CN105693632B - A kind of preparation method of polysubstituted quinoxaline derivant - Google Patents

A kind of preparation method of polysubstituted quinoxaline derivant Download PDF

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CN105693632B
CN105693632B CN201610028051.4A CN201610028051A CN105693632B CN 105693632 B CN105693632 B CN 105693632B CN 201610028051 A CN201610028051 A CN 201610028051A CN 105693632 B CN105693632 B CN 105693632B
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CN105693632A (en
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崔秀灵
沈金海
程国林
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Huaqiao University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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

The invention discloses a kind of preparation method of polysubstituted quinoxaline derivant, the reaction equation of this method are as follows：

Description

A kind of preparation method of polysubstituted quinoxaline derivant
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of preparation method of polysubstituted quinoxaline derivant.
Background technology
Quinoxaline derivant be it is a kind of it is important there are benzopyrazines heterocyclic compounds, there is extensive bioactivity, Important application value is respectively provided with antitumor, antidepression, anti-inflammatory and anti HIV-1 virus medicine.Therefore, quinoxaline compounds And the like novel synthesis research there is important applying value, paid close attention to be subject to association area researcher.
The synthesis of traditional quinoxaline compounds mainly passes through o-phenylenediamine and 1, double dehydrating condensations of 2- dicarbonyl compounds Reaction obtains.In the method, when asymmetric o-phenylenediamine and 1,2- of asymmetry dicarbonyl compounds react, the area of reaction Field selectivity is unable to control, and generally yields isomers, rather than single product.
The content of the invention
It is an object of the invention to overcome prior art defect, there is provided a kind of preparation side of polysubstituted quinoxaline derivant Method.
The concrete technical scheme of the present invention is as follows：
A kind of preparation method of polysubstituted quinoxaline derivant, the structural formula of prepared polysubstituted quinoxaline derivant is such as Under：
Wherein, R1 is hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
R2For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
R3For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
R4For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
R5For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
R6For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
The reaction equation of this method is as follows：
The solvent one is water, methanol, ethanol, isopropanol, toluene；The solvent two is dimethyl sulfoxide, N, N- dimethyl Formamide, n,N-dimethylacetamide or n-methyl-2-pyrrolidone.
Include the following steps in a preferred embodiment of the invention：
(1) corresponding acetylenic ketone or derivatives thereof, corresponding o-phenylenediamine or derivatives thereof and solvent one are placed in reaction to hold In device, 4~22h is reacted in 48~85 DEG C；
(2) solvent one in step (1) resulting material is evaporated, adds alkali and solvent two, react 1 in 20~55 DEG C~ 6h, adds suitable quantity of water after the completion of reaction or sodium chloride solution terminates reaction；
(3) after the reaction product of step (2) is diluted with ethyl acetate, then through washing, organic phase is obtained；
(4) organic phase obtained by step (3) is purified through drying, filtering, concentration and column chromatography, obtains the polysubstituted quinoline Quinoline derivant；
Wherein, the molar ratio of corresponding acetylenic ketone or derivatives thereof, corresponding o-phenylenediamine or derivatives thereof and alkali for 1: 1~ 1.5: 1.5~2.5, the corresponding 2~12L solvents one of every mole of corresponding acetylenic ketone or derivatives thereof and 2~12L solvents two.
In a preferred embodiment of the invention, corresponding acetylenic ketone or derivatives thereof and corresponding o-phenylenediamine Or derivatives thereof molar ratio be 1: 1.2.
In a preferred embodiment of the invention, the corresponding 3~10L of every mole of corresponding acetylenic ketone or derivatives thereof Solvent one and 3~10L solvents two.
In a preferred embodiment of the invention, the alkali is sodium hydroxide, potassium hydroxide, potassium tert-butoxide, uncle Sodium butoxide, sodium methoxide or cesium carbonate.
In a preferred embodiment of the invention, the reaction temperature of the step (1) is 50~80 DEG C, the reaction time For 5~20h.
In a preferred embodiment of the invention, the reaction temperature of the step (2) is 20~50 DEG C, the reaction time For 1~5h.
