CN109293593A - A method of synthesis iodo isoxazoles compound - Google Patents

A method of synthesis iodo isoxazoles compound Download PDF

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CN109293593A
CN109293593A CN201811277748.0A CN201811277748A CN109293593A CN 109293593 A CN109293593 A CN 109293593A CN 201811277748 A CN201811277748 A CN 201811277748A CN 109293593 A CN109293593 A CN 109293593A
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ketoxime
butyl
alkene
phenyl
formula
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李小青
王鑫强
许响生
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Zhejiang University of Technology ZJUT
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Zhejiang University of Technology ZJUT
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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
    • C07D261/04—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
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a kind of synthetic methods of iodo isoxazoles compound shown in formula (II), the method are as follows: ketoxime shown in formula (I), propiodal and oxidant are mixed and are dissolved in solvent, under the conditions of existing for the inert gas, 7~15h is reacted at 25 DEG C~60 DEG C, obtains that reaction solution is post-treated to obtain isoxazoles compound shown in formula (II).The present invention carries out intramolecular cyclization reaction directly using ketoxime as raw material, and whole process does not need metallic catalyst, avoids the residual of metal, and Atom economy is high, and reagent is inexpensively environmentally friendly, and operation is simple, more conducively its application in medicine synthesis.

Description

A method of synthesis iodo isoxazoles compound
(1) technical field
The present invention relates to a kind of synthetic methods of iodo isoxazoles compound.
(2) background technique
Isoxazoles compound is a kind of critically important structural unit, can be converted into a variety of other important organic compounds Object.
Such as the compound for the isoxazoline part contained in its molecule shows impressive anti-inflammatory, resists very Bacterium and antibacterial activity.Such compound applies also for synthesizing a kind of simple isoxazoline derivative, which is a kind of Very effective dnmt rna inhibitor.Although there are reports for the synthetic method of such compound, reported The synthetic method of these documents, which has, has used expensive metallic catalyst, and conditional operation is complicated, and atom utilization is not high to be lacked Point has very important significance to scientific research tool so developing synthetic method that is novel and meeting Green Chemistry.
(3) summary of the invention
The object of the present invention is to provide a kind of new methods for synthesizing iodo isoxazoles compound.
The technical solution adopted by the invention is as follows:
A kind of synthetic method of iodo isoxazoles compound shown in formula (II), the synthetic method is by following step It is rapid to carry out:
Ketoxime shown in formula (I), propiodal and oxidant are mixed and are dissolved in solvent, under the conditions of existing for the inert gas, 7~15h is reacted at 25 DEG C~60 DEG C, obtains that reaction solution is post-treated to obtain isoxazoles compound shown in formula (II)； The ratio between amount for the substance that feeds intake of ketoxime shown in the formula (I) and propiodal, oxidant is 1:0.5~1:1~2.5；The oxygen Agent is selected from one of following: tert-butyl hydroperoxide, di-tert-butyl peroxide, benzoyl peroxide or peroxidating Hydrogen；
In formula (I) or formula (II),
R1For C1~8Alkyl, phenyl, naphthalene, furyl, thienyl or by halogen, hydroxyl, trifluoromethyl, nitro, methyl Or methoxy-substituted phenyl；
R2、R3Or R4Respectively stand alone as hydrogen or methyl.
Further, it is preferred that R1For phenyl, 4- chlorphenyl, 4- aminomethyl phenyl, 4- bromophenyl, 4- nitrobenzophenone, naphthalene, 3,4- Dimethoxyphenyl, furyl, 3- bromophenyl, 3- nitrobenzophenone, 4- fluorophenyl, 4- isopropyl phenyl, thienyl, 4- (trifluoromethyl) phenyl, 2- hydroxy phenyl, 4- methyl formate phenyl or normal octane base.
Synthetic method of the present invention, ketoxime shown in the preferably described formula (I) are selected from one of following: 1- phenyl butyl- 3- Alkene -1- ketoxime, 1- (4- chlorphenyl) butyl- 3- alkene -1- ketoxime, 1- (p-methylphenyl) butyl- 3- alkene -1- ketoxime, 1- (4- bromophenyl) Butyl- 3- alkene -1- ketoxime, 1- (4- nitrobenzophenone) butyl- 3- alkene -1- ketoxime, 1- (naphthalene -2- base) butyl- 3- alkene -1- ketoxime, 1- (3,4- Dimethoxyphenyl) butyl- 3- alkene -1- ketoxime, 1- (furans -2- base) butyl- 3- alkene -1- ketoxime, 1- (3- bromophenyl) butyl- 3- alkene - 1- ketoxime, 1- (3- nitrobenzophenone) butyl- 3- alkene -1- ketoxime, 1- (4- fluorophenyl) butyl- 3- alkene -1- ketoxime, 1- (4- cumene Base) butyl- 3- alkene -1- ketoxime, 1- (thiophene -2- base) butyl- 3- alkene -1- ketoxime, 1- (4- (trifluoromethyl) phenyl) butyl- 3- alkene -1- Ketoxime, 1- (2- hydroxy phenyl) butyl- 3- alkene -1- ketoxime, 4- (1- (oxyimino) butyl- 3- alkene -1- base) methyl benzoate, 2, 2- dimethyl-1- phenyl butyl- 3- alkene-1- ketoxime, 3- methyl-1-phenyl butyl- 3- alkene-1- ketoxime, 12 carbon-1- alkene-4- ketoximes, 2,3- dimethyl -1- phenyl butyl- 3- alkene -1- ketoxime, 1- (4- methoxyphenyl) butyl- 3- alkene -1- ketoxime or hexamethylene -2- alkene -1- Base (phenyl) ketoxime.
