阅读说明：本技术 一种2-喹啉酮类化合物的合成方法 (A kind of synthetic method of 2- quinolinones compound ) 是由 张书宇 陈超 丁同梅 于 2018-05-24 设计创作，主要内容包括：本发明涉及一种2-喹啉酮类化合物的合成方法,将苯炔前体与具有导向基团的异丁烯酰胺,在催化剂、无机碱、添加剂、溶剂以及氧化剂的共同作用下,进行碳-氢键和氮-氢键活化环化反应,生成2-喹啉酮类化合物核心骨架,再脱除导向基团,合成2-喹啉酮类化合物。与现有技术相比,本发明方法采用廉价易得和环境友好的铜盐催化得到2-喹啉酮类化合物,反应条件较温和,底物适用性广,为2-喹啉酮类化合物的合成提供了新的方法,具有很好的应用前景。(The present invention relates to a kind of synthetic methods of 2- quinolinones compound, by aryne precursor and with the methacrylamide of homing device, under the collective effect of catalyst, inorganic base, additive, solvent and oxidant, it carries out carbon-hydrogen link and nitrogen-hydrogen bond activates cyclization, generate 2- quinolinones compound core skeleton, homing device is removed again, synthesizes 2- quinolinones compound.Compared with prior art, the method of the present invention is catalyzed to obtain 2- quinolinones compound using mantoquita cheap and easy to get and environmental-friendly, and reaction condition is milder, and substrate applicability is wide, new method is provided for the synthesis of 2- quinolinones compound, is had a good application prospect.)

1. a kind of synthetic method of 2- quinolinones compound, which is characterized in that this method is by aryne precursor and has guiding base The methacrylamide of group carries out carbon-under the collective effect of copper salt catalyst, inorganic base, additive, solvent and oxidant Hydrogen bond and nitrogen-hydrogen bond activate cyclization, generate 2- quinolinones compound core skeleton, then remove homing device, that is, synthesize 2- quinolinones compound.

2. a kind of synthetic method of 2- quinolinones compound according to claim 1, which is characterized in that this method is specific Using following steps:

(1) by aryne precursor with homing device methacrylamide in copper salt catalyst, additive, organic solvent, oxidation Under the action of agent, inorganic base, carries out carbon-hydrogen link and nitrogen-hydrogen bond activates cyclization, then purified through vacuum distillation, column chromatography, obtained To 2- quinolinones compound core skeleton；

(2) 2- quinolinones compound core skeleton made from step (1) and Boron tribromide are reacted at room temperature in methylene chloride 12-20h dissolves by acetonitrile, water mixed solvent, then with trifluoracetic acid iodobenzene reacts 2-3h in 0 DEG C, through extraction, vacuum distillation, Column chromatography purification, obtains the 2- quinolinones compound.

3. a kind of method of synthesis of indole quinolines according to claim 1 or 2, which is characterized in that

The chemical structural formula of the methacrylamide are as follows:

The chemical structural formula of the aryne precursor are as follows:

The chemical structural formula of the 2- quinolinones compound core skeleton are as follows:

The chemical structural formula of the 2- quinolinones compound are as follows:

Wherein, R¹Selected from H, alkyl, branched alkyl, naphthenic base, aromatic radical, the aromatic radical containing substituent group, heterocycle, contain substituent group Heterocycle or halogenic substituent；

R²Selected from H, alkyl, branched alkyl, naphthenic base, aromatic radical, the aromatic radical containing substituent group, heterocycle, containing the heterocycle of substituent group Base or halogenic substituent；

R³Selected from 8- aminoquinoline base, the chloro- 8- aminoquinoline base of 5-, 5- methoxyl group -8- aminoquinoline base or 2- phenyl -4,5- two Hydrogen oxazole, preferably 8- aminoquinoline base.

4. a kind of synthetic method of 2- quinolinones compound according to claim 1 or 2, which is characterized in that step (1) The copper salt catalyst be stannous chloride, trifluoroacetic acid copper, trifluoromethayl sulfonic acid copper, copper sulphate, Kocide SD, copper bromide or One kind of copper acetate, preferably copper acetate.

5. a kind of synthetic method of 2- quinolinones compound according to claim 1 or 2, which is characterized in that step (1) The additive includes tetrabutylammonium bromide or tetrabutylammonium iodide, and the inorganic base includes sodium fluoride, cesium fluoride or fluorine Change potassium.

6. a kind of synthetic method of 2- quinolinones compound according to claim 1 or 2, which is characterized in that described Oxidant includes oxygen, silver acetate or potassium peroxydisulfate, preferably oxygen.

