CN105001169B - A kind of synthetic method of 3 aminoquinoxaline 2 (1H) ketone compounds - Google Patents
A kind of synthetic method of 3 aminoquinoxaline 2 (1H) ketone compounds Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- 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
- C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
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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
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Abstract
The invention discloses a kind of synthetic method of 3 aminoquinoxaline 2 (1H) ketone compounds, quinoxaline 2 (1H) ketone derivatives, organic amine and copper acetate are dissolved in dimethyl sulfoxide (DMSO), under air conditionses, after 95~110 DEG C are reacted 10~25 hours, through isolating and purifying, 3 aminoquinoxaline 2 (1H) ketone compounds are produced, the wherein mol ratio of quinoxaline 2 (1H) ketone derivatives, organic amine and copper acetate is 0.9~1.2:2.8~3.3:0.03~0.06, every mM of quinoxaline 2 (1H) ketone derivatives need 2~3mL dimethyl sulphoxide solutions, and the general structure of above-mentioned quinoxaline 2 (1H) ketone derivatives is as follows：Wherein R1For hydrogen, alkyl, aryl, halogen or alkoxy, R2For hydrogen, benzyl, alkyl or ester group.The method of the present invention is raw materials used to be easy to get, and reaction condition is gentle, adds additive without extra, catalyst throwing amount is low, high income；Substrate spectrum is wide, and reaction selectivity is strong, post processing simplicity and green.
Description
Technical field
The invention belongs to technical field of organic synthesis, and in particular to a kind of 3- aminoquinoxalines -2 (1H) -one class compound
Synthetic method.
Background technology
3- aminoquinoxalines -2 (1H) -one class compound is the conventional pharmacophore in drug design field, contains the structure
The derivative of parent nucleus has a variety of pharmacological activity, is widely used as antitumor agent, anticancer, aldose reductase inhibitor, antibacterial
Agent etc., is the potential multipurpose lead compound of a class, is used in different clinical tests, should with wide exploitation
Use prospect.Chemists are attempting always in recent years.Some systems have been applied successfully to this reaction, achieve certain
Result of study.But there are problems, such as：Reactions steps complexity, severe reaction conditions, reaction time length, accessory substance are more, receive
Rate is low, substrate spectrum is narrower, it is necessary to unafforested environmentally friendly reagent such as strong oxidizer etc..
The content of the invention
It is an object of the invention to overcome prior art defect, there is provided a kind of 3- aminoquinoxalines -2 (1H) -one class chemical combination
The synthetic method of thing.
The concrete technical scheme of the present invention is as follows：
A kind of synthetic method of 3- aminoquinoxalines -2 (1H) -one class compound, by (1H) -one of quinoxaline -2 derivative,
Organic amine and copper acetate are dissolved in dimethyl sulfoxide (DMSO), under air conditionses, after 95~110 DEG C are reacted 10~25 hours, through dividing
From purifying, 3- aminoquinoxalines -2 (1H) the -one class compound, wherein (1H) -one of quinoxaline -2 derivative, organic amine are produced
Mol ratio with copper acetate is 0.9~1.2:2.8~3.3:0.03~0.06, every mM of quinoxaline -2 (1H) -one derivative
2~3mL dimethyl sulphoxide solutions are needed, the general structure of above-mentioned quinoxaline -2 (1H) -one derivative is as follows：
Wherein R1For hydrogen, alkyl, aryl, halogen or alkoxy, R2For hydrogen, benzyl, alkyl or ester group.
In a preferred embodiment of the invention, the R1For methyl or Cl, R2For hydrogen, benzyl, ethyl, acetic acid second
Ester group or 4- methoxy-benzyls.
In a preferred embodiment of the invention, (1H) -one of quinoxaline -2 derivative be quinoxaline -2 (1H) -
Ketone, 6,7- dimethyl-quinoxaline -2 (1H) -one, 6,7- bis- chloro- quinoxaline -2 (1H) -one, Benzoquinoxalines -2 (1H) -one, 1-
Benzyl-quinoxaline -2 (1H) -one, 1- ethyls-quinoxaline -2 (1H) -one, 1- ethyl acetate bases-quinoxaline -2 (1H) -one, 4- first
Oxy-benzyl-quinoxaline -2 (1H) -one, 6,7- dimethyl -1- benzyls-(1H) -one of quinoxaline -2 or the chloro- 1- benzyls of 6,7- bis- -
Quinoxaline -2 (1H) -one.
In a preferred embodiment of the invention, the organic amine is fatty amine.It is further preferred that described organic
Amine is morpholine, piperidines, nafoxidine, n-propylamine, isopropylamine, isopropylamine, cyclohexylamine, benzylamine, 4- methylbenzylamines, 2- methyl benzyls
Amine, 4- methoxybenzylamines, trifluoromethyl benzylamine, Alpha-Methyl benzylamine, benzhydrylamine or monoethanolamine.