Further, the propiodal is selected from one of following: iodine, sodium iodide, potassium iodide, N- N-iodosuccinimide or Tetrabutyl iodate amine, preferably iodine.
Further, the preferably described oxidant is tert-butyl hydroperoxide.
Further, the solvent is selected from one of following: water, ethyl acetate, toluene, ether, methylene chloride or 1,2- bis- Chloroethanes, preferably water.
Further, the additional amount of the solvent with the amount of the substance of ketoxime shown in formula (I) be calculated as 4ml/mmol~ 16ml/mmol。
Further, the ratio between amount for the substance that feeds intake of ketoxime shown in the preferably described formula (I) and propiodal and oxidant is 1: 0.5:2.
Further, the inert gas is preferably argon gas.
Synthetic method of the present invention, preferable reaction temperature are room temperature, reaction time 15h.
Recommend the reaction solution post-processing approach are as follows: after reaction, sodium sulfite is first added into the reaction solution Saturated solution removes the complete iodine of unreacted, is then extracted with ethyl acetate again 3~5 times, merges organic phase and uses anhydrous sodium sulfate It is dry, it carries out being concentrated under reduced pressure to give crude product again after dry, finally carries out column chromatography for separation, the stone for being 5~20:1 with volume ratio Oily ether/ethyl acetate mixtures are eluant, eluent, collect and merge the eluent containing target compound, be evaporated off after solvent dry to get To the iodo isoxazoles compound.
More specifically, recommend the synthetic method of the isoxazoles compound are as follows:
Ketoxime, propiodal and oxidant shown in formula (I) are mixed in solvent and react 15h at room temperature, by reaction solution elder generation Sodium sulfite saturated solution is added and removes the complete iodine of unreacted, is then extracted with ethyl acetate again three times, merges organic phase and is used in combination Anhydrous sodium sulfate is dry, carries out being concentrated under reduced pressure to give crude product again after dry, finally carries out column chromatography for separation, with volume ratio for 5 The petrol ether/ethyl acetate mixed liquor of~20:1 is eluant, eluent, collects and merges the eluent containing target compound, after solvent is evaporated off Dry, i.e., described in gained iodo isoxazoles compound；Ketoxime shown in the formula (I) and propiodal and oxidant feed intake The ratio between amount of substance is 1:0.5:2；The additional amount of the solvent is calculated as 8ml/ with the amount of the substance of oxime shown in formula (I) mmol；Ketoxime shown in the formula (I) is selected from one of following: 1- phenyl butyl- 3- alkene -1- ketoxime, 1- (4- chlorphenyl) butyl- 3- Alkene -1- ketoxime, 1- (p-methylphenyl) butyl- 3- alkene -1- ketoxime, 1- (4- bromophenyl) butyl- 3- alkene -1- ketoxime, 1- (4- nitrobenzene Base) butyl- 3- alkene -1- ketoxime, 1- (naphthalene -2- base) butyl- 3- alkene -1- ketoxime, 1- (3,4- Dimethoxyphenyl) butyl- 3- alkene -1- ketone Oxime, 1- (furans -2- base) butyl- 3- alkene -1- ketoxime, 1- (3- bromophenyl) butyl- 3- alkene -1- ketoxime, 1- (3- nitrobenzophenone) butyl- 3- Alkene -1- ketoxime, 1- (4- fluorophenyl) butyl- 3- alkene -1- ketoxime, 1- (4- isopropyl phenyl) butyl- 3- alkene -1- ketoxime, 1- (thiophene - 2- yl) butyl- 3- alkene -1- ketoxime, 1- (4- (trifluoromethyl) phenyl) butyl- 3- alkene -1- ketoxime, 1- (2- hydroxy phenyl) butyl- 3- alkene - 1- ketoxime, 4- (1- (oxyimino) butyl- 3- alkene -1- base) methyl benzoate, 2,2- dimethyl -1- phenyl butyl- 3- alkene -1- ketone Oxime, 3- methyl-1-phenyl butyl- 3- alkene-1- ketoxime, 12 carbon-1- alkene-4- ketoximes, 2,3- dimethyl-1- phenyl butyl- 3- alkene-1- Ketoxime, 1- (4- methoxyphenyl) butyl- 3- alkene -1- ketoxime, hexamethylene -2- alkene -1- base (phenyl) ketoxime；The propiodal is single Matter iodine；The oxidant is tert-butyl hydroperoxide；The solvent is water.
