CN105949119A - Method for synthesizing polysubstituted-2(1H)-quinolinone compounds - Google Patents
Method for synthesizing polysubstituted-2(1H)-quinolinone compounds Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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Abstract
The invention relates to a method for synthesizing polysubstituted-2(1H)-quinolinone compounds. The method comprises the following steps: adding 2-(arylacetylenyl)aniline and diaryliodoonium salt as raw materials, adding a catalyst, adding additives, introducing carbon dioxide, and stirring to react at 40-120 DEG C in an organic solvent for 6-24 hours; after the reaction finishes, cooling to room temperature, and slowly releasing unreacted carbon dioxide to atmospheric pressure; carrying out water washing, extraction, washing, drying and reduced pressure concentration on the reaction solution to obtain a crude product; and purifying by column chromatography to obtain the series polysubstituted-2(1H)-quinolinone compounds. By adopting the multicomponent one-pot process, the synthesis method overcomes the defects of multiple steps and complex operation in the traditional synthesis process of the compounds. The method provided by the invention has the advantages of mild reaction conditions and safe and simple operation. Therefore, the synthesis method is beneficial to industrial production, and has favorable application prospects in organic, medical and pesticide synthesis.
Description
Technical field
The present invention relates to medication chemistry synthesis technical field, be specifically related to polysubstituted 2 (the 1H)-quinolinones chemical combination of a kind of synthesis
The method of thing.
Background technology
2 (1H)-quinolinones and derivant thereof are the nitrogen-containing heterocycle compounds that a class is important, are present in a lot of natural plants, as
(McCormick, J.L. in the alkaloid of Evodia；McKee,T.C.；Cardellina,J.H.,II；Boyd,M.R.J.Nat.
Prod.1996,59,469；Yang,S.S.；Cragg,G.M.；Newman,D.J.；Bader,J.P.J.Nat.Prod.2001,64,
265).Different substituted 2 (1H)-quinolinones compounds have different biological activitys and wide physiology, pharmacologically active,
Thus have a wide range of applications in chemical industry, medicine and pesticide each side.At field of medicaments, 2 (1H)-quinolinones compound tools
Have the effect such as antitumor, schizophrenia, antiplatelet aggregation, positive inotropic action, antiulcer (D.；Kling,R.
C.；Skultety,M.；Leuner,K.；Gmeine,P.J.Med.Chem.2014,57,4861；Jayashree,B.
S.；Thomas,S.；Nayak,Y.Med.Chem.Res.2010,19,193；Raitio,K.H.；Savinainen,J.R.；J.；Laitinen,J.T.；Poso,A.；T.；Nevalaine,T.J.Med.Chem.2006,49,
2022；Rowley,M.；Kulagowski,J.J.；Watt,A.P.；Rathbone,D.；Stevenson,G.I.；Carling,R.W.；
Baker,R.；Marshall,G.R.；Kemp,J.A.；Foster,A.C.；Grimwood,S.；Hargreaves,R.；Hurley,C.；
Saywell,K.L.；Tricklebank,M.D.；Leeson, P.D.J.Med.Chem.1997,40,4053), such as novel anti-essence
The sick medicine Aripiprazole (Aripiprazole) of god, treats intermittent claudication medicine cilostazol (Cilostazol) and can be used for controlling
Treat chronic congestion sexual exhaustion medicine vesnarinone (Vesnarinone), be all 2 (1H)-quinolinones compound (Braun, D.E.；
Gelbrich,T.；Kahlenberg,V.；Tessadri,R.；Wieser,J.；Griesser,U.J.Cryst.Growth Des.2009,9,
1054；Roma,G.；Braccio,M.D.；Grossi,G.；Piras,D.；Leoncini,G.；Bruzzese,D.；Signorello,M.
G.；Fossa,P.；Mosti,L.J.Med.Chem.2007,50,2886；Gardner,L.；M.；Zahid,N.；
Uetrecht,J.P.Chem.Res.Toxicol.2005,18,1384).In terms of pesticide, 2 (1H)-quinolinones compounds are by extensively
General as herbicide, insecticide and bacteria remover etc..Just because of its importance, its synthetic method is constantly subjected to the extensive of people
Pay close attention to.
The method of conventional synthesis 2 (1H)-quinolinones compound typically will be through several synthesis steps, and process complexity is loaded down with trivial details, or
Person needs reaction condition (McQuaid, the L.A. of harshness；Lodge,E.C.R.S.D.；Pralong,E.；Calligaro,J.E.W.
D.O.；O'Malley,P.J.J.Med.Chem.1992,35,3423；DeVita,R.J.；Hollings,D.D.；Goulet,M.T.；
Wyvratt,M.J.；Fisher,M.H.；Lo,J.-L.；Yang,Y.-T.；Cheng,K.；Smith,R.G.Bioorg.Med.Chem.