In a preferred embodiment of the invention, it is (1H) -one of quinoxaline -2 derivative, organic amine and copper acetate is molten
In dimethyl sulfoxide (DMSO), under air conditionses, reacted 12~24 hours in 100 DEG C.
In a preferred embodiment of the invention, (1H) -one of quinoxaline -2 derivative, organic amine and copper acetate rub
You are than being 1:3:0.05.
In a preferred embodiment of the invention, every mM of quinoxaline -2 (1H) -one derivative needs 2mL dimethyl
Sulfoxide solution.
In a preferred embodiment of the invention, it is described isolate and purify including：Room temperature is dropped to after completion of the reaction, is added
Ethyl acetate dilutes, and is extracted with water, after organic phase is refiltered with anhydrous sodium sulfate drying, is produced through column chromatography separating purification described
3- aminoquinoxalines -2 (1H) -one class compound.
The beneficial effects of the invention are as follows：
1st, (1H) -one of quinoxaline -2 derivative, organic amine and copper acetate are dissolved in organic solvent by synthetic method of the invention
In, under air conditionses, after 95~110 DEG C are reacted 10~25 hours, through isolating and purifying, produce the 3- aminoquinoxalines -2
(1H) -one class compound, raw material is easy to get, and reaction condition is gentle, adds additive without extra, catalyst throwing amount is low, high income
(up to 98%)；Substrate spectrum is wide, and reaction selectivity is strong, post processing simplicity and green.
2nd, the system scope of application of synthetic method of the invention is wider, compatible halogen, methyl, methoxyl group, trifluoromethyl etc.
A variety of groups.
Embodiment
Technical scheme is further detailed and described below by way of embodiment.
Embodiment 1
The preparation of morpholinyl quinoxaline -2 (1H) -one
Quinoxaline -2 (1H) -one 0.2mmol, morpholine 0.6mmol, copper acetate 0.01mmol, dimethyl sulfoxide (DMSO) 2.0mL are added
In the reaction tube for entering 10mL, in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, be cooled to room temperature.Reaction
Liquid is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering is obtained through pillar layer separation
44.8mg target products, yield is 97%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ10.83(s,
1H),7.57–7.51(m,1H),7.26–7.18(m,2H),7.15–7.09(m,1H),4.07–4.00(m,4H),3.90–3.85
(m,4H)ppm；13C NMR(100MHz,CDCl3):δ153.4,150.8,133.1,128.5,126.0,125.3,124.3,
114.3,66.9,47.3ppm；HRMS(ESI,m/z):calculated for C12H13N3O2[M+H]+:232.1086,
found:232.1082.
Embodiment 2
The preparation of 6,7- dimethyl-morpholinyl quinoxaline -2 (1H) -one
By 6,7- dimethyl-quinoxaline -2 (1H) -one 0.2mmol, morpholine 0.6mmol, copper acetate 0.01mmol, dimethyl
Sulfoxide 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, cooling
To room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through column chromatography
Isolated 50.3mg target products, yield is 97%.The compound is characterized as below：1H NMR(400MHz,DMSO):δ
12.02 (s, 1H), 7.21 (s, 1H), 6.94 (s, 1H), 3.90-3.75 (m, 4H), 3.75-3.62 (m, 4H), 2.23 (d, J=
2.5Hz,6H)ppm；13C NMR(101MHz,DMSO):δ152.9,151.8,134.6,132.3,131.2,128.2,126.6,
115.6,67.0,47.7,20.3,19.9ppm；HRMS(ESI,m/z):calculated for C14H17N3O2[M+H]+:
260.1399,found:260.1397.
Embodiment 3
The preparation of chloro- morpholinyl quinoxaline -2 (1H) -one of 6,7- bis-
By 6,7- bis- chloro- quinoxaline -2 (1H) -one 0.2mmol, morpholine 0.6mmol, copper acetate 0.01mmol, dimethyl is sub-
Sulfone 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, be cooled to
Room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through column chromatography point
From 55.2mg target products are obtained, yield is 92%.The compound is characterized as below：1H NMR(400MHz,DMSO):δ12.23
(s,1H),7.55(s,1H),7.29(s,1H),3.95(s,4H),3.70(s,4H)ppm；13C NMR(100MHz,DMSO):δ
152.7,152.1,133.3,130.0,126.6,126.5,125.7,116.1,67.0,47.6ppm；HRMS(ESI,m/z):
calculated for C12H11Cl2N3O2[M+H]+:300.0307,found:300.0303.
