CN104529925B - 5-(4-nitrobenzophenone)-3-hydroxyl isoxazole and preparation technology thereof and purposes - Google Patents
5-(4-nitrobenzophenone)-3-hydroxyl isoxazole and preparation technology thereof and purposes Download PDFInfo
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- CN104529925B CN104529925B CN201410798040.5A CN201410798040A CN104529925B CN 104529925 B CN104529925 B CN 104529925B CN 201410798040 A CN201410798040 A CN 201410798040A CN 104529925 B CN104529925 B CN 104529925B
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- 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
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/12—Oxygen atoms
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
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Abstract
The present invention relates to 5-(4-nitrobenzophenone)-3-hydroxyl isoxazole and preparation technology thereof and purposes, include following steps: 1) with 4-nitrobenzaldehyde, triphenyl phosphorus and ethyl chloroformate for initiation material, utilize Witting reaction to generate corresponding 3-(4-nitrobenzophenone) ethyl acrylate；2) 3-(4-nitrobenzophenone) ethyl acrylate is generated corresponding 3-(4-nitrobenzophenone)-2,3-bis-ethyl bromide with bromine generation additive reaction；3) cyclization that reacted with oxammonium hydrochloride. under sodium hydroxide effect again by 3-(4-nitrobenzophenone)-2,3-bis-ethyl bromide generates corresponding 5-aryl-3-hydroxyl isoxazole。The beneficial effects of the present invention is: can develop as insecticide, be with a wide range of applications。
Description
Technical field
The present invention relates to 5-(4-nitrobenzophenone)-3-hydroxyl isoxazole and preparation technology thereof and purposes。
Background technology
Isoxazole compounds has antibacterial, the parasite killing of high-efficiency broad spectrum, kills the physiologically active such as demodicid mite and weeding, has significantly high agricultural value and medical value。3-hydroxy-5-methyl base isoxazole trade name hymexazol, is one of the most successful systemic fungicide so far, and it has protection and therapeutical effect concurrently, can be absorbed by plants, transporting in plant, go upward to stem and leaf, come downwards to root, has the sterilization of brute force, bacteriostasis。Isoxazole phosphine (isoxathion) is to be the high-efficient contact Insecticidal and acaricidal agent of broad spectrum activity by Sankyo Co., Ltd of Japan with exploitation in 1970。David in 1993 etc. have synthesized the novel isoxazole series derivates of similar nicotine structure, with ethyl parathion for reference, measure its insecticidal activity, and result shows that all compounds have killing activity in various degree to for examination insecticide。
Summary of the invention
The technical problem to be solved is to propose a kind of noval chemical compound 5-(4-nitrobenzophenone)-3-hydroxyl isoxazole for above-mentioned prior art, it is GABA (γ-aminobutyric acid) receptor antagonist, can develop as insecticide, be with a wide range of applications。
This invention address that the technical scheme is that 5-of above-mentioned technical problem (4-nitrobenzophenone)-3-hydroxyl isoxazole, its structural formula is:
The technical scheme of preparation method of the present invention is: the preparation method of 5-(4-nitrobenzophenone)-3-hydroxyl isoxazole, includes following steps:
1) with 4-nitrobenzaldehyde, triphenyl phosphorus and ethyl chloroformate for initiation material, Witting reaction is utilized to generate corresponding 3-(4-nitrobenzophenone) ethyl acrylate；
Wherein, ratio 4-nitrobenzaldehyde: triphenyl phosphorus: ethyl chloroformate=1:(1～2): (1～5)；