Lett.1999,9,2621).In order to overcome these shortcomings, nearest chemist has developed the cyclization that some are transition metal-catalyzed
New method, including: the adjacent Iodoaniline of (1) palladium chtalyst, alkynes and cyclization (Kadnikov, the D.V. of carbon monoxide；
Larock,R.C.J.Org.Chem.2004,69,6772)；(2) the N-pyridine radicals aniline of palladium chtalyst, interior alkynes and Mo (CO)6
[3+2+1] cyclization (Chen, J.；Natte,K.；Spannenberg,A.；Neumann,H.；Beller,M.；Wu,X.-F.
Chem.Eur.J.2014,20,14189)；(3) cyclization (Iwai, the T. of N-arylamino formyl chloride and the interior alkynes of iridium catalysis；
Fujihara,T.；Terao,J.；Tsuji,Y.J.Am.Soc.Chem.2010,132,9602)；(4) Benzoylamide of rhodium catalysis with
Oxidative cyclization reaction (Ackermann, the L. of interior alkynes；Lygin,A.V.；Hofman,N.Angew.Chem.Int.Ed.2011,
50,6379)；And three component oxidative cyclizations of the aniline of (5) rhodium catalysis, carbon monoxide and interior alkynes react (Li, X.；Li,X.；
Jiao,N.J.Am.Soc.Chem.2015,137,9246)。
Although the Study of synthesis method of 2-(1H)-one compounds has been achieved with the biggest progress, but some method needs also exist for
Expensive metallic catalyst, uses the poisonous carbonyl source such as carbon monoxide, needs the problems such as high reaction temperature.The most still
Need to develop the new synthetic method of 2 easy, efficient, safe (1H)-quinolinones compounds.
Summary of the invention
The invention provides a kind of method synthesizing polysubstituted 2 (1H)-quinolinones compounds, its principle be with carbon dioxide with
2-(aryl ethane base) aniline, first under the effect of silver salt and alkali, generates 4-hydroxyl-2 (1H)-quinolinones compound intermediate,
Diaryl group iodized salt generation arylation reaction under the effect of alkali again, polysubstituted 2 (the 1H)-quinolinones compounds of one-step synthesis.
The method is with carbon dioxide as carbonyl source, environmentally friendly, and method is simple, operates safety, has potential practical value.
The purpose of the present invention is achieved through the following technical solutions:
A kind of method synthesizing polysubstituted 2 (1H)-quinolinones compounds, in autoclave, adds 2-(aryl ethane
Base) aniline and diaryl group iodized salt be raw material, after adding catalyst, add additive, with organic solvent as solvent, be passed through
Carbon dioxide, stirring reaction 6～24 hours at 40～120 DEG C, reaction is cooled to room temperature after terminating, and slowly release is the most anti-
The carbon dioxide answered to normal pressure, reactant liquor through washing, extract, wash, being dried, after concentrating under reduced pressure crude product, through post layer
Analysis purifies polysubstituted 2 (the 1H)-quinolinones compounds obtained described in series；
Its reaction is shown below:
Wherein, R1Including methyl, fluorine-based, chloro, bromo or trifluoromethyl；
R2Including methyl, fluorine-based, chloro, bromo, methoxyl group, cyano group, dimethyl or trifluoromethyl；
R3And R4Including fluorine-based, chloro, bromo, cyano group, methyl, trifluoromethyl, the tert-butyl group, nitro or trimethyl.
In said method, described R1Including 5-methyl, 5-fluorine, 5-chlorine, 5-bromine, 5-trifluoromethyl, 4-fluorine, 4-chlorine, 4-first
Base, 4,6-dichloro or 4-bromine；
Described R2Including 2-fluorine, 2-chlorine, 2-bromine, 2-methyl, 3-fluorine, 3-chlorine, 3-bromine, 3-methyl, 3-methoxyl group, 4-fluorine,
4-chlorine, 4-bromine, 4-methyl, 4-trifluoromethyl, 4-cyano group or 2,4-dimethyl；
Described R3And R4Including 2-fluorine, 3-fluorine, 2-fluorine, 2-chlorine, 4-chlorine, 2-cyano group, 3-methyl, 4-bromine, 4-trifluoromethyl,
The 4-tert-butyl group, 4-nitro or 2,4,6-trimethyl；
Described catalyst is silver salt；Described additive is alkali.
In said method, autoclave uses gap type high-pressure reactor or continuous high pressure reactor；2-(aryl ethane
Base) mol ratio of aniline and diaryl group iodized salt is 1:(1～1.5).
In said method, described silver salt is silver acetate, silver nitrate, Disilver carbonate, silver chloride, Argentous fluoride or silver tetrafluoroborate.
In said method, adding the amount of catalyst with the mol ratio of 2-(aryl ethane base) aniline is (0.1～0.5): 1.
In said method, described additive is sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, the tert-butyl alcohol
Lithium, 1,4-diazabicylo [2.2.2] octane, 1,5,7-tri-azabicyclic [4.4.0] decyl-5-alkene or 1,8-diazabicylo [5.4.0] ten
One carbon-7-alkene.
In said method, adding the amount of alkali with the mol ratio of 2-(aryl ethane base) aniline is (0.1～1): 1.
In said method, solvent is dimethyl sulfoxide.