Embodiment 4
The preparation of morpholinyl-Benzoquinoxalines -2 (1H) -one
By Benzoquinoxalines -2 (1H) -one 0.2mmol, morpholine 0.6mmol, copper acetate 0.01mmol, dimethyl sulfoxide (DMSO)
2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, be cooled to room
Temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through pillar layer separation
43.3mg target products are obtained, yield is 77%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ9.42(s,
1H), 7.98 (s, 1H), 7.86 (d, J=7.4Hz, 1H), 7.79 (d, J=7.6Hz, 1H), 7.50-7.35 (m, 3H), 4.13-
4.01(m,4H),3.96–3.80(m,4H)ppm；13C NMR(100MHz,CDCl3):δ153.1,150.3,132.6,131.0,
131.0,128.3,127.8,126.6,125.9,124.9,123.3,109.7,67.0,47.4ppm；HRMS(ESI,m/z):
calculated for C16H15N3O2[M+H]+:282.1243,found:282.1239.
Embodiment 5
The preparation of 1- benzyls-morpholinyl quinoxaline -2 (1H) -one
By 1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, morpholine 0.6mmol, copper acetate 0.01mmol, dimethyl sulfoxide (DMSO)
2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, be cooled to room
Temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through pillar layer separation
62.9mg target products are obtained, yield is 98%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ7.61–
7.51(m,1H),7.30(ddd,J1=7.5Hz, J2=6.2Hz, J3=1.3Hz, 2H), 7.26-7.04 (m, 6H), 5.47 (s,
2H),4.05–3.95(m,4H),3.86(dd,J1=6.0Hz, J2=3.5Hz, 4H) ppm；13C NMR(100MHz,CDCl3):δ
152.3,150.8,135.5,133.2,130.2,128.9,127.5,127.0,126.7,125.4,123.9,114.1,67.0,
47.6,46.1ppm；HRMS(ESI,m/z):calculated for C19H19N3O2[M+H]+:322.1556,found:
322.1554.
Embodiment 6
The preparation of 1- ethyls-morpholinyl quinoxaline -2 (1H) -one
By 1- ethyls-quinoxaline -2 (1H) -one 0.2mmol, morpholine 0.6mmol, copper acetate 0.01mmol, dimethyl sulfoxide (DMSO)
2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, be cooled to room
Temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through pillar layer separation
49.2mg target products are obtained, yield is 95%.The compound is characterized as below：1H NMR(400MHz,DMSO):δ7.50–
7.42(m,2H),7.31(dd,J1=8.3Hz, J2=1.3Hz, 1H), 7.27-7.21 (m, 1H), 4.24 (q, J=7.1Hz,
2H), (t, J=7.1Hz, the 3H) ppm of 3.91-3.80 (m, 4H), 3.76-3.65 (m, 4H), 1.23；13C NMR(100MHz,
DMSO)δ151.7,151.3,133.5,130.3,127.3,126.3,124.3,114.8,67.0,48.0,37.9,13.2ppm；
HRMS(ESI,m/z):calculated for C14H17N3O2[M+H]+:260.1399,found:260.1396.
Embodiment 7
It is prepared by 1- ethyl acetate bases-morpholinyl quinoxaline -2 (1H) -one
By 1- ethyl acetate bases-quinoxaline -2 (1H) -one 0.2mmol, morpholine 0.6mmol, copper acetate 0.01mmol, diformazan
Base sulfoxide 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, it is cold
But to room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through post color
Isolated 62.1mg target products are composed, yield is 98%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ
7.59-7.52 (m, 1H), 7.26-7.22 (m, 2H), 7.01-6.93 (m, 1H), 4.99 (s, 2H), 4.25 (q, J=7.2Hz,
2H),4.01–3.93(m,4H),3.88–3.80(m,4H),1.31–1.24(m,3H)ppm；13C NMR(100MHz,CDCl3)δ
167.3,152.0,150.2,133.1,123.0,127.1,125.5,124.1,112.7,67.0,62.0,47.5,43.9,
14.1ppm；HRMS(ESI,m/z):calculated for C16H19N3O4[M+H]+:318.1454,found:318.1451.
Embodiment 8
The preparation of 4- methoxy-benzyls-morpholinyl quinoxaline -2 (1H) -one
By 4- methoxy-benzyls-quinoxaline -2 (1H) -one 0.2mmol, morpholine 0.6mmol, copper acetate 0.01mmol, diformazan
Base sulfoxide 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, it is cold
But to room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through post color
Isolated 65.4mg target products are composed, yield is 93%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ
7.58–7.53(m,1H),7.23–7.16(m,5H),6.86–6.79(m,2H),5.41(s,2H),4.01–3.95(m,4H),
3.89–3.84(m,4H),3.76(s,3H)ppm；13C NMR(100MHz,CDCl3):δ159.0,152.3,150.9,133.2,
130.2,128.2,127.5,127.0,125.4,123.8,114.2,114.1,67.0,55.3,47.6,45.6ppm；HRMS
(ESI,m/z):calculated for C20H21N3O3[M+H]+:352.1661,found:352.1657.
