preferably 10mL/mmol) in terms of the amount of the substance of the substituted alkyne represented by the formula (II).

Preferably, the alkyne compound of formula (I) is one of the following:

preferably, the aldoxime compound represented by the formula (II) is one of the following:

further, the post-treatment comprises the following steps: extracting the reaction liquid by using ethyl acetate, combining organic phases, evaporating the solvent under reduced pressure, and mixing solid residues by using petroleum ether with the volume ratio of 1: 2: and (3) carrying out column chromatography separation on the ethyl acetate mixed solution, collecting eluent containing the target product, and carrying out reduced pressure evaporation to remove the solvent to obtain the isoxazole compound shown in the formula (III).

The surfactants used in the invention, namely Sodium Dodecyl Sulfate (SDS), polyethylene glycol octyl phenyl ether (Trition X-100) and Cetyl Trimethyl Ammonium Bromide (CTAB), are commercially available products, and the tocopherol methoxypolyethylene glycol succinate (TPGS-750-M, water-soluble vitamin E) can be commercially available products, and the surfactant used in the invention is self-made, preferably 2 wt.% of TPGS-750-M;

further preferably, the TPGS-750-M is prepared as follows:

(1) triethylamine was added to a toluene solution of tocopherol and succinic anhydride with stirring. Stirring was then continued. After completion of the reaction, water was added to the reaction mixture, followed by extraction with dichloromethane. The combined organic layers were washed with 1mol/L hydrochloric acid and water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure in vacuo to give a yellow liquid, which was purified using silica gel column chromatography. Removing the solvent from the eluent under vacuum reduced pressure to obtain tocopherol succinate in a white solid state;

(2) the toluene mixture containing tocopherol succinate, polyethylene glycol monomethyl ether-750 and p-toluenesulfonic acid was refluxed using a dean-Stark trap. After the reaction was completed, it was cooled to room temperature, and the mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure in vacuo to give the desired product.

Compared with the prior art, the invention has the beneficial effects that: water is used as a reaction solvent, so that the use amount of an organic solvent is reduced, and zero emission of the solvent is realized; the excellent physical and chemical properties of water are fully utilized, the reaction condition is mild and efficient, and the surfactant TPGS-750-M can be recycled through treatment, so that the method completely accords with the environment-friendly principle; the reaction substrate has wide applicability, can be applied to the synthesis of isoxazole from aldoxime and alkyne, and provides a simple and environment-friendly preparation method for the synthesis of isoxazole. The invention screens different substrates and reaction conditions, and finally finds the substrates and the reaction conditions which are suitable for efficient and green reaction in TPGS-750-M aqueous solution.

Drawings

FIG. 1 is a water soluble vitamin E (TPGS-750-M)¹H NMR spectrum;

FIG. 2 is a water soluble vitamin E (TPGS-750-M)¹³C NMR spectrum.

Detailed Description

The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:

the surfactants used in the invention, Sodium Dodecyl Sulfate (SDS) and polyethylene glycol octyl phenyl ether (Trition X-100), are commercially available products, and the tocopherol methoxypolyethylene glycol succinate solution (TPGS-750-M, water-soluble vitamin E) can be purchased, but the TPGS-750-M of the invention is self-made, and is preferably 2 wt.% TPGS-750-M.

The surfactant TPGS-750-M used in the examples was self-made and the preparation method was as follows:

first step of

Second step of

The first step is as follows: to a stirred solution of tocopherol (4.3g, 10mmol) and succinic anhydride (1.5g, 15mmol) in toluene (20mL) was added triethylamine (0.35mL, 2.5 mmol). Subsequently, stirring was continued at 60 ℃ for 5 h. After completion of the reaction, water (10mL) was added to the reaction mixture, followed by extraction with dichloromethane (3X 10 mL). The combined organic layers were washed with 1mol/L hydrochloric acid (3X 50mL) and water (2X 30mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give crude tocopherol succinate, which was finally recrystallized to give tocopherol succinate as a white solid (5.25g, 99% yield). The crystallization conditions were: the crystallization time is 26 hours, the crystallization temperature is 4 ℃, and the dosage of n-hexane/tocopherol succinate crude product is 8 mL/g.

The second step is that: a mixture of tocopherol succinate (2.97g, 5.6mmol), polyethylene glycol monomethyl ether-750 (4g, 5.33mmol) and p-toluenesulfonic acid (0.15g, 0.79mmol) in toluene (20mL) was refluxed using a dean-Stark trap for 5 hours. After the reaction was completed, it was cooled to room temperature, and the mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane (3X 10 mL). The combined organic layers were washed with saturated sodium bicarbonate (3 × 50mL), saturated sodium chloride (2 × 30mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure in vacuo to give the title product (6.6g, 98%) in 80% yield as a pale yellow waxy solid.