2) 3-(4-nitrobenzophenone) ethyl acrylate is generated corresponding 3-(4-nitrobenzophenone)-2,3-bis-ethyl bromide with bromine generation additive reaction；
Wherein, ratio 3-(4-nitrobenzophenone) ethyl acrylate: bromine=1:(1～5)；
3) cyclization that reacted with oxammonium hydrochloride. under sodium hydroxide effect again by 3-(4-nitrobenzophenone)-2,3-bis-ethyl bromide generates corresponding 5-aryl-3-hydroxyl isoxazole；
Wherein, ratio 3-(4-nitrobenzophenone)-2,3-bis-ethyl bromide: oxammonium hydrochloride .=1:(1～3.0)。
By such scheme, step 1) reaction temperature 40～100 DEG C, the response time is 0.5～3h。
By such scheme, step 3) reaction be back flow reaction, the response time is 0.5～3h。
Reaction equation involved in the present invention is:
The beneficial effects of the present invention is: test through electro physiology, compound 5-(4-the nitrobenzophenone)-3-hydroxyl isoxazole GABA receptor antagonist of the present invention, the Cl-currents suppressing the GABA induction of 10 μMs under 100 μMs of concentration of patch-clamp electrophysiological detection is 54.1 ± 2.8%, can develop as insecticide, be with a wide range of applications。
Detailed description of the invention
For being further appreciated by the present invention, below in conjunction with instantiation, the present invention is elaborated。
Embodiment 1:
The synthesis of intermediate 3-(4-nitrobenzophenone) ethyl acrylate (2)
100mL round-bottomed flask is sequentially added into triphenyl phosphorus 3.9g (15mmol), saturated sodium bicarbonate 50mL, 4-nitrobenzaldehyde 1g (10mmol), ethyl chloroformate 1.8g (20mmol), system 60 DEG C of stirring reaction 1h of intensification。TLC monitors reaction process, reacting complete, reactant liquor is cooled to room temperature, adjusts pH to 4-5 with dilute sulfuric acid, with dichloromethane extraction (2 × 50mL), organic facies anhydrous sodium sulfate dries, and filters, concentration, crude product column chromatography, select petroleum ether: ethyl acetate=6:1, as eluant, obtains colorless oil 1.9g, productivity 89%；
The synthesis of intermediate 3-(4-nitrobenzophenone)-2,3-bis-ethyl bromide (3)
100mL round-bottomed flask adds 3-(4-nitrobenzophenone) ethyl acrylate (2) (1.8g, 8mmol), glacial acetic acid 50mL, dichloromethane 50mL, add the dichloromethane solution 10mL of bromine (2.56g, 16mmol) while stirring。System lucifuge stirring reaction 1h, TLC monitor reaction process, react complete, and reactant liquor concentrating under reduced pressure removes excessive bromine and solvent, crude product petroleum ether drip washing, dries, obtains white solid, 2.8g, productivity 93%, fusing point: 65-70 DEG C；
The synthesis of target product 5-(4-nitrobenzophenone)-3-hydroxyl isoxazole (4)
100mL round-bottomed flask adds sodium hydroxide (0.2g, 5mmol), absolute methanol 30mL, oxammonium hydrochloride. (0.35 is added under ice bath, 5mmol), stirring reaction 10min, the ethanol/methylene of dropping 3-(4-nitrobenzophenone)-2,3-bis-ethyl bromide (1.9g, 5mmol): 1:1 solution 20mL, dropwise, stirring reaction 0.5h under ice bath, then adds sodium hydroxide (0.6g, 15mmol), continue stirring reaction 0.5h, reactant liquor temperature rising reflux reaction 2h。TLC monitors reaction process, reacts complete, reactant liquor concentrating under reduced pressure remove methanol, residue add water 20mL dissolve, with dilute hydrochloric acid adjust pH value to 4-5, have solid to precipitate out, filtration, filter cake respectively use water, petroleum ether drip washing。Crude product petrol ether/ethyl acetate system recrystallization, obtains white solid。5-(4-nitrobenzophenone)-3-hydroxyl isoxazole (4) 0.65g: bright yellow solid, productivity 63%。Fusing point: 230-232 DEG C。1HNMR(400MHz,CDCl3): δ 8.34 (2H, d, J=9.8), 7.91 (2H, d, J=9.8), 6.39 (1H, s)；MS (ESI): 207 (M+1)；E.A.:calculated (C, 52.43；H, 2.93；N, 13.59), found (C, 52.57；H, 2.87；N, 13.43)；
