CN113666882A - Aqueous phase preparation method of isoxazoline compound participated by vitamin E micelle - Google Patents

Aqueous phase preparation method of isoxazoline compound participated by vitamin E micelle Download PDF

Info

Publication number
CN113666882A
CN113666882A CN202110926236.8A CN202110926236A CN113666882A CN 113666882 A CN113666882 A CN 113666882A CN 202110926236 A CN202110926236 A CN 202110926236A CN 113666882 A CN113666882 A CN 113666882A
Authority
CN
China
Prior art keywords
formula
iii
aqueous phase
reaction
ethyl acetate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202110926236.8A
Other languages
Chinese (zh)
Other versions
CN113666882B (en
Inventor
王宇光
吴梦静
刘贝
陈圆
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang University of Technology ZJUT
Original Assignee
Zhejiang University of Technology ZJUT
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang University of Technology ZJUT filed Critical Zhejiang University of Technology ZJUT
Priority to CN202110926236.8A priority Critical patent/CN113666882B/en
Publication of CN113666882A publication Critical patent/CN113666882A/en
Application granted granted Critical
Publication of CN113666882B publication Critical patent/CN113666882B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
    • C07F7/083—Syntheses without formation of a Si-C bond
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
    • C08G65/3328—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof heterocyclic
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides a water phase synthesis method of isoxazoline compounds shown in a formula (III), which comprises the following steps: taking benzaldehyde oxime shown in a formula (I) as a substrate, reacting with an alkene compound shown in a formula (II) in an aqueous solution of a surfactant with the mass concentration of 1-5 wt% under the combined action of N-chlorosuccinimide and an alkaline substance at room temperature for 6-16h, and carrying out aftertreatment on the obtained reaction liquid to obtain an isoxazoline 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