¹H NMR(400MHz,CDCl₃)δ4.27(m,2H),3.70-3.65(m,60H),3.55(m,2H),3.38(s,3H),2.93(t,J＝7.2Hz,2H),2.79(t,J＝7.2Hz,2H),2.58(t,J＝6.8Hz,2H),2.08(s,3H),2.01(s,3H),1.97(s,3H),1.81-1.75(m,2H),1.52(m,3H),1.38(m,3H),1.27-1.23(m,12H),1.14(s,3H),1.07(s,3H),0.87-0.84(m,12H)；¹³C NMR(100MHz,CDCl₃) δ 172.2,170.9,149.5,140.6,126.7,125.0,123.0,117.4, 75.1,72.0,70.6,70.58-70.33(m, carbons), 69.1,64.0,59.0,39.4,37.55-37.29(m, carbons), 32.79-32.69(m,4C),29.2,28.9,28.0,24.816,24.805,24.5,22.8,22.7,21.1,20.6,19.77-19.61(m, carbons), 113.0, 12.1,11.8.

Example 1: synthesis of 3, 5-diphenyl isoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1 m) were addedmol)Et₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 20.8mg of 3, 5-diphenylisoxazole shown in the formula (III-1) as a white solid with the yield of 94%. Purity by HPLC 98.5%.

The structure of formula (III-1) is characterized as follows:

¹H NMR(600MHz,CDCl₃)δ7.86(dd,J＝17.0,7.9Hz,4H),7.53-7.43(m,6H),6.84(s,1H)；¹³C NMR(151MHz,CDCl₃)δ170.44,163.01,130.26,130.05,129.15,129.04,128.96,127.49,126.84,125.87,97.50；GC-MS(EI):m/z 221[M⁺].

example 2: synthesis of 3, 5-diphenyl isoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 7. mu.L (0.05mmol) of Et were added in succession₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 14 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate (v/v) ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 12.8mg of 3, 5-diphenylisoxazole shown in the formula (III-1), wherein the yield is 58% and the purity is 95% by HPLC (high performance liquid chromatography).

Example 3: synthesis of 3, 5-diphenyl isoxazole

In a 5mL reaction flaskTo this was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the bottle and the mixture was stirred at room temperature for 4 hours. After four hours, 21. mu.L (0.15mmol) of Et were added successively₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 7 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 20.6mg of 3, 5-diphenylisoxazole shown in the formula (III-1) as a white solid with the yield of 93 percent. Purity by HPLC 98.4%.

Example 4: synthesis of 3, 5-diphenyl isoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 28. mu.L (0.2mmol) of Et were added successively₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 7 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 20.0mg of 3, 5-diphenylisoxazole shown in the formula (III-1) as a white solid with the yield of 90%. Purity by HPLC 98%.

Example 5: synthesis of 3, 5-diphenyl isoxazole

A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and the mixture was placed in the chamberStirred at room temperature for 4 hours. After four hours, 23.6mg (0.1mmol) of Cs are added₂CO₃10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 15 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain the trace 3, 5-diphenyl isoxazole shown as the formula (III-1).

Example 6: synthesis of 3, 5-diphenyl isoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 4mg (0.1mmol) of NaOH and 10.2mg (0.1mmol) of phenylacetylene (II-1) were successively added and reacted at room temperature for 16 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 2.7mg of 3, 5-diphenylisoxazole shown in the formula (III-1) as a white solid with the yield of 12%.

Example 7: synthesis of 3, 5-diphenyl isoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 13.8mg (0.1mmol) of K are added₂CO₃10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 15 hours. After the reaction is finished, adding 2mL of ethyl acetate into the reaction bottle, stirring for 5min, standing for layering, and collectingAdding 2mL of ethyl acetate into the lower-layer water phase after the upper-layer organic phase is added, stirring for 5min, standing for layering, collecting the upper-layer organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 1.8mg of 3, 5-diphenylisoxazole shown in the formula (III-1) as a white solid with the yield of 8%.

Example 8: synthesis of 3, 5-diphenyl isoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 10.2. mu.L (0.1mmol) of piperidine and 10.2mg (0.1mmol) of phenylacetylene (II-1) were sequentially added and reacted at room temperature for 10 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 14.4mg of 3, 5-diphenylisoxazole shown in the formula (III-1) as a white solid with the yield of 65%. Purity by HPLC was 94%.

Example 9: synthesis of 3, 5-diphenyl isoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into the reaction bottle, stirring for 5min, standing for layering, collecting the upper organic phase, adding 2mL ethyl acetate into the lower aqueous phase, stirring for 5min, standing for layering, collecting the upper organic phase, combining the two organic phases, evaporating the solvent under reduced pressure, and passing the solid residue through the column layerSeparating and separating, wherein the eluent is petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 20.8mg of 3, 5-diphenylisoxazole shown in the formula (III-1) as a white solid with the yield of 94%. Purity by HPLC 98.1%.

Example 10: synthesis of 3, 5-diphenyl isoxazole

A5 mL reaction flask was charged with 24.1mg (0.18mmol) of NCS, 18.2mg (0.15mmol) of benzaldoxime (I-1), and then 1mL of SDS (15 mol%) was added to the flask, and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 9 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 12.2mg of 3, 5-diphenylisoxazole shown in the formula (III-1) as a white solid with the yield of 55%. Purity by HPLC was 91%.

Example 11: synthesis of 3, 5-diphenyl isoxazole

To a 5mL reaction flask were added 24.1mg (0.18mmol) of NCS, 18.2mg (0.15mmol) of benzaldoxime (I-1), then 1mL of Triton X-100 was added to the flask, and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 9 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 13.3mg of 3, 5-diphenylisoxazole shown in the formula (III-1) as a white solid with the yield of 60%. HPLThe purity of the C test sample was 93%.

