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Method for synthesizing 4-hydroxyl coumarin and derivant thereof

A technology for hydroxycoumarin and derivatives, which is applied in the field of synthesizing 4-hydroxycoumarin and derivatives thereof, can solve the problems of high price of o-hydroxyacetophenone, increased industrial production danger, strict reaction conditions, etc. It is beneficial to large-scale industrial production, the reaction process is less difficult, and the equipment investment is less.

Inactive Publication Date: 2008-07-16
BOHAI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] The above-mentioned methods 1, 2, and 3 have long reaction processes, complex processes, more reagents, and expensive reagents; method 4 has simple processes and relatively cheap raw materials, but the synthesis route has a high reaction temperature and uses a large amount of Sodium metal greatly increases the risk of industrial production, and the yield is low; method 5 needs to use ZnCl 2 , POCl 3 As an acylating reagent, the condensing agent requires anhydrous, strict reaction conditions, a large amount of hydrogen chloride is removed in the reaction, post-reaction treatment is difficult, and the yield is low; the o-hydroxyacetophenone used in method 6 is expensive

Method used

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  • Method for synthesizing 4-hydroxyl coumarin and derivant thereof
  • Method for synthesizing 4-hydroxyl coumarin and derivant thereof
  • Method for synthesizing 4-hydroxyl coumarin and derivant thereof

Examples

Experimental program
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Embodiment 1

[0043] Using phenol or its derivatives and Meldrum's acid as raw materials, it is monitored by thin layer method (TLC). After the reaction is complete, the by-product acetone in the middle is removed under reduced pressure, and the acetone can be recycled to further realize clean production; The product does not need to be separated, and it is directly dehydrated with Ito's reagent (Eaton's Reagent) for intramolecular dehydration and ring closure reaction. Finally, water is added to precipitate the precipitate, filtered, and recrystallized to obtain the final product, namely 4-hydroxycoumarin and its derivatives. The reaction formula is as follows:

[0044]

[0045] in:

[0046] The substituent R can be one or more electron-donating groups or electron-withdrawing groups, and the substituent R electron-donating groups can be methyl, ethyl, tert-butyl and other alkyl groups, methoxy groups, ethyl groups, etc. An alkoxy group such as oxy group can also be a benzene ring; an el...

Embodiment 2

[0049] Phenol (1.0 mmol) and Michaelis acid (1.0 mmol) were added into a 10 mL round bottom flask and mixed, heated and stirred at 100° C. for 3 hours, and cooled to room temperature. vacuum filtration to remove residual acetone; and recycle acetone. Add 3mL Ito reagent, heat and stir at 70°C for 5 hours, cool to room temperature, add 20mL water while stirring, then cool to room temperature, filter to obtain crude product, recrystallize with 3-5mL ethanol and 1-3mL water to obtain 4-Hydroxycoumarin, yellow solid, yield 60.5%, melting point: 213.0-214.3°C.

Embodiment 3

[0051] Add p-tert-butylphenol (1.0 mmol) and Michaelis acid (1.0 mmol) into a 10 mL round-bottomed flask, mix, heat and stir at 100° C. for 3 hours, and cool to room temperature. vacuum filtration to remove residual acetone; and recycle acetone. Add 3 mL of Ito reagent, heat and stir at 70°C for 1 hour, cool to room temperature, add 20 mL of water while stirring, then cool to room temperature, filter to obtain a crude product, recrystallize with 3-5 mL of ethanol and 1-3 mL of water to obtain 4 -Hydroxy-6-tert-butylcoumarin, yellow powder, yield 82.6%, melting point: 216.0-218.2°C.

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Abstract

A specific technique of a method of synthesizing 4-hydroxycoumarin and derivatives of 4-hydroxycoumarin is as follows: taking a phenol or the derivatives of the phenol and an Meldrum's acid as the raw materials, using a thin layer method to monitor and then decompressing to remove an acetone after complete reaction; with no necessity of separating an intermediate product, directly carrying out intermolecular dehydration with an ito agent or a polyphosphoric and ring-closing reaction and finally adding water to precipitate a sedimentation, filtrating and then recrystallizing to get a final product---4-hydroxycoumarin and the derivatives of 4-hydroxycoumarin. The proportion of the phenol, the derivatives of the phenol, the Meldrum's acid, the ito agent or the polyphosphoric is 1.0mmol:1.0mmol:1-3ml or 1 to 2g. The temperature of intermolecular ring-closing reaction when adding the ito agent is 60 DEG C to 70 DEG C; the reaction time is 1 to 5 hours. The temperature of intermolecular ring-closing reaction when adding the polyphosphoric is 110 DEG C to 120DEG C; the reaction time is 3 to 7 hours. The method has the advantages of easy raw material obtaining, mild reaction condition, simple operation condition and less pollution. Furthermore, the yield varies from medium to excellence; no catalyst is needed; the method also assures a high yield ratio.

Description

Technical field: [0001] The invention relates to a method for synthesizing 4-hydroxycoumarin and its derivatives in one pot with phenol and Meldrum's acid (Meldrum's acid, isopropylidene malonate) as raw materials. technical background: [0002] 4-Hydroxycoumarin and its derivatives are a kind of biological activity, and they are also intermediates for the synthesis of many medicines, pesticides and dyes. It can be used to prepare anticoagulant rodenticides (such as mirfarum, etc.), antifungal agents and drugs for treating cardiovascular diseases (such as nibenzylcoumarol, dicoumarol, new anticoagulant, etc.) ). Medical reports pointed out that 4-hydroxycoumarin is also of great research value in the research of anticancer drugs. 4-Hydroxycoumarin and its derivatives can also be used to synthesize wedelide compounds. Wedelide is a main component of the Chinese herbal medicine Eclipta eclipta. [0003] Existing methods for synthesizing 4-hydroxycoumarin: [0004] method 1...

Claims

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Application Information

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IPC IPC(8): C07D311/44
CPCY02P20/582Y02P20/584
Inventor 高文涛侯文端常明琴崔岩李阳王祥汤立军孙曙光
Owner BOHAI UNIV
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