7. a kind of synthetic method of 2- quinolinones compound according to claim 1 or 2, which is characterized in that step (1) The organic solvent include one of N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile or dioxane or It is several, preferably n,N-dimethylacetamide or acetonitrile.

8. according to right want 1 or 2 described in a kind of synthetic method of 2- quinolinones compound, which is characterized in that step (1) institute The molar ratio of the aryne precursor stated and the methacrylamide with homing device is 2:1.

9. a kind of synthetic method of 2- quinolinones compound according to claim 2, which is characterized in that step (1) institute The molar ratio of catalyst, additive, inorganic base and the methacrylamide stated is 0.1-1:0.2-2:0.5-3:1.

10. a kind of synthetic method of 2- quinolinones compound according to claim 2, which is characterized in that step (1) institute The temperature for the activation cyclization stated is 30-120 DEG C, reaction time 4-24h.

Technical field

The invention belongs to organic chemical synthesis technical fields, more particularly, to a kind of synthesis side of 2- quinolinones compound Method.

Background technique

Quinolinone is a kind of common wide spectrum heterocycle structure skeleton, is widely present in a variety of natural products and drug molecule In, there are the bioactivity such as anticancer, anti-oxidant, anti-inflammatory, anti-hypertension.The study found that -2 quinolinone of 3- phenyl of 4- substitutions There is good affinity with the Glycine site of N-methyl-D-aspartate receptor, can be applied to treatment central nervous system System disorder.Therefore, new thinking can be provided for the synthesis of drug molecule by developing new method and carrying out synthesis of quinoline ketone compound.

Currently, the most common method of synthesis of quinoline ketone compound is that the acid of amido aldehyde, amino ketones and enolization and ester exist Friedlander condensation reaction under base catalysis, but the substrate of condensation reaction is limited, and yield is lower. CN104529894A discloses a kind of qualone derivative and preparation method thereof, using 3- halogenated Oxoindole 0-100 DEG C, It being obtained under organic solvent, alkaline condition with O- tosyl-N- alkoxy carbonyl group azanol reaction, product yield significantly improves, but It is that substrate preparation process is complicated.CN104628643A discloses one kind with the halogenated benzonitrile class compound of 2- Raw material, mantoquita are catalyst, and cyclization reaction occurs under the conditions of inorganic base and generates a series of isoquinolinone derivatives, and yield is higher, Mild condition, but the substrate scope of application is small, is only capable of obtaining the compound of isobioquin group that 3- aromatic radical replaces.Jiao Ning Carbonylation cyclization Deng the aniline, alkynes and the CO that are catalyzed by Rh efficiently synthesizes 2- quinolinones compound, and aniline is not necessarily to Activation, substrate applicability are relatively wide (J.Am.Chem.Soc.2015,137,9246.).The noble metal that the prior art generally uses is urged Agent, substrate restricted application.

Summary of the invention

It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of favorable repeatabilities, urge Agent is cheap and easy to get, wide application range of substrates, the synthetic method of the 2- quinolinones compound of good economy performance.

The purpose of the present invention can be achieved through the following technical solutions:

A kind of synthetic method of 2- quinolinones compound, by aryne precursor with homing device methacrylamide, Under the collective effect of copper salt catalyst, inorganic base, additive, solvent and oxidant, carries out carbon-hydrogen link and nitrogen-hydrogen bond is living Change cyclization, generate 2- quinolinones compound core skeleton, then remove homing device, is i.e. synthesis 2- quinolinones chemical combination Object specifically uses following steps:

(1) by aryne precursor with homing device methacrylamide copper salt catalyst, additive, organic solvent, Under the action of oxidant, inorganic base, carries out carbon-hydrogen link and nitrogen-hydrogen bond activates cyclization, then mentioned through vacuum distillation, column chromatography It is pure, obtain 2- quinolinones compound core skeleton；

(2) room temperature in methylene chloride by 2- quinolinones compound core skeleton made from step (1) and Boron tribromide 12-20h is reacted, is dissolved by acetonitrile, water mixed solvent, then react 2-3h in 0 DEG C with trifluoracetic acid iodobenzene, is extracted, depressurized Distillation, column chromatography purification, obtain the 2- quinolinones compound.