Example 12: synthesis of 3, 5-diphenyl isoxazole

In a 5mL reaction flask were added 24.1mg (0.18mmol) of NCS, 18.2mg (0.15mmol) of benzaldoxime (I-1), then 1mL of CTAB was added to the flask, and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 12 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 2.7mg of 3, 5-diphenylisoxazole shown in the formula (III-1) as a white solid with the yield of 12%.

Example 13: synthesis of 5-phenyl-3- (p-tolyl) isoxazole

In a 50mL reaction flask was added 241mg (1.8mmol) NCS, 202.5mg (1.5mmol) 4-methylbenzaldehyde oxime (I-2), then 10mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 140. mu.L (1mmol) of Et were added₃N, 102mg (1mmol) of phenylacetylene (II-1) were reacted at room temperature for 8 hours. After the reaction is finished, adding 15mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 15mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the objective product, and evaporating the solvent under reduced pressure to obtain 223.5mg of 5-phenyl-3- (p-tolyl) isoxazole represented by the formula (III-2) as a white solid with a yield of 95%.Purity by HPLC 98.7%. The structure of the product is characterized as follows:

¹H NMR(600MHz,CDCl₃)δ7.83(d,J＝7.7Hz,2H),7.76(d,J＝7.8Hz,2H),7.49-7.42(m,3H),7.28(d,J＝7.8Hz,2H),6.80(s,1H),2.41(s,3H)；13C NMR(151MHz,CDCl₃)δ170.24,162.96,140.18,130.19,129.65,129.02,127.56,126.73,126.29,125.85,97.45,21.47；GC-MS(EI):m/z 235[M⁺].

example 14: synthesis of 3- (4-isopropylphenyl) -5-phenylisoxazole

A50 mL reaction flask was charged with 241mg (1.8mmol) NCS, 245mg (1.5mmol) 4-isopropylbenzaldehyde oxime (I-3), then 10mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and the mixture was stirred at room temperature for 4 hours. After four hours, 140. mu.L (1mmol) of Et were added₃N, 102mg (1mmol) of phenylacetylene (II-1) were reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the target product, and evaporating the solvent under reduced pressure to obtain 239.6mg of 3- (4-isopropylphenyl) -5-phenylisoxazole represented by the formula (III-3) with a yield of 91%. Purity by HPLC 98%. The structure of the product is characterized as follows:

¹H NMR(600MHz,CDCl₃)δ7.85-7.79(m,4H),7.51-7.44(m,3H),7.35(d,J＝8.1Hz,2H),6.81(s,1H),3.00-2.95(m,1H),1.29(d,J＝6.9Hz,6H)；¹³C NMR(151MHz,CDCl₃)δ170.23,162.96,151.09,130.17,129.01,127.57,127.05,126.84,126.66,125.85,97.45,34.10,23.87；GC-MS(EI):m/z 263[M⁺].

example 15: synthesis of 3- (4-fluorophenyl) -5-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 20.9mg (0.15mmol) 4-fluorobenzaldoxime (I-4), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the target product, and evaporating the solvent under reduced pressure to obtain 20.8mg of 3- (4-fluorophenyl) -5-phenylisoxazole represented by the formula (III-4) as a white solid with the yield of 87%. Purity by HPLC was 97.2%. The structure of the product is characterized as follows:

¹H NMR(600MHz,CDCl₃)δ7.90-7.77(m,4H),7.53-7.44(m,3H),7.20-7.15(m,2H),6.79(s,1H)；¹³C NMR(151MHz,CDCl₃)δ170.62,164.68,162.08,130.35,129.06,128.75(d,J＝8.5Hz),127.36,125.87,125.37(d,J＝3.3Hz),116.07(d,J＝21.9Hz),97.33；GC-MS(EI):m/z 239[M⁺].

example 16: synthesis of 3- (2-chlorophenyl) -5-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 20.9mg (0.15mmol) 2-chlorobenzaldehyde oxime (I-5), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N，10.2mg(0.1mmol) Phenylacetylene (II-1) reacts for 8h at room temperature. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the target product, and evaporating the solvent under reduced pressure to obtain 22.7mg of 3- (2-chlorophenyl) -5-phenylisoxazole represented by the formula (III-5) as a white solid with a yield of 89%. Purity by HPLC was 96.9%. The structure of the product is characterized as follows:

¹H NMR(600MHz,CDCl₃)δ7.84(d,J＝7.3Hz,2H),7.79(dd,J＝7.4,1.6Hz,1H),7.52-7.44(m,4H),7.41-7.35(m,2H),6.99(s,1H)；GC-MS(EI):m/z 255[M⁺].¹³C NMR(151MHz,CDCl₃)δ169.78,161.63,132.96,131.01,130.91,130.47,130.28,129.05,128.44,127.43,127.17,125.89,100.83；GC-MS(EI):m/z 255[M⁺].