In said method, the pressure of carbon dioxide is 0.5～6MPa.
In said method, reaction uses column chromatography that product is isolated and purified after terminating；Described column chromatography eluent is petroleum ether and second
The mixed solvent of acetoacetic ester；Volume ratio between petroleum ether and ethyl acetate is (1～5): 1.
The present invention has the following advantages and effect relative to existing technology:
The synthetic method of polysubstituted 2 (the 1H)-quinolinones compounds of the present invention uses multicomponent one kettle way, overcomes conventional synthesis to be somebody's turn to do
Compounds step is many, the shortcoming of complex operation；And reaction condition is gentle, operates safe and simple；Owing to have employed titanium dioxide
Carbon is as carbonyl source, it is to avoid use poisonous and hazardous carbonyl source (such as phosgene and carbon monoxide), environmental friendliness；Substrate applicability
Extensively, functional group tolerance is high.Therefore this synthetic method is conducive to commercial production, has in organic, medical and pesticide synthesis
Good application prospect.
Accompanying drawing explanation
Fig. 1 is embodiment 1-12 products therefrom hydrogen spectrogram；
Fig. 2 is embodiment 1-12 products therefrom carbon spectrogram；
Fig. 3 is embodiment 13 products therefrom hydrogen spectrogram；
Fig. 4 is embodiment 13 products therefrom carbon spectrogram；
Fig. 5 is embodiment 14 products therefrom hydrogen spectrogram；
Fig. 6 is embodiment 14 products therefrom carbon spectrogram；
Fig. 7 is embodiment 15 products therefrom hydrogen spectrogram；
Fig. 8 is embodiment 15 products therefrom carbon spectrogram；
Fig. 9 is embodiment 16 products therefrom hydrogen spectrogram；
Figure 10 is embodiment 16 products therefrom carbon spectrogram；
Figure 11 is embodiment 17 products therefrom hydrogen spectrogram；
Figure 12 is embodiment 17 products therefrom carbon spectrogram；
Figure 13 is embodiment 18 products therefrom hydrogen spectrogram；
Figure 14 is embodiment 18 products therefrom carbon spectrogram；
Figure 15 is embodiment 19 products therefrom hydrogen spectrogram；
Figure 16 is embodiment 19 products therefrom carbon spectrogram；
Figure 17 is embodiment 20 products therefrom hydrogen spectrogram；
Figure 18 is embodiment 20 products therefrom carbon spectrogram；
Figure 19 is embodiment 21 products therefrom hydrogen spectrogram；
Figure 20 is embodiment 21 products therefrom carbon spectrogram.
Detailed description of the invention
Below in conjunction with specific embodiments and the drawings, the present invention is described in further detail, but embodiments of the present invention and
The substrate adapted to is not limited to this.
Embodiment 1
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.240 mM of double (2,4,6-front three is added in autoclave
Base phenyl) iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2] octane
(DABCO), 2 milliliters of DMSO, it is filled with the CO of 1MPa2, 60 DEG C stirring reaction 8 hours after, stop heating and
Stirring, is cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then is extracted with ethyl acetate three
Secondary (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through column chromatography
Isolated and purified, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate mixes
Solvent, productivity 85%.
Embodiment 2
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.30 mM of double (2,4,6-front three is added in autoclave
Base phenyl) iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2] octane
(DABCO), 2 milliliters of DMSO, it is filled with the CO of 1MPa2, 60 DEG C stirring reaction 8 hours after, stop heating and
Stirring, is cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then is extracted with ethyl acetate three
Secondary (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through column chromatography
Isolated and purified, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate mixes
Solvent, productivity 86%.
Embodiment 3
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.240 mM of double (2,4,6-front three is added in autoclave
Base phenyl) iodine fluoroform sulphonate, 0.10 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2] octane
(DABCO), 2 milliliters of DMSO, it is filled with the CO of 1MPa2, 60 DEG C stirring reaction 8 hours after, stop heating and
Stirring, is cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then is extracted with ethyl acetate three
Secondary (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through column chromatography
Isolated and purified, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate mixes
Solvent, productivity 76%.
Embodiment 4
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.240 mM of double (2,4,6-front three is added in autoclave
Base phenyl) iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.10 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2] octane
(DABCO), 2 milliliters of DMSO, it is filled with the CO of 1MPa2, 60 DEG C stirring reaction 8 hours after, stop heating and
Stirring, is cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then is extracted with ethyl acetate three
Secondary (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through column chromatography
Isolated and purified, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate mixes
Solvent, productivity 88%.
Embodiment 5
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.24 mM of double (2,4,6-front three is added in autoclave
Base phenyl) iodine fluoroform sulphonate, 0.04 mM of Argentous fluoride, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2] octane
(DABCO), 2 milliliters of DMSO, it is filled with the CO of 1MPa2, 60 DEG C stirring reaction 8 hours after, stop heating and
Stirring, is cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then is extracted with ethyl acetate three
Secondary (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through column chromatography
Isolated and purified, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate mixes
Solvent, productivity 82%.
