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Bisindole alkaloid derivative, and synthesis method and application thereof

A technology of indole alkaloids and indole derivatives, which is applied in the direction of drug combination, organic chemistry, anti-infective drugs, etc., can solve the problems of cumbersome operation, low yield, high cost, etc., and achieve simple and safe operation and high yield Effect

Inactive Publication Date: 2013-08-21
EAST CHINA NORMAL UNIV
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  • Abstract
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Problems solved by technology

However, the traditional chemical synthesis method of bisindole alkaloid derivatives uses indole as a raw material to synthesize bisindole alkaloid derivatives through a four-step reaction (J.Med.Chem.2010, 53, 5155-5164). With the disadvantages of high cost, low yield and cumbersome operation

Method used

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  • Bisindole alkaloid derivative, and synthesis method and application thereof
  • Bisindole alkaloid derivative, and synthesis method and application thereof
  • Bisindole alkaloid derivative, and synthesis method and application thereof

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Experimental program
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Embodiment 1

[0030]

[0031] N-methylindole (0.3mmol), Rh 2 (OAc) 4 (0.0025mmol), N-methyl indigo (0.3mmol) red was dissolved in toluene (1ml), then, phenyldiazoacetate (0.25mmol,) dissolved in toluene (1.0ml) in 1 hour Add it dropwise into the reaction system, and the reaction system is at 0°C. After the dropwise addition, stir for 1 hour, and remove the solvent by rotary evaporation under reduced pressure to obtain a crude product, whose structure is shown in formula (2-1). The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:20~1:3) to obtain a pure product. Yield 81%, d.r > 20:1. nuclear magnetic resonance 1 H NMR, 13 C NMR spectrum as figure 1 As shown, the product 2-1 1 H NMR (400MHz, CDCl3) δ (ppm) 8.53 (s, 1H), 7.72 (d, J=6.7Hz, 1H), 7.30-7.32 (m, 1H), 7.04-7.15 (m, 3H), 6.98 ( m, 2H), 6.77-6.84(m, 4H), 6.68-6.70(m, 1H), 6.69(d, J=7.6Hz, 1H), 3.93(s, 3H), 3.74(s, 3H), 2.81 (s, 3H); 13 C NMR(100Hz,CDCl3)δ(ppm)175.96,174.40,143.65,131....

Embodiment 2

[0033]

[0034] N-methylindole (0.3mmol), N-methylisatin (0.3mmol), Rh 2 (OAc) 4(0.0025mmol), dissolved in dichloromethane (1ml), then, methyl p-methoxyphenyldiazoacetate (0.25mmol,) dissolved in dichloromethane (1.0ml) was added dropwise in 1 hour Into the reaction system, the reaction system was at 50°C, after the dropwise addition was completed, stirred for 1 hour, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, the structure of which was shown in formula (2-2). The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:20~1:10) to obtain a pure product. Yield 73%, d.r > 20:1. nuclear magnetic resonance 1 H NMR, 13 C NMR spectrum as figure 2 As shown, the product 2-2 1 H NMR (400MHz, CDCl3) δ (ppm) 8.42 (s, 1H), 7.63 (d, J = 5.9Hz, 1H), 7.22-7.24 (m, 1H), 6.99-7.05 (m, 3H), 6.66- 6.74(m, 5H), 6.24-6.60(m, 3H), 3.84(s, 3H), 3.66(s, 3H), 3.56(s, 3H), 2.75(s, 3H); 13 C NMR(100Hz,CDCl...

Embodiment 3

[0036]

[0037] N-methylindole (0.3mmol), N-methylisatin (0.3mmol), Rh 2 (OAc) 4 (0.0025mmol) was dissolved in xylene (1ml), then, 4-bromophenyldiazoacetic acid methyl ester (0.25mmol,) dissolved in xylene (1.0ml) was added dropwise to the reaction system within 1 hour , the reaction system was at -10°C, after the dropwise addition was completed, it was stirred for 1 hour, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, the structure of which was shown in formula (2-3). The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:20~1:5) to obtain a pure product. Yield 82%, d.r > 20:1. nuclear magnetic resonance 1 H NMR, 13 C NMR spectrum as image 3 As shown, the products 2-3 1 H NMR (400MHz, CDCl 3 )δ (ppm) 8.51 (s, 1H), 7.71 (m, 1H), 7.31-7.33 (m, 1H), 7.11-7.13 (m, 3H), 6.98 (m, 2H), 6.82-6.83 (m, 2H), 6.65-6.67(m, 2H), 6.37(d, J=6.8Hz, 1H), 3.93(s, 3H), 3.74(s, 3H), 2.86(s, 3H); 1...

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Abstract

The invention discloses a synthesis method of a bisindole alkaloid derivative. A diazo compound, an indole derivative and isatin derivative are used as raw materials, rhodium acetate is used as a catalyst, an organic solvent is used as a solvent, and the raw materials, the catalyst and the solvent are reacted in one step at the temperature of minus 10 DEG C to 50 DEG C to obtain the indole alkaloid derivative. The synthesis method has the advantages of high-efficiency atom economy, high selectivity, high yield, low consumption of the catalyst, simplicity and safety in operation and the like. The bisindole alkaloid derivative can be used as an active molecule precursor to be widely applied in the medical chemical field.

Description

technical field [0001] The invention belongs to the fields of synthetic medicine and chemical industry, and mainly relates to a bisindole alkaloid derivative and its synthesis method and application. Background technique [0002] The bisindole alkaloid derivatives are widely found in nature and are important skeleton structures of natural products and medicines. In 2010, it was reported in Science that a bisindole alkaloid derivative has a very good antimalarial effect (Science 2010, 329, 1175-1180). In the same year, Novartis Research Institute in Singapore also reported structurally optimized bisindole alkaloid derivative antimalarial compounds (J. Med. Chem. 2010, 53, 5155-5164). Recently, the Institute of Tropical Agriculture, Chinese Academy of Sciences also isolated bisindole alkaloid derivatives from tropical plants (Org. Lett. 2013, DOI: 10.1021 / o14002619). However, the traditional chemical synthesis method of bisindole alkaloid derivatives uses indole as a raw mat...

Claims

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Application Information

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IPC IPC(8): C07D209/38A61P33/06
Inventor 胡文浩邱晃金伟峰刘顺英付蕾孙迟
Owner EAST CHINA NORMAL UNIV
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