Compared with prior art, the invention has the following advantages that
(1) Atom economy is high, and reagent is inexpensively environmentally friendly, easy to operate, the more mild feature of reaction condition.
(2) substrate adaptability is good, and a variety of substituent groups can realize the synthesis of corresponding isoxazoles compound.
(3) directly using ketoxime as raw material, intramolecular cyclization reaction is carried out, whole process does not need metallic catalyst, avoids The residual of metal, operation is simple, more conducively its application in medicine synthesis.
(4) specific embodiment
The present invention is described in further detail combined with specific embodiments below, but protection scope of the present invention and not only It is limited to this.
Tert-butyl hydroperoxide used in the present invention is the tert-butyl hydroperoxide aqueous solution that mass fraction is 70%.
Embodiment 1
By 1- phenyl butyl- 3- alkene -1- ketoxime (40.3,0.25mmol), iodine (31.8mg, 0.125mmol) and uncle Butylhydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added in argon gas protection reaction flask, finally adds water 2ml, then 15h is reacted at room temperature, after reaction, with column chromatography chromatogram method (eluent: petrol ether/ethyl acetate volume ratio 10:1) isolated compound 1 (57.4mg), yield 80%.
Characterization of The Products: white solid；m.p.72-73℃；1H NMR(500MHz,CDCl3)δ7.71–7.63(m,2H), 7.48-7.38 (m, 3H), 4.95-4.89 (m, 1H), 3.52 (dd, J=17.0,10.4Hz, 1H), 3.42 (dd, J=10.0, 4.1Hz,1H),3.28–3.18(m,2H).
Embodiment 2
By 1- (4- chlorphenyl) butyl- 3- alkene -1- ketoxime (48.9,0.25mmol), iodine (31.8mg, 0.125mmol) And tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added in argon gas protection reaction flask, finally again Water 2ml is added, then reacts 15h at room temperature, after reaction, with column chromatography chromatogram method (eluent: petrol ether/ethyl acetate Volume ratio 10:1) isolated compound 2 (67.5mg), yield 84%.
Characterization of The Products: white solid: m.p.98-99 DEG C；1H NMR(500MHz,CDCl3)δ7.65–7.55(m,2H), 7.46-7.31 (m, 2H), 4.96-4.90 (m, 1H), 3.49 (dd, J=17.0,10.4Hz, 1H), 3.42 (dd, J=10.1, 4.0Hz,1H),3.29–3.10(m,2H).
Embodiment 3
By 1- (p-methylphenyl) butyl- 3- alkene -1- ketoxime (43.8,0.25mmol), iodine (31.8mg, 0.125mmol) And tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added in argon gas protection reaction flask, finally again Water 2ml is added, then reacts 15h at room temperature, after reaction, with column chromatography chromatogram method (eluent: petrol ether/ethyl acetate Volume ratio 10:1) isolated compound 3 (48.2mg), yield 64%.
Characterization of The Products: white solid；m.p.96–97℃；1H NMR(500MHz,CDCl3)δ7.61–7.50(m,2H), 7.22 (d, J=8.0Hz, 2H), 4.94-4.88 (m, 1H), 3.50 (dd, J=17.0,10.3Hz, 1H), 3.42 (dd, J= 10.0,4.1Hz,1H),3.27–3.16(m,2H),2.38(s,3H).
Embodiment 4
By 1- (4- bromophenyl) butyl- 3- alkene -1- ketoxime (60.0,0.25mmol), iodine (31.8mg, 0.125mmol) And tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added in argon gas protection reaction flask, finally again Water 2ml is added, then reacts 15h at room temperature, after reaction, with column chromatography chromatogram method (eluent: petrol ether/ethyl acetate Volume ratio 10:1) isolated compound 4 (80.5mg), yield 88%.
Characterization of The Products: white solid: m.p.119-120 DEG C；1H NMR(500MHz,CDCl3)δ7.58–7.50(m,4H), 4.96-4.90 (m, 1H), 3.49 (dd, J=17.0,10.4Hz, 1H), 3.42 (dd, J=10.1,4.1Hz, 1H), 3.26- 3.16(m,2H).