Embodiment 6
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.24 mM of double (2,4,6-front three is added in autoclave
Base phenyl) iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of potassium carbonate, 2 milliliters of DMSO, fill
Enter the CO of 1MPa2, after 60 DEG C of stirring reactions 8 hours, stop heating and stirring, be cooled to room temperature, slowly emptying is not
The CO of reaction2.Reactant liquor 10mL washes, then is extracted with ethyl acetate three times (every time with 10mL), and organic facies merges
Dried through anhydrous sodium sulfate, decompression is distilled off solvent, then through column chromatographic isolation and purification, obtains target product.Used
Column chromatography eluent be volume ratio be the petroleum ether of 2:1: ethyl acetate mixed solvent, productivity 60%.
Embodiment 7
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.24 mM of double (2,4,6-front three is added in autoclave
Base phenyl) iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of 1,8-diazabicylo [5.4.0] 11 carbon
-7-alkene (DBU), 2 milliliters of DMSO, it is filled with the CO of 1MPa2, after 60 DEG C of stirring reactions 8 hours, stop heating
And stirring, it is cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then is extracted with ethyl acetate
Three times (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through post layer
Analyse isolated and purified, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate is mixed
Bonding solvent, productivity 79%.
Embodiment 8
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.24 mM of double (2,4,6-front three is added in autoclave
Base phenyl) iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2] octane
(DABCO), 2 milliliters of DMSO, it is filled with the CO of 1MPa2, after 60 DEG C of stirring reactions 24 hours, stop heating
And stirring, it is cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then is extracted with ethyl acetate
Three times (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through post layer
Analyse isolated and purified, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate is mixed
Bonding solvent, productivity 89%.
Embodiment 9
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.24 mM of double (2,4,6-front three is added in autoclave
Base phenyl) iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2] octane
(DABCO), 2 milliliters of DMSO, it is filled with the CO of 1MPa2, 60 DEG C stirring reaction 6 hours after, stop heating and
Stirring, is cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then is extracted with ethyl acetate three
Secondary (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through column chromatography
Isolated and purified, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate mixes
Solvent, productivity 51%.
Embodiment 10
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.24 mM of double (2,4,6-front three is added in autoclave
Base phenyl) iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2] octane
(DABCO), 2 milliliters of DMSO, it is filled with the CO of 1MPa2, after 120 DEG C of stirring reactions 8 hours, stop heating
And stirring, it is cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then is extracted with ethyl acetate
Three times (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through post layer
Analyse isolated and purified, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate is mixed
Bonding solvent, productivity 43%.
Embodiment 11
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.24 mM of double (2,4,6-front three is added in autoclave
Base phenyl) iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2] octane
(DABCO), 2 milliliters of DMSO, it is filled with the CO of 0.5MPa2, after 60 DEG C of stirring reactions 8 hours, stop heating
And stirring, it is cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then is extracted with ethyl acetate
Three times (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through post layer
Analyse isolated and purified, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate is mixed
Bonding solvent, productivity 29%.
Embodiment 12
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.24 mM of double (2,4,6-front three is added in autoclave
Base phenyl) iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2] octane
(DABCO), 2 milliliters of DMSO, it is filled with the CO of 6MPa2, 60 DEG C stirring reaction 8 hours after, stop heating and
Stirring, is cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then is extracted with ethyl acetate three
Secondary (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through column chromatography
Isolated and purified, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate mixes
Solvent, productivity 89%.
The structural characterization data of embodiment 1-12 products therefrom are as follows (nuclear magnetic spectrogram is as depicted in figs. 1 and 2):
1H NMR(400MHz,CDCl3): δ=12.00 (s, 1H), 8.05 (d, J=8.0,1H), 7.43 (t, J=8.0,1H),
7.2 (q, J=4.0,2H), 7.14-6.99 (m, 5H), 6.48 (s, 2H), 2.11 (s, 3H), 1.99 (s, 6H).
13C NMR(100MHz,CDCl3): δ=165.35,158.08,150.55,137.76,133.62,132.06,130.77,
129.76,129.11,128.26,127.08,126.84,123.55,122.17,116.67,116.35,116.07,20.33,16.83.
IR(KBr):3180,2921,1647,1600,1481,1355,1201,1151cm-1.
MS (EI): m/z (%)=355 [M+],338(100),278,165,162,91,77.
HRMS-ESI(m/z):calcd for C24H21NO2Na(M+Na)+:378.1470,found:378.1464.
Infer that according to data above the structure of products therefrom is as follows:
Embodiment 13
Autoclave adds 0.20 mM of 2-((4-fluorophenyl) acetenyl) aniline, 0.24 mM double (2,4,
6-trimethylphenyl) iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2]
Octane (DABCO), 2 milliliters of DMSO, it is filled with the CO of 1MPa2, after 60 DEG C of stirring reactions 8 hours, stop adding
Heat and stirring, be cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then extracts by ethyl acetate
Taking three times (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through post
Chromatography purification, obtains target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate
Mixed solvent, productivity 84%.