Embodiment 9
The preparation of 6,7- dimethyl -1- benzyls-morpholinyl quinoxaline -2 (1H) -one
By 6,7- dimethyl -1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, morpholine 0.6mmol, copper acetate
0.01mmol, dimethyl sulfoxide (DMSO) 2.0mL are added in 10mL reaction tube, in the oil bath for being placed in 100 DEG C, are reacted under air conditionses
12h.Stop reaction, be cooled to room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4It is dry
Dry, filtering obtains 54.5mg target products, yield is 78% through pillar layer separation.The compound is characterized as below：1H NMR
(400MHz,CDCl3):δ7.38–7.27(m,3H),7.24(dt,J1=12.0Hz, J2=4.1Hz, 3H), 6.92 (s, 1H),
(d, J=9.4Hz, the 6H) ppm of 5.44 (s, 2H), 3.96-3.83 (m, 8H), 2.26；13C NMR(100MHz,CDCl3):δ
152.2,150.7,135.7,134.7,132.6,131.3,128.8,128.2,127.5,127.4,126.7,114.7,66.9,
47.7,46.0,20.2,19.1ppm；HRMS(ESI,m/z):calculated for C21H23N3O2[M+H]+:350.1869,
found:350.1865.
Embodiment 10
The preparation of the chloro- 1- benzyls of 6,7- bis--morpholinyl quinoxaline -2 (1H) -one
By the chloro- 1- benzyls of 6,7- bis--quinoxaline -2 (1H) -one 0.2mmol, morpholine 0.6mmol, copper acetate 0.01mmol,
Dimethyl sulfoxide (DMSO) 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop anti-
Should, it is cooled to room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filter, warp
Pillar layer separation obtains 60.1mg target products, and yield is 77%.The compound is characterized as below：1H NMR(400MHz,
CDCl3):δ7.60(s,1H),7.39–7.27(m,3H),7.23–7.16(m,3H),5.38(s,2H),4.07–4.00(m,
4H),3.87–3.81(m,4H)ppm；13C NMR(101MHz,CDCl3):δ151.8,150.6,134.6,132.9,129.4,
129.1,128.3,127.9,127.5,127.4,126.7,115.3,66.947.5,46.4ppm；HRMS(ESI,m/z):
calculated for C19H17Cl2N3O2[M+H]+:390.0776,found:390.0773.
Embodiment 11
The preparation of 3- piperidyls -1- benzyls-quinoxaline -2 (1H) -one
By 1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, piperidines 0.6mmol, copper acetate 0.01mmol, dimethyl sulfoxide (DMSO)
2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, be cooled to room
Temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through pillar layer separation
60.0mg target products are obtained, yield is 94%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ7.53(s,
1H), 7.29 (d, J=7.3Hz, 2H), 7.23 (t, J=8.1Hz, 3H), 7.12 (dd, J1=17.3Hz, J2=14.4Hz, 3H),
(s, the 6H) ppm of 5.47 (s, 2H), 3.89 (d, J=5.3Hz, 4H), 1.72；13CNMR(101MHz,CDCl3):δ152.5,
151.4,135.7,133.7,130.0,128.8,127.4,126.7,126.6,124.6,123.7,114.0,48.4,46.1,
26.1,24.9ppm；HRMS(ESI,m/z):calculated for C20H21N3O[M+H]+:320.1763,found:
320.1761.
Embodiment 12
The preparation of 3- nafoxidine base -1- benzyls-quinoxaline -2 (1H) -one
By 1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, nafoxidine 0.6mmol, copper acetate 0.01mmol, dimethyl
Sulfoxide 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, cooling
To room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through column chromatography
Isolated 44.6mg target products, yield is 73%.The compound is characterized as below：1HNMR(400MHz,CDCl3):δ
7.51–7.44(m,1H),7.34–7.27(m,2H),7.24(dt,J1=13.3Hz, J2=4.3Hz, 3H), 7.17-7.10 (m,
1H),7.03(dd,J1=6.1Hz, J2=1.4Hz, 2H), 5.44 (s, 2H), 3.99 (s, 4H), 1.99-1.92 (m, 4H) ppm
；13C NMR(100MHz,CDCl3):δ152.8,149.0,135.8,134.9,129.3,128.8,127.4,126.6,125.8,
123.8,123.3,113.9,49.7,45.8ppm；HRMS(ESI,m/z):calculated for C19H19N3O[M+H]+:
306.1606,found:306.1604.