The beneficial effects of the invention are as follows：
1st, the present invention can synthesize the quinoxaline derivant with a variety of substituents that other methods are difficult to obtain；
2nd, method of the invention is raw materials used is easy to get, and high income, reaction condition is gentle, and the reaction time is short, and substrate spectrum is wide, It is strong to react specificity, post processing is easy and green.
Embodiment
Technical scheme is further detailed and described below by way of embodiment.
Embodiment 1
The preparation of 2,3- diphenylquinoxalines
1,3- diphenylprop -2- alkynes -1- ketone 0.5mmol, o-phenylenediamine 0.6mmol, methanol 5mL are added into the reaction of 10mL Guan Zhong, is placed in 50 DEG C of oil bath, reacts 24h；Methanol is boiled off, adds potassium hydroxide 1mmol, dimethyl sulfoxide 3mL, is placed in 20 DEG C Oil bath in, react 5h.Add suitable quantity of water or sodium chloride solution stops reaction, be cooled to room temperature.Reaction solution ethyl acetate dilutes, Wash three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifies to obtain 112.8mg target products, and yield is 80%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3) δ 8.23-8.11 (m, 2H), 7.80-7.74 (m, 2H), 7.57-7.48 (m, 4H), 7.39-7.30 (m, 6H)；13C NMR (100MHz, CDCl3) δ 153.4,141.2,139.0, 129.9,129.8,129.2,128.7,128.2..
Embodiment 2
The preparation of 5- methyl -2,3- diphenylquinoxalines
1,3- diphenylprop -2- alkynes -1- ketone 0.5mmol, 3- methyl-o-phenylenediamine 0.6mmol, ethanol 3mL are added into 10mL Reaction tube in, be placed in 80 DEG C of oil bath, react 24h；Ethanol is boiled off, adds potassium hydroxide 1mmol, 1-methyl-2-pyrrolidinone 2mL, is placed in 30 DEG C of oil bath, reacts 5h.Add suitable quantity of water or sodium chloride solution stops reaction, be cooled to room temperature.Reaction solution Ethyl acetate dilutes, and washes three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifies to obtain 91.8mg mesh Mark product, yield 62%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3) δ 8.00 (d, J=8.2Hz, 1H), 7.69-7.48 (m, 6H), 7.33 (dd, J=12.4,5.1Hz, 6H), 2.86 (s, 3H)；13C NMR (100MHz, CDCl3) δ 152.8,151.7,141.1,140.4,139.4,139.3,137.6,130.1,129.8,129.7,128.7,128.3, 128.1,126.9,17.1.
Embodiment 3
The preparation of 5- methyl -2,3- diphenylquinoxalines
1,3- diphenylprop -2- alkynes -1- ketone 0.5mmol, 4- methyl-o-phenylenediamine 0.6mmol, isopropanol 5mL are added In the reaction tube of 10mL, it is placed in 60 DEG C of oil bath, reacts 18h；Isopropanol is boiled off, adds potassium tert-butoxide 1mmol, dimethyl sulfoxide 3mL, is placed in 25 DEG C of oil bath, reacts 2h.Add suitable quantity of water or sodium chloride solution stops reaction, be cooled to room temperature.Reaction solution Ethyl acetate dilutes, and washes three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifies to obtain 93.2mg mesh Mark product, yield 63%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3) δ 8.06 (d, J=8.5Hz, 1H), 7.95 (s, 1H), 7.60 (dd, J=8.6,1.8Hz, 1H), 7.54-7.46 (m, 4H), 7.38-7.30 (m, 6H), 2.61 (s, 3H)；13C NMR (100MHz, CDCl3) δ 153.3,152.6,141.3,140.5,139.7,139.2,132.3,129.8, 129.8,128.7,128.7,128.6,128.2,128.0,21.9.