The structural characterization data of embodiment 13 products therefrom are as follows (nuclear magnetic spectrogram is as shown in Figure 3 and Figure 4):
1H NMR(400MHz,CDCl3): δ=12.15 (s, 1H), 8.07 (d, J=8.0,1H), 7.43 (t, J=6.0,1H),
7.20 (q, J=8.0,2H), 7.00 (q, J=6.0,2H), 6.78 (t, J=8.0,2H), 6.53 (s, 2H), 2.15 (s, 3H),
1.99(s,6H).
13C NMR(100MHz,CDCl3): δ=165.31,163.17,160.73,158.37,150.43,137.76,133.97,
131.40 (d, J=8.0), 130.91,129.15,128.21,127.93,123.55,122.30,116.51,116.07,115.03,
114.10,113.89,77.32,20.33,16.78.
IR(KBr):3184,2916,1645,1599,1510,1355,1200,1153,756.
MS (EI): m/z (%)=373 [M+],356(100),336,183,162,91,77.
HRMS-ESI(m/z):calcd for C24H20FNO2Na(M+Na)+:396.1370,found:396.1371.
Infer that according to data above the structure of products therefrom is as follows:
Embodiment 14
0.20 mM of 2-((4-(trifluoromethyl) phenyl) acetenyl) aniline, 0.24 mmoles is added in autoclave
Double (2,4,6-trimethylphenyl) the iodine fluoroform sulphonates of that, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two are folded
Nitrogen dicyclo [2.2.2] octane (DABCO), 2 milliliters of DMSO, it is filled with the CO of 4MPa2, 60 DEG C of stirring reactions 8 hours
After, stop heating and stirring, be cooled to room temperature, be slowly vented unreacted CO2.Reactant liquor 10mL washes, then uses
Ethyl acetate extracts three times (every time with 10mL), and organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent,
Again through column chromatographic isolation and purification, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1:
Ethyl acetate mixed solvent, productivity 83%.
The structural characterization data of embodiment 14 products therefrom are as follows (nuclear magnetic spectrogram is as shown in Figure 5 and Figure 6):
1H NMR(400MHz,CDCl3): δ=11.68 (s, 1H), 8.13 (d, J=8.0,1H), 7.51 (t, J=6.0,1H),
7.30 (t, J=8.0,3H), 7.22 (d, J=8.0,1H), 7.11 (d, J=8.0,2H), 6.46 (s, 2H), 2.10 (s, 3H),
1.99(s,6H).
13C NMR(100MHz,CDCl3): δ=150.09,137.71,134.59,131.30,130.05,129.17,128.44,
123.84 (q, J=6.0), 122.58,116.37,115.90,20.13,16.71.
IR(KBr):3134,3088,3005,2887,2229,1638,1602,1321,1285,1200,1155,1121,758.
MS (EI): m/z (%)=423 [M+],406(100),304,233,190,161,120,91,77.
HRMS-ESI(m/z):calcd for C25H20F3NO2Na(M+Na)+:446.1338,found:446.1339.
Infer that according to data above the structure of products therefrom is as follows:
Embodiment 15
Autoclave adds 0.20 mM of 2-((4-(4-ethylcyclohexyl) phenyl) acetenyl) aniline, 0.24
MM double (2,4,6-trimethylphenyl) iodine fluoroform sulphonates, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-
Two nitrine dicyclo [2.2.2] octanes (DABCO), 2 milliliters of DMSO, it is filled with the CO of 4MPa2, stir reaction 8 at 60 DEG C
After hour, stop heating and stirring, be cooled to room temperature, be slowly vented unreacted CO2.Reactant liquor 10mL washes,
Being extracted with ethyl acetate three times (every time with 10mL) again, organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off
Solvent, then through column chromatographic isolation and purification, obtain target product.Column chromatography eluent used be volume ratio be the stone of 2:1
Oil ether: ethyl acetate mixed solvent, productivity 58%.
The structural characterization data of embodiment 15 products therefrom are as follows (nuclear magnetic spectrogram is as shown in Figure 7 and Figure 8):
1H NMR(400MHz,CDCl3): δ=11.31 (s, 1H), 8.08 (d, J=8.0,1H), 7.47 (t, J=8.0,1H),
7.25-7.20 (m, 2H), 6.88 (q, J=24.0,4H), 6.44 (s, 2H), 2.37-2.31 (m, 1H), 2.08 (s, 3H), 1.96 (s,
6H), 1.85 (q, J=40.0,4H), 1.41-1.25 (m, 5H), 1.09-0.99 (m, 2H), 0.93 (t, J=8.0,3H).
13C NMR(100MHz,CDCl3): δ=158.10,150.40,146.55,137.40,133.36,130.75,129.34,
129.07,128.92,128.21,128.21,125.59,123.72,122.34,116.86,115.82,44.43,39.15,34.34,
33.20,30.02,20.44,16.91,11.53.
IR(KBr):2922,2852,2362,1730,1646,1355,1262,757.
MS (EI): m/z (%)=423 [M+],337,320,207,72,59(100).
HRMS-ESI(m/z):calcd for C32H36NO2(M+H)+:466.2741,found:466.2744.
