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Beta-carboline derivatives, gamma-carboline derivatives as well as preparation methods and use thereof

A derivative, carboline technology, applied in the field of biosynthesis, can solve the problems of strict reaction conditions, difficult control, human and environmental hazards, etc.

Inactive Publication Date: 2017-07-25
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Regarding β-carboline derivatives and their preparation, CN102617569B proposes a synthetic route for β-carboline derivatives as shown in general formula (12), but highly toxic sodium azide and Explosive nitromethane, with a long reaction route, will cause harm to human body and environment
Compound (10) is a derivative of the natural product eudistomin U, and eudistomin U has good inhibitory activity on mouse leukemia cell lines; however, most of the synthesis of eudistomin U uses the dangerous reagent DDQ, which requires strict reaction conditions , not easy to control

Method used

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  • Beta-carboline derivatives, gamma-carboline derivatives as well as preparation methods and use thereof
  • Beta-carboline derivatives, gamma-carboline derivatives as well as preparation methods and use thereof
  • Beta-carboline derivatives, gamma-carboline derivatives as well as preparation methods and use thereof

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preparation example Construction

[0069] The synthetic method of the β-carboline derivative provided by the invention specifically comprises the following steps:

[0070] Using compound (N.1) as a starting material, react with N,O-dimethylhydroxylamine hydrochloride to generate compound (N.2);

[0071] Described compound (N.2) is mixed with NaH again, CH 3 I reacts to generate compound (N.3);

[0072] The compound (N.3) undergoes a nucleophilic substitution reaction with a Grignard reagent to generate compound (N.4);

[0073] The compound (N.4) is oximated and formed into an ester to generate compound (N.5);

[0074] The compound (N.5) and the ring-closing reagent (A) or (B) are reacted at 45-150° C. for 8-36 hours in an appropriate reaction solvent under the action of a palladium reagent or a rhodium reagent as a catalyst, and then The β-carboline derivative (N.6) is obtained.

[0075] The compound (N.6) undergoes a further reaction to obtain the compound (N). The reaction formula is:

[0076]

[007...

Embodiment 1

[0085] Example 1: Synthesis of 1,9-dimethyl-9H-β-carboline-3-carboxylic acid methyl ester

[0086] S1: Dissolve 1.61g (10.0mmol) of indole-2-carboxylic acid in 80.0mL of anhydrous DCM (dichloromethane), add 1.17g (1.2eq) of N,O-dimethylhydroxylamine hydrochloride and react for 15 minutes , 2.1mL (1.2eq) DIPEA (N, N-diisopropylethylamine) was added dropwise, 2.30g (1.2eq) EDCI (carbodiimide) was added at 0°C, 0.06g (0.05eq) DMAP ( 4-dimethylaminopyridine), the reaction temperature was gradually raised to room temperature, reacted for 12 hours, and TLC (thin layer chromatography) showed that the raw materials disappeared; Dry over sodium sulfate, distill off DCM under reduced pressure to obtain 1.58 g of white solid, which is compound (1.2), Yield: 98.3%.

[0087] The structure of compound (1.2) is as follows:

[0088]

[0089] S2: Dissolve 0.80g (2.0eq) of 60% NaH in 80.0mL of dry DMF. After blowing the bottle with nitrogen, dissolve it in 20.0mL of dry DMF (N,N-dimethylfo...

Embodiment 2

[0098] Example 2: Synthesis of 9-methyl-1-phenyl-9H-β-carboline-3-carboxylic acid methyl ester:

[0099] Steps S1-S2 are the same as those in Embodiment 1, and will not be repeated here.

[0100] S3: After dissolving 1.10 g (5 mmol) of compound (2.3) {that is, compound (1.3) in Example 1} in 30 mL of anhydrous THF, under nitrogen protection, 3.8 mL (1.5 eq, 2 M n-hexane solution) phLi, ​​the reaction temperature was gradually raised to room temperature, reacted for 1 hour, TLC showed that the raw materials disappeared; slowly added ice water at 0°C to quench the reaction, extracted 2-3 times with ethyl acetate, washed once with saturated sodium chloride solution , dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain 0.92 g of white solid (1-methyl-1H-indol-2-yl)-phenyl-methanone, Yield: 83.6%.

[0101] S4: After dissolving 0.94g (4mmol) (1-methyl-1H-indole)-2-phenyl-methanone in 20mL absolute ethanol, add 0.81g (3.0eq) NH 2 OH·HCl and 0.98g (3...

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Abstract

The invention relates to beta-carboline derivatives, gamma-carboline derivatives as well as preparation methods and use thereof. The general structural formulas of the beta-carboline derivatives and the gamma-carboline derivatives are respectively described in the description. The invention provides the preparation methods of the beta-carboline derivatives and the gamma-carboline derivatives; the preparation methods are simple in operation, easy in obtaining of reaction raw materials and reaction reagents, and high in yield.

Description

technical field [0001] The invention relates to the field of biosynthesis, in particular to β-carboline and γ-carboline derivatives, their preparation methods and applications. Background technique [0002] Carboline alkaloids are mainly β-carboline alkaloids, which have antibacterial, antiviral, antitumor and central nervous system inhibitory activities. Among them, in anti-tumor aspect, due to its advantages of multi-target and broad anti-tumor spectrum, it has received widespread attention. Other carboline alkaloids exist less in nature, and their functions are less known. In recent years, research results have initially shown that some alkaloid compounds with carboline core structure have good anti-tumor activity, but also have greater neurotoxicity. Therefore, it is of great practical significance to discover a series of new carbolines and develop new synthetic routes using carbolines as the mother nucleus. [0003] Regarding β-carboline derivatives and their prepara...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/437A61P31/04A61P31/12A61P35/00
CPCC07D471/04
Inventor 张志伟李海玲刘守信董玉冯娟李军章
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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