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Preparation method of disubstituted quinazoline medicine compounds containing triazole parent nucleus

A compound, triazole technology, applied in the field of synthesis of disubstituted quinazoline drug intermediates, achieving the effect of simple raw materials, increased product yield, and high yield

Inactive Publication Date: 2018-08-24
张海英
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] As mentioned above, although a variety of synthetic methods of quinazoline derivatives and 1,2,3-triazole derivatives have been disclosed in the prior art, for compounds containing quinazoline and 1,2,3-triazole There are very few reports on the compound synthesis methods of azole complex units, especially the efficient synthesis methods of synchronously introducing alkyl trifluoromethyl substituents, and there is still a need for further research, which is exactly the purpose and motivation of the present invention.

Method used

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  • Preparation method of disubstituted quinazoline medicine compounds containing triazole parent nucleus
  • Preparation method of disubstituted quinazoline medicine compounds containing triazole parent nucleus
  • Preparation method of disubstituted quinazoline medicine compounds containing triazole parent nucleus

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Experimental program
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Effect test

Embodiment 1

[0061] Azide intermediate product preparation

[0062]

[0063] In the tubular reactor, vacuumize and replace twice with nitrogen, under the atmosphere of nitrogen protection, add 10ml of methyl tert-butyl ether solvent, mix 1mmol of the above formula (II) compound, 2mmol of the above formula iodide compound, 2.5mmol of Nitrotrimethylsilane, 2mmol tert-butyl peroxyphenylacetate and 0.02mmol tetraacetonitrile copper hexafluorophosphate catalyst were dissolved in the above solvent, stirred and reacted at 30°C for 2 hours, after the reaction was completed, the reaction solution was cooled to room temperature, After filtration, the solvent was distilled off under reduced pressure, separated and purified by column chromatography to obtain the compound of formula III with a yield of 92.7%. IR (KBr): ν3329, 3050, 2961, 2904, 2870, 2811, 2732, 2101, 1634, 1523, 1441, 1141, 875cm -1 .

Embodiment 2

[0065] Azide intermediate product preparation

[0066]In the tubular reactor, vacuumize and replace twice with nitrogen, under nitrogen protection atmosphere, add 10ml of dichloroethane solvent, 1mmol of the compound of formula (II) shown in Example 1, 2mmol of iodide shown in Example 1 Alkane compound, 2.5mmol azidotrimethylsilane, 2mmol benzoyl peroxide and 0.02mmol ferrous trifluoromethanesulfonate catalyst were dissolved in the above dichloroethane solvent, stirred and reacted at room temperature for 3 hours, and the reaction ended Afterwards, the reaction liquid was filtered at room temperature, the solvent was distilled off under reduced pressure, separated and purified by column chromatography to obtain 0.87 mmol of the compound of formula III with a yield of 87.5%.

Embodiment 3-5

[0067] Embodiment 3-5: prepare following formula I triazole product

[0068]

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Abstract

The invention provides a preparation method of trifluoromethyl substituted and 1,2,3-triazole structure unit containing 2,4-disubstituted quinazoline medicine compounds shown in the following formula(I). The method comprises the steps as follows: an alkenyl quinoline compound reacts with trifluoromethyl substituted alkyl iodide and azidotrimethylsilane in an organic solvent in the presence of a peroxide free radical initiator and an organic metal salt catalyst, and an intermediate compound is obtained; the intermediate compound and a cycloaddition reagent are subjected to a cycloaddition reaction under the protection of nitrogen in an organic solvent in the presence of alkali and bis(2-diphenylphosphinophenyl)ether ligand, and the compound shown in the formula (I) is obtained. The cycloaddition reagent is selected from beta-carbonyl carboxylate or alkyne compounds.

Description

technical field [0001] The invention provides a method for synthesizing a disubstituted quinazoline drug intermediate, in particular to a method for synthesizing a trifluoromethyl-substituted 2,4-disubstituted quinazoline drug containing a triazole core, in the field of organic chemistry. Background technique [0002] As a class of important nitrogen-containing heterocyclic compounds, triazoles and quinazolines have biological activity and pharmacological effects, and can be used as structural fragments of active drugs, and are widely used in many specific application fields such as medicine, pesticide and chemical industry prospect. Among them, quinazoline compounds are a class of nitrogen-containing heterocyclic compounds with good biological activity, which have shown excellent activities in antibacterial, anti-inflammatory, anti-hypertensive and anti-cancer aspects. Currently, quinazoline drugs on the market include: Ralitrexed, a drug that inhibits thymidylate synthas...

Claims

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Application Information

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IPC IPC(8): C07D403/06C07D239/94
CPCC07D239/94C07D403/06
Inventor 张海英周兰兰
Owner 张海英
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