example 17: synthesis of 3- (3-chlorophenyl) -5-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 20.9mg (0.15mmol) 3-chlorobenzaldehyde oxime (I-6), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain the compound shown as the formula (III-6)3- (3-chlorophenyl) -5-phenylisoxazole 21.7mg, white solid, yield 85%. Purity by HPLC was 96.5%. The structure of the product is characterized as follows:

¹H NMR(600MHz,CDCl₃)δ7.88-7.81(m,3H),7.78-7.74(m,1H),7.51-7.41(m,5H),6.81(s,1H)；¹³C NMR(151MHz,CDCl₃)δ170.83,161.90,134.98,130.90,130.44,130.26,130.06,129.09,127.25,126.96,125.88,124.94,97.38；GC-MS(EI):m/z255[M⁺].

example 18: synthesis of 3- (4-chlorophenyl) -5-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 20.9mg (0.15mmol) 4-chlorobenzaldehyde oxime (I-7), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the objective product, and evaporating the solvent under reduced pressure to obtain 23.7mg of 3- (4-chlorophenyl) -5-phenylisoxazole represented by the formula (III-7) as a white solid with a yield of 93%. Purity by HPLC was 97.1%. The structure of the product is characterized as follows:

¹H NMR(600MHz,CDCl₃)δ7.85-7.80(m,4H),7.50-7.45(m,5H),6.81(s,1H)；¹³C NMR(151MHz,CDCl₃)δ170.73,162.02,136.06,130.39,129.23,129.07,128.09,127.63,127.29,125.86,97.30；GC-MS(EI):m/z 255[M⁺].

example 19: synthesis of 3- (4-methoxyphenyl) -5-phenylisoxazole

In a 5mL reaction flask was added 241mg (1.8mmol) NCS, 227mg (1.5mmol) 4-methoxyphenylcarbaldehyde oxime (I-8), then 10mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 140. mu.L (1mmol) of Et were added₃N, 102mg (1mmol) of phenylacetylene (II-1) were reacted at room temperature for 8 hours. After the reaction is finished, adding 15mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 15mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the target product, and evaporating the solvent under reduced pressure to obtain 246.3mg of 3- (4-methoxyphenyl) -5-phenylisoxazole represented by the formula (III-8) as a white solid with a yield of 98%. Purity by HPLC 98.9%. The structure of the product is characterized as follows:

¹H NMR(600MHz,CDCl₃)δ7.88-7.76(m,4H),7.50-7.43(m,3H),7.01-6.97(m,2H),6.78(s,1H),3.86(s,3H)；¹³C NMR(151MHz,CDCl₃)δ170.17,162.61,161.03,130.16,129.01,128.22,127.57,125.84,121.65,114.34,97.29,55.39；GC-MS(EI):m/z 251[M⁺].

example 20: synthesis of 3- (3-methoxyphenyl) -5-phenylisoxazole

A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 22.7mg (0.15mmol) 3-methoxyphenylaldoxime (I-9), and thenThen 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the bottle and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the target product, and evaporating the solvent under reduced pressure to obtain 18.3mg of 3- (3-methoxyphenyl) -5-phenylisoxazole represented by the formula (III-9) as a white solid with a yield of 73%. Purity by HPLC was 96%. The structure of the product is characterized as follows:

¹H NMR(600MHz,CDCl₃)δ7.83(dd,J＝8.2,1.3Hz,2H),7.48-7.38(m,6H),7.02-6.99(m,1H),6.81(s,1H),3.88(s,3H)；¹³C NMR(151MHz,CDCl₃)δ170.43,162.94,160.00,130.39,130.27,130.01,129.04,127.46,125.86,119.35,116.17,111.74,97.62,55.43；GC-MS(EI):m/z 251[M⁺].

example 21: synthesis of 3-cyclohexyl-5-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 19.1mg (0.15mmol) cyclohexanecarboxaldehyde oxime (I-10), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into the reaction bottle, stirring for 5min, standing for layering, collecting the upper organic phase, adding 2mL ethyl acetate into the lower aqueous phase, stirring for 5min, standing for layering, collecting the upper organic phase, combining the two organic phases, evaporating the solvent under reduced pressure, and separating the solid residue by column chromatographyAnd (3) carrying out chromatographic separation, wherein the eluent is petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 18.2mg of 3-cyclohexyl-5-phenylisoxazole shown in the formula (III-10) as a white solid with the yield of 80%. Purity by HPLC was 96.7%. The structure of the product is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.77(dd,J＝8.2,1.3Hz,2H),7.48-7.38(m,3H),6.40(s,1H),2.85-2.75(m,1H),1.90-1.73(m,4H),1.56-1.38(m,4H),1.34-1.24(m,2H)；¹³C NMR(126MHz,CDCl₃)δ169.27,169.02,129.85,128.86,127.76,125.70,97.77,35.94,32.10,25.97,25.88；GC-MS(EI):m/z 227[M⁺].