Embodiment 5
Characterization of The Products: white solid；By 1- (4- nitrobenzophenone) butyl- 3- alkene -1- ketoxime (51.6,0.25mmol), simple substance Iodine (31.8mg, 0.125mmol) and tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) are added to argon gas It protects in reaction flask, finally adds water 2ml, then react 15h at room temperature, after reaction, with (the elution of column chromatography chromatogram method Liquid: petrol ether/ethyl acetate volume ratio 5:1) isolated compound 5 (64.8mg), yield 78%.
Characterization of The Products: white solid: m.p.150-151 DEG C；1H NMR(500MHz,CDCl3)δ8.36–8.18(m,2H), 7.95-7.68 (m, 2H), 5.03-4,97 (m, 1H), 3.55 (dd, J=17.0,10.6Hz, 1H), 3.45 (dd, J=10.2, 4.0Hz,1H),3.32–3.20(m,2H).
Embodiment 6
By 1- (naphthalene -2- base) butyl- 3- alkene -1- ketoxime (52.8,0.25mmol), iodine (31.8mg, 0.125mmol) with And tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added in argon gas protection reaction flask, is finally added again Enter water 2ml, then reacts 15h at room temperature.After reaction, with column chromatography chromatogram method (eluent: petrol ether/ethyl acetate body Product is than 10:1) isolated compound 6 (65.7mg), yield 78%.
Characterization of The Products: white solid: m.p.110-111 DEG C；1H NMR(500MHz,CDCl3) δ 7.96 (dd, J=8.6, 1.7Hz, 1H), 7.91 (s, 1H), 7.86 (dd, J=9.0,5.9Hz, 3H), 7.57-7.50 (m, 2H), 5.01-4.96 (m, 1H), 3.63 (dd, J=16.8,10.4Hz, 1H), 3.46 (dd, J=10.1,4.1Hz, 1H), 3.35 (dd, J=16.8, 6.6Hz, 1H), 3.28 (dd, J=10.0,9.1Hz, 1H)
Embodiment 7
By 1- (3,4- Dimethoxyphenyl) butyl- 3- alkene -1- ketoxime (55.3,0.25mmol), iodine (31.8mg, 0.125mmol) and tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added to argon gas protection reaction flask In, finally add water 2ml, then react 15h at room temperature, after reaction, with column chromatography chromatogram method (eluent: petroleum ether/ Ethyl acetate volume ratio 5:1) isolated compound 7 (44.3mg), yield 51%.
Characterization of The Products: white solid: m.p.124-125 DEG C；1H NMR(500MHz,CDCl3) δ 7.37 (d, J=1.9Hz, 1H), 7.04 (dd, J=8.3,2.0Hz, 1H), 6.85 (dd, J=9.8,5.7Hz, 1H), 4.93-4.87 (m, 1H), 3.91 (s, 6H), 3.50 (dd, J=16.9,10.3Hz, 1H), 3.41 (dd, J=10.0,4.1Hz, 1H), 3.21 (m, J=13.1, 7.7Hz,2H).
Embodiment 8
By 1- (furans -2- base) butyl- 3- alkene -1- ketoxime (37.8,0.25mmol), iodine (31.8mg, 0.125mmol) And tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added in argon gas protection reaction flask, finally again Water 2ml is added, then reacts 15h at room temperature again.After reaction, with column chromatography chromatogram method (eluent: petroleum ether/acetic acid second Ester volume ratio 10:1) isolated compound 8 (29.1mg), yield 42%.
Characterization of The Products: yellow liquid；1H NMR(500MHz,CDCl3) δ 7.56-7.49 (m, 1H), 6.74 (d, J= 3.4Hz, 1H), 6.50 (dd, J=3.5,1.8Hz, 1H), 4.92-4.86 (m, 1H), 3.47 (dd, J=17.1,10.3Hz, 1H), 3.40 (dd, J=10.1,4.1Hz, 1H), 3.25-3.16 (m, 2H)
Embodiment 9
By 1- (3- bromophenyl) butyl- 3- alkene -1- ketoxime (60.0,0.25mmol), iodine (31.8mg, 0.125mmol) And tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added in argon gas protection reaction flask, finally again Water 2ml is added, then reacts 15h at room temperature, after reaction, with column chromatography chromatogram method (eluent: petrol ether/ethyl acetate Volume ratio 10:1) isolated compound 9 (75.0mg), yield 82%.