Embodiment 4
The preparation of fluoro- 2, the 3- diphenylquinoxalines of 6-
1,3- diphenylprop -2- alkynes -1- ketone 0.5mmol, 4- fluorine o-phenylenediamine 0.6mmol, methanol 1.5mL are added into 10mL Reaction tube in, be placed in 60 DEG C of oil bath, react 18h；Methanol is boiled off, adds potassium tert-butoxide 1mmol, N, N- dimethyl formyl Amine 5mL, is placed in 30 DEG C of oil bath, reacts 5h.Add suitable quantity of water or sodium chloride solution stops reaction, be cooled to room temperature.Reaction Liquid ethyl acetate dilutes, and washes three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifies to obtain 108.0mg Target product, yield 72%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3) δ 8.17 (dd, J= 9.2,5.7Hz, 1H), 7.80 (dd, J=9.2,2.8Hz, 1H), 7.60-7.48 (m, 5H), 7.43-7.29 (m, 6H)13C NMR (100MHz, CDCl3) δ 164.1,161.6,154.2,152.8 (d, J=3.2Hz), 141.9 (d, J=13.3Hz), 138.8, 138.7,138.4 (d, J=0.6Hz), 131.2 (d, J=10.1Hz), 129.8,129.8,129.0 128.9,128.3, 120.3 (d, J=26.1Hz), 112.6 (d, J=21.5Hz).
Embodiment 5
The preparation of chloro- 2, the 3- diphenylquinoxalines of 6-
1,3- diphenylprop -2- alkynes -1- ketone 0.5mmol, 4- chlorine o-phenylenediamine 0.6mmol, water 4mL are added into the anti-of 10mL Ying Guanzhong, is placed in 80 DEG C of oil bath, reacts 18h；Water is boiled off, adds sodium tert-butoxide 1mmol, n,N-Dimethylformamide 5mL, It is placed in 20 DEG C of oil bath, reacts 5h.Add suitable quantity of water or sodium chloride solution stops reaction, be cooled to room temperature.Reaction solution acetic acid Ethyl ester dilutes, and washes three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifies to obtain the production of 91.6mg targets Thing, yield 58%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3) δ 8.17 (d, J=2.2Hz, 1H), 8.10 (d, J=8.9Hz, 1H), 7.70 (dd, J=8.9,2.3Hz, 1H), 7.57-7.46 (m, 4H), 7.43-7.26 (m, 6H) ；13C NMR (100MHz, CDCl3) δ 154.2,153.6,141.4,139.7,138.7,138.6,135.6,131.0,130.4, 129.8,129.8,129.1,129.0,128.3,128.3,128.0.
Embodiment 6
The preparation of 6- tert-butyl group -2,3- diphenylquinoxalines
1,3- diphenylprop -2- alkynes -1- ketone 0.5mmol, 4- tert-butyl os phenylenediamine 0.6mmol, ethanol 2mL are added In the reaction tube of 10mL, it is placed in 40 DEG C of oil bath, reacts 24h；Ethanol is boiled off, adds sodium methoxide 1mmol, dimethyl sulfoxide 5mL, It is placed in 40 DEG C of oil bath, reacts 1h.Add suitable quantity of water or sodium chloride solution stops reaction, be cooled to room temperature.Reaction solution acetic acid Ethyl ester dilutes, and washes three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifies to obtain the production of 131.8mg targets Thing, yield 78%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3) δ 8.13 (dd, J=9.5, 5.4Hz, 2H), 7.87 (dd, J=8.9,2.1Hz, 1H), 7.58-7.43 (m, 4H), 7.42-7.26 (m, 6H), 1.47 (s, 9H)；13C NMR (100MHz, CDCl3) δ 153.5,153.3,152.8,141.1,139.6,139.2,139.2,129.8, 129.7,128.9,128.6,128.6,128.5,128.2,128.2,124.4,35.3,31.1.
Embodiment 7
The preparation of 2,3- diphenyl benzo [g] quinoxalines
1,3- diphenylprop -2- alkynes -1- ketone 0.5mmol, 2,3- neighbour naphthylenediamine 0.6mmol, methanol 5mL are added 10mL's In reaction tube, it is placed in 80 DEG C of oil bath, reacts 5h；Methanol is boiled off, adds potassium tert-butoxide 1mmol, dimethyl sulfoxide 5mL, is placed in In 50 DEG C of oil bath, 1h is reacted.Add suitable quantity of water or sodium chloride solution stops reaction, be cooled to room temperature.Reaction solution ethyl acetate Dilution, is washed three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifies to obtain 76.4mg target products, receives Rate is 46%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3) δ 8.73 (s, 2H), 8.10 (dd, J= 6.4,3.3Hz, 2H), 7.61-7.52 (m, 6H), 7.41-7.32 (m, 6H)；13C NMR (100MHz, CDCl3) δ 154.1, 139.1,137.9,134.0,129.8,129.0,128.5,128.2,127.5,126.7.