example 22: synthesis of 3- (pentane-3-yl) -5-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 17.2mg (0.15mmol) 2-ethylbutyraldehyde oxime (I-11), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 16.8mg of 3- (pentane-3-yl) -5-phenylisoxazole shown in the formula (III-11) as a white solid with the yield of 78 percent and the purity of 96 percent by HPLC detection. . The structure of the product is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.79(dd,J＝8.1,1.3Hz,2H),7.48-7.41(m,3H),6.36(s,1H),2.73-2.65(m,1H),1.77-1.71(m,2H),1.66-1.60(m,2H),0.90(t,J＝7.4Hz,6H)；¹³C NMR(126MHz,CDCl₃)δ169.45,167.82,129.87,128.87,127.76,125.70,97.39,40.71,27.36,11.79；GC-MS(EI):m/z 215[M⁺].

example 23: synthesis of 5-phenyl-3- [ (2, 4-dinitro) ] isoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 31.7mg (0.15mmol)2, 4-dinitrobenzaldehyde oxime (I-12), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 10.2mg (0.1mmol) of phenylacetylene (II-1) was reacted at room temperature for 8 hours. After the reaction was completed, the reaction solution was checked by TLC, and it was found that no target product was produced.

Example 24: synthesis of 3-phenyl-5- (p-tolyl) isoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 11.6mg (0.1mmol) of p-methylphenylacetylene (II-2) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, the eluate containing the objective product was collected, and the solvent was distilled off under reduced pressure to give 21.6mg of 3-phenyl-5- (p-tolyl) isoxazole represented by the formula (III-12) as a white solid in a yield of 92%. Purity by HPLC 98%. Of the productThe structure is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.91-7.86(m,2H),7.79-7.72(m,2H),7.52-7.47(m,3H),7.31(d,J＝8.0Hz,2H),6.79(s,1H),2.44(s,3H)；¹³C NMR(126MHz,CDCl₃)δ170.65,162.97,140.54,129.96,129.71,129.31,128.92,126.85,125.82,124.85,96.91,21.50；GC-MS(EI):m/z 235[M⁺].

example 25: synthesis of 5- (4-fluorophenyl) -3-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 12.0mg (0.1mmol) of p-fluoroacetylene (II-3) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the target product, and evaporating the solvent under reduced pressure to obtain 21.5mg of 5- (4-fluorophenyl) -3-phenylisoxazole represented by the formula (III-13) as a white solid with a yield of 90%. Purity by HPLC was 97.8%. The structure of the product is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.89-7.82(m,4H),7.51-7.47(m,3H),7.23-7.17(m,2H),6.79(s,1H)；¹³C NMR(126MHz,CDCl₃)δ169.48,164.83,162.97(d,J＝32.5Hz),130.10,128.97,127.98,127.91,126.84,123.91(d,J＝3.6Hz),116.25(d,J＝22.3Hz),97.31；GC-MS(EI):m/z 239[M⁺].

example 26: synthesis of 5- (4-pentylphenyl) -3-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 17.2mg (0.1mmol) of p-pentylphenylacetylene (II-4) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the objective product, and evaporating the solvent under reduced pressure to obtain 26.5mg of 5- (4-pentylbenzene) -3-phenylisoxazole represented by the formula (III-14) as a white solid with a yield of 91%. Purity by HPLC was 97%. The structure of the product is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.92-7.87(m,2H),7.80-7.75(m,2H),7.53-7.46(m,3H),7.31(d,J＝8.0Hz,2H),6.80(s,1H),2.70-2.66(m,2H),1.71-1.64(m,2H),1.40-1.33(m,4H),0.93(t,J＝6.8Hz,3H)；¹³C NMR(126MHz,CDCl₃)δ170.68,162.94,145.57,129.94,129.32,129.07,128.92,126.84,125.84,125.03,96.90,35.87,31.46,30.91,22.53,14.01；GC-MS(EI):m/z 291[M⁺].

example 27: synthesis of 5- (4-bromophenyl) -3-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 18.0mg (0.1mmol) of p-bromophenylacetylene (II-5) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 26.6mg of 5- (4-bromophenyl) -3-phenylisoxazole shown in the formula (III-15) as a white solid with the yield of 89%. Purity by HPLC was 96.5%. The structure of the product is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.90-7.86(m,2H),7.75-7.72(m,2H),7.66-7.64(m,2H),7.52-7.48(m,3H),6.85(s,1H)；¹³C NMR(125MHz,CDCl3):δ170.41,163.03,130.24,130.03,129.27,129.03,128.96,127.58,126.89,125.87,97.59；GC-MS(EI):m/z 299[M⁺].

example 28: synthesis of 5- (3-bromophenyl) -3-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 18.0mg (0.1mmol) of p-bromophenylacetylene (II-6) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain the 5- (3-bromophenyl) -3-phenylisoxazole 28 shown in the formula (III-16)1mg, white solid, yield 94%. Purity by HPLC 98.6%. The structure of the product is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ8.02-7.98(m,1H),7.91-7.85(m,2H),7.81-7.76(m,1H),7.61-7.58(m,1H),7.52-7.48(m,3H),7.38(t,J＝7.9Hz,1H),6.86(s,1H)；¹³C NMR(126MHz,CDCl₃)δ168.80,163.10,133.15,130.61,130.19,129.33,129.01,128.91,128.83,126.86,124.38,123.13,98.33；GC-MS(EI):m/z 299[M⁺].