Embodiment 13
The preparation of 3- n-propylamine base -1- benzyls-quinoxaline -2 (1H) -one
By 1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, n-propylamine 0.6mmol, copper acetate 0.01mmol, dimethyl is sub-
Sulfone 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 24h is reacted under air conditionses.Stop reaction, be cooled to
Room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through column chromatography point
From 53.4mg target products are obtained, yield is 91%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ7.55
(dd,J1=8.0Hz, J2=1.3Hz, 1H), 7.35-7.26 (m, 3H), 7.25-7.04 (m, 5H), 6.44 (s, 1H), 5.50 (s,
2H),3.59–3.49(m,2H),1.74(dd,J1=14.5Hz, J2=7.3Hz, 2H), 1.04 (t, J=7.4Hz, 3H) ppm；13C NMR(100MHz,CDCl3):δ152.7,149.0,135.3,134.5,128.9,128.6,127.6,126.7,126.2,
124.1,123.8,114.4,46.2,42.7,22.4,11.6ppm；HRMS(ESI,m/z):calculated for C18H19N3O
[M+H]+:294.1606,found:294.1604.
Embodiment 14
The preparation of 3- isopropylamine bases -1- benzyls-quinoxaline -2 (1H) -one
By 1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, isopropylamine 0.6mmol, copper acetate 0.01mmol, dimethyl is sub-
Sulfone 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 24h is reacted under air conditionses.Stop reaction, be cooled to
Room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through column chromatography point
From 56.9mg target products are obtained, yield is 97%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ7.55
(d, J=7.8Hz, 1H), 7.32 (dd, J1=11.4, J2=4.2Hz, 2H), 7.26-7.04 (m, 6H), 6.29 (d, J=
7.6Hz,1H),5.50(s,2H),4.35(dd,J1=14.1, J2=6.7Hz, 1H), 1.33 (d, J=6.5Hz, 6H) ppm；13C
NMR(101MHz,CDCl3):δ152.2,148.1,135.4,134.6,128.9,128.5,127.6,126.8,126.2,
124.1,123.7,114.4,46.2,42.4,22.5ppm；HRMS(ESI,m/z):calculated for C18H19N3O[M+H
]+:294.1606,found:294.1604.
Embodiment 15
The preparation of 3- n-butylamine-baseds -1- benzyls-quinoxaline -2 (1H) -one
By 1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, n-butylamine 0.6mmol, copper acetate 0.01mmol, dimethyl is sub-
Sulfone 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 24h is reacted under air conditionses.Stop reaction, be cooled to
Room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through column chromatography point
From 60.2mg target products are obtained, yield is 98%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ7.55
(dd,J1=7.9Hz, J2=1.2Hz, 1H), 7.38-7.26 (m, 3H), 7.25-7.16 (m, 3H), 7.15-7.02 (m, 2H),
6.41(s,1H),5.50(s,2H),3.57(td,J1=7.1Hz, J2=5.9Hz, 2H), 1.77-1.64 (m, 2H), 1.48 (dq,
J1=14.5Hz, J2=7.3Hz, 2H), 0.99 (t, J=7.4Hz, 3H) ppm；13C NMR(100MHz,CDCl3)δ152.2,
149.0,135.3,134.5,128.9,128.6,127.6,126.7,126.2,124.1,123.8,114.4,46.2,40.6,
31.3,20.2,13.8ppm；HRMS(ESI,m/z):calculated for C19H21N3O[M+H]+:3081763,found:
308.1761.
Embodiment 16
The preparation of 3- cyclohexylaminos -1- benzyls-quinoxaline -2 (1H) -one
By 1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, cyclohexylamine 0.6mmol, copper acetate 0.01mmol, dimethyl is sub-
Sulfone 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 24h is reacted under air conditionses.Stop reaction, be cooled to
Room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through column chromatography point
From 32.0mg target products are obtained, yield is 48%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ7.54
(dd, J=8.0,1.3Hz, 1H), 7.37-7.27 (m, 2H), 7.26-7.00 (m, 6H), 6.36 (d, J=8.1Hz, 1H), 5.49
(s,2H),4.14–4.00(m,1H),2.17–2.06(m,2H),1.86–1.74(m,2H),1.61–0.98(m,6H)ppm；13C
NMR(100MHz,CDCl3):δ152.2,148.0,135.4,134.6,128.9,128.5,127.6,126.8,126.2,
124.1,123.6,114.3,53.4,49.1,46.2,32.8,25.7,24.8ppm；HRMS(ESI,m/z):calculated
for C21H23N3O[M+H]+:334.1919,found:334.1917.