Embodiment 8
The preparation of 2- phenyl -3- p-methylphenyl quinoxalines
By 3- phenyl -1- p-methylphenyls -propyl- 2- alkynes -1- ketone 0.5mmol, o-phenylenediamine 0.6mmol, methanol 5mL are added In the reaction tube of 10mL, it is placed in 80 DEG C of oil bath, reacts 5h；Methanol is boiled off, adds sodium hydroxide 1mmol, N, N- dimethyl Acetamide 5mL, is placed in 20 DEG C of oil bath, reacts 5h.Add suitable quantity of water or sodium chloride solution stops reaction, be cooled to room temperature. Reaction solution ethyl acetate dilutes, and washes three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifies to obtain 115.4mg target products, yield 78%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3)δ8.23- 8.07 (m, 2H), 7.74 (dd, J=6.3,3.6Hz, 2H), 7.57-7.50 (m, 2H), 7.41 (d, J=8.1Hz, 2H), 7.37- 7.29 (m, 3H), 7.13 (d, J=7.9Hz, 2H), 2.35 (s, 3H)；13C NMR (100MHz, CDCl3) δ 153.4,153.4, 141.2,141.0,139.2,138.8,136.1,129.8,129.8,129.7,129.70,129.1,128.9,128.7, 128.2,21.2.
Embodiment 9
The preparation of 2- p-methoxyphenyl -3- phenyl quinoxalines
By 3- phenyl -1- p-methoxyphenyls -propyl- 2- alkynes -1- ketone 0.5mmol, o-phenylenediamine 0.6mmol, isopropanol 3mL Add in the reaction tube of 10mL, be placed in 70 DEG C of oil bath, react 18h；Isopropanol is boiled off, adds potassium hydroxide 1mmol, N, N- Dimethylformamide 1.5mL, is placed in 20 DEG C of oil bath, reacts 4h.Add suitable quantity of water or sodium chloride solution stops reaction, cooling To room temperature.Reaction solution ethyl acetate dilutes, and washes three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifying Obtain 118.6mg target products, yield 76%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3)δ 8.19-8.12 (m, 2H), 7.78-7.70 (m, 2H), 7.57-7.52 (m, 2H), 7.51-7.45 (m, 2H), 7.36 (dd, J= 5.4,1.7Hz, 3H), 6.89-6.82 (m, 2H), 3.81 (s, 3H)；13C NMR (100MHz, CDCl3) δ 160.2,153.4, 153.0,141.3,141.0,139.4,131.3,131.3,129.8,129.7,129.6,129.1,129.0,128.7, 128.3,113.7,55.3.
Embodiment 10
The preparation of 2- p-fluorophenyl -3- phenyl quinoxalines
By 3- phenyl -1- p-fluorophenyls -propyl- 2- alkynes -1- ketone 0.5mmol, o-phenylenediamine 0.6mmol, methanol 4mL are added In the reaction tube of 10mL, it is placed in 50 DEG C of oil bath, reacts 24h；Methanol is boiled off, adds potassium tert-butoxide 1mmol, N, N- dimethyl Formamide 5mL, reacts 2h.Add suitable quantity of water or sodium chloride solution stops reaction, be cooled to room temperature.Reaction solution ethyl acetate is dilute Release, wash three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifies to obtain 99.0mg target products, yield For 66%.