The chemical structural formula of the methacrylamide are as follows:

The chemical structural formula of the aryne precursor are as follows:

The chemical structural formula of the 2- quinolinones compound core skeleton are as follows:

The chemical structural formula of the 2- quinolinones compound are as follows:

Wherein, R¹Selected from H, alkyl, branched alkyl, naphthenic base, aromatic radical, the aromatic radical containing substituent group, heterocycle, containing taking The heterocycle or halogenic substituent of Dai Ji；

R²Selected from H, alkyl, branched alkyl, naphthenic base, aromatic radical, the aromatic radical containing substituent group, heterocycle, contain substituent group Heterocycle or halogenic substituent；

R³Selected from 8- aminoquinoline base, the chloro- 8- aminoquinoline base of 5-, 5- methoxyl group -8- aminoquinoline base or phenyl -4 2-, 5- dihydro-oxazole, preferably 8- aminoquinoline base.

Methacrylamide with homing device is prepared using following methods: being reacted and is made with amine by acyl chlorides or carboxylic acid. At 0 DEG C, triethylamine and acryloyl chloride are added into the dichloromethane solution of 8- aminoquinoline, 12h is stirred at room temperature；Or to acrylic acid Dichloromethane solution in be added thionyl chloride and catalytic amount n,N-Dimethylformamide, flow back 5h at 55 DEG C, decompression steam Solvent is removed in distillation, after crude product is re-dissolved, 8- aminoquinoline and triethylamine is added at 0 DEG C, 12h is stirred at room temperature.Reaction It is quenched after completely with saturated sodium bicarbonate, methylene chloride extraction, after organic phase water and saturated salt solution washs respectively, through doing Dry, vacuum distillation, column chromatography purify up to the methacrylamide with homing device.

The copper salt catalyst includes stannous chloride, trifluoroacetic acid copper, trifluoromethayl sulfonic acid copper, copper sulphate, hydroxide One kind of copper, copper bromide or copper acetate, preferably copper acetate.

The additive includes one of tetrabutylammonium bromide or tetrabutylammonium iodide, and the inorganic base includes fluorine Change one of sodium, cesium fluoride or potassium fluoride.

The oxidant includes one of oxygen, silver acetate or potassium peroxydisulfate, preferably oxygen.

The organic solvent includes in N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetonitrile or dioxane One or more, preferably n,N-dimethylacetamide and acetonitrile.

The molar ratio of the aryne precursor and the methacrylamide with homing device is 2:1.

The catalyst, additive, inorganic base and methacrylamide molar ratio be 0.1-1:0.2-2:0.5-3:1.

The temperature of activation cyclization is 30-120 DEG C in step (1), reaction time 4-24h.

The synthetic route of this method is as follows:

The mentality of designing of the method for the present invention is the methacrylamide that will have homing device and aryne precursor in copper catalyst Under the action of carbon-to-carbon/carbon-nitrogen bond constructed by carbon-hydrogen/nitrogen-one step of hydrogen bond priming reaction, efficiently synthesize 2- quinolinones chemical combination Object core skeleton, then homing device is removed to get 2- quinolinones compound is arrived.

The present invention using with guiding base acrylamide and 2- (trimethyl silicon substrate) phenyl trifluoromethanesulfonate methane sulfonates as Substrate realizes the synthesis of 2- quinolinone compounds.2- (trimethyl silicon substrate) phenyl trifluoromethanesulfonate methane sulfonates are in tetrabutylammonium iodide With the intermediate species benzyne of in-situ preparation high activity under the collective effect of cesium fluoride, then with react generated in metal-have Machine intermediate is inserted into, and a series of reaction occurs, and obtains 2- quinolinones compound.Copper acetate as with N, N- bidentate It is oriented to the transition-metal catalyst of polymerization of olefin using catalyst, the C-H bond of activated carbon-carbon double bond and the hydrogen bound to nitrogen of amide while coordination, with Rear center body occurs reduction elimination and obtains corresponding 2- quinolinones compound, while the monovalence copper generated is in Green Oxidant oxygen Divalent copper acetate is oxidized under the action of gas, to realize the catalytic cycle entirely reacted.

Copper acetate is as lewis acid catalyst, to (2- carbonyl -2- benzene the second of 2- generated in reaction in traditional handicraft Base) cyano in benzonitrile activated, so that carbon atom has more electrophilicity in cyano, and then subsequent series reaction occurs Corresponding compound of isobioquin group is generated, is not related to the catalytic cycle of copper in reaction.

Compared with prior art, the invention has the characteristics that:

1) for the method for the present invention using oxygen cheap and easy to get as oxygen source, reaction condition is relatively mild；

2) the method for the present invention avoids making for noble metal in traditional handicraft using cheap mantoquita as catalyst With；

3) substrate of the method for the present invention has diversity, can synthesize the 2- quinolinones chemical combination of a variety of different substituents Object.