Embodiment 17
The preparation of 3- benzamido groups -1- benzyls-quinoxaline -2 (1H) -one
By 1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, benzylamine 0.6mmol, copper acetate 0.01mmol, dimethyl sulfoxide (DMSO)
2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, be cooled to room
Temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through pillar layer separation
58.7mg target products are obtained, yield is 86%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ7.59(d,
J=7.9Hz, 1H), 7.47-7.26 (m, 7H), 7.26-7.18 (m, 4H), 7.18-7.05 (m, 2H), 6.70 (s, 1H), 5.51
(s, 2H), 4.77 (d, J=5.8Hz, 2H) ppm；13C NMR(100MHz,CDCl3):δ152.1,148.7,138.2,135.3,
134.3,128.9,128.8,128.7,128.1,127.6,127.5,126.8,126.4,124.2,124.1,114.4,46.2,
45.0ppm；HRMS(ESI,m/z):calculated for C22H19N3O[M+H]+:342.1606,found:342.1602.
Embodiment 18
The preparation of 3- (4- methylbenzylamines base) -1- benzyls-quinoxaline -2 (1H) -one
By 1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, 4- methylbenzylamine 0.6mmol, copper acetate 0.01mmol, diformazan
Base sulfoxide 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, it is cold
But to room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through post color
Isolated 65.4mg target products are composed, yield is 92%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ
7.58 (d, J=7.8Hz, 1H), 7.31 (t, J=7.4Hz, 4H), 7.26-7.05 (m, 8H), 6.67 (s, 1H), 5.50 (s,
2H), 4.72 (d, J=5.7Hz, 2H), 2.35 (s, 3H) ppm；13C NMR(100MHz,CDCl3):δ152.1,148.7,
137.2,135.3,135.1,134.3,129.3,128.9,128.8,128.1,127.6,126.7,126.4,124.2,
124.0,114.4,46.2,44.8,21.1ppm；HRMS(ESI,m/z):calculated for C23H21N3O[M+H]+:
356.1763,found:356.1759.
Embodiment 19
The preparation of 3- (2- methylbenzylamines base) -1- benzyls-quinoxaline -2 (1H) -one
By 1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, 2- methylbenzylamine 0.6mmol, copper acetate 0.01mmol, diformazan
Base sulfoxide 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, it is cold
But to room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through post color
Isolated 57.5mg target products are composed, yield is 81%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ
7.59 (d, J=7.9Hz, 1H), 7.41-7.28 (m, 3H), 7.26-7.06 (m, 9H), 6.55 (s, 1H), 5.50 (s, 2H),
4.74 (d, J=5.5Hz, 2H), 2.42 (s, 3H) ppm；13C NMR(100MHz,CDCl3):δ152.0,148.6,136.7,
135.9,135.3,134.3,130.5,128.9,128.9,128.8,127.8,127.6,126.8,126.4,126.2,
124.2,124.1,114.4,46.2,43.2,19.2ppm；HRMS(ESI,m/z):calculated for C23H21N3O[M+H
]+:356.1763,found:356.1759.
Embodiment 20
The preparation of 3- (4- methoxybenzyls amido) -1- benzyls-quinoxaline -2 (1H) -one
By 1- benzyls-(1H) -one 0.2mmol, 4- methoxybenzylamine 0.6mmol of quinoxaline -2, copper acetate 0.01mmol, two
Methyl sulfoxide 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction,
It is cooled to room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through post
Chromatographic isolation obtains 70.5mg target products, and yield is 95%.The compound is characterized as below：1H NMR(400MHz,CDCl3):
δ 7.58 (d, J=7.9Hz, 1H), 7.39-7.27 (m, 4H), 7.26-7.06 (m, 6H), 6.94-6.79 (m, 2H), 6.64 (s,
1H), (s, the 3H) ppm of 5.49 (s, 2H), 4.69 (d, J=5.7Hz, 2H), 3.80；13C NMR(101MHz,CDCl3):δ159.1,
152.1,148.7,135.3,134.3,130.2,129.5,128.9,128.8,127.6,126.7,126.4,124.2,
124.0,114.4,114.1,55.3,46.2,44.5ppm；HRMS(ESI,m/z):calculated for C23H21N3O2[M+
H]+:372.1712,found:372.1708.