Embodiment 11
The preparation of 2- (2- naphthyls) -3- phenyl quinoxalines
By 3- phenyl -1- (2- naphthyls) -propyl- 2- alkynes -1- ketone 0.5mmol, o-phenylenediamine 0.6mmol, ethanol 4mL are added In the reaction tube of 10mL, it is placed in 80 DEG C of oil bath, reacts 15h；Ethanol is boiled off, adds sodium tert-butoxide 1mmol, dimethyl sulfoxide 3mL, is placed in 40 DEG C of oil bath, reacts 3h.Add suitable quantity of water or sodium chloride solution stops reaction, be cooled to room temperature.Reaction solution Ethyl acetate dilutes, and washes three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifies to obtain 134.5mg mesh Mark product, yield 81%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3) δ 8.24-8.16 (m, 2H), 8.14 (s, 1H), 7.77 (ddd, J=18.9,13.0,7.9Hz, 5H), 7.58-7.43 (m, 5H), 7.37-7.26 (m, 3H)；13C NMR (100MHz, CDCl3) δ 153.5,153.2,141.3,141.2,139.0,136.5,133.2,133.1,130.0, 129.8,129.8,129.2,129.2,128.8,128.6,128.3,127.6,127.6,127.0,126.8,126.2.
Embodiment 12
The preparation of 2- (2- furyls) -3- phenyl quinoxalines
By 3- phenyl -1- (2- furyls) -propyl- 2- alkynes -1- ketone 0.5mmol, o-phenylenediamine 0.6mmol, toluene 1.5mL add In the reaction tube for entering 10mL, it is placed in 50 DEG C of oil bath, reacts 24h；Toluene is boiled off, adds sodium hydroxide 1mmol, dimethyl sulfoxide 2mL, is placed in 30 DEG C of oil bath, reacts 3h.Add suitable quantity of water or sodium chloride solution stops reaction, be cooled to room temperature.Reaction solution Ethyl acetate dilutes, and washes three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifies to obtain 78.9mg mesh Mark product, yield 58%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3) δ 8.21 (dd, J=8.1, 1.2Hz, 1H), 8.11 (dd, J=8.1,1.3Hz, 1H), 7.80-7.71 (m, 2H), 7.62-7.46 (m, 6H), 6.36 (dd, J =3.5,1.7Hz, 1H), 6.15 (d, J=3.4Hz, 1H)；13C NMR (100MHz, CDCl3) δ 152.5,150.9,144.7, 143.1,141.0,140.3,139.3,130.3,129.9,129.2,129.1,129.0,128.8,128.6,114.8, 111.7。
Embodiment 13
The preparation of 2- cyclohexyl -3- phenyl quinoxalines
3- phenyl -1- cyclohexyl -propyl- 2- alkynes -1- ketone 0.5mmol, o-phenylenediamine 0.6mmol, methanol 5mL is added into 10mL Reaction tube in, be placed in 80 DEG C of oil bath, react 24h；Methanol is boiled off, adds potassium tert-butoxide 1mmol, N, N- dimethyl formyl Amine 5mL, is placed in 50 DEG C of oil bath, reacts 2h.Add suitable quantity of water or sodium chloride solution stops reaction, be cooled to room temperature.Reaction Liquid ethyl acetate dilutes, and washes three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifies to obtain 102.2mg Target product, yield 71%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3) δ 8.09 (dd, J= 7.5,2.3Hz, 2H), 7.74-7.66 (m, 2H), 7.58 (dt, J=8.1,2.1Hz, 2H), 7.55-7.47 (m, 3H), 3.18- 3.07 (m, 1H), 1.82 (dd, J=14.7,5.9Hz, 6H), 1.38-1.19 (m, 4H)；13C NMR (100MHz, CDCl3)δ 159.9,154.7,141.7,140.4,139.2,129.4,129.1,129.0,128.8,128.7,128.6,128.4,42.3, 32.4,26.3,25.8.
Embodiment 14
The preparation of 5- methyl -3- (2- naphthyls) -2- phenyl quinoxalines
By 3- phenyl -1- (2- naphthyls) -propyl- 2- alkynes -1- ketone 0.5mmol, 3- methyl-o-phenylenediamine 0.6mmol, methanol 3mL Add in the reaction tube of 10mL, be placed in 60 DEG C of oil bath, react 18h；Methanol is boiled off, adds sodium tert-butoxide 1mmol, N- methyl Pyrrolidones 2mL, is placed in 25 DEG C of oil bath, reacts 2h.Add suitable quantity of water or sodium chloride solution stops reaction, be cooled to room Temperature.Reaction solution ethyl acetate dilutes, and washes three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifies to obtain 84.0mg target products, yield 48%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3) δ 8.13 (s, 1H), 8.03 (d, J=8.1Hz, 1H), 7.83-7.73 (m, 3H), 7.70-7.59 (m, 3H), 7.56 (dd, J=7.9,1.5Hz, 2H), 7.51-7.44 (m, 2H), 7.37-7.28 (m, 3H), 2.89 (s, 3H)；13C NMR (100MHz, CDCl3) δ 152.9, 151.6,141.1,140.5,139.4,137.6,136.8,133.2,133.1,130.0,129.8,129.8,129.7, 128.7,128.6,128.6,127.6,127.5,127.4,126.9,126.7,126.3,17.2.