example 29: synthesis of 5- (4-methoxyphenyl) -3-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 13.2mg (0.1mmol) of p-bromophenylacetylene (II-7) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the target product, and evaporating the solvent under reduced pressure to obtain 23.3mg of 5- (4-methoxyphenyl) -3-phenylisoxazole represented by the formula (III-17) as a white solid with a yield of 93%. Purity by HPLC 98.3%. The structure of the product is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.88(d,J＝8.0Hz,2H),7.83-7.76(m,2H),7.49(d,J＝7.4Hz,3H),7.05-6.98(m,2H),6.72(s,1H),3.88(s,3H)；¹³C NMR(126MHz,CDCl₃)δ170.40,162.94,161.14,129.92,129.29,128.89,127.43,126.80,120.32,114.42,96.13,55.40；GC-MS(EI):m/z 251[M⁺].

example 30: synthesis of 3-phenyl-5- (thien-3-yl) isoxazoles

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 10.8mg (0.1mmol) of 3-ethynylthiophene (II-9) was reacted at room temperature for 8 h. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the target product, and evaporating the solvent under reduced pressure to obtain 20.0mg of 3-phenyl-5- (thiophen-3-yl) isoxazole represented by the formula (III-19) as a white solid with a yield of 88%. Purity by HPLC was 96.8%. The structure of the product is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.93-7.81(m,3H),7.52-7.43(m,5H),6.70(s,1H)；¹³C NMR(126MHz,CDCl₃)δ166.62,162.87,130.03,129.14,128.94,127.05,126.86,125.40,124.36,97.29；GC-MS(EI):m/z 227[M⁺].

example 31: synthesis of 5-benzyl-3-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 11.6mg (0.1mmol) of propane-2-alkyn-1-ylbenzene (II-10) at room temperature for 8 h. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 21.2mg of 5-benzyl-3-phenylisoxazole shown in the formula (III-20) as a white solid with the yield of 90%. Purity by HPLC was 96.8%. The structure of the product is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.80-7.76(m,2H),7.44(dd,J＝5.2,2.0Hz,3H),7.40-7.35(m,2H),7.34-7.30(m,3H),6.23(s,1H),4.15(s,2H)；¹³C NMR(126MHz,CDCl₃)δ172.71,162.49,135.96,129.87,129.23,128.89,128.86,128.84,127.20,126.78,100.02,33.34；GC-MS(EI):m/z 235[M⁺].

example 32: synthesis of 5-butyl-3-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 8.2mg (0.1mmol) of 1-hexyne (II-11) are reacted at room temperature for 8 h. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the target product, and evaporating the solvent under reduced pressure to obtain 16.7mg of 5-butyl-3-phenylisoxazole represented by the formula (III-21) as a colorless oily substanceThe yield thereof was found to be 83%. Purity by HPLC was 96.2%. The structure of the product is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.81(dd,J＝7.6,2.0Hz,2H),7.45(d,J＝7.3Hz,3H),6.30(s,1H),2.81(t,J＝7.6Hz,2H),1.78-1.72(m,2H),1.49-1.41(m,2H),0.98(t,J＝7.4Hz,3H)；13C NMR(126MHz,CDCl₃)δ174.28,162.32,129.75,129.45,128.82,126.74,98.76,29.60,26.50,22.20,13.69；GC-MS(EI):m/z 201[M⁺].

example 33: synthesis of 5-pentyl-3-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 9.6mg (0.1mmol) of 1-heptyne (II-12) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the objective product, and evaporating the solvent under reduced pressure to obtain 18.9mg of 5-pentyl-3-phenylisoxazole represented by the formula (III-22) as a white solid with a yield of 88%. Purity by HPLC 98.5%. The structure of the product is characterized as follows:¹H NMR(500MHz,CDCl₃)δ7.81(dd,J＝7.6,2.0Hz,2H),7.51-7.42(m,3H),6.30(s,1H),2.80(t,J＝7.6Hz,2H),1.77(p,J＝7.4Hz,2H),1.40(p,J＝3.6Hz,4H),0.94(t,J＝7.0Hz,3H)；¹³C NMR(126MHz,CDCl₃)δ174.31,162.32,129.76,129.46,128.83,126.75,98.76,31.25,27.23,26.77,22.31,13.92；GC-MS(EI):m/z 215[M⁺].

example 34: synthesis of 5-octyl-3-phenylisoxazole

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 13.8mg (0.1mmol) of 1-quinyne (II-13) were reacted at room temperature for 8 h. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the target product, and evaporating the solvent under reduced pressure to obtain 22.9mg of 5-octyl-3-phenylisoxazole represented by the formula (III-23) as a yellow liquid with a yield of 89%. Purity by HPLC was 96.7%. The structure of the product is characterized as follows:

¹H NMR(600MHz,CDCl₃)δ7.79(dd,J＝7.8,1.8Hz,2H),7.47-7.42(m,3H),6.28(s,1H),2.79(t,J＝7.6Hz,2H),1.74(p,J＝7.6Hz,2H),1.43-1.26(m,10H),0.88(t,J＝7.0Hz,3H)；¹³C NMR(151MHz,CDCl₃)δ174.32,162.32,129.76,129.45,128.83,126.75,98.76,31.82,29.22,29.15,29.12,27.56,26.83,22.65,14.10；GC-MS(EI):m/z 257[M⁺].