Infer that according to data above the structure of products therefrom is as follows:
Embodiment 16
Autoclave adds 0.20 mM of 2-((2,4-3,5-dimethylphenyl) acetenyl) aniline, 0.24 mM double
(2,4,6-trimethylphenyl) iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine are double
Ring [2.2.2] octane (DABCO), 2 milliliters of DMSO, it is filled with the CO of 4MPa2, after 60 DEG C of stirring reactions 8 hours,
Stop heating and stirring, be cooled to room temperature, be slowly vented unreacted CO2.Reactant liquor 10mL washes, then uses acetic acid
Ethyl ester extracts three times (every time with 10mL), and organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then
Through column chromatographic isolation and purification, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: second
Acetoacetic ester mixed solvent, productivity 52%.
The structural characterization data of embodiment 16 products therefrom are as follows (nuclear magnetic spectrogram is as shown in Figure 9 and Figure 10):
1H NMR(400MHz,CDCl3): δ=11.57 (s, 1H), 8.00 (d, J=8.0,1H), 7.44 (t, J=8.0,1H),
7.25-7.16 (m, 2H), 6.84 (s, 1H), 6.68-6.64 (m, 2H), 6.51 (d, J=20.0,2H), 2.24 (s, 3H), 2.14 (s,
3H),2.09(s,3H),2.00(s,3H),1.92(s,3H).
13C NMR(100MHz,CDCl3): δ=164.77,159.14,151.34,137.76,136,92,136.78,133.42,
130.65,130.03,129.93,129.07,129.05,128.68,128.52,128.21,125.50,123.57,122.16,116.84,
115.98,21.13,20.41,19.86,17.15,16.74.
IR(KBr):3138,2923,2853,1645,1602,1352,1263,1200,1150,754.
MS (EI): m/z (%)=383 [M+],368,352,248(100),207,91,77.
HRMS-ESI(m/z):calcd for C26H25NO2Na(M+Na)+:406.1777,found:406.1783.
Infer that according to data above the structure of products therefrom is as follows:
Embodiment 17
0.20 mM of 5-bromo-2-(phenylene-ethynylene) aniline, 0.24 mM of double (2,4,6-is added in autoclave
Trimethylphenyl) iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2]
Octane (DABCO), 2 milliliters of DMSO, it is filled with the CO of 4MPa2, after 60 DEG C of stirring reactions 8 hours, stop adding
Heat and stirring, be cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then extracts by ethyl acetate
Taking three times (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through post
Chromatography purification, obtains target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate
Mixed solvent, productivity 55%.
The structural characterization data of embodiment 17 products therefrom are as follows (nuclear magnetic spectrogram is as is illustrated by figs. 11 and 12):
1H NMR(400MHz,CDCl3): δ=12.09 (s, 1H), 8.21 (d, J=4.0,1H), 7.43 (d, J=8.0,1H),
7.10-7.03 (m, 3H), 6.96 (q, J=16.0,3H), 6.45 (s, 2H), 2.09 (s, 3H), 1.96 (s, 6H).
13C NMR(100MHz,CDCl3): δ=156.97,150.12,136.53,133.95,133.76,131.51,129.52,
129.10,128.20,127.12,126.02,118.18,117.87,115.07,20.34,16.82.
IR(KBr):2920,2853,1643,1593,1346,1267,699,637.
MS (EI): m/z (%)=433 [M+],417(100),369,352,219,190,162,91,77.
HRMS ESI(m/z):calcd for C24H20BrNO2Na(M+Na)+:456.0570,found:456.0570.
Infer that according to data above the structure of products therefrom is as follows:
Embodiment 18
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.24 mM of double (2,4,6-front three is added in autoclave
Base phenyl) iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2] octane
(DABCO), 2 milliliters of DMSO, it is filled with the CO of 1MPa2, 60 DEG C stirring reaction 8 hours after, stop heating and
Stirring, is cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then is extracted with ethyl acetate three
Secondary (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through column chromatography
Isolated and purified, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate mixes
Solvent, productivity 61%.
The structural characterization data of embodiment 18 products therefrom are as follows (nuclear magnetic spectrogram is as shown in Figure 13 and Figure 14):
1H NMR(400MHz,CDCl3): δ=12.14 (s, 1H), 8.37 (s, 1H), 7.53 (d, J=8.0,1H),
7.12-7.05 (m, 4H), 6.97 (d, J=8.0,2H), 6.47 (s, 2H), 2.10 (s, 3H), 1.97 (s, 6H).
13C NMR(100MHz,CDCl3): δ=165.54,157.63,150.10,139.66,134.19,131.37,129.53,
(129.17,128.25,127.21,125.47,121.42 q, J=12.0), 116.85 (d, J=16.0), 116.31,20.33,16.81.
IR(KBr):3179,3056,2924,2732,1660,1475,1353,1268,1123,848,740,702.
MS (EI): m/z (%)=423 [M+],406(100),230,91,77.
HRMS-ESI(m/z):calcd for C25H21F3NO2(M+H)+:424.1519,found 424.1521.