Aqueous phase preparation method of isoxazoline compound participated by vitamin E micelle
Technical Field
The invention relates to a water-phase synthesis method of an isoxazoline compound participated by water-soluble vitamin E micelle.
Background
Isoxazolines, a five-membered heterocyclic compound containing N, O, have been widely used as intermediates in the synthesis of natural products with biological activity. Isoxazolines also act as the molecular skeleton of drugs, for example, in the novel broad spectrum veterinary drugs like frairan, valdecoxib, which is an anti-inflammatory drug, and flucloxacillin, which is an antibacterial drug, isoxazolines all act as the molecular skeleton. In addition, it is also widely used in the synthesis of antidepressants, antituberculosis drugs, and the like. Due to their unique heterocyclic structures, isoxazolines have been the subject of intense research.
Micheli et al, 1986, achieved oxime and olefin in NaHCO3The 1, 3-dipolar epoxidation reaction is realized in the presence of the catalyst, bromine substituted isoxazoline is generated at the same time, and then the synthesis of the three-position methoxy isoxazoline is realized under the action of alkali and methanol. The subject group of the good strategy in 2020 realized the synthesis of the final product isoxazoline derivative by the steps of 1, 3-dipolar cycloaddition and the like under the catalytic action of Cu, wherein the nitrogen source and the oxygen source of the isoxazoline derivative in the reaction are both derived from nitro compounds (formula I). Study by Xubin et al found Cu (NO)3)2Mediated [2+2+1 ] of alkenes and alkynes]Cyclization reaction to synthesize isoxazoline.
Figure BDA0003209376260000011
Is like
To reduce the impact on tolerance and regioselectivity during isoxazoline synthesis, korean ice et al first initiated a free-radical cyclization reaction of β, γ -unsaturated alkene oxime molecules in 2012 with excess TEMPO (formula two). In the reaction process, TEMPO is used as a free radical trapping agent to capture an isoxazoline skeleton intermediate, so that the target molecule isoxazoline is obtained. 2016, et al suggested that copper acetate also catalyzes the free radical reaction of β, γ -and γ, δ -unsaturated ketoximes with electron-rich aryl and aliphatic amines, and can be used to synthesize isoxazolines and their derivatives.
Figure BDA0003209376260000021
Formula II
However, these reactions have the disadvantages of low yield, many synthesis steps, severe reaction conditions in part, high toxicity of the catalyst used, expensive price in part, and the like. Therefore, it is desirable to establish a simple synthesis method for preparing isoxazoline by aqueous 1, 3-dipolar cycloaddition reaction involving TPGS-750-M (water-soluble vitamin E) micelles (micelle). Since 2 wt.% of the TPGS-750-M aqueous solution readily formed micelles, the hydrophilic ends (PEG ends) of the micelles faced outward, dispersed among the aqueous phase; and the oleophilic end (vitamin E end) faces inwards, so that an oleophilic environment is formed inside the micelle for the chemical reaction to complete, and the chemical reaction is carried out in the water phase. Compared with the prior method, the method has the main advantages that water is used as a solvent for reaction, the method is green and environment-friendly, the reaction condition is simple, the yield is high, and the purity is high.
Disclosure of Invention
In order to solve the problems of high pollution, more wastes and the like in the prior art, the invention provides a green and simple synthesis method of isoxazoline compounds shown in formula (III), which completes the synthesis of the isoxazoline compounds in a water phase under the participation of micro micelle formed by TPGS-750-M.
Figure BDA0003209376260000022
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a water phase synthesis method of isoxazoline compounds shown in a formula (III), which comprises the following steps:
taking benzaldehyde oxime shown in formula (I) as a substrate, reacting with an alkene compound shown in 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 isoxazoline compound shown in formula (III); the amount ratio of the alkene compound shown in the formula (II), the benzaldehyde oxime shown in the formula (I), N-chlorosuccinimide and alkaline substances is 1:1-1.5:1-1.8:0.5-2 (preferably 1:1.5:1.8: 1.3);
Figure BDA0003209376260000031
wherein R is1、R2、R3Each independently is H, C1-C6Alkyl, phenyl,
Figure BDA0003209376260000032
Or
Figure BDA0003209376260000033
Or R3And R1Are linked to form a ring and form a five-membered carbocyclic ring with the carbon between the two, and R2Is H;
