Preparation and application of trans-1,2-(1,4-diazulyl)ethene derivative

A technology of guaiac and azulene, which is applied in the field of chemical preparation and application of guaiac aldehyde dicondensate, can solve problems such as no reports of biological activity, and achieve the effect of enriching the library of antiviral active compounds

Inactive Publication Date: 2019-07-23
OCEAN UNIV OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There is no report on the biolo

Method used

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  • Preparation and application of trans-1,2-(1,4-diazulyl)ethene derivative
  • Preparation and application of trans-1,2-(1,4-diazulyl)ethene derivative
  • Preparation and application of trans-1,2-(1,4-diazulyl)ethene derivative

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Embodiment 1

[0017] Embodiment 1: the synthesis of azulene, reference (Takekuma S, Matsuoka H, ​​Minematsu T et al. Tetrahedron, 2010, 66 (16): 3004-3015.) carry out the following operations:

[0018] Add dry 3mL DMF to a dry and clean 50mL three-necked round-bottom flask, slowly add phosphorus oxychloride dropwise through a constant pressure dropping funnel under ice bath conditions, and stir for 35min. Then add the DMF solution of guaiazulene dropwise through the dropping funnel from the other side, and transfer to a 35°C water bath after adding. After reacting for 10 h, the reaction solution was poured into a sufficient amount of ice water and stirred evenly. The pH of the reaction solution was adjusted to about 8 with an aqueous solution of potassium hydroxide. Stir for a few minutes, heat to 90°C, and drive out the dimethylamine gas generated by the reaction. Then it was extracted three times with dichloromethane, the combined extracts were evaporated to dryness, separated and purif...

Embodiment 2

[0019] Embodiment 2: the synthesis of pipecolic acid ethyl ester, reference (McFarlane A K, Thomas G, WhitingA.Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry, 1995, (21): 2803-2808. ) to perform the following operations:

[0020] Add 1.46g (10.0mmol) lysine to a 100mL round bottom flask, and add 50mL methanol. Thionyl chloride (1.5mL, 20.6mmol) was added dropwise while stirring at 0°C. After reacting for 3 hours, a sample was taken for TLC detection, and it was found that the lysine raw material was not completely reacted, and the reaction system was still a suspension. The reaction solution was transferred to an oil bath at 70°C, and after reflux for 4 hours, a sample was taken for TLC detection, and the lysine raw material disappeared. After the reaction was completed, the reaction solution was poured into 50 mL of ice water, adjusted to pH 6-7 with sodium hydroxide solution (10 mol / L), and evaporated to dryness to obtain a white s...

Embodiment 3

[0021] Embodiment 3: the synthesis of P2C

[0022] ① Fresh tert-butyl hypochlorite: add 5mL sodium hypochlorite solution (active chlorine content ≥ 5.2%, available chlorine ≥ 8.0mmol), 1mL (52.4mmol) tert-butanol in a 25mL round bottom flask, and place at 0°C Add 1 mL (17.2 mmol) of glacial acetic acid dropwise to the flask in a low-temperature constant-temperature stirring reaction bath, and react in the dark for about 5 minutes. After the reaction was completed, the reaction bottle was left to stand for 2 minutes, and the yellow oily liquid (ie tert-butyl hypochlorite) in the upper layer of the reaction bottle was absorbed, and placed in another light-proof glass vial for subsequent use.

[0023] ②N-Chlorination reaction: Add 500mg (2.6mmol) pipecolic acid ethyl ester hydrochloride into a 50mL round bottom flask, add 30mL anhydrous ether, ultrasonically dissolve (most of the materials are insoluble), then pump out the air in the bottle, quickly Seal the mouth of the bottle ...

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Abstract

The invention belongs to the field of synthetic medical chemistry and particularly relates to chemical preparation and application of a trans-1,2-(1,4-diazulyl)ethene derivative. During chemical synthesis study of a framework with guaiazulene and piperidine as raw materials, the trans-1,2-(1,4-diazulyl)ethene derivative is found, in-vitro H1N1 influenza virus test results indicate that the compound has in-vitro antiviral activity superior to a positive drug ribavirin at the concentration level of 25 mM. In-vivo activity tests find that the compound can inhibit pneumonic symptoms, reduce lung virus titer and increase survival rate of mice and can significantly increase the survival rate of virus infected mice and reduce lung virus titer by gavage at the dosage of 5 mg/kg/day in particular.In conclusion, the compound has in-vivo activity equivalent to oseltamivir effect, so that the compound can be used for preparing antiviral drugs. A new way is opened up for deep research and development of novel antiviral drugs.

Description

technical field [0001] The invention belongs to the field of synthetic medicinal chemistry, and in particular relates to the chemical preparation and application of guaiazulene dicondensate. Background technique [0002] Guaiazulene sesquiterpene alkaloid Muriceidine A is a new skeleton molecule isolated by our research group from the high-collared gorgonian Muriceides collaris collected from Weizhou Island in the South my country Sea. Preliminary biological activity tests show that this type of compound It has good anti-tumor and anti-adhesion activities. When our research group used guaiazulene and pipecolic acid as raw materials to study the chemical synthesis of this framework, we discovered the dicondensate of azulene aldehyde. At present, there is only one literature report about this compound, that is, azulene undergoes self-condensation at high temperature (150-200° C.), and the yield is about 0.6%. There is no report on the biological activity of this compound. Si...

Claims

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Application Information

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IPC IPC(8): C07C47/45C07C45/68C07C45/00C07D211/60C07D211/78A61P31/12
CPCC07C45/00C07C45/68C07C47/45C07D211/60C07D211/78
Inventor 李国强李平林唐旭利刘小玲
Owner OCEAN UNIV OF CHINA
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