Embodiment 15
The preparation of 5- methyl -3- (2- furyls) -2- phenyl quinoxalines
By 3- phenyl -1- (2- furyls) -propyl- 2- alkynes -1- ketone 0.5mmol, 3- methyl-o-phenylenediamine 0.6mmol, isopropyl Alcohol 4mL is added in the reaction tube of 10mL, is placed in 80 DEG C of oil bath, reacts 22h；Isopropanol is boiled off, adds potassium tert-butoxide 1mmol, n,N-Dimethylformamide 3mL, is placed in 50 DEG C of oil bath, reacts 2h.Add suitable quantity of water or sodium chloride solution stops Reaction, is cooled to room temperature.Reaction solution ethyl acetate dilutes, and washes three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, Column chromatography purifies to obtain 80.1mg target products, yield 56%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3) δ 7.94 (d, J=8.3Hz, 1H), 7.72-7.59 (m, 3H), 7.54 (d, J=7.0Hz, 1H), 7.52-7.42 (m, 3H), 7.39 (d, J=5.0Hz, 1H), 6.95-6.85 (m, 1H), 6.79 (d, J=3.7Hz, 1H), 2.79 (s, 3H)；13C NMR (101MHz, CDCl3) δ 151.0,146.3,142.9,141.0,139.7,139.7,137.5,129.8,129.6,129.5, 129.0,128.9,128.4,127.6,126.6,17.1
Embodiment 16
The preparation of 5- methyl -3- cyclohexyl -2- phenyl quinoxalines
3- phenyl -1- cyclohexyl -propyl- 2- alkynes -1- ketone 0.5mmol, 3- methyl-o-phenylenediamine 0.6mmol, ethanol 5mL are added In the reaction tube for entering 10mL, it is placed in 60 DEG C of oil bath, reacts 24h；Ethanol is boiled off, adds potassium tert-butoxide 1mmol, N, N- diformazan Yl acetamide 3mL, is placed in 30 DEG C of oil bath, reacts 2h.Add suitable quantity of water or sodium chloride solution stops reaction, be cooled to room Temperature.Reaction solution ethyl acetate dilutes, and washes three times, organic phase anhydrous Na2SO4It is dry, filter, concentration, column chromatography purifies to obtain 96.6mg target products, yield 64%.The nuclear-magnetism of the compound is characterized as below：1H NMR (400MHz, CDCl3) δ 7.92 (dd, J=7.8,1.4Hz, 1H), 7.62-7.44 (m, 7H), 3.16-3.04 (m, 1H), 2.83 (s, 3H), 1.87-1.77 (m, 6H), 1.74-1.67 (m, 1H), 1.42-1.18 (m, 4H)；13C NMR (100MHz, CDCl3) δ 158.4,154.0,140.7,140.4, 139.4,137.1,129.2,128.8,128.7,128.5,128.4,126.8,42.35 (s), 32.8,26.3,25.9,17.0.
Those of ordinary skill in the art understand, when technical scheme changes in following ranges, remain able to To same as the previously described embodiments or similar technique effect：
The structural formula of prepared polysubstituted quinoxaline derivant is as follows：
Wherein, R1For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
R2For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
R3For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
R4For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
R5For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
R6For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
The reaction equation of this method is as follows：
The solvent one is water, methanol, ethanol, isopropanol, toluene；The solvent two is dimethyl sulfoxide, N, N- dimethyl Formamide, n,N-dimethylacetamide or n-methyl-2-pyrrolidone.
