4-(substituted-1,3-diyne)-4-(trifluoromethyl)-3,4-dihydro substituted quinazoline-2-ketone compound as well as preparation method and application thereof

A technology for trifluoromethylquinazoline and ketone compounds, which is applied in 3 fields and achieves the effects of simple and feasible synthesis method, high yield and good application value

Inactive Publication Date: 2011-05-18
TIANJIN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

4-(Substituted-1,3-diynyl)-4-(trifluoromethyl)-3,4-dihydro-substituted quinazolin-2-one compounds, preparation method and anti-HIV, HBV and HCV Not reported in existing literature

Method used

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  • 4-(substituted-1,3-diyne)-4-(trifluoromethyl)-3,4-dihydro substituted quinazoline-2-ketone compound as well as preparation method and application thereof
  • 4-(substituted-1,3-diyne)-4-(trifluoromethyl)-3,4-dihydro substituted quinazoline-2-ketone compound as well as preparation method and application thereof
  • 4-(substituted-1,3-diyne)-4-(trifluoromethyl)-3,4-dihydro substituted quinazoline-2-ketone compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0017] Example 1: 6-Chloro-4-(penta-1,3-diynyl)-4-trifluoromethyl-3,4-dihydroquinazolin-2(1H)-one (1)

[0018]

[0019] At 0°C, 1.2M methylzinc-n-hexane solution (2.6mL, 3.0mmol) was added dropwise into a toluene solution (5mL) dissolved in 1,3-pentadiyne (192mg, 3.0mmol) for 10 minutes. After that, stir at the same temperature for 30 minutes. The reactant was then cooled to -15°C, a toluene solution (7 mL) dissolved with 6-chloro-4-trifluoromethylquinazolin-2(1H)-one (248.6 mg, 1.0 mmol) was added, and the reaction mixture Stir at 0°C for 24 hours. Cool to -10°C, add 3N HCl to quench the reaction and adjust the pH to 7, add 25 mL of ethyl acetate to the mixture, transfer the mixture to a separatory funnel, separate the organic layer, and wash with aqueous sodium chloride, The organic layer was dried by adding anhydrous sodium sulfate. After filtration, the solvent was distilled off, and rapid silica gel column separation was performed to obtain the target compound 1 (28...

example 2

[0020] Example 2: 6-fluoro-4-(penta-1,3-diynyl)-4-trifluoromethyl-3,4-dihydroquinazolin-2(1H)-one (2)

[0021]

[0022] At -78°C, 1.6M butyllithium n-hexane solution (0.6mL, 1.0mmol) was added dropwise into a tetrahydrofuran solution (10mL) dissolved in 1,3-decadiyne (134.2mg, 1.0mmol), 10 After 1 minute, the mixture was stirred at the same temperature for 30 minutes. Then the reactant was raised to -15°C, a tetrahydrofuran solution (6 mL) dissolved with 6-fluoro-4-trifluoromethylquinazolin-2(1H)-one (232.1 mg, 1.0 mmol) was added, and the reaction The mixture was stirred at 0°C for 24 hours and at room temperature for 6 hours. Cool to -10 ° C, add 3N HCl to quench the reaction and adjust the pH to 7, add 20 mL of ethyl acetate to the mixture, transfer the mixture to a separatory funnel, separate the organic layer, and then wash with aqueous sodium chloride, organic The layer was dried by adding anhydrous sodium sulfate. After filtration, the solvent was distilled off, a...

example 3

[0023] Example 3: 6-Chloro-4-(cyclopropan-1,3-diynyl)-4-trifluoromethyl-3,4-dihydroquinazolin-2(1H)-one (3)

[0024]

[0025] At 0°C, 1.5M ethylmagnesium bromide in ether (1.4mL, 2.0mmol) was added dropwise to cyclopropane-1,3-diyne (180.2mg, 2.0mmol) in ether (10mL) In 8 minutes, the addition was completed, and stirred at the same temperature for 30 minutes. The reactant was then cooled to -10°C, and a solution of ether (5 mL) dissolved with 6-chloro-4-trifluoromethylquinazolin-2(1H)-one (248.6 mg, 1.0 mmol) was added, and the reaction mixture Stir at 0°C for 24 hours. Cool to -10°C, add 3N HCl to quench the reaction and adjust the pH to 7, add 25 mL of ethyl acetate to the mixture, transfer the mixture to a separatory funnel, separate the organic layer, and wash with aqueous sodium chloride, The organic layer was dried by adding anhydrous sodium sulfate. After filtration, the solvent was distilled off, and rapid silica gel column separation was performed to obtain the ...

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Abstract

The invention relates to a 4-(substituted-1,3-diyne)-4-(trifluoromethyl)-3,4-dihydro substituted quinazoline-2-ketone compound as well as a preparation method and application thereof. The preparation method comprises the following steps of: completely reacting 4-substituted-1,3-diyne with 4-trifluoromethylquinazoline-2-ketone at -78-40 DEG C in an organic solvent under the action of alkali by using a chiral alkamine reagent as a ligand; and washing, extracting and separating to obtain the target product 4-(substituted-1,3-diyne)-4-(trifluoromethyl)-3,4-dihydro substituted quinazoline-2-ketone, wherein the molar ratio of the 4-substituted-1,3-diyne to the alkali to the 4-trifluoromethylquinazoline-2-ketone is (1-3):(1-3):1. The structural general formula of the compound is shown as I, wherein R is a 1-6 carbon alkyl group, a 3-7-membered ring alkyl group or an aromatic group such as a phenyl group, a naphthyl group, a furan group and a pyridyl group; and R1 is halogen on the 5th, 6th, 7th or 8th site, a 1-3 carbon alkyl group or a 1-3 alkoxyl group. The compound can be used for treating virus infections, particularly the infections of HBV (Hepatitis B Virus), HCV (Hepatitis C Virus) or HIV (Human Immunodeficiency Virus).

Description

technical field [0001] The present invention relates to a class of 3,4-dihydro-substituted quinazolin-2-one compounds and their preparation methods and applications, and specifically discloses a class of 4-(substituted-1,3-diynyl)- 4-(trifluoromethyl)-3,4-dihydro-substituted quinazolin-2-one compounds, their preparation method and application. Background technique [0002] AIDS (HIV) is a vicious infectious disease that threatens people's health. Currently developed chemotherapeutic drugs for AIDS are all reverse transcriptase inhibitors, which can prevent the extension of mDNA and interfere with the reverse transcription process of HIV. According to different mechanisms of action, reverse transcriptase inhibitors are divided into nucleoside and non-nucleoside reverse transcriptase inhibitors. [0003] Among them, non-nucleoside reverse transcriptase inhibitors are an important class of anti-HIV drugs, such as Nevirapine, Delavirdine and Efavirenz, etc. These drugs have be...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/80C07D401/06C07D405/06A61K31/517A61P31/20A61P31/14A61P1/16A61P31/18
Inventor 马军安张发光聂晶
Owner TIANJIN UNIV
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