Characterization of The Products: pale brown oil liquid；1H NMR(500MHz,CDCl3) δ 7.80 (s, 1H), 7.60 (d, J= 7.8Hz, 1H), 7.54 (dd, J=8.0,0.8Hz, 1H), 7.28 (dd, J=10.9,5.0Hz, 1H), 4.96-4.90 (m, 1H), 3.48 (dd, J=17.0,10.5Hz, 1H), 3.42 (dd, J=10.1,4.1Hz, 1H), 3.24 (dd, J=10.1,8.8Hz, 1H), 3.18 (dd, J=17.0,6.7Hz, 1H)
Embodiment 10
By 1- (3- nitrobenzophenone) butyl- 3- alkene -1- ketoxime (51.6,0.25mmol), iodine (31.8mg, 0.125mmol) and tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added to argon gas protection reaction flask In, water 2ml is finally added, then react 15h at room temperature.After reaction, with column chromatography chromatogram method (eluent: petroleum ether/ Ethyl acetate volume ratio 5:1) isolated compound 10 (76.4mg), yield 92%.
Characterization of The Products: white solid；m.p.87-88℃；1H NMR(500MHz,CDCl3) δ 8.42 (t, J=1.9Hz, 1H), 8.32-8.23 (m, 1H), 8.12-8.02 (m, 1H), 7.61 (t, J=8.0Hz, 1H), 5.02-4.96 (m, 1H), 3.57 (dd, J=17.0,10.5Hz, 1H), 3.45 (dd, J=10.2,4.0Hz, 1H), 3.34-3.21 (m, 2H)
Embodiment 11
By 1- (4- fluorophenyl) butyl- 3- alkene -1- ketoxime (44.8,0.25mmol), iodine (31.8mg, 0.125mmol) And tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added in argon gas protection reaction flask, finally again Water 2ml is added, then reacts 15h at room temperature, after reaction, with column chromatography chromatogram method (eluent: petrol ether/ethyl acetate Volume ratio 10:1) isolated compound 11 (59.5mg), yield 78%.
Characterization of The Products: white solid；m.p.93-94℃；1H NMR(500MHz,CDCl3)δ7.72–7.60(m,2H), 7.16-7.03 (m, 2H), 4.95-4.89 (m, 1H), 3.50 (dd, J=17.0,10.4Hz, 1H), 3.42 (dd, J=10.1, 4.1Hz, 1H), 3.22 (m, J=18.3,13.5,7.8Hz, 2H)
Embodiment 12
By 1- (4- isopropyl phenyl) butyl- 3- alkene -1- ketoxime (50.8,0.25mmol), iodine (31.8mg, 0.125mmol) and tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added to argon gas protection reaction flask In, finally add water 2ml, then react 15h at room temperature, after reaction, with column chromatography chromatogram method (eluent: petroleum ether/ Ethyl acetate volume ratio 10:1) isolated compound 12 (52.7mg), yield 64%.
Characterization of The Products: white solid；m.p.81-82℃；1H NMR(500MHz,CDCl3)δ7.64–7.56(m,2H), 7.31-7.23 (m, 2H), 4.94-4.88 (m, 1H), 3.50 (dd, J=17.0,10.3Hz, 1H), 3.41 (dd, J=10.0, 4.1Hz,1H),3.26–3.18(m,2H),2.98–2.88(m,1H),1.27(s,3H),1.25(s,3H).
Embodiment 13
By 1- (thiophene -2- base) butyl- 3- alkene -1- ketoxime (41.8,0.25mmol), iodine (31.8mg, 0.125mmol) And tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added in argon gas protection reaction flask, finally again Water 2ml is added, then reacts 15h at room temperature.After reaction, with column chromatography chromatogram method (eluent: petrol ether/ethyl acetate Volume ratio 10:1) isolated compound 13 (68.9mg), yield 94%.
Characterization of The Products: light green oily liquids；1H NMR(500MHz,CDCl3) δ 7.40 (dd, J=5.1,1.1Hz, 1H), 7.22 (dd, J=3.6,1.1Hz, 1H), 7.06 (dd, J=5.1,3.7Hz, 1H), 4.94-4.88 (m, 1H), 3.52 (dd, J= 16.8,10.3Hz, 1H), 3.40 (dd, J=10.1,4.1Hz, 1H), 3.27-3.19 (m, 2H)
Embodiment 14
By 1- (4- (trifluoromethyl) phenyl) butyl- 3- alkene -1- ketoxime (57.3,0.25mmol), iodine (31.8mg, 0.125mmol) and tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added to argon gas protection reaction flask In, finally add water 2ml, then react 15h at room temperature, after reaction, with column chromatography chromatogram method (eluent: petroleum ether/ Ethyl acetate volume ratio 10:1) isolated compound 14 (83.4mg), yield 94%.
