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Synthesis method of 2-quinolinone compound

A technology of quinolinones and synthesis methods, applied in the direction of organic chemistry, etc., can solve the problems of limited condensation reaction substrates, low yield, complex substrate preparation process, etc., achieve mild reaction conditions and avoid the use of precious metals.

Active Publication Date: 2019-12-03
SHANGHAI JIAO TONG UNIV
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Problems solved by technology

[0003] At present, the most commonly used method for the synthesis of quinolinones is the Friedlander condensation reaction of aminoaldehydes, aminoketones, and enolized acids and esters under base catalysis, but the substrates of the condensation reaction are limited and the yields are low.
CN104529894A discloses a quinolinone derivative and a preparation method thereof, using 3-halogenated oxindole and O-toluenesulfonyl-N-alkoxycarbonyl hydroxylamine at 0-100°C, organic solvent, and alkaline conditions The reaction is obtained, and the product yield is significantly improved, but the substrate preparation process is complicated
CN104628643A discloses that a series of isoquinolinone derivatives are generated by cyclization reaction under inorganic alkali conditions with 2-halogenated benzonitrile compounds and ketone compounds as raw materials and copper salt as catalyst, with high yield. The conditions are mild, but the scope of substrate application is small, and only 3-aryl-substituted isoquinolinones can be obtained
The noble metal catalysts generally used in the prior art have a limited scope of substrate application

Method used

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  • Synthesis method of 2-quinolinone compound
  • Synthesis method of 2-quinolinone compound
  • Synthesis method of 2-quinolinone compound

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preparation example Construction

[0037] Above-mentioned synthetic method specifically adopts the following steps:

[0038] (1) Carry out carbon-hydrogen bond and nitrogen-hydrogen bond activated cyclization reaction with the methacrylamide with directing group under the action of copper salt catalyst, additive, organic solvent, oxidizing agent, inorganic base, temperature The temperature is 30-120°C, the reaction time is 4-24h, the molar ratio of benzyne precursor and methacrylamide with directing group is 2:1, and the molar ratio of catalyst, additive, inorganic base and methacrylamide is 0.1-1: 0.2-2: 0.5-3: 1 and then purified by vacuum distillation and column chromatography to obtain the core skeleton of 2-quinolinone compounds;

[0039] (2) The core skeleton of the 2-quinolinone compound obtained in step (1) is reacted with boron tribromide in dichloromethane at room temperature for 12-20h, then dissolved in acetonitrile and water mixed solvent, and then mixed with trifluoroacetic acid Iodobenzene was r...

Embodiment 1

[0050] Preparation of compound intermediate (I-1)

[0051] 0.2mmol 2-fluoro-acryloyl-8-quinolinamine, 0.4mmol 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, 0.1mmol Cu(OAc)2, 0.24mmol cesium fluoride, Add 0.3mmol of tetrabutylammonium iodide, 1mL of N,N-dimethylacetamide, and 1mL of MeCN into the reaction flask, purging with oxygen, sealing and heating to 80°C for 12h, cooling to room temperature, distillation and purification under reduced pressure Finally, a white solid compound (I-1) was obtained with a yield of 39%.

[0052] Compound (I-1) is:

[0053] 1H NMR (500MHz, CDCl3) δ8.79 (dd, J = 4.1, 1.5Hz, 1H), 8.26 (dd, J = 8.3, 1.5Hz, 1H), 8.05-8.02 (m, 1H), 7.76-7.73 ( m,2H),7.62-7.59(m,2H),7.43(dd,J=8.3,4.2Hz,1H),7.22-7.19(m,2H),6.47-6.44(m,1H).

[0054] 13C NMR (125MHz, CDCl3) δ156.6(d, J=26.8Hz), 151.5, 150.9(d, J=253.5Hz), 144.0, 138.6, 136.3, 134.5(d, J=1.1Hz), 130.2, 129.9 ,129.8,129.0(d,J=2.7Hz),128.0(d,J=6.2Hz),126.6,122.9,122.1,119.1(d,J=17.0Hz),118.7(d,J=...

Embodiment 2

[0057] The preparation of compound intermediate (I-2)

[0058] 0.2mmol 2-benzyl-acryloyl-8-quinolinamine, 0.4mmol 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, 0.1mmol Cu(OAc)2, 0.24mmol cesium fluoride , 0.3mmol tetrabutylammonium iodide, 1mL N,N-dimethylacetamide, and 1mL MeCN were added to the reaction flask, purged with oxygen, sealed and heated to 80°C for 12h, cooled to room temperature, and then distilled under reduced pressure. After purification, a white solid compound (I-2) was obtained with a yield of 72%.

[0059] Compound (I-2) is:

[0060] 1H NMR (500MHz, CDCl3) δ8.82 (dd, J = 4.2, 1.7Hz, 1H), 8.27 (dd, J = 8.3, 1.7Hz, 1H), 8.02 (dd, J = 7.0, 2.7Hz, 1H) ,7.76-7.71(m,2H),7.51-7.49(m,2H),7.43(dd,J=8.3,4.2Hz,1H),7.40-7.35(m,4H),7.29-7.26(m,1H) ,7.18-7.15(m,1H),7.13-7.10(m,1H),6.43(d,J=8.3Hz,1H),4.10(d,J=16.3Hz,1H),4.01(d,J=16.3 Hz,1H).

[0061] 13C NMR(125MHz,CDCl3)δ162.6,151.4,144.4,140.5,139.1,136.8,136.3,135.9,133.9,130.3,129.73,129.65,129.35,129.1,12...

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Abstract

The invention relates to a synthesis method of a 2-quinolinone compound. The synthesis method comprises the steps that a benzyne precursor and methacrylamide with a guiding group are subjected to a carbon-hydrogen bond and nitrogen-hydrogen bond activation cyclization reaction under combined action of a catalyst, an inorganic base, an additive, a solvent and an oxidant to form a core skeleton of the 2-quinolinone compound, and then the guide group is removed to synthesize the 2-quinolinone compound. Compared with the prior art, the method uses a cheap, readily available and environment-friendly copper salt to catalyze synthesis of the 2-quinolinone compound, reaction conditions are relatively mild, applicability of substrates is wide, a new method for synthesizing 2-quinolinone compounds is provided, and thus the method has a good application prospect.

Description

technical field [0001] The invention belongs to the technical field of organic chemical synthesis, and in particular relates to a synthesis method of 2-quinolinone compounds. Background technique [0002] Quinolinone is a common broad-spectrum heterocyclic structure skeleton, which widely exists in a variety of natural products and drug molecules, and has biological activities such as anti-cancer, anti-oxidation, anti-inflammation, and anti-hypertension. Studies have found that the 4-substituted 3-phenyl-2-quinolinone has a good affinity with the glycine site of the N-methyl-D-aspartic acid receptor, and can be used to treat central nervous system disorders. Therefore, the development of new methods to synthesize quinolinones can provide new ideas for the synthesis of drug molecules. [0003] At present, the most commonly used method for the synthesis of quinolinones is the Friedlander condensation reaction of aminoaldehydes, aminoketones, and enolized acids and esters unde...

Claims

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Application Information

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IPC IPC(8): C07D215/40C07D405/14C07D403/14C07D221/12C07D491/052C07D491/056C07D401/04
CPCC07D215/40C07D405/14C07D403/14C07D221/12C07D491/052C07D491/056C07D401/04
Inventor 张书宇陈超丁同梅
Owner SHANGHAI JIAO TONG UNIV
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