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Azepineindole alkaloid and preparation and anti-malarial application thereof

An azepine and indole technology, which is applied in the preparation of aza-indole alkaloids and enzymatic chemical methods, and the application field in the preparation of anti-malarial drugs, can solve the problem of the stereoselective PS method and the synthetic method without manual Sexual selectivity, etc.

Active Publication Date: 2019-05-31
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The synthesis methods of azazoindole compounds have been reported in the literature, but most of the synthesis methods have no chiral selectivity, including a PS method without stereoselectivity

Method used

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  • Azepineindole alkaloid and preparation and anti-malarial application thereof
  • Azepineindole alkaloid and preparation and anti-malarial application thereof
  • Azepineindole alkaloid and preparation and anti-malarial application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0019] Embodiment 1: Preparation of azazoindole isososidine (IV)

[0020] Dissolve compound II (0.4g, 2.5mmol) and compound III (1.1g, 2.5mmol) in KPi (50mM, pH=7.0, 200ml) respectively, add STR1 5mg, and incubate at 26°C for 12h. After the reaction is complete, no After purification, it was directly used in the reaction of Example 2.

Embodiment 2

[0021] Example 2: (10S, 11R, 11aS, 12aR)-10-(((2S, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H -pyran-2-yl)oxy)-11-ethenyl 10,11,11a,12,12a,14 hexahydro-4H-pyrano[4",3":4',5']pyrido Preparation of [1',2':1,2]aza[3,4,5-cd]indol-7(5H)-one (V).

[0022] Add 5% sodium carbonate solution (500ml) to the reaction solution of Example 1 and mix to obtain a suspension, and react at 70°C for 2 hours. After the reaction is completed, the solvent is removed by distillation under reduced pressure, and flash column chromatography obtains a yellow solid 4 , 14g, yield 86%. 1 HNMR (500MHz, CD 3 OD): δ7.35 (1H, d, J = 2.0Hz), 7.21 (1H, d, J = 8.0Hz), 7.18 (1H, d, J = 1.5Hz), 7.03 (1H, t, J = 8.0 Hz),6.84(1H,d,J=8.0Hz),5.64(1H,dt,J=17.0,10.0Hz),5.39(1H,d,J=2.0Hz),5.36(1H,dd,J=17.0 ,2.0Hz),5.29(1H,dd,J=10.0,2.0Hz),4.98(1H,d,J=5.0Hz),4.76(1H,dt,J=13.5,3.5Hz),4.58(1H,d ,J=8.0Hz),3.86(1H,dd,J=12.0,2.0Hz),3.64(1H,dd,J=12.0,6.0Hz),3.49(1H,m),3.07-3.26(6H,m) ,2.97(1H,ddd,J=8.5...

Embodiment 3

[0023] Example 3: Preparation of reduced azaindole lactamized isosidine (VI)

[0024] Compound V (3.00g, 6.00mmol) was dissolved in 50ml of methanol, and 10% palladium carbon (300mg) was added to react overnight at room temperature. The palladium carbon was removed by filtration, and the solvent was distilled off under reduced pressure to obtain 2.98g of a yellow solid with a yield of 98%. .

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Abstract

The invention provides anazepineindole alkaloid and a preparation method and an anti-malarial application thereof.The preparation method utilizes tryptamine and split ring strychnine as initial raw materials to obtain two diastereoisomers after being catalyzed and chemically modified by strictosidinesynthetase and phosphoric acid.According to the method, two diastereoisomers of the azepineindole alkaloid are synthesized through a simple enzymatic chemical reaction and a purification method, a research shows that compounds and pharmaceutical salts thereof have outstanding anti-malarial activityand can be applied to the preparation of anti-malarial drugs.The structural formula of the two compounds is shown in the description.

Description

field of invention [0001] The invention belongs to the field of medicinal chemistry and pharmacology, and relates to the preparation of azazoindole alkaloids and enzymatic chemical method, and the application of the compounds in the preparation of antimalarial drugs. Background of the invention [0002] The asymmetric Pictet-Spengler (PS) reaction is one of the important methods to construct indole alkaloids with chiral centers, but the asymmetry often relies on complex structures, high prices, and ligand-bound metal catalysts. Strictosidine Synthase (STR1) is an enzyme that can catalyze the Pictet-Spengler (PS) reaction, and is also one of the important enzymes in the biosynthesis of monoterpene indole alkaloids in higher plants. , high selectivity and so on. Despite the multiple advantages of the enzymatic chemistry of STR1, its strict substrate adaptability requirement limits its application in the biomimetic synthesis of monoterpene indole alkaloids. Exploring new subs...

Claims

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Application Information

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IPC IPC(8): C07D487/22A61P33/06
Inventor 邹宏斌蔡云瑞邵娜娜
Owner ZHEJIANG UNIV
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