Infer that according to data above the structure of products therefrom is as follows:
Embodiment 19
Autoclave adds 0.40 mM of 2,4-bis-chloro-6-(phenylene-ethynylene) aniline, 0.04 mM of silver acetate,
0.20 mM of double (2,4,6-trimethylphenyl) iodine fluoroform sulphonate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2]
Octane (DABCO), 2 milliliters of DMSO, it is filled with the CO of 4MPa2, after 60 DEG C of stirring reactions 8 hours, stop adding
Heat and stirring, be cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then extracts by ethyl acetate
Taking three times (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through post
Chromatography purification, obtains target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate
Mixed solvent, productivity 71%.
The structural characterization data of embodiment 19 products therefrom are as follows (nuclear magnetic spectrogram is as shown in Figure 15 and Figure 16):
1H NMR(400MHz,CDCl3): δ=9.32 (s, 1H), 8.08 (d, J=4.0,1H), 7.61 (d, J=4.0,1H),
7.06-7.00 (m, 3H), 6.90 (d, J=8.0,2H), 6.44 (s, 2H), 2.08 (s, 3H), 1.97 (s, 6H).
13C NMR(100MHz,CDCl3): δ=163.17,156.15,149.84,134.23,132.50,130.64,130.43,
129.12,128.08,127.46,1276.33,127.15,122.62,119.76,118.90,117.61,99.90,20.30,16.77.
IR(KBr):3029,2922,2855,1647,1436,1341,751,698,563,522.
MS (EI): m/z (%)=423 [M+],408,406(100),303,230,190,91,77.
HRMS-ESI(m/z):calcd for C24H19Cl2NO2Na(M+Na)+:446.0685,found 446.0685.
Infer that according to data above the structure of products therefrom is as follows:
Embodiment 20
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.24 mM of 4 bromo-4 '-methoxyl group is added in autoclave
Diphenyl iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2] octane
(DABCO), 2 milliliters of DMSO, it is filled with the CO of 1MPa2, 60 DEG C stirring reaction 8 hours after, stop heating and
Stirring, is cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then is extracted with ethyl acetate three
Secondary (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through column chromatography
Isolated and purified, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate mixes
Solvent, productivity 88%.
The structural characterization data of embodiment 20 products therefrom are as follows (nuclear magnetic spectrogram is as shown in Figure 17 and Figure 18):
1H NMR(600MHz,DMF-d7): δ=11.98 (s, 1H), 7.64-7.57 (m, 3H), 7.47 (d, J=12.0,2H),
7.42 (d, J=6.0,2H), 7.31 (t, J=9.0,2H), 7.25 (t, J=9.0,1H), 7.21 (t, J=9.0,1H), 6.95 (d, J
=12.0,2H).
13C NMR(150MHz,DMF-d7): δ=157.70,156.05,140.27,133.69,133.30,132.25,131.45,
128.72,128.57,125.78,124.54,123.14,118.89,116.88,116.80,116.61,115.19.
IR(KBr):3062,2922,2853,1703,1665,1613,1486,1353,700.
MS (EI): m/z (%)=347 [M+],228,200,165(100),146,119.
HRMS-ESI(m/z):calcd for C21H14BrNO2Na(M+Na)+:370.0605,found 370.0611.
Infer that according to data above the structure of products therefrom is as follows:
Embodiment 21
0.20 mM of 2-(phenylene-ethynylene) aniline, 0.24 mM of 2-cyano group-4 is added in autoclave '-methoxy
Base diphenyl iodine fluoroform sulphonate, 0.04 mM of silver acetate, 0.02 mM of Isosorbide-5-Nitrae-two nitrine dicyclo [2.2.2] octane
(DABCO), 2 milliliters of DMSO, it is filled with the CO of 1MPa2, 60 DEG C stirring reaction 8 hours after, stop heating and
Stirring, is cooled to room temperature, is slowly vented unreacted CO2.Reactant liquor 10mL washes, then is extracted with ethyl acetate three
Secondary (every time with 10mL), organic facies merges through anhydrous sodium sulfate dried, and decompression is distilled off solvent, then through column chromatography
Isolated and purified, obtain target product.Column chromatography eluent used be volume ratio be the petroleum ether of 2:1: ethyl acetate mixes
Solvent, productivity 80%.
The structural characterization data of embodiment 21 products therefrom are as follows (nuclear magnetic spectrogram is as illustrated in figures 19 and 20):
1H NMR(600MHz,DMF-d7): δ=12.11 (s, 1H), 7.76 (d, J=12.0,1H), 7.67 (q, J=6.0,2
H), 7.63 (d, J=6.0,1H), 7.50 (q, J=6.0,3H), 7.33-7.24 (m, 4H), 7.14 (t, J=6.0,1H), 7.06 (d,
J=6.0,1H).
13C NMR(150MHz,DMF-d7): δ=162.47,158.50,154.76,139.41,135.20,134.18,132.05,
131.80,130.62,128.13,127.90,124.70,123.39,123.25,122.67,115.96,115.91,115.89,115.60,
101.71.