example 35: synthesis of 2- (3-phenylisoxazol-5-yl) propan-2-ol

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1 m) were addedmol)Et₃N, 8.4mg (0.1mmol) 2-methyl-3-butyn-2-ol (II-14) are reacted at room temperature for 8 h. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the target product, and evaporating the solvent under reduced pressure to obtain 16.2mg of 2- (3-phenylisoxazol-5-yl) propan-2-ol represented by the formula (III-24) as a white solid with a yield of 80%. Purity by HPLC was 96%. The structure of the product is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.82-7.76(m,2H),7.46(dd,J＝5.1,1.9Hz,3H),6.49(s,1H),1.69(s,6H)；¹³C NMR(126MHz,Chloroform-d)δ178.44,162.31,130.00,129.02,128.91,126.80,97.43,69.27,29.05；GC-MS(EI):m/z 203[M⁺].

example 36: synthesis of 3-phenylisoxazole-5-carboxylic acid ethyl ester

To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I-1), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, a further 14. mu.L (0.1mmol) of Et are added₃N, 9.8mg (0.1mmol) of ethyl propiolate (II-15) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the target product, and evaporating the solvent under reduced pressure to obtain 18.7mg of ethyl 3-phenylisoxazole-5-carboxylate represented by the formula (III-25)A colored solid in 86% yield. Purity by HPLC was 96.5%. The structure of the product is characterized as follows:

¹H NMR(500MHz,CDCl₃)δ7.68(dd,J＝7.6,2.1Hz,2H),7.44-7.39(m,3H),5.16(dd,J＝10.8,7.5Hz,1H),4.27(q,J＝7.2Hz,2H),1.32(t,J＝7.1Hz,3H)；¹³C NMR(126MHz,CDCl₃)δ170.13,155.95,130.43,128.73,128.58,126.88,78.07,61.92,38.80,14.05；GC-MS(EI):m/z 217[M⁺].

example 37: synthesis of 3, 5-diphenyl isoxazole

In a 50mL reaction flask was added 241mg (1.8mmol) NCS, 182mg (1.5mmol) benzaldoxime (I-1), then 10mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 168. mu.L (1.2mmol) of Et were added successively₃N, 102mg (1mmol) of phenylacetylene (II-1) were reacted at room temperature for 8 hours. After the reaction is finished, adding 15mL of ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 15mL of ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, extracting TPGS-750-M in the lower aqueous phase with dichloromethane to obtain separation and recovery (see example 38), combining the organic phases obtained in two times, evaporating the solvent under reduced pressure, and separating solid residues through column chromatography, wherein the eluent is petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 214.6mg of 3, 5-diphenylisoxazole shown in the formula (III-1) as a white solid with the yield of 97%. Purity by HPLC 98.6%.

Example 38: synthesis of 3, 5-diphenyl isoxazole

To a 500mL reaction flask was added 2.41g (18mmol) NCS, 1.82g (15mmol) benzaldoxime (I-1), then 100mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and the mixture was stirred at room temperature for 4.5 hours. Then, 1.82mL (13mmol) of Et was added₃N, 1.02g (10mmol) of phenylacetylene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 50mL of ethyl acetate into the reaction bottle, stirring for 5min, standing for layering, collecting the upper ethyl acetate phase, adding 50mL of ethyl acetate into the lower water phase, and stirring for 5minStanding for layering after min, collecting an upper ethyl acetate phase, extracting TPGS-750-M in a lower water phase with 50mL of dichloromethane twice respectively, combining dichloromethane extract, evaporating dichloromethane under reduced pressure, and recovering to obtain 1.6g of TPGS-750-M; and (3) combining the ethyl acetate phases obtained in the two steps, evaporating the solvent under reduced pressure, and separating solid residues by column chromatography, wherein the eluent is petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 2.168g of 3, 5-diphenyl isoxazole shown in the formula (III-1) and a white solid with the yield of 98%. Purity by HPLC was 99%.

Example 39: synthesis of 3, 5-diphenyl isoxazole

In a 50mL reaction flask was added 241mg (1.8mmol) NCS, 182mg (1.5mmol) benzaldoxime (I-1), then 10mL of freshly prepared 1 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 168. mu.L (1.2mmol) of Et were added successively₃N, 102mg (1mmol) of phenylacetylene (II-1) were reacted at room temperature for 8 hours. After the reaction is finished, adding 15mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 15mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the solid residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 152.6mg of 3, 5-diphenylisoxazole shown in the formula (III-1) as a white solid with the yield of 69%. Purity by HPLC was 93%.

Example 40: synthesis of 3, 5-diphenyl isoxazole

In a 50mL reaction flask was added 241mg (1.8mmol) NCS, 182mg (1.5mmol) benzaldoxime (I-1), then 10mL of freshly prepared 5 wt.% aqueous TPGS-750-M solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 168. mu.L (1.2mmol) of Et were added successively₃N, 102mg (1mmol) of phenylacetylene (II-1) were reacted at room temperature for 8 hours. After the reaction is finished, adding 15mL of ethyl acetate into the reaction bottle, stirring for 5min, standing for layering, collecting the upper organic phase, adding 15mL of ethyl acetate into the lower aqueous phase, and stirringStirring for 5min, standing for layering, collecting upper organic phase, mixing the two organic phases, evaporating under reduced pressure to remove solvent, separating solid residue by column chromatography, eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 177.0mg of 3, 5-diphenylisoxazole shown in the formula (III-1) as a white solid with the yield of 80%. Purity by HPLC was 95%.