Embodiment 21
The preparation of 3- (4- trifluoromethyl benzylamines base) -1- benzyls-quinoxaline -2 (1H) -one
By 1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, trifluoromethyl benzylamine 0.6mmol, copper acetate 0.01mmol, two
Methyl sulfoxide 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction,
It is cooled to room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through post
Chromatographic isolation obtains 43.4mg target products, and yield is 53%.The compound is characterized as below：1H NMR(400MHz,CDCl3):
δ7.75–7.44(m,5H),7.39–7.26(m,3H),7.25–7.04(m,5H),6.79(s,1H),5.51(s,2H),4.84
(d, J=6.1Hz, 2H) ppm；13C NMR(100MHz,CDCl3):δ152.01(s),148.67(s),142.57(s),135.19
(s), 134.06 (s), 129.69 (q, J=32.4Hz), 128.94 (s), 128.91 (s), 128.16 (s), 127.71 (s),
126.76 (s), 126.52 (s), 125.57 (q, J=3.7Hz), 124.47 (s), 124.30 (s), 122.45 (q, J=
270.5Hz),114.51(s),46.25(s),44.36(s)ppm；19F NMR(376MHz,CDCl3)δ-62.42(s,3F)ppm；
HRMS(ESI,m/z):calculated for C23H18F3N3O[M+H]+:410.1480,found:410.1475.
Embodiment 22
The preparation of 3- (Alpha-Methyl benzamido group) -1- benzyls-quinoxaline -2 (1H) -one
By 1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, Alpha-Methyl benzylamine 0.6mmol, copper acetate 0.01mmol, diformazan
Base sulfoxide 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, it is cold
But to room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through post color
Isolated 54.7mg target products are composed, yield is 77%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ
7.52 (d, J=8.0Hz, 1H), 7.46 (d, J=7.5Hz, 2H), 7.38-7.26 (m, 5H), 7.25-7.04 (m, 6H), 6.69
(d, J=7.8Hz, 1H), 5.50 (t, J=13.3Hz, 2H), 5.41 (dd, J1=13.5Hz, J2=6.2Hz, 1H), 1.65 (d, J
=6.9Hz, 3H) ppm；13C NMR(100MHz,CDCl3):δ152.0,147.9,143.6,135.3,134.4,128.9,
128.7,128.6,127.6,127.2,126.8,126.5,126.4,124.1,124.0,114.3,50.0,46.2,
22.2ppm；HRMS(ESI,m/z):calculated for C23H21N3O[M+H]+:356.1763,found:356.1761.
Embodiment 23
The preparation of 3- (benzhydrylamine base) -1- benzyls-quinoxaline -2 (1H) -one
By 1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, benzhydrylamine 0.6mmol, copper acetate 0.01mmol, dimethyl
Sulfoxide 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, cooling
To room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through column chromatography
Isolated 39.2mg target products, yield is 47%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ
7.50 (d, J=7.8Hz, 1H), 7.32 (ddd, J1=20.0Hz, J2=11.5Hz, J3=7.1Hz, 12H), 7.25-6.95 (m,
6H), (s, the 1H) ppm of 6.55 (d, J=8.2Hz, 1H), 5.50 (s, 2H), 1.56；13C NMR(100MHz,CDCl3):δ152.0,
147.8,141.9,135.3,134.2,128.9,128.6,127.6,127.4,126.8,126.7,124.3,124.1,
114.3,58.1,46.3ppm；HRMS(ESI,m/z):calculated for C28H23N3O[M+H]+:418.1919,found:
418.1911.
Embodiment 24
The preparation of 3- ethanol amido -1- benzyls-quinoxaline -2 (1H) -one
By 1- benzyls-quinoxaline -2 (1H) -one 0.2mmol, monoethanolamine 0.6mmol, copper acetate 0.01mmol, dimethyl is sub-
Sulfone 2.0mL is added in 10mL reaction tube, and in the oil bath for being placed in 100 DEG C, 12h is reacted under air conditionses.Stop reaction, be cooled to
Room temperature.Reaction solution is diluted with ethyl acetate, is extracted three times with water, organic phase anhydrous Na2SO4Dry, filtering, through column chromatography point
From 39.0mg target products are obtained, yield is 66%.The compound is characterized as below：1H NMR(400MHz,CDCl3):δ7.55–
7.48(m,1H),7.30(dd,J1=15.4Hz, J2=7.9Hz, 3H), 7.25-7.08 (m, 5H), 6.87 (s, 1H), 5.50 (s,
2H),4.50(s,1H),3.96–3.88(m,2H),3.75(dd,J1=9.4Hz, J2=5.6Hz, 2H) ppm；13C NMR
(100MHz,CDCl3):δ152.1,149.9,135.1,133.3,128.9,128.8,127.7,126.7,125.9,124.5,
124.4,114.5,63.5,46.3,45.0ppm；HRMS(ESI,m/z):calculated for C17H17N3O2[M+H]+:
296.1399,found:296.1397.
Skilled person will appreciate that, when technical parameter of the invention changes in sub-ranges, remain to access with it is upper
The same or like technique effect of embodiment is stated, protection scope of the present invention is come under：
A kind of synthetic method of 3- aminoquinoxalines -2 (1H) -one class compound, by (1H) -one of quinoxaline -2 derivative,
Organic amine (preferred fat amine) and copper acetate are dissolved in dimethyl sulfoxide (DMSO), under air conditionses, and 10~25 are reacted in 95~110 DEG C
After hour (being preferable over 100 DEG C to react 12~24 hours), through isolating and purifying, 3- aminoquinoxalines -2 (1H) the -one class is produced
The mol ratio of compound, wherein quinoxaline -2 (1H) -one derivative, organic amine and copper acetate is 0.9~1.2:2.8~3.3:
0.03~0.06, every mM of (1H) -one of quinoxaline -2 derivative needs 2~3mL dimethyl sulphoxide solutions, above-mentioned quinoxaline -2
The general structure of (1H) -one derivative is as follows：
Wherein R1For hydrogen, alkyl, aryl, halogen or alkoxy, R2For hydrogen, benzyl, alkyl or ester group.
It is preferred that R1For methyl or Cl, R2For hydrogen, benzyl, ethyl, ethyl acetate base or 4- methoxy-benzyls.
The foregoing is only a preferred embodiment of the present invention, therefore can not 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 synthetic method of (1H) -one class compound of 3- amidos quinoxaline -2, it is characterised in that：By quinoxaline -2 (1H) -
Ketone derivatives, organic amine and copper acetate are dissolved in dimethyl sulfoxide (DMSO), under air conditionses, small in 95~110 DEG C of reactions 10~25
Shi Hou, through isolating and purifying, produces 3- aminoquinoxalines -2 (1H) the -one class compound, wherein quinoxaline -2 (1H) -one derives
The mol ratio of thing, organic amine and copper acetate is 0.9~1.2:2.8~3.3:0.03~0.06, every mM of quinoxaline -2 (1H) -
Ketone derivatives need 2~3mL dimethyl sulphoxide solutions, and above-mentioned organic amine is fatty amine, above-mentioned quinoxaline -2 (1H) -one derivative
General structure is as follows：
Wherein R1For methyl or Cl, R2For hydrogen, benzyl, ethyl, ethyl acetate base or 4- methoxy-benzyls.
2. synthetic method as claimed in claim 1, it is characterised in that：(1H) -one of quinoxaline -2 derivative be quinoxaline -
2 (1H) -one, 6,7- dimethyl-quinoxaline -2 (1H) -one, 6,7- bis- chloro- quinoxaline -2 (1H) -one, Benzoquinoxalines -2
(1H) -one, 1- benzyls-quinoxaline -2 (1H) -one, 1- ethyls-quinoxaline -2 (1H) -one, 1- ethyl acetate bases-quinoxaline -2
(1H) -one, 4- methoxy-benzyls-quinoxaline -2 (1H) -one, 6,7- dimethyl -1- benzyls-(1H) -one of quinoxaline -2 or 6,7-
Two chloro- 1- benzyls-quinoxaline -2 (1H) -one.
3. synthetic method as claimed in claim 1, it is characterised in that：The organic amine is morpholine, piperidines, nafoxidine, just
Propylamine, isopropylamine, cyclohexylamine, benzylamine, 4- methylbenzylamines, 2- methylbenzylamines, 4- methoxybenzylamines, trifluoromethyl benzylamine, α-first
Base benzylamine, benzhydrylamine or monoethanolamine.
4. synthetic method as claimed in claim 1 or 2, it is characterised in that：By (1H) -one of quinoxaline -2 derivative, organic amine
It is dissolved in dimethyl sulfoxide (DMSO), under air conditionses, is reacted 12~24 hours in 100 DEG C with copper acetate.
5. synthetic method as claimed in claim 1 or 2, it is characterised in that：(1H) -one of quinoxaline -2 derivative, organic amine and
The mol ratio of copper acetate is 1:3:0.05.
6. synthetic method as claimed in claim 1 or 2, it is characterised in that：Every mM of (1H) -one of quinoxaline -2 derivative is needed
2mL dimethyl sulphoxide solutions.
7. synthetic method as claimed in claim 1 or 2, it is characterised in that：It is described isolate and purify including：Drop to after completion of the reaction
Room temperature, adds ethyl acetate dilution, is extracted with water, pure through pillar layer separation after organic phase is refiltered with anhydrous sodium sulfate drying
Change produces (1H) -one class compound of 3- amidos quinoxaline -2.
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