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A chiral [3.3.1] aza-bridged ring indole alkaloid derivative and its preparation method and application

A technology for indole alkaloids and derivatives, applied in organic chemistry methods, drug combinations, organic chemistry, etc., can solve the problems of low total yield, complicated operation, and low efficiency, and achieve high enantioselectivity and synthetic methods Simple, well-water-soluble effects

Active Publication Date: 2021-10-22
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are occasional sporadic reports, most of the reported examples are constructed through total synthesis or semi-synthesis, which requires multi-step reactions and chiral substrate synthesis.
The shortcomings of these methods are very obvious: 1) the reaction process is lengthy and the operation is complicated; 2) the total yield is very low and the efficiency is low; 3) the stereoselectivity of the product is low; 4) the product structure is single and very limited
It is worth mentioning that there has been no report on the catalytic asymmetric synthesis methodology of this kind of backbone molecules.

Method used

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  • A chiral [3.3.1] aza-bridged ring indole alkaloid derivative and its preparation method and application
  • A chiral [3.3.1] aza-bridged ring indole alkaloid derivative and its preparation method and application
  • A chiral [3.3.1] aza-bridged ring indole alkaloid derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Methyl-(6R,7S,13S)-8,13-Dimethyl-7-(2-oxo-2-phenylethyl)-5,7,8,13-tetrahydro-6H-6,13 - Preparation of cycloiminobenzo[4,5]cyclooctane[1,2-b]indole-6-carboxylate (I-1):

[0081] Add 26.1mg of compound 1a (0.1mmol) and 24.0mg of compound 2a (0.12mmol), 15.2mg (0.15mmol) of triethylamine, catalyst 4a (0.01mmol) and 1mL of acetonitrile into the reaction flask, stir and mix well at 20°C Reaction takes place under the following conditions. This reaction catalyst load is 10mol%, reacts 6h, TLC shows that raw material 1a consumes completely, extracts with ethyl acetate, concentrates direct concentration column chromatography (petroleum ether / ethyl acetate, v / v=40 / 1 ), to obtain 44.5mg of product I-1, whose single crystal structure is shown in figure 1 .

[0082]

[0083] Characterization data: 96% yield, white solid, melting point: 173.6-174.4°C; 1 H NMR (400MHz, CDCl 3 )δ7.99(d, J=7.2Hz, 1H), 7.68(d, J=7.3Hz, 1H), 7.62(d, J=7.9Hz, 1H), 7.55(dd, J=10.5, 4.4Hz, 1H),7.45(...

Embodiment 2

[0088] Methyl-(6R, 7S, 13S)-7-(2-(4-methoxyphenyl)-2-oxoethyl)-8,13-dimethyl-5,7,8,13-tetra Preparation of Hydrogen-6H-6,13-cycloiminobenzo[4,5]cyclooctane[1,2-b]indole-6-carboxylate (I-6):

[0089]

[0090] The preparation method of this embodiment is similar to that of Example 1, except that the raw materials and reaction conditions have changed during the reaction. The organic solvent used in the preparation process is ethyl acetate, the base is diisopropylethylamine, and the catalyst is 4b , the reaction temperature is 20°C, and the reaction time is 6h.

[0091] Characterization data: 92% yield, white solid, melting point: 150.4-151.2°C;

[0092] 1 H NMR (400MHz, CDCl 3 )δ7.98(d, J=8.8Hz, 1H), 7.68(d, J=7.6Hz, 1H), 7.62(d, J=7.9Hz, 1H), 7.23–7.15(m, 1H), 7.11( dd,J=11.3,3.8Hz,1H),7.03(dd,J=12.9,6.9Hz,1H),6.92(dd,J=7.0,5.0Hz,1H),4.19(dd,J=6.1,3.0Hz ,1H),3.89(dd,J=17.7,6.3Hz,1H),3.85(s,3H),3.67(s,3H),3.47(s,3H),3.26(d,J=17.8Hz,1H) ,2.93(dd,J=17.7,3.0Hz,1H),2.71(d,J=...

Embodiment 3

[0097] Methyl-(6R, 7S, 13S)-8,13-dimethyl-7-(2-oxo-2-(1H-pyrrol-2-yl)ethyl)-5,7,8,13- Preparation of tetrahydro-6H-6,13-cycloiminobenzo[4,5]cyclooctane[1,2-b]indole-6-carboxylate (I-16):

[0098]

[0099] The preparation method of this embodiment is similar to that of Example 1, except that the raw materials and reaction conditions have changed in the reaction process. The organic solvent used in the preparation process is dichloromethane, the alkali is potassium carbonate, the catalyst is 4c, and the reaction temperature is 20 °C, the reaction time is 8h.

[0100] Characterization data: 90% yield, white solid, melting point: 150.4-151.2°C;

[0101] 1 H NMR (400MHz, CDCl 3 )δ9.53(s,1H),7.65(dd,J=23.8,7.7Hz,2H),7.20(dd,J=15.4,7.8Hz,2H),7.13(t,J=7.4Hz,1H), 7.09–6.99(m,3H),6.92(d,J=6.6Hz,2H),6.26(d,J=3.6Hz,1H),4.08(dd,J=6.3,3.1Hz,1H),3.71(s ,3H),3.69–3.63(m,1H),3.45(s,3H),3.22(d,J=17.8Hz,1H),2.86(dd,J=16.8,3.1Hz,1H),2.69(d, J=17.8Hz,1H),2.15(s,3H).; 13 C NMR (101MHz, CD...

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Abstract

The invention provides a chiral [3.3.1] aza-bridged ring indole alkaloid derivative and its preparation method and application. The preparation method comprises: under the action of a chiral quaternary phosphonium salt catalyst, compound A and compound B is dissolved in an organic solvent, and a base is added to react to obtain a chiral [3.3.1] azabridged ring indole alkaloid derivative. The preparation method of the present invention has simple process, mild reaction conditions and high yield, and the obtained product has excellent enantioselectivity and diastereoselectivity, and is the core skeleton of many natural product molecules, chiral drugs and intermediates thereof, and has Strong practical application value. The compounds provided by the present invention can effectively inhibit various tumor cells, such as human colon cancer cells, lung cancer cells, melanoma cells, breast cancer cells, pancreatic cancer cells in situ and pancreatic cancer cells, and are used in the preparation of drugs for preventing and / or treating tumors. has broad prospects.

Description

technical field [0001] The invention belongs to the technical field of chemical industry and medicine, and specifically relates to a chiral [3.3.1] aza-bridged ring indole alkaloid derivative and a preparation method and application thereof. Background technique [0002] Indole alkaloids widely exist in nature and are the core structural units of many natural products and important pharmaceutically active molecules. [3.3.1] The aza-bridged ring skeleton molecule is the core skeleton of indole alkaloids such as Macroine and Sarpagine. These natural alkaloids often exhibit many important physiological and pharmaceutical activities and are widely used in disease treatment, such as It has a wide range of applications in the treatment of nervous system diseases, Alzheimer's disease, anti-tumor, sedation, and anti-virus. Due to its unique structure, rigidity, and bicyclic nitrogen-bridged ring skeleton, its synthesis, especially asymmetric synthesis, has always been a research di...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/18A61P35/00
CPCA61P35/00C07B2200/07C07B2200/13C07D471/18
Inventor 王天利谭建平李可晗
Owner SICHUAN UNIV
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