Cyclobutyl-1-enamine compound, preparation method thereof and application of cyclobutyl-1-enamine compound in medicine

A compound and enamine technology, applied in the field of organic chemical synthesis, can solve the problems of blank research status, high price, unfriendly environment, etc., and achieve the effect of simple post-processing, short reaction path, and environmental friendliness

Active Publication Date: 2022-05-06
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2010, Hsung's group reported for the first time that alkyne amides and enones in CuCl 2 and AgSbF 6 Under the action of catalysis, an intermolecular Ficini[2+2] cycloaddition reaction occurred to synthesize cyclobut-1-enamine (Org. Lett., 2010, 12, 3780-3783), and Cu(I), Ru (II), Rh(I), etc. catalyze the [2+2] cycloaddition reaction of alkyne amides to construct cyclobut-1-enamine, but most methods are only suitable for alkyne amides with substituents at the end of the alkynyl group, because This kind of alkyne amides is relatively stable, and the highly active alkyne amides without substituents at the end has almost no [2+2] cycloaddition product cyclobut-1-enamine; in addition, most of the reported methods use price Expensive heavy metal catalysts, not friendly to the environment
Therefore, it is of great research significance to develop efficient, environmentally friendly and atom-economical methods for the construction of cyclobut-1-enamines, especially for the construction of cyclobut-1- Enamine is still in a blank research state

Method used

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  • Cyclobutyl-1-enamine compound, preparation method thereof and application of cyclobutyl-1-enamine compound in medicine
  • Cyclobutyl-1-enamine compound, preparation method thereof and application of cyclobutyl-1-enamine compound in medicine
  • Cyclobutyl-1-enamine compound, preparation method thereof and application of cyclobutyl-1-enamine compound in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1: the synthesis of TMS-EBX iodide 4

[0058]

[0059] The specific synthesis steps of TMS-EBX iodide 4 are as follows:

[0060] 1) Dissolve o-iodobenzoic acid 5 (7.44g, 30mmol) and sodium periodate (6.74g, 31.5mmol) in 30% (v:v) aqueous glacial acetic acid (50mL) and reflux for 4.0h until the reaction is complete. Add ice water (30mL) to the reaction system, and cool to room temperature under the condition of avoiding light, filter out the white solid, wash with ice water (60mL) and ice acetone (60mL), and dry at room temperature under avoiding light to obtain 1- Hydroxy-1,2-benzotriazol-3-one compound 6 (7.13 g, 27 mmol), yield 90%.

[0061] 2) Under nitrogen protection, put 1-hydroxy-1,2-benzotriazol-3-one 6 (5.28g, 20mmol) in a round bottom flask, add dichloromethane (30mL), and slowly Add trimethylsilyl trifluoromethanesulfonate (5.44mL, 30mmol), rise to room temperature and stir for 0.5h; then add bis(trimethylsilyl)acetylene (4.99mL, 22mmol), stir...

Embodiment 2

[0062] Embodiment 2: the synthesis of alkyne amide raw material 1a-1i

[0063] In particular, the abbreviation in the compound structure: Ts represents p-toluenesulfonyl, and Mbs represents p-methoxybenzenesulfonyl.

[0064]

[0065] Taking the specific synthesis steps of alkyne amide 1a as an example, add sulfonamide 3a (123.7mg, 0.50mmol) and cesium carbonate (211.8mg, 0.65mmol) to a 25mL round-bottomed flask in sequence, and seal the mouth of the bottle with a well-sealed flip-top rubber stopper And carry out nitrogen protection, then add dried N,N-dimethylformamide (1.0mL), stir at room temperature for 0.5h; dissolve TMS-EBX iodide 4 (258.2mg, 0.75mmol) in dichloromethane (2.5 mL), slowly added to the reaction system at 0°C in the dark, raised to room temperature and stirred for 0.5h; the reaction progress was monitored by thin-layer chromatography, and after the reaction was completed, it was filtered through silica gel, and the solvent was removed under reduced pressu...

Embodiment 3

[0085] Embodiment 3: the synthesis of compound 2a-2i

[0086]

[0087] Taking the specific synthesis steps of compound 2a as an example, under the protection of nitrogen, add alkyne amide 1a (81.4mg, 0.3mmol) into a dry reaction flask, and heat the reaction system until it is in a molten state (100°C). Maintaining its molten state, the progress of the reaction was monitored by thin-layer chromatography, and the reaction was completed after 2.0 h. The obtained crude product was separated by column chromatography using petroleum ether / ethyl acetate (3.5:1) as eluent to obtain the white solid product 2a (70.8 mg, 0.131 mmol), with a yield of 87%.

[0088] The alkyne amide intermediates 1b-1i prepared in Example 2 were prepared according to the above-mentioned method in this example to prepare compound 2, corresponding to obtain compound 2b-2i (Ts represents p-toluenesulfonyl, Mbs represents p-methoxybenzene sulfonyl).

[0089]

[0090] Compound 2a: white solid, 87% yield,...

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Abstract

The invention belongs to the field of organic chemical synthesis, and discloses cyclobutyl-1-enamine compounds, a preparation method thereof and application of the cyclobutyl-1-enamine compounds in antiviral and antitumor drugs. The compound has a structure of a general formula (I), and EWG is selected from alkyl or aryl substituted sulfonyl; r is selected from alkyl, alkoxy, halogen and nitryl. The preparation method comprises the following steps: heating an alkyne amide raw material to a molten state under thermal driving, and carrying out [2 + 2] cycloaddition reaction among molecules to obtain the polysubstituted cyclobutyl-1-enamine compound. The method has the advantages of easily available raw materials, simple steps, no catalyst, no solvent, high yield and the like. The compound has anti-SARS-CoV-2, 5637, Hela, SW480, Hep G2, A549 and MCF-7 activity, and has a good application prospect in the aspect of treating novel coronavirus, bladder cancer, cervical cancer, colon cancer, liver cancer, lung cancer and breast cancer. (I).

Description

technical field [0001] The invention relates to the field of organic chemical synthesis, in particular to cyclobut-1-enamine compounds, their preparation methods and their application in antiviral and antitumor drugs. Background technique [0002] Functionalized cyclobut-1-enamine is an important structural unit present in many pharmaceutically active compounds and natural products. In addition, cyclobut-1-enamine is often used as a reaction substrate to construct other important organic functional group molecules due to the good reactivity endowed by the strain of the four-membered ring. Therefore, the research on the synthesis method of cyclobut-1-enamine compounds has always been a hot spot that chemists pay attention to. [0003] The traditional construction of cyclobut-1-enamine compounds is realized through the Ficini [2+2] cycloaddition reaction, that is, the [2+2] cycloaddition reaction of alkyne amide and cyclic enone to generate cyclobutan-1 - Enamine. In 2010, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C317/30C07C315/04A61P35/00A61P31/14
CPCC07C317/30C07C315/04A61P35/00A61P31/14C07C2601/04Y02P20/55
Inventor 王晓娜丁利霞常俊标
Owner ZHENGZHOU UNIV
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