IR(KBr):2924,2854,2362,2232,1731,1642,1256,698.
MS (EI): m/z (%)=338 [M+],321,310,236,190,165,120(100),92,77.
HRMS-ESI(m/z):calcd for C22H14N2O2Na(M+Na)+:361.0947,found:361.0944.
Infer that according to data above the structure of products therefrom is as follows:
The above embodiment of the present invention is only for clearly demonstrating example of the present invention, and is not the enforcement to the present invention
The restriction of mode.For those of ordinary skill in the field, can also be made other not on the basis of the above description
Change or variation with form.Here without also cannot all of embodiment be given exhaustive.All spirit in the present invention and
Any amendment, equivalent and the improvement etc. made within principle, should be included in the protection domain of the claims in the present invention
Within.
Claims (10)
1. the method synthesizing polysubstituted 2 (1H)-quinolinones compounds, it is characterised in that in autoclave, adds
2-(aryl ethane base) aniline and diaryl group iodized salt are raw material, after adding catalyst, add additive, with organic solvent
For solvent, it is passed through carbon dioxide, stirring reaction 6～24 hours at 40～120 DEG C, reaction is cooled to room temperature after terminating,
Slowly discharging unreacted carbon dioxide to normal pressure, reactant liquor must slightly through wash, extract, wash, being dried, after concentrating under reduced pressure
Product, purifies polysubstituted 2 (the 1H)-quinolinones compounds obtained described in series through column chromatography；
Its reaction is shown below:
Wherein, R1Including methyl, fluorine-based, chloro, bromo or trifluoromethyl；
R2Including methyl, fluorine-based, chloro, bromo, methoxyl group, cyano group, dimethyl or trifluoromethyl；
R3And R4Including fluorine-based, chloro, bromo, cyano group, methyl, trifluoromethyl, the tert-butyl group, nitro or trimethyl.
A kind of method synthesizing polysubstituted 2 (1H)-quinolinones compounds the most according to claim 1, it is characterised in that
Described R1Including 5-methyl, 5-fluorine, 5-chlorine, 5-bromine, 5-trifluoromethyl, 4-fluorine, 4-chlorine, 4-methyl, 4,6-dichloro
Or 4-bromine；
Described R2Including 2-fluorine, 2-chlorine, 2-bromine, 2-methyl, 3-fluorine, 3-chlorine, 3-bromine, 3-methyl, 3-methoxyl group, 4-fluorine,
4-chlorine, 4-bromine, 4-methyl, 4-trifluoromethyl, 4-cyano group or 2,4-dimethyl；
Described R3And R4Including 2-fluorine, 3-fluorine, 2-fluorine, 2-chlorine, 4-chlorine, 2-cyano group, 3-methyl, 4-bromine, 4-trifluoromethyl,
The 4-tert-butyl group, 4-nitro or 2,4,6-trimethyl；
Described catalyst is silver salt；Described additive is alkali.
A kind of method synthesizing polysubstituted 2 (1H)-quinolinones compounds the most according to claim 1, it is characterised in that
Autoclave uses gap type high-pressure reactor or continuous high pressure reactor；2-(aryl ethane base) aniline and diaryl
The mol ratio of iodine salt is 1:(1～1.5).
A kind of method synthesizing polysubstituted 2 (1H)-quinolinones compounds the most according to claim 1, it is characterised in that institute
Stating silver salt is silver acetate, silver nitrate, Disilver carbonate, silver chloride, Argentous fluoride or silver tetrafluoroborate.
A kind of method synthesizing polysubstituted 2 (1H)-quinolinones compounds the most according to claim 4, it is characterised in that: add
Entering the amount of catalyst with the mol ratio of 2-(aryl ethane base) aniline is (0.1～0.5): 1.
A kind of method synthesizing polysubstituted 2 (1H)-quinolinones compounds the most according to claim 1, it is characterised in that: institute
Stating additive is sodium carbonate, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, tert-butyl alcohol lithium, 1,4-diazabicylo [2.2.2]
Octane, 1,5,7-tri-azabicyclic [4.4.0] decyl-5-alkene or 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene.
A kind of method synthesizing polysubstituted 2 (1H)-quinolinones compounds the most according to claim 6, it is characterised in that: add
Entering the amount of alkali with the mol ratio of 2-(aryl ethane base) aniline is (0.1～1): 1.
A kind of method synthesizing polysubstituted 2 (1H)-quinolinones compounds the most according to claim 1, it is characterised in that: molten
Agent is dimethyl sulfoxide.
A kind of method synthesizing polysubstituted 2 (1H)-quinolinones compounds the most according to claim 1, it is characterised in that: two
The pressure of carbonoxide is 0.5～6MPa.
A kind of method synthesizing polysubstituted 2 (1H)-quinolinones compounds the most according to claim 1, it is characterised in that
Reaction uses column chromatography that product is isolated and purified after terminating；Described column chromatography eluent is that the mixing of petroleum ether and ethyl acetate is molten
Agent；Volume ratio between petroleum ether and ethyl acetate is (1～5): 1.
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