A kind of method for synthesizing indole quinoline compounds

A technology of indoquinoline and compounds, applied in the field of organic chemical synthesis, can solve the problems of unavailable, expensive raw materials, high cost, etc., and achieve the effect of mild reaction conditions and good repeatability

Active Publication Date: 2021-10-08
SHANGHAI JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Isoneocryptolepine was synthesized in 2006 by Dhanabal et al. using halogen-substituted quinoline and aniline derivatives as raw materials through photocatalytic cyclization reaction. The raw materials used are expensive and difficult to obtain, and the cost is relatively high
[0006] Chinese patent CN104513240A discloses the preparation method and application of isobaline derivatives, and specifically relates to a class of 5-desmethylisoalvanine derivatives at positions 8 and 11. The invention also discloses this type of The preparation method of phyllene derivatives and its application in the preparation of anti-tumor drugs, the ring-closing steps of the method adopted are cumbersome, and the applicability of the substrate is not wide

Method used

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  • A kind of method for synthesizing indole quinoline compounds
  • A kind of method for synthesizing indole quinoline compounds
  • A kind of method for synthesizing indole quinoline compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Preparation of indoquinoline compound intermediate (I-1)

[0063] 0.2mmol 1-methyl-N-(8 aminoquinoline)-1H-3-amide, 0.1mmol Cu(OAc) 2 , 0.24mmol cesium fluoride, 0.2mmol tetrabutylammonium iodide, 0.4mmol 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, 1mL N,N-dimethylformamide, 1mL MeCN were added to the reaction The bottle was purged with oxygen, sealed and heated to 80°C for 12 hours. After cooling to room temperature, it was distilled under reduced pressure and purified to obtain a colorless crystalline compound (I-1) with a yield of 81%.

[0064] Compound (I-1) is:

[0065] 1 H NMR (DMSO, 400MHz, ppm): δ8.70(d, J=2.6Hz, 1H), 8.65-8.63(m, 1H), 8.56(d, J=7.3Hz, 1H), 8.26-8.21(m ,2H),7.89-7.85(m,3H),7.59(dd,J=8.2,4.1Hz,1H),7.47(t,J=7.2Hz,1H),7.35-7.29(m,3H),6.52- 6.50(m,1H),4.43(s,3H); 13 C NMR (DMSO, 100MHz, ppm) δ151.2, 144.3, 140.8, 139.7, 136.7, 135.8 131.4, 129.5, 129.0, 127.0, 124.4, 123.7, 123.6, 122.2, 121.7, 120.8, 117.0, 113.3, 1107; HRMS: calcula...

Embodiment 2

[0067] Preparation of indoquinoline compound intermediate (I-2)

[0068] 0.2mmol 1,5-dimethyl-N-(8 aminoquinoline)-1H-3-amide, 0.1mmol Cu(OAc) 2 , 0.24mmol cesium fluoride, 0.2mmol tetrabutylammonium iodide, 0.4mmol 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, 1mL N,N-dimethylformamide, 1mL MeCN were added to the reaction flask , purged with oxygen, sealed and heated to 80° C. for 12 h, cooled to room temperature, distilled under reduced pressure and purified to obtain a colorless crystal compound (I-2) with a yield of 86%.

[0069] Compound (I-2) is:

[0070] 1 H NMR (CD 2 Cl 2 ,400MHz,ppm):δ8.74(dd,J=4.1,1.5Hz,1H),8.43(dd,J=8.1,1.4Hz,1H),8.35(dd,J=8.3,1.5Hz,1H), 8.21(s,1H),8.13-8.08(m,1H),7.84-7.79(m,2H),7.47-7.44(m,2H),7.29-7.20(m,3H),6.62(dd,J=8.2 ,0.9Hz,1H),4.30(s,3H),2.49(s,3H); 13 C NMR (CD 2 Cl 2 ,100MHz,ppm)δ160.4,151.5,145.2,141.5,140.4,138.7,136.9,136.7,131.8,131.7,130.2,129.6,128.6,127.2,126.3,124.9,123.3,1262.3,1271.8,101.1,12 , 107.6, 34.1, 21.5...

Embodiment 3

[0072] Preparation of indoquinoline compound intermediate (I-3)

[0073] 0.2mmol 1-methyl-5-methoxy-N-(8 aminoquinoline-)-1H-3-amide, 0.1mmol Cu(OAc) 2 , 0.24mmol cesium fluoride, 0.2mmol tetrabutylammonium iodide, 0.4mmol 2-(trimethylsilyl)phenyltrifluoromethanesulfonate, 1mL N,N-dimethylformamide, 1mL MeCN were added to the reaction flask , purged with oxygen, sealed and heated to 80° C. for 12 h, cooled to room temperature, distilled under reduced pressure and purified to obtain a colorless crystal compound (I-3) with a yield of 68%.

[0074] Compound (I-3) is:

[0075] 1 H NMR (CDCl 3 ,400MHz,ppm):δ8.80(dd,J=4.2,1.7Hz,1H),8.41(dd,J=8.1,1.8Hz,1H),8.29(dd,J=8.3,1.7Hz,1H), 8.05(dd, J=8.1,1.6Hz,1H),8.01(d,J=2.6Hz,1H),7.83(dd,J=7.2,1.6Hz,1H),7.78(t,J=7.9Hz,1H ),7.44-7.40(m,2H),7.28-7.20(m,2H),7.07(dd,J=9.0,2.6Hz,1H),6.66(dd,J=8.1,1.1Hz,1H),4.32( s,3H),3.85(s,3H); 13 C NMR (CDCl 3 ,100MHz,ppm)δ160.7,155.8,151.6,145.2,141.0,140.2,136.5,136.4,134.9,131.4,130.0,129.4,128....

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Abstract

The invention relates to a method for synthesizing indole quinoline compounds. Indole amide having a directing group and a benzyne precursor are subjected to carbon-hydrogen synthesis under the combined action of a catalyst, an inorganic base, an additive, a solvent and oxygen. The bond / nitrogen-hydrogen bond activates the cyclization reaction to generate the core skeleton of the indole quinoline compound, and then removes the directing group, and undergoes multi-step chemical transformation to synthesize the indole quinoline compound. Compared with the prior art, the method of the present invention can synthesize indoquinoline compounds under the action of cheap, easy-to-obtain and environment-friendly copper catalyst, the reaction conditions are relatively mild, and the reproducibility is good. The Isocryptolepine, which is synthesized by the method of the present invention, Isoneocryptolepine and other indolequinoline alkaloids can fight against malaria that affects human life, which is of great significance to the development of new drugs and 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 method for synthesizing indoquinoline compounds. Background technique [0002] As a kind of natural medicine, white leaf vine has been paid close attention to all the time. The vine plant is rich in indolequinoline alkaloids, such as cryptolepine, neocryptolepine, isocryptolepine, etc., which have significant antimalarial activity , anti-tumor cells, anti-fungal, anti-meningitis, anti-microbial, anti-bacterial, anti-inflammatory, hypoglycemic, anti-hypertensive, inhibitory norepinephrine receptors and antithrombotic activities. [0003] Isocryptolepine is a natural alkaloid extracted from the West African plant Cryptolepis sanguinolenta, which has significant antimalarial activity. Isolophylline and its derivatives have good physiological activity on diabetes, fungal infection, pain relief and anti-inflammation, upper respiratory tract infection...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCC07D471/04Y02A50/30
Inventor 张书宇张婷玉丁同梅
Owner SHANGHAI JIAOTONG UNIV
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