Characterization of The Products: white solid；m.p.83-84℃；1H NMR(500MHz,CDCl3) δ 7.79 (d, J=8.2Hz, 2H), 7.67 (d, J=8.3Hz, 2H), 5.00-4.94 (m, 1H), 3.53 (dd, J=17.0,10.5Hz, 1H), 3.44 (dd, J =10.2,4.0Hz, 1H), 3.29-3.20 (m, 2H)
Embodiment 15
By 1- (2- hydroxy phenyl) butyl- 3- alkene -1- ketoxime (44.3,0.25mmol), iodine (31.8mg, 0.125mmol) and tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added to argon gas protection reaction flask In, finally add water 2ml, then react 15h at room temperature, after reaction, with column chromatography chromatogram method (eluent: petroleum ether/ Ethyl acetate volume ratio 10:1) isolated compound 15 (72.0mg), yield 95%.
Characterization of The Products: pale yellow oily liquid；1H NMR(500MHz,CDCl3)δ9.63(s,1H),7.36–7.31(m, 1H), 7.19 (dd, J=7.8,1.6Hz, 1H), 7.03 (dd, J=8.3,1.0Hz, 1H), 6.93 (td, J=7.7,1.1Hz, 1H), 4.91-4.85 (m, 1H), 3.58 (dd, J=17.0,10.4Hz, 1H), 3.42 (dd, J=10.2,4.2Hz, 1H), 3.31 (dd, J=17.0,6.6Hz, 1H), 3.25 (dd, J=10.2,8.6Hz, 1H)
Embodiment 16
By 4- (1- (oxyimino) butyl- 3- alkene -1- base) methyl benzoate (54.8,0.25mmol), iodine (31.8mg, 0.125mmol) and tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) are added to argon gas guarantor It protects in reaction flask, finally adds water 2ml, then react 15h at room temperature, after reaction, with (the elution of column chromatography chromatogram method Liquid: petrol ether/ethyl acetate volume ratio 5:1) isolated compound 16 (78.5mg), yield 91%.
Characterization of The Products: white solid；m.p.168-169℃；1H NMR(500MHz,CDCl3)δ8.10–8.04(m,2H), 7.76-7.70 (m, 2H), 5.00-4.95 (m, 1H), 3.93 (s, 3H), 3.53 (dd, J=17.0,10.5Hz, 1H), 3.43 (dd, J=10.1,4.1Hz, 1H), 3.24 (m, 2H)
Embodiment 17
By 2,2- dimethyl -1- phenyl butyl- 3- alkene -1- ketoxime (47.3,0.25mmol), iodine (31.8mg, 0.125mmol) and tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added to argon gas protection reaction flask In, finally add water 2ml, then react 15h at room temperature, after reaction, with column chromatography chromatogram method (eluent: petroleum ether/ Ethyl acetate volume ratio 10:1) isolated compound 17 (11.8mg), yield 15%.
Characterization of The Products: yellow liquid；1H NMR(500MHz,CDCl3)δ7.62–7.58(m,2H),7.46–7.35(m, 3H), 4.49 (dd, J=7.3,6.5Hz, 1H), 3.42-3.37 (m, 1H), 3.30 (dd, J=10.5,6.5Hz, 1H), 1.48 (s,3H),1.31(s,3H).
Embodiment 18
By 3- methyl-1-phenyl butyl- 3- alkene-1- ketoxime (43.8,0.25mmol), iodine (31.8mg, 0.125mmol) And tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added in argon gas protection reaction flask, finally again Water 2ml is added, then reacts 15h at room temperature, after reaction, with column chromatography chromatogram method (eluent: petrol ether/ethyl acetate Volume ratio 10:1) isolated compound 18 (70.0mg), yield 93%.
Characterization of The Products: colourless oil liquid；1H NMR(500MHz,CDCl3)δ7.68–7.60(m,2H),7.45–7.36 (m, 3H), 3.47 (d, J=16.9Hz, 1H), 3.41 (d, J=1.2Hz, 2H), 3.15 (d, J=17.0Hz, 1H), 1.71 (s, 3H).
Embodiment 19
By 12 carbon -1- alkene -4- ketoximes (49.3,0.25mmol), iodine (31.8mg, 0.125mmol) and tertiary fourth Base hydrogen peroxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added in argon gas protection reaction flask, finally adds water 2ml, then 15h is reacted at room temperature, after reaction, with column chromatography chromatogram method (eluent: petrol ether/ethyl acetate volume ratio 10:1) isolated compound 19 (17.8mg), yield 22%.
Characterization of The Products: yellow oily liquid；1H NMR(500MHz,CDCl3) δ 4.73-4.67 (m, 1H), 3.32 (dd, J= 10.0,4.0Hz, 1H), 3.17-3.06 (m, 2H), 2.78 (dd, J=17.4,6.4Hz, 1H), 2.36-2.31 (m, 2H), 1.59-1.53 (m, 2H), 1.35-1.25 (m, 10H), 0.88 (t, J=7.0Hz, 3H)
Embodiment 20
By 2,3- dimethyl -1- phenyl butyl- 3- alkene -1- ketoxime (47.3,0.25mmol), iodine (31.8mg, 0.125mmol) and tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added to argon gas protection reaction flask In, finally add water 2ml, then react 15h at room temperature, after reaction, with column chromatography chromatogram method (eluent: petroleum ether/ Ethyl acetate volume ratio 10:1) isolated compound 20 (68.5mg), yield 87%.