the alkaline substance is selected from one of the following substances: sodium hydroxide (NaOH), potassium carbonate (K)2CO3) Triethylamine (Et)3N), piperidine (preferably triethylamine or piperidine, most preferably triethylamine); the surfactant is tocopherol methoxypolyethylene glycol succinate (TPGS-750-M).
The reaction formula is as follows:
Figure BDA0003209376260000034
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, R1Is phenyl, hexyl,
Figure BDA0003209376260000035
Or
Figure BDA0003209376260000036
R2Is H, methyl or phenyl, R3Is H or phenyl.
Further preferably, the alkene compound represented by the formula (II) is one of the following:
Figure BDA0003209376260000041
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).
Further, 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) can be a commercially available product, which is self-made in the invention, and is 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 synthesizing isoxazoline from aldoxime and olefin, and provides a simple and environment-friendly preparation method for synthesizing the isoxazoline.
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:
further, the surfactants Sodium Dodecyl Sulfate (SDS) and polyethylene glycol octyl phenyl ether (Trition X-100) used in the invention 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 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:
Figure BDA0003209376260000051
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 (4 g, 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(100 MHz,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-4, 5-dihydroisoxazoline
Figure BDA0003209376260000061
A50 mL reaction flask was charged with 241mg (1.8mmol) NCS and 182mg (1.5mmol) benzaldoxime (I), then 10mL of a freshly prepared 2 wt.% aqueous solution of TPGS-750-M was added to the flask, and after stirring at room temperature for 4 hours, 182. mu.L (1.3mmol) of Et was added in that order3N and 104mg (1mmol) of styrene (II-1), reacting for 8 hours at room temperature, finishing the reaction, 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, separating and recovering, see example 5), combining the two obtained organic phases, evaporating the solvent under reduced pressure, separating a solid residue through column chromatography, and eluting with petroleum ether: ethyl acetate (v/v, same below) 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 217.7mg of 3, 5-diphenylisoxazoline shown in the formula (III-1) as a white solid with the yield of 97.5%. Purity by HPLC 98.6%. The structure of formula (III-1) is characterized as follows:
1H NMR(500MHz,CDCl3)δ7.73(dd,J＝6.6,2.9Hz,2H),7.46-7.38(m,7H), 7.37-7.33(m,1H),5.76(dd,J＝11.0,8.3Hz,1H),3.80(dd,J＝16.5,11.0Hz,1H), 3.37(dd,J＝16.6,8.3Hz,1H)；13C NMR(126MHz,CDCl3)δ156.08,140.93, 130.10,129.49,128.73,128.71,128.20,126.73,125.85,82.56,43.13；GC–MS(EI):m/z 223[M+].
example 2: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline
A50 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and after stirring at room temperature for 4 hours, 7. mu.L (0.05mmol) of Et was added in succession3N and 10.4mg (0.1mmol) of styrene (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 two organic phases, evaporating the solvent under reduced pressure, separating the residue by column chromatography, eluting the eluentIs petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 13.8mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 62%. Purity by HPLC was 95%.
Example 3: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline
A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and after stirring at room temperature for 4 hours, 21. mu.L (0.15mmol) of Et was added sequentially3N and 10.4mg (0.1mmol) of styrene (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 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 21.0mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 94 percent. Purity by HPLC was 97%.
Example 4: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline
A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and after stirring the mixture at room temperature for 4 hours, 28. mu.L (0.2mmol) Et was added sequentially3N, 10.4mg (0.1mmol) of styrene (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 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 3, 5-diphenyl-4, 5-dihydroisoxazole shown in the formula (III-1)Lin 20.3mg, white solid, yield 91%. Purity by HPLC was 96.9%.
Example 5: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline
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, 1.04g (10mmol) of styrene (II-1) were reacted at room temperature for 8 hours. After the reaction is finished, adding 50mL of ethyl acetate into a reaction bottle, stirring for 5min, standing for layering, collecting an upper ethyl acetate phase, adding 50mL of ethyl acetate into a lower water phase, stirring for 5min, standing for layering, collecting an upper ethyl acetate phase, extracting TPGS-750-M in the lower water phase twice with 50mL of dichloromethane respectively, combining dichloromethane extraction solutions, 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: and 2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain the 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1). 2.188g of white solid, yield 98%. Purity by HPLC 98.9%.
Example 6: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline
A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS and 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of a freshly prepared 2 wt.% aqueous solution of TPGS-750-M was added to the flask, and the mixture was stirred at room temperature for 4 hours, then 6mg (0.15mmol) NaOH and 10.4mg (0.1mmol) styrene (II-1) were added in that order, and 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 eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 3.8mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 17%.
Example 7: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline
A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of a freshly prepared 2 wt.% aqueous solution of TPGS-750-M was added to the flask, and after stirring the mixture at room temperature for 4 hours, 20.7mg (0.15mmol) of K was added in succession2CO310.4mg (0.1mmol) of styrene (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 2min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 2min, 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 eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 2.9mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 13%.
Example 8: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline
To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), 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, 30.7mg (0.13mmol) of Cs are added2CO310.4mg (0.1mmol) of styrene (II-1) were reacted at room temperature for 8 hours. After completion of the reaction, the reaction mixture was checked by TLC, and it was found that the target product (III-1) was not produced.
Example 9: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline
A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS and 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of a freshly prepared 2 wt.% aqueous solution of TPGS-750-M was added to the flask, and the mixture was stirred at room temperature for 4 hours, then 13. mu.L (0.13mmol) piperidine and 10.4mg (0.1mmol) styrene (II-1) were added in that order and reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL ethyl acetate into a reaction bottle, stirring for 2min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 2min, 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 eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 17.2mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 77 percent. Purity by HPLC was 96%.
Example 10: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline
A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 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, 10.4mg (0.1mmol) of styrene (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 2min, standing for layering, collecting an upper organic phase, adding 2mL ethyl acetate into a lower aqueous phase, stirring for 2min, 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 eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 20.8mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 93 percent. Purity by HPLC was 97.1%.
Example 11: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline
To a 5mL reaction flask were added 24.1mg (0.18mmol) of NCS, 18.2mg (0.15mmol) of benzaldoxime (I), 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, 18.2. mu.L (0.13mmol) of Et were added successively3N, 10.4mg (0.1mmol) of styrene (II-1) was reacted at room temperature for 8 hours. After the reaction is finished, adding 2mL of ethyl acetate into the reaction bottle, stirring for 5min, standing for layering, collecting the upper organic phase, adding 2mL of ethyl acetate into the lower aqueous phase, stirring for 5min, standing for layering, collecting the upper organic phase, and collecting the lower organic phaseCombining the organic phases obtained in two times, evaporating the solvent under reduced pressure, and separating the residue 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 12.7mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 57%.
Example 12: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline
To a 5mL reaction flask were added 24.1mg (0.18mmol) of NCS, 18.2mg (0.15mmol) of benzaldoxime (I), then 1mL of TritonX-100 was added to the flask, and the mixture was stirred at room temperature for 4 hours. After four hours, 18.2. mu.L (0.13mmol) of Et were added successively3N, 10.4mg (0.1mmol) of styrene (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 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 15.0mg of 3, 5-diphenyl-4, 5-dihydroisoxazoline shown in the formula (III-1) as a white solid with the yield of 67%.
Example 12: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline
A5 mL reaction flask was charged with 24.1mg (0.18mmol) of NCS and 18.2mg (0.15mmol) of benzaldoxime (I), 1mL of CTAB was added to the flask, and after the mixture was stirred at room temperature for 4 hours, 18.2. mu.L (0.13mmol) of Et was further added3N, 10.4mg (0.1mmol) of styrene (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 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 3, 5-diphenyl-4, 5-di-benzene shown in the formula (III-1)Hydroisoxazoline 4.9mg, white solid, yield 22%.
Example 13: synthesis of 3-phenyl-3 a,5,6,6 a-tetrahydrocyclopentylisoxazoline
Figure BDA0003209376260000111
Figure BDA0003209376260000121
To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), 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, 18.2. mu.L (0.13mmol) of Et were added successively3N, 6.8mg (0.1mmol) of cyclopentene (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 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 18.35mg of 3-phenyl-3 a,5,6,6 a-tetrahydrocyclopentylisoxazoline shown in the formula (III-2) as a white solid with the yield of 98%. Purity by HPLC was 99%. The structure of formula (III-2) is characterized as follows:
1H NMR(500MHz,CDCl3)δ7.76-7.67(m,2H),7.44-7.37(m,3H),5.23(dd,J ＝8.8,4.9Hz,1H),4.14-3.97(m,1H),2.23-2.16(m,1H),2.01-1.94(m,1H), 1.93-1.86(m,1H),1.82-1.72(m,2H),1.61-1.50(m,1H)；13C NMR(126MHz, CDCl3)δ158.47,129.60,129.41,128.67,126.92,87.71,52.06,35.84,31.59,23.44； GC-MS(EI):m/z 187[M+].
example 14: synthesis of 3,4, 5-triphenyl-4, 5-dihydroisoxazoline
Figure BDA0003209376260000122
A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), then 1mL of freshly prepared 2 wt.% aqueous TPGS-750-M solution was added to the flask, and after stirring the mixture at room temperature for 4 hours, 18.2. mu.L (0.13mmol) Et was added sequentially3N, 18mg (0.1mmol) of 1, 2-diphenylethylene (II-3) 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 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 28.4mg of 3,4, 5-triphenyl-4, 5-dihydro-isoxazoline shown in the formula (III-3) and white solid with the yield of 95%. Purity by HPLC 98.7%. The structure of formula (III-3) is characterized as follows:
1H NMR(500MHz,CDCl3)δ7.65-7.59(m,2H),7.43-7.28(m,13H),5.55(d,J ＝5.5Hz,1H),4.71(d,J＝5.5Hz,1H)；13C NMR(126MHz,CDCl3)δ157.59, 140.87,139.19,129.88,129.46,128.89,128.59,128.27,127.88,127.57,127.36,125.33,91. 75,63.30；GC-MS(EI):m/z 299[M+].
example 15: synthesis of 5-hexyl 3-phenyl-4, 5-dihydroisoxazoline
Figure BDA0003209376260000131
To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), 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, 18.2. mu.L (0.13mmol) of Et were added successively3N, 11.2mg (0.1mmol) of oct-1-ene (II-4) are reacted at room temperature for 8 h. After the reaction, 2mL of ethyl acetate was added to the reaction flask, followed by stirringStirring for 5min, standing for layering, collecting upper organic phase, adding 2mL ethyl acetate into lower water phase, stirring for 5min, standing for layering, collecting upper organic phase, mixing the organic phases, evaporating under reduced pressure to remove solvent, separating 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 21.8mg of 5-hexyl 3-phenyl-4, 5-dihydro isoxazoline shown in the formula (III-4) as a white solid with the yield of 94%. Purity by HPLC 98.3%. The structure of formula (III-4) is characterized as follows:
1H NMR(500MHz,CDCl3)δ7.72-7.64(m,2H),7.47-7.36(m,3H),4.81-4.68 (m,1H),3.40(dd,J＝16.4,10.4Hz,1H),2.98(dd,J＝16.4,8.2Hz,1H),1.87-1.76 (m,1H),1.67-1.59(m,1H),1.52-1.28(m,8H),0.91(t,J＝6.7Hz,3H)；13C NMR (126MHz,CDCl3)δ156.36,129.98,129.84,128.64,126.57,81.51,39.94,35.35,31.72, 29.12,25.49,22.55,14.03；GC-MS(EI):m/z 231[M+].
example 16: synthesis of 5-methyl-3, 5-diphenyl-4, 5-dihydroisoxazoline
Figure BDA0003209376260000141
To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), 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, 18.2. mu.L (0.13mmol) of Et were added successively3N, 11.8mg (0.1mmol) of 2-phenyl-1-propene (II-5) 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 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-methyl-3, 5-diphenyl-4, 5-dihydro-isoxazole shown in the formula (III-5)Oxazoline 22.5mg, white solid, yield 95%. Purity by HPLC 98.4%. The structure of formula (III-5) is characterized as follows:
1H NMR(500MHz,CDCl3)δ7.70-7.66(m,2H),7.52(dd,J＝7.9,1.6Hz,2H), 7.43-7.38(m,5H),7.31(d,J＝7.6Hz,1H),3.58-3.46(m,2H),1.83(s,3H)；13C NMR(126MHz,CDCl3)δ156.16,145.51,129.98,129.92,1 2 8.68,128.51,127.38, 126.57,124.70,88.10,48.75,28.24；GC-MS(EI):m/z 237[M+].
example 17: synthesis of 3-phenyl-4, 5-dihydroisoxazoline-5-carboxylic acid ethyl ester
Figure BDA0003209376260000142
To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), 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, 18.2. mu.L (0.13mmol) of Et were added successively3N, 10.0mg (0.1mmol) of ethyl acrylate (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 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-phenyl-4, 5-dihydro-isoxazoline-5-carboxylic acid ethyl ester shown in the formula (III-6) as a yellow solid with the yield of 94%. Purity by HPLC 98%. The structure of formula (III-6) is characterized as follows:
1H NMR(500MHz,CDCl3)δ7.89-7.80(m,2H),7.50-7.47(m,3H),5.17(s, 1H),4.29-4.25(m,2H),3.65-3.63(m,2H),1.34(t,J＝7.1Hz,3H)；13C NMR(126 MHz,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 219[M+].
example 19: synthesis of 3-phenyl-5- (trimethylsilyl) -4, 5-dihydroisoxazoline
Figure BDA0003209376260000151
To a 5mL reaction flask was added 24.1mg (0.18mmol) NCS, 18.2mg (0.15mmol) benzaldoxime (I), 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, 18.2. mu.L (0.13mmol) of Et were added successively3N, 11.4mg (0.1mmol) of allyltrimethylsilane (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 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 20mg of 3-phenyl-5- (trimethylsilyl) -4, 5-dihydroisoxazoline represented by the formula (III-7) as a white solid with a yield of 91%. Purity by HPLC was 97.3%. The structure of formula (III-7) is characterized as follows:
1H NMR(500MHz,CDCl3)δ7.67(dd,J＝6.6,3.1Hz,2H),7.44-7.37(m,3H), 3.40(dd,J＝16.2,9.8Hz,1H),2.90(dd,J＝16.1,9.2Hz,1H),1.34-1.06(m,2H), 0.13(s,9H)；13C NMR(126MHz,CDCl3)δ156.71,129.80,128.63,126.50,80.18, 42.15,24.29,-0.99；GC-MS(EI):m/z 219[M+].
example 20: synthesis of 5-phenyl-3- [ (2, 4-dinitro) ] isoxazoline
Figure BDA0003209376260000161
A5 mL reaction flask was charged with 24.1mg (0.18mmol) NCS, 31.7mg (0.15mmol) 2, 4-dinitrobenzaldehyde oxime (I-12), and 1mL freshly prepared 2 wt.% TPGS-750-M was dissolved in waterThe solution was added to the flask and the mixture was stirred at room temperature for 4 hours. After four hours, 18.2. mu.L (0.13mmol) of Et were added successively3N, 10.4mg (0.1mmol) of styrene (II-1) was reacted at room temperature for 8 hours. After completion of the reaction, the reaction mixture was checked by TLC, and it was found that the objective product (III-8) was not produced.
Example 21: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline
Figure BDA0003209376260000162
A50 mL reaction flask was charged with 241mg (1.8mmol) NCS and 182mg (1.5mmol) benzaldoxime (I), then 10mL of a freshly prepared 1 wt.% aqueous solution of TPGS-750-M was added to the flask, and after stirring at room temperature for 4 hours, 182. mu.L (1.3mmol) of Et was added in that order3N and 104mg (1mmol) of styrene (II-1), reacting for 8 hours at room temperature, finishing the reaction, 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, combining organic phases obtained in two times, 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 149.6 mg of 3, 5-diphenylisoxazoline shown in the formula (III-1) as a white solid with the yield of 67%.
Example 22: synthesis of 3, 5-diphenyl-4, 5-dihydroisoxazoline
Figure BDA0003209376260000171
A50 mL reaction flask was charged with 241mg (1.8mmol) NCS and 182mg (1.5mmol) benzaldoxime (I), then 10mL of a freshly prepared 5 wt.% aqueous TPGS-750-M solution was added to the flask, stirred at room temperature for 4 hours, and then 182. mu.L (1.3mmol) Et was added sequentially3N and 104mg (1mmol) of styrene (II-1) react at room temperature for 8 hours, then the reaction is finished, 15mL of ethyl acetate is added into a reaction bottle, the mixture is stirred for 5 minutes and then stands for layering, and the upper layer is collectedAnd (3) after an organic phase, adding 15mL of ethyl acetate into a lower water phase, stirring for 5min, standing for layering, collecting an upper organic phase, (extracting TPGS-750-M in the lower water phase by using dichloromethane, separating and recovering, see example 5), combining the organic phases obtained by two times, evaporating under reduced pressure to remove the solvent, and separating a solid residue by column chromatography, wherein an eluent is petroleum ether: ethyl acetate ═ 1:2, collecting the eluent containing the target product, and evaporating the solvent under reduced pressure to obtain 180.9mg of 3, 5-diphenylisoxazoline shown as the formula (III-1) as a white solid with the yield of 81 percent. Purity by HPLC was 96.1%.