This method specifically comprises the following steps：
(1) corresponding acetylenic ketone or derivatives thereof, corresponding o-phenylenediamine or derivatives thereof and solvent one are placed in reaction to hold In device, 4~22h (preferably 50~80 DEG C 5~20h of reaction) is reacted in 48~85 DEG C；
(2) solvent one in step (1) resulting material is evaporated, adds alkali and solvent two, react 1~6h in 20~55 DEG C (preferably 20~50 DEG C 1~5h of reaction), adds suitable quantity of water or sodium chloride solution terminates reaction after the completion of reaction,
(3) after the reaction product of step (2) is diluted with ethyl acetate, then through washing, organic phase is obtained；
(4) organic phase obtained by step (3) is purified through drying, filtering, concentration and column chromatography, obtains the polysubstituted quinoline Quinoline derivant；
Wherein, the molar ratio of corresponding acetylenic ketone or derivatives thereof, corresponding o-phenylenediamine or derivatives thereof and alkali for 1: 1~ 1.5: 1.5~2.5, the corresponding 2~12L solvents one of every mole of corresponding acetylenic ketone or derivatives thereof and 2~12L solvents two.
Corresponding 3~10L the solvents one of every mole of corresponding acetylenic ketone or derivatives thereof and 3~10L solvents two.
The alkali is sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide or cesium carbonate.
The foregoing is only a preferred embodiment of the present invention, therefore cannot limit the scope that the present invention is implemented according to this, i.e., The equivalent changes and modifications made according to the scope of the claims of the present invention and description, all should still belong in the range of the present invention covers.

Claims (7)

  1. A kind of 1. preparation method of polysubstituted quinoxaline derivant, it is characterised in that：Prepared polysubstituted quinoxaline derivant Structural formula it is as follows：
    Wherein, R1For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
    R2For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
    R3For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
    R4For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
    R5For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
    R6For hydrogen, halogen, alkyl, aryl, substituted aryl, acyl group, amino, nitro or alkoxy；
    The reaction equation of this method is as follows：
    The solvent one is water, methanol, ethanol, isopropanol, toluene；The solvent two is dimethyl sulfoxide, N, N- dimethyl formyls Amine, n,N-dimethylacetamide or n-methyl-2-pyrrolidone.
  2. 2. preparation method as claimed in claim 1, it is characterised in that：Include the following steps：
    (1) corresponding acetylenic ketone or derivatives thereof, corresponding o-phenylenediamine or derivatives thereof and solvent one are placed in reaction vessel, 4~22h is reacted in 48~85 DEG C；
    (2) solvent one in step (1) resulting material is evaporated, adds alkali and solvent two, react 1~6h in 20~55 DEG C, instead Suitable quantity of water is added after the completion of answering or sodium chloride solution terminates reaction；
    (3) after the reaction product of step (2) is diluted with ethyl acetate, then through washing, organic phase is obtained；
    (4) organic phase obtained by step (3) is purified through drying, filtering, concentration and column chromatography, obtains the polysubstituted quinoxaline and spread out Biology；
    Wherein, the molar ratio of corresponding acetylenic ketone or derivatives thereof, corresponding o-phenylenediamine or derivatives thereof and alkali is 1:1~1.5: 1.5~2.5, the corresponding 2~12L solvents one of every mole of corresponding acetylenic ketone or derivatives thereof and 2~12L solvents two.
  3. 3. preparation method as claimed in claim 2, it is characterised in that：Corresponding acetylenic ketone or derivatives thereof and corresponding neighbour The molar ratio of phenylenediamine or derivatives thereof is 1:1.2.
  4. 4. preparation method as claimed in claim 2, it is characterised in that：Every mole of corresponding acetylenic ketone or derivatives thereof is corresponding 3~10L solvents one and 3~10L solvents two.
  5. 5. preparation method as claimed in claim 2, it is characterised in that：The alkali is sodium hydroxide, potassium hydroxide, the tert-butyl alcohol Potassium, sodium tert-butoxide, sodium methoxide or cesium carbonate.
  6. 6. preparation method as claimed in claim 2, it is characterised in that：The reaction temperature of the step (1) is 50~80 DEG C, instead It is 5~20h between seasonable.
  7. 7. preparation method as claimed in claim 2, it is characterised in that：The reaction temperature of the step (2) is 20~50 DEG C, instead It is 1~5h between seasonable.
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