Example 41: synthesis of 3, 5-diphenyl isoxazole

To a 5mL reaction flask was added 1.2mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution, then 88.4mg (0.73mmol) of benzaldoxime (I-1) and 50mg (0.49mmol) of phenylacetylene (II-1) were added to the reaction flask, and di (trifluoroacetic acid) iodobenzene (PIFA) was added to the reaction flask in three portions every two hours [ 3X 105mg (0.243mmol) ]. After stirring for 7 hours, the reaction mixture was checked by TLC, and it was found that 3, 5-diphenylisoxazole represented by the formula (III-1) was not produced as the target product.

Example 42: synthesis of 3-phenyl-5- (4-N, N-dimethylanilino) isoxazole

A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (formula 1), then 1mL of freshly degassed 2 wt.% aqueous TPGS-750-M solution was added to the flask, and after stirring the mixture at room temperature for 4 hours, 14. mu.L (0.1mmol) Et was added sequentially₃N, 14.5mg (0.1mmol) of 4-dimethylaminophenylacetylene are reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 5min, standing for layering, collecting an upper organic phase, combining the organic phases obtained twice, evaporating the solvent under reduced pressure, separating the residue by column chromatography, and eluting with petroleum ether: ethyl acetate ═ 1:2, collecting the eluate containing the target product, and evaporating the solvent under reduced pressure to obtain 24.8mg of 3-phenyl-5- (4-N, N-dimethylanilino) isoxazole represented by the formula (III-26) as a white solid with a yield of 94%. Purity by HPLC 98.2%. The structure of the product is characterized as follows:¹H NMR(600MHz,CDCl₃)δ7.89(dd,J＝7.9,1.4Hz,2H),7.73(d,J＝8.9Hz,2H),7.51-7.45(m,3H),6.78(d,J＝8.9Hz,2H),6.65(s,1H),3.06(s,6H)；¹³C NMR(126MHz,CDCl₃)δ171.25,162.84,151.44,129.75,129.62,128.84,127.11,126.81,111.87,94.66,40.21GC-MS(EI):m/z 264[M⁺].

Claims

1. a green synthesis method of an isoxazole compound shown in a formula (III) is characterized by comprising the following steps:

taking an aldoxime compound shown in a formula (I) as a substrate, reacting with an alkyne compound shown in a formula (II) for 6-16h at room temperature under the combined action of N-chlorosuccinimide and an alkaline substance in an aqueous solution of a surfactant with the mass concentration of 1-5 wt%, and carrying out aftertreatment on the obtained reaction liquid to obtain an isoxazole compound shown in a formula (III); the mass ratio of the alkyne compound shown in the formula (II), the aldoxime compound shown in the formula (I), the N-chlorosuccinimide and the alkaline substance is 1:1-1.5:1-1.8: 0.5-2;

The alkaline substance is one of the following substances: sodium hydroxide, potassium carbonate, triethylamine, piperidine; the surfactant in the water solution of the surfactant is tocopherol methoxypolyethylene glycol succinic acid.

2. A green synthesis method of isoxazoles of formula (III) according to claim 1, characterized in that: the volume of the aqueous solution of the surfactant is 5 to 20mL/mmol in terms of the amount of the substance of the substituted alkyne represented by the formula (II).

3. A green synthesis method of isoxazoles of formula (III) according to claim 1, characterized in that: the mass concentration of the aqueous solution of the surfactant is 2 wt%.

4. A green synthesis method of isoxazoles of formula (III) according to claim 1, characterized in that: the reaction time was 8 h.

5. A green synthesis method of isoxazoles of formula (III) according to claim 1, characterized in that: the mass ratio of the alkyne compound shown in the formula (II), the aldoxime compound shown in the formula (I), the N-chlorosuccinimide and the alkaline substance is 1:1.5:1.8: 1.3.

6. A green synthesis method of isoxazoles of formula (III) according to claim 1, characterized in that: the alkaline substance is triethylamine or piperidine.

7. A green synthesis method of isoxazoles of formula (III) according to claim 1, characterized in that: the alkaline substance is triethylamine.

8. The method for green synthesis of isoxazoles of formula (III) according to claim 1, wherein the aldoxime of formula (I) is one of the following:

9. a green synthesis method of isoxazoles of formula (III) according to claim 1, characterized in that: the alkyne compound shown in the formula (II) is one of the following compounds:

10. a process for the green synthesis of isoxazoles of formula (III) according to claim 1, characterized in that the work-up is: extracting the reaction liquid by using ethyl acetate, combining organic phases, evaporating the solvent under reduced pressure, and mixing solid residues by using petroleum ether with the volume ratio of 1: 2: and (3) carrying out column chromatography separation on the ethyl acetate mixed solution, collecting eluent containing the target product, and carrying out reduced pressure evaporation to remove the solvent to obtain the isoxazole compound shown in the formula (III).