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4-1,2,3-triazole-coumarin derivative and its preparation method and application

A technology of coumarin derivatives and triazoles, which is applied in the field of chemical medicine and can solve the problems of poor drug selectivity, restrictions on drug use, and toxic and side effects

Inactive Publication Date: 2012-10-24
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the selectivity of traditional drugs is poor. While killing tumor cells, it will also kill normal tissue cells, resulting in serious toxic and side effects, which restricts the use of certain drugs.

Method used

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  • 4-1,2,3-triazole-coumarin derivative and its preparation method and application
  • 4-1,2,3-triazole-coumarin derivative and its preparation method and application
  • 4-1,2,3-triazole-coumarin derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1 Preparation of 4-azido-6-bromocoumarin

[0081] The synthetic route is as follows:

[0082]

[0083] 1, the preparation of p-bromoacetate phenol

[0084]It is prepared from p-bromophenol according to the existing published method, for example: p-bromophenol (10g, 57.8mmol) and acetic anhydride (25ml, 232mmol) are mixed and added to pyridine (22ml). After the addition was complete, the mixture was heated to 100°C for 3.5 hours. After completion of the reaction, cool the reaction, add 150ml of water, acidify with dilute hydrochloric acid, then extract with ethyl acetate, then wash the organic layer with saturated sodium bicarbonate solution until no bubbles are generated. The organic layer was dried with anhydrous sodium sulfate, spin-dried, and dried under reduced pressure at room temperature to obtain a colorless oily liquid (12.1 g, yield 96%).

[0085] Phenyl p-bromoacetate is also commercially available.

[0086] 2, Preparation of 5-bromo-2-hydroxyac...

Embodiment 2

[0099] Example 2 Compound Ia: 4-(4-(((o-methoxyformyl)phenoxy)methyl)-1H-1,2,3-triazole-1-)-6-bromocoumarin preparation of

[0100]

[0101] Dissolve 4-azido-6-bromocoumarin (70mg, 0.26mmol, 1 equivalent) with methyl 4-(3-propynyloxy)benzoate (74.1mg, 0.39mmol, 2.5 equivalents) In tert-butanol (6ml), add 0.5 equivalent of copper powder and 0.5 equivalent of copper sulfate pentahydrate, heat up to 72°C and react overnight. After the reaction was monitored by TLC, it was extracted with dichloromethane, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated and then column chromatographed to obtain an off-white solid (95 mg, yield 80%) after drying.

[0102] 1 H NMR (CDCl 3 , 400MHz): 4.02(s, 3H), 5.35(s, 2H), 6.44(s, 1H), 6.93(t, J=7.2Hz, 1H), 7.10(d, J=8.0Hz, 1H), 7.31 ~7.38(m, 2H), 7.59(d, J=8.0Hz, 1H), 7.77(d, J=8.8Hz, 1H), 8.10(s, 1H), 8.17(s, 1H)

Embodiment 3

[0103] Example 3 Compound Ib: Preparation of 4-(4-((p-fluorophenoxy)methyl)-1H-1,2,3-triazole-1-)-6-bromocoumarin

[0104]

[0105] Dissolve 4-azido-6-bromocoumarin (70 mg, 0.26 mmol, 1 equivalent) and 3-(p-fluorophenoxy) propyne (59 mg, 0.39 mmol, 1.5 equivalents) in tert-butanol (6ml), add 0.5 equivalent of copper powder and 0.5 equivalent of copper sulfate pentahydrate, and heat up to 65°C to react overnight. After the reaction was monitored by TLC, it was extracted with dichloromethane, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated, followed by column chromatography and dried to obtain a colorless flaky solid (97 mg, yield 85%).

[0106] 1 H NMR (CDCl 3 , 400MHz): 5.31(s, 2H), 6.57(s, 1H), 7.02(m, J=9.2Hz, 4H), 7.36(d, J=8.4Hz, 1H), 7.58(dd, J=2.0Hz , 8.8Hz, 1H), 8.08(t, J=4.1Hz, 2H)

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Abstract

The invention relates to a 4-1,2,3-triazole-coumarin derivative and its preparation method and application, belonging to the field of chemical medicine. The present invention needs to achieve the technical purpose of providing a novel 4-1,2,3-triazole-coumarin derivative of formula I. The derivative has antitumor activity, and provides the development and application of antitumor drugs with a new selection.

Description

technical field [0001] The invention relates to 4-1,2,3-triazole-coumarin derivatives, a preparation method and application thereof, and belongs to the field of chemical medicine. Background technique [0002] Malignant tumors are currently a major threat to human health. In China, with the intensification of environmental pollution, the incidence of malignant tumors is on the rise year by year, and the medical expenses are increasing year by year, which seriously restricts the sustainable development of the country. According to the latest "Report on Chronic Diseases in China" released by the Ministry of Health, the cancer mortality rate in my country has increased by 29% in the past 20 years. The average 5-year survival rate of cancer patients is still very low. According to statistics from the Cancer Hospital of the Chinese Academy of Medical Sciences, the current cancer cure rate (5-year survival rate) in my country is still hovering around 20%-30%. Among them, only 10...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04C07D417/14C07D405/14C07D311/58A61K31/625A61K31/4439A61K31/427A61K31/4192A61P35/00
Inventor 李锐赵瀛兰宋相容魏于全
Owner SICHUAN UNIV
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