Claims (10)

1. An aqueous phase synthesis method of isoxazoline compounds shown in formula (III), which is characterized in that the method comprises the following steps:
taking benzaldehyde oxime shown in a formula (I) as a substrate, reacting with an alkene compound shown in a formula (II) in an aqueous solution of a surfactant with the mass concentration of 1-5 wt% under the combined action of N-chlorosuccinimide and an alkaline substance at room temperature for 6-16h, and carrying out aftertreatment on the obtained reaction liquid to obtain an isoxazoline compound shown in a formula (III); the mass ratio of the alkene compound shown in the formula (II), the benzaldehyde oxime shown in the formula (I), the N-chlorosuccinimide and the alkaline substance is as follows: 1:1-1.5:1-1.8: 0.5-2;
Figure FDA0003209376250000011
wherein R is1、R2、R3Each independently is H, C1-C6Alkyl, phenyl,
Figure FDA0003209376250000012
Figure FDA0003209376250000013
Or R3And R1Are linked to form a ring and form a five-membered carbocyclic ring with the carbon between the two, and R2Is H;
the alkaline substance is selected from one of the following substances: sodium hydroxide, potassium carbonate, triethylamine, piperidine; the surfactant is tocopherol methoxypolyethylene glycol succinic acid.
2. The method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 1, wherein: 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. The method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 1, wherein: r1Is phenyl, hexyl,
Figure FDA0003209376250000014
R2Is H, methyl or phenyl, R3Is H or phenyl.
4. The method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 3, characterized in that the alkene compound of formula (II) is one of the following:
Figure FDA0003209376250000021
5. the method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 1, wherein: the mass concentration of the aqueous solution of the surfactant is 2 wt%.
6. The method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 1, wherein: the reaction time was 8 h.
7. The method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 1, wherein: the mass ratio of the alkene compound shown in the formula (II), the benzaldehyde oxime shown in the formula (I), the N-chlorosuccinimide and the alkaline substance is 1:1.5:1.8: 1.3.
8. The method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 1, wherein: the alkaline substance is triethylamine or piperidine.
9. The method for aqueous phase synthesis of isoxazolines of formula (III) according to claim 1, wherein: the alkaline substance is triethylamine.
10. The process for the aqueous synthesis of isoxazolines 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).
CN202110926236.8A 2021-08-12 2021-08-12 Water phase preparation method of isoxazoline compound with participation of vitamin E micro-micelle Active CN113666882B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110926236.8A CN113666882B (en) 2021-08-12 2021-08-12 Water phase preparation method of isoxazoline compound with participation of vitamin E micro-micelle