Specific embodiment

The present invention is described in detail combined with specific embodiments below.Following embodiment will be helpful to the technology of this field Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill of this field For personnel, without departing from the inventive concept of the premise, various modifications and improvements can be made.These belong to the present invention Protection scope.

In present embodiment, the hydrogen nuclear magnetic resonance spectrum of compound (¹H NMR) by Bruker AVANCE III HD 400 or Bruker AVANCE III HD 500 is measured；Mass spectrum (ESI-MS) is by WatersACQUITYTM UPLC&Q-TOF MS Premier measurement；Agents useful for same is commercial reagent.

The synthetic method of 2- quinolinones compound, by aryne precursor and with the methacrylamide of homing device, in copper Salt catalyst, inorganic base, additive, solvent and oxidant collective effect under, carry out carbon-hydrogen link and nitrogen-hydrogen bond activate ring Change reaction, generate 2- quinolinones compound core skeleton, then remove homing device, is i.e. synthesis 2- quinolinones compound, closes It is as follows at route:

Above-mentioned synthetic method specifically uses following steps:

(1) by aryne precursor with homing device methacrylamide copper salt catalyst, additive, organic solvent, It under the action of oxidant, inorganic base, carries out carbon-hydrogen link and nitrogen-hydrogen bond and activates cyclization, temperature is 30-120 DEG C, when reaction Between be 4-24h, the molar ratio of aryne precursor and the methacrylamide with homing device is 2:1, catalyst, additive, inorganic The molar ratio of alkali and methacrylamide is that 0.1-1:0.2-2:0.5-3:1 is purified through vacuum distillation, column chromatography again, obtains 2- quinoline Ketone compounds core skeleton；

(2) room temperature in methylene chloride by 2- quinolinones compound core skeleton made from step (1) and Boron tribromide 12-20h is reacted, is dissolved by acetonitrile, water mixed solvent, then react 2-3h in 0 DEG C with trifluoracetic acid iodobenzene, is extracted, depressurized Distillation, column chromatography purification, obtain the 2- quinolinones compound.

The chemical structural formula of methacrylamide are as follows:

The chemical structural formula of aryne precursor are as follows:

The chemical structural formula of 2- quinolinones compound core skeleton are as follows:

The chemical structural formula of 2- quinolinones compound are as follows:

Wherein, R¹Selected from H, alkyl, branched alkyl, naphthenic base, aromatic radical, the aromatic radical containing substituent group, heterocycle, containing taking The heterocycle or halogenic substituent of Dai Ji；R²Selected from H, alkyl, branched alkyl, naphthenic base, aromatic radical, containing the fragrance of substituent group Base, heterocycle, heterocycle or halogenic substituent containing substituent group；R³Selected from 8- aminoquinoline base, the chloro- 8- aminoquinoline base of 5-, 5- methoxyl group -8- aminoquinoline base or 2- phenyl -4,5- dihydro-oxazole, preferred embodiment can use 8- aminoquinoline Base.

Methacrylamide with homing device is prepared using following methods: being reacted and is made with amine by acyl chlorides or carboxylic acid. At 0 DEG C, triethylamine and acryloyl chloride are added into the dichloromethane solution of 8- aminoquinoline, 12h is stirred at room temperature；Or to acrylic acid Dichloromethane solution in be added thionyl chloride and catalytic amount n,N-Dimethylformamide, flow back 5h at 55 DEG C, decompression steam Solvent is removed in distillation, after crude product is re-dissolved, 8- aminoquinoline and triethylamine is added at 0 DEG C, 12h is stirred at room temperature.Reaction It is quenched after completely with saturated sodium bicarbonate, methylene chloride extraction, after organic phase water and saturated salt solution washs respectively, through doing Dry, vacuum distillation, column chromatography purify up to the methacrylamide with homing device.

The copper salt catalyst of use includes stannous chloride, trifluoroacetic acid copper, trifluoromethayl sulfonic acid copper, copper sulphate, hydroxide One kind of copper, copper bromide or copper acetate, preferred embodiment can use copper acetate.Additive include tetrabutylammonium bromide or One of tetrabutylammonium iodide, inorganic base include one of sodium fluoride, cesium fluoride or potassium fluoride.Oxidant include oxygen, One of silver acetate or potassium peroxydisulfate, preferred embodiment can use oxygen.Organic solvent includes N, N- dimethyl methyl One or more of amide, n,N-dimethylacetamide, acetonitrile or dioxane, preferred embodiment can use N, N- Dimethyl acetamide and acetonitrile.

Synthetic method of the invention can prepare 2- quinolinones compound skeleton structure (Q=8- amino as follows Quinoline):