Characterization of The Products: pale yellow oily liquid；(dr=3:1)；1H NMR(500MHz,CDCl3)δ7.72–7.65(m, 4H), 7.45-7.38 (m, 6H), 3.68 (q, J=7.4Hz, 1H), 3.46 (d, J=10.2Hz, 1H), 3.41-3.35 (m, 3H), 3.34-3.28 (m, 1H), 1.60 (d, J=9.6Hz, 6H), 1.27 (d, J=7.3Hz, 5H), 1.19 (d, J=7.4Hz, 1H)
Embodiment 21
By 1- (4- methoxyphenyl) butyl- 3- alkene -1- ketoxime (47.8,0.25mmol), iodine (31.8mg, 0.125mmol) and tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added to argon gas protection reaction flask In, finally add water 2ml, then react 15h at room temperature, after reaction, with column chromatography chromatogram method (eluent: petroleum ether/ Ethyl acetate volume ratio 5:1) isolated compound 21 (49.2mg), yield 62%.
Characterization of The Products: white solid；m.p.124-126℃；1H NMR(500MHz,CDCl3) δ 7.60 (d, J=8.8Hz, 2H), 6.93 (t, J=5.8Hz, 2H), 4.89 (m, J=10.3,6.4,4.1Hz, 1H), 3.84 (s, 3H), 3.49 (dd, J= 16.9,10.3Hz, 1H), 3.41 (dd, J=10.0,4.1Hz, 1H), 3.27-3.15 (m, 2H)
Embodiment 22
By hexamethylene -2- alkene -1- base (phenyl) ketoxime (50.3,0.25mmol), iodine (31.8mg, 0.125mmol) And tert-butyl hydroperoxide (64.4mg, 0.5mmol, 70%wt aqueous solution) is added in argon gas protection reaction flask, finally again Water 2ml is added, then reacts 15h at room temperature, after reaction, with column chromatography chromatogram method (eluent: petrol ether/ethyl acetate Volume ratio 10:1) isolated compound 22 (61.3mg), yield 75%.
Characterization of The Products: white solid；m.p.158-160℃；1H NMR(500MHz,CDCl3)δ7.74–7.63(m,2H), 7.46-7.34 (m, 3H), 4.90-4.76 (m, 2H), 3.63 (m, J=10.6,6.7Hz, 1H), 2.11-2.01 (m, 2H), 1.92 (m, J=14.7,11.1,3.4Hz, 1H), 1.83-1.71 (m, 1H), 1.63-1.55 (m, 1H), 1.45-1.32 (m, 1H)

Claims (10)

1. a kind of synthetic method of iodo isoxazoles compound shown in formula (II), it is characterised in that: the synthesis side Method carries out as follows:
Ketoxime shown in formula (I), propiodal and oxidant are mixed and are dissolved in solvent, under the conditions of existing for the inert gas, 25 DEG C~60 DEG C at react 7~15h, obtain that reaction solution is post-treated to obtain isoxazoles compound shown in formula (II)；It is described The ratio between amount for the substance that feeds intake of ketoxime shown in formula (I) and propiodal, oxidant is 1:0.5~1:1~2.5；The oxidant Selected from one of following: tert-butyl hydroperoxide, di-tert-butyl peroxide, benzoyl peroxide or hydrogen peroxide；
In formula (I) or formula (II),
R1For C1~8Alkyl, phenyl, naphthalene, furyl, thienyl or by halogen, hydroxyl, trifluoromethyl, nitro, methyl or first The phenyl that oxygroup replaces；
R2、R3Or R4Respectively stand alone as hydrogen or methyl.
2. synthetic method as described in claim 1, it is characterised in that: R1For phenyl, 4- chlorphenyl, 4- aminomethyl phenyl, 4- bromobenzene Base, 4- nitrobenzophenone, naphthalene, 3,4- Dimethoxyphenyl, furyl, 3- bromophenyl, 3- nitrobenzophenone, 4- fluorophenyl, 4- are different Propyl phenyl, thienyl, 4- (trifluoromethyl) phenyl, 2- hydroxy phenyl, 4- methyl formate phenyl or normal octane base.