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110926236.8A CN113666882B (en) 2021-08-12 2021-08-12 Water phase preparation method of isoxazoline compound with participation of vitamin E micro-micelle

Publications (2)

Publication Number Publication Date
CN113666882A true CN113666882A (en) 2021-11-19
CN113666882B CN113666882B (en) 2023-05-23

Family

ID=78542515

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110926236.8A Active CN113666882B (en) 2021-08-12 2021-08-12 Water phase preparation method of isoxazoline compound with participation of vitamin E micro-micelle

Country Status (1)

Country Link
CN (1) CN113666882B (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102892504A (en) * 2009-12-01 2013-01-23 麦赛尔科技有限责任公司 Surfactant-enabled transition metal-catalyzed chemistry
US20170217850A1 (en) * 2016-01-29 2017-08-03 AbbVie Deutschland GmbH & Co. KG Organic reactions carried out in aqueous solution in the presence of a hydroxyalkyl(alkyl)cellulose or an alkylcellulose
CN109761862A (en) * 2019-01-24 2019-05-17 西北师范大学 A kind of synthetic method of β-carbonyl sulfone compound
US20200299281A1 (en) * 2016-03-29 2020-09-24 Novartis Ag Reaction medium containing water-surfactant mixture

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102892504A (en) * 2009-12-01 2013-01-23 麦赛尔科技有限责任公司 Surfactant-enabled transition metal-catalyzed chemistry
US20170217850A1 (en) * 2016-01-29 2017-08-03 AbbVie Deutschland GmbH & Co. KG Organic reactions carried out in aqueous solution in the presence of a hydroxyalkyl(alkyl)cellulose or an alkylcellulose
US20200299281A1 (en) * 2016-03-29 2020-09-24 Novartis Ag Reaction medium containing water-surfactant mixture
CN109761862A (en) * 2019-01-24 2019-05-17 西北师范大学 A kind of synthetic method of β-carbonyl sulfone compound

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ELENA TASCA等: "Micellar promoted multi-component synthesis of 1,2,3-triazoles in water at room temperature" *
LIANG WANG等: "Convenient synthesis of 4,5-unsubstituted 3-aroylisoxazoles from methyl aryl ketones and (vinylsulfonyl)benzene in water" *
SOFIA SICILIANO等: "Synthesis of 2-Substitued Indoles via Pd-Catalysed Cyclization in an Aqueous Micellar Medium" *
TEPPEI NOGUCHI等: "Rhodium-Catalyzed Cascade Annulative Coupling of 3,5-Diaryl-isoxazoles with Alkynes" *
蔡东霖等: "水溶性维生素E(TPGS)生产工艺的研究" *

Also Published As

Publication number Publication date
CN113666882B (en) 2023-05-23

Similar Documents

Publication Publication Date Title
EP1756095B1 (en) Cyanopyrrole containing cyclic carbamate and thiocarbamate biaryls and methods for preparing the same
CN110776501B (en) Preparation method of drug toxin PNU-159682 for antibody drug conjugate and intermediate thereof
FR2697522A1 (en) Process for the preparation of taxane derivatives.
RU2233276C2 (en) Method for preparing taxanes and intermediate compound for their preparing
CN112028848B (en) Method for preparing isoxazoline
CN113666882A (en) Aqueous phase preparation method of isoxazoline compound participated by vitamin E micelle
Chen et al. An efficient route to diverse 2H-pyrano [3, 2-c] quinolin-5 (6H)-ones via electrophilic cyclization reactions
CN114426510A (en) Synthesis method of fully-substituted beta-lactam
CN109912640B (en) Preparation method of 2-pyrrolidone compound
CN101130528A (en) Process for the preparation of baccatin iii derivatives
CN108285415B (en) Preparation method of 1, 5-diketone compound
CN113582937B (en) Green preparation method of isoxazole compound participated in by water-soluble vitamin E
CN108299198B (en) Preparation method of 1, 4-diketone compound
CN113248418B (en) 3-alkynyl-2, 4-diester-based pyrrole compound and preparation method thereof
WO2008075834A1 (en) Method of preparing taxane derivatives and intermediates used therein
CN110669021B (en) Synthesis method of 3-aryl-4, 5-dihydroisoxazol-5-yl methyl sulfonate and analogue
CN112159375B (en) Green preparation method of 2, 3-dihydrofuran compound
CN109956936B (en) Preparation method of Psymberin
NO332367B1 (en) Taxane derivatives functionalized at the 14th position
CN110330456B (en) Synthetic method of 2,2, 2-trifluoroethyl substituted phenanthridine compound
CN115353540B (en) Synthetic method and application of phenolic steroid compound
Tilekar et al. ‘One-pot’organocatalyzed enantioselective synthesis of highly functionalized 3, 4, 5, 6-tetrasubstituted dihydropyrans by sequential Knoevenagel condensation/Michael addition and hemiacetalization
CN105461652B (en) It is a kind of using aldoxime to the method for nitrogen heterocycle propane compound cyclization
CN114031612A (en) (+/-) -Nicotletrone A and synthesis method of epimer thereof
CN115960030A (en) Preparation method of 3-subunit oxindole derivative

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant