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Method for catalytic synthesis of dicoumarin compound through lipases

A technology of dicoumarin and lipase, which is applied in the field of biocatalysis, can solve the problems of difficult catalyst preparation, difficult recycling, high reaction temperature, etc., and achieve the effects of wide application range of substrates, high catalytic activity, and simple operation

Active Publication Date: 2019-03-12
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These synthetic methods use difficult-to-recover DMF or volatile organic solvents, require high reaction temperature, difficult to prepare catalysts or difficult to recycle, narrow substrate spectrum, and sometimes can only obtain products with moderate yields

Method used

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  • Method for catalytic synthesis of dicoumarin compound through lipases
  • Method for catalytic synthesis of dicoumarin compound through lipases
  • Method for catalytic synthesis of dicoumarin compound through lipases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Add 1mmol of p-chlorobenzaldehyde and 2mmol of 4-hydroxycoumarin into a 10mL reaction flask, then add 50mg of lipase RMIM, 5mL of water, stir the reaction at 45°C, TLC (n-hexane / ethyl acetate, 1 / 2, v / v) Monitoring the progress of the reaction. After 20 hours, filter and recover the water, add 1,4-epoxyhexacycline to the filter residue to dissolve and filter to recover the enzyme, reduce the pressure and rotate the filtrate to recover the 1,4-epoxyhexane ring, wash the filter residue with cold ethanol to obtain the crude product, and use the crude product Hot ethanol recrystallization to obtain the purified target product, the target product is a white solid, the yield is 93%, mp: 257-258 ° C; 1 H NMR (400MHz, DMSO-d 6 )δ11.54(s,1H),11.32(s,1H),8.07(d,J=7.8Hz,1H),7.99(d,J=7.8Hz,1H),7.67–7.60(m,2H), 7.47–7.34 (m, 4H), 7.30 (s, 1H), 7.26 (s, 1H), 7.15 (d, J=7.8Hz, 2H), 6.04 (s, 1H).

Embodiment 2

[0039] Add 1mmol benzaldehyde and 2mmol 4-hydroxycoumarin to a 10mL reaction flask, then add 150mg lipase RMIM, 5mL water, stir the reaction at 65°C, TLC (n-hexane / ethyl acetate, 1 / 2, v / v ) to monitor the progress of the reaction. After 2 hours, filter and recover the water, add 1,4-epoxyhexacycline to the filter residue to dissolve and filter to recover the enzyme, reduce the pressure and rotate the filtrate to recover the 1,4-epoxyhexane ring, wash the filter residue with cold ethanol to obtain the crude product, and use Hot ethanol recrystallization to obtain the purified target product, the target product is a white solid, the yield is 89%, m.p.: 231.9-232.3 ° C; 1 H NMR (400MHz, DMSO-d 6 )δ7.91–7.85(m,2H),7.62–7.54(m,2H),7.42–7.26(m,4H),7.26–7.18(m,2H),7.14(d,J=7.4Hz,3H) ,6.35(s,1H).

Embodiment 3

[0041] Add 1mmol p-methoxybenzaldehyde and 2mmol4-hydroxycoumarin to a 10mL reaction flask, then add 5mg lipase RMIM, 5mL water, stir the reaction at 25°C, TLC (n-hexane / ethyl acetate, 1 / 2 , v / v) to monitor the progress of the reaction. After 48 hours, filter and recover water, add 1,4-epoxyhexacycline to the filter residue to dissolve and filter to recover the enzyme, reduce pressure and rotate the filtrate to recover 1,4-epoxyhexane ring, wash the filter residue with cold ethanol to obtain the crude product, and use Hot ethanol recrystallization to obtain the purified target product, the target product is a white solid, the yield is 96%, m.p.: 249-250 ° C; 1 H NMR (400MHz, DMSO-d 6 )δ11.05(s,1H),7.89(dd,J=7.9,1.4Hz,2H),7.64–7.52(m,2H),7.36(d,J=8.0Hz,2H),7.34–7.27(m , 2H), 7.05 (d, J=8.1Hz, 2H), 6.79 (d, J=8.8Hz, 2H), 6.28 (s, 1H), 3.70 (s, 3H).

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Abstract

The invention discloses a method for catalytic synthesis of a dicoumarin compound through lipases. The method comprises the step: 4-hydroxycoumarin is adopted as a substrate, and subjected to a Knoevenagel-Michael cascade reaction through lipase catalyzing to generate the dicoumarin compound with a compound in the formula II. The dicoumarin compound can be used for treating thrombus, resisting HIV, and treating asthma, skin cancer and snake venom, and can further be used for antimicrobial treatment of certain staphylococcus aureus and staphylococcus epidermidis and preparing of analytical reagents; and according to the method, reacting conditions are mild, aftertreatment is easy, the substrate is widespread, a catalyst can be recycled, and the method is an economical and environment-friendly new method for synthesizing the dicoumarin compound.

Description

technical field [0001] The invention belongs to the technical field of biocatalysis, and in particular relates to a method for synthesizing dicoumarin compounds by lipase catalyzing the Knoevenagel-Michael cascade reaction of aromatic aldehydes and 4-hydroxycoumarin in a pure water phase. Background technique [0002] Dicoumarins are widely used because of their active pharmacological and biological activities. It can be used as a