3. synthetic method as described in claim 1, it is characterised in that: ketoxime shown in the formula (I) is selected from one of following: 1- Phenyl butyl- 3- alkene -1- ketoxime, 1- (4- chlorphenyl) butyl- 3- alkene -1- ketoxime, 1- (p-methylphenyl) butyl- 3- alkene -1- ketoxime, 1- (4- bromophenyl) butyl- 3- alkene -1- ketoxime, 1- (4- nitrobenzophenone) butyl- 3- alkene -1- ketoxime, 1- (naphthalene -2- base) butyl- 3- alkene -1- ketone Oxime, 1- (3,4- Dimethoxyphenyl) butyl- 3- alkene -1- ketoxime, 1- (furans -2- base) butyl- 3- alkene -1- ketoxime, 1- (3- bromobenzene Base) butyl- 3- alkene -1- ketoxime, 1- (3- nitrobenzophenone) butyl- 3- alkene -1- ketoxime, 1- (4- fluorophenyl) butyl- 3- alkene -1- ketoxime, 1- (4- isopropyl phenyl) butyl- 3- alkene -1- ketoxime, 1- (thiophene -2- base) butyl- 3- alkene -1- ketoxime, 1- (4- (trifluoromethyl) phenyl) Butyl- 3- alkene -1- ketoxime, 1- (2- hydroxy phenyl) butyl- 3- alkene -1- ketoxime, 4- (1- (oxyimino) butyl- 3- alkene -1- base) benzene Methyl formate, 2,2- dimethyl-1- phenyl butyl- 3- alkene-1- ketoxime, 3- methyl-1-phenyl butyl- 3- alkene-1- ketoxime, 12 carbon- 1- alkene -4- ketoxime, 2,3- dimethyl -1- phenyl butyl- 3- alkene -1- ketoxime, 1- (4- methoxyphenyl) butyl- 3- alkene -1- ketoxime or Hexamethylene -2- alkene -1- base (phenyl) ketoxime.
4. synthetic method as described in claim 1, it is characterised in that: the propiodal is selected from one of following: iodine, iodate Sodium, potassium iodide, N- N-iodosuccinimide or tetrabutyl iodate amine.
5. synthetic method as claimed in claim 4, it is characterised in that: the propiodal is iodine.
6. synthetic method as described in claim 1, it is characterised in that: the oxidant is tert-butyl hydroperoxide.
7. synthetic method as described in claim 1, it is characterised in that: the solvent is selected from one of following: water, acetic acid second Ester, toluene, ether, methylene chloride or 1,2- dichloroethanes.
8. synthetic method as described in claim 1, it is characterised in that: the additional amount of the solvent is with ketone shown in formula (I) The amount of the substance of oxime is calculated as 4ml/mmol~16ml/mmol.
9. synthetic method as described in claim 1, it is characterised in that: the inert gas is argon gas.
10. synthetic method as described in claim 1, it is characterised in that: the post-processing approach of the reaction solution are as follows: reaction terminates Afterwards, sodium sulfite saturated solution is first added into the reaction solution and removes the complete iodine of unreacted, is then extracted again with ethyl acetate It takes 3~5 times, merging organic phase is simultaneously dry with anhydrous sodium sulfate, carries out being concentrated under reduced pressure to give crude product again after dry, finally carry out Column chromatography for separation, the petrol ether/ethyl acetate mixed liquor for being 5~20:1 using volume ratio are collected and are merged containing targeted as eluant, eluent The eluent for closing object is dried after solvent is evaporated off to get the iodo isoxazoles compound is arrived.
CN201811277748.0A 2018-10-30 2018-10-30 A method of synthesis iodo isoxazoles compound Pending CN109293593A (en)

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CN110669021A (en) * 2019-10-30 2020-01-10 淮北师范大学 Synthesis method of 3-aryl-4, 5-dihydroisoxazol-5-yl methyl sulfonate and analogue
CN115232084A (en) * 2022-07-28 2022-10-25 新乡市博源生物科技有限公司 Method for recycling and applying iodine in isoxazole synthesis process
CN115785016A (en) * 2022-11-28 2023-03-14 江苏恒盛药业有限公司 Method for preparing 5-substituted chiral isoxazoline derivatives

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Publication number Priority date Publication date Assignee Title
CN110669021A (en) * 2019-10-30 2020-01-10 淮北师范大学 Synthesis method of 3-aryl-4, 5-dihydroisoxazol-5-yl methyl sulfonate and analogue
CN110669021B (en) * 2019-10-30 2021-04-27 淮北师范大学 Synthesis method of 3-aryl-4, 5-dihydroisoxazol-5-yl methyl sulfonate and analogue
CN115232084A (en) * 2022-07-28 2022-10-25 新乡市博源生物科技有限公司 Method for recycling and applying iodine in isoxazole synthesis process
CN115785016A (en) * 2022-11-28 2023-03-14 江苏恒盛药业有限公司 Method for preparing 5-substituted chiral isoxazoline derivatives

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