More than reacting three step total recoverys is 52%。
Embodiment 2:
The synthesis of intermediate 3-(4-nitrobenzophenone) ethyl acrylate (2)
100mL round-bottomed flask is sequentially added into triphenyl phosphorus 7.8g (30mmol), saturated sodium bicarbonate 50mL, 4-nitrobenzaldehyde 3.0g (20mmol), ethyl chloroformate 3.6g (40mmol), system 50 DEG C of stirring reaction 1.5h of intensification。TLC monitors reaction process, reacting complete, reactant liquor is cooled to room temperature, adjusts pH to 4-5 with dilute sulfuric acid, with dichloromethane extraction (2 × 50mL), organic facies anhydrous sodium sulfate dries, and filters, concentration, crude product column chromatography, select petroleum ether: ethyl acetate: 6:1, as eluant, obtains colorless oil 1.6g, productivity 72%。
The synthesis of intermediate 3-(4-nitrobenzophenone)-2,3-bis-ethyl bromide (3)
Hereinafter reaction is identical with embodiment 1, obtains 5-(4-nitrobenzophenone)-3-hydroxyl isoxazole, and three step total recoverys are 42%。
Embodiment 3:
The synthesis of intermediate 3-(4-nitrobenzophenone)-2,3-bis-ethyl bromide (3)
Intermediate 3-(4-nitrobenzophenone) ethyl acrylate (2) (2.21g is obtained by the production method in embodiment 1,10mmol) it is added in 200mL round-bottomed flask, glacial acetic acid 100mL, dichloromethane 100mL, add the dichloromethane solution 15mL of bromine (2.56g, 16mmol) while stirring。System lucifuge stirring reaction 1.5h, TLC monitors reaction process, react complete, reactant liquor concentrating under reduced pressure removes excessive bromine and solvent, crude product petroleum ether drip washing, dries, obtain white solid intermediate 3-(4-nitrobenzophenone)-2,3-bis-ethyl bromide (3), 2.5g, productivity 90%；
The synthesis of target product 5-(4-nitrobenzophenone)-3-hydroxyl isoxazole (4)
200mL round-bottomed flask adds sodium hydroxide (0.4g, 10mmol), absolute methanol 50mL, oxammonium hydrochloride. (0.70 is added under ice bath, 10mmol), stirring reaction 10min, the ethanol/methylene of dropping 3-(4-nitrobenzophenone)-2,3-bis-ethyl bromide (1.9g, 5mmol): 1:1 solution 20mL, dropwise, stirring reaction 1h under ice bath, then adds sodium hydroxide (0.8g, 20mmol), continue stirring reaction 1h, reactant liquor temperature rising reflux reaction 2h。TLC monitors reaction process, reacts complete, reactant liquor concentrating under reduced pressure remove methanol, residue add water 20mL dissolve, with dilute hydrochloric acid adjust pH value to 4-5, have solid to precipitate out, filtration, filter cake respectively use water, petroleum ether drip washing。Crude product petrol ether/ethyl acetate system recrystallization, obtains white solid。5-(4-nitrobenzophenone)-3-hydroxyl isoxazole (4) 0.60g: bright yellow solid, productivity 59%。
More than reacting three step total recoverys is 47%。
Embodiment 4:
Frog oocytes dissection obtained, injects housefly GABA receptor RdlcRNA, cultivates through a period of time, then carries out electrophysiology。Use the glass microelectrode exposing cell surface of tip diameter 1～2 micron, form tight sealing-in with cell, then break cell membrane, form whole-cell recording technique pattern。Compound 5-(4-the nitrobenzophenone)-3-hydroxyl isoxazole synthesized through patch-clamp electrophysiological detection embodiment 1 suppresses the 10 micromolar GABA Cl-currents induced to be 54.1 ± 2.8% under 100 micro-molar concentrations。Compound 5-(4-the nitrobenzophenone)-3-hydroxyl isoxazole of the proof present invention is GABA receptor antagonist。
Claims (1)
1.5-(4-nitrobenzophenone)-3-hydroxyl isoxazole is for preparing the application of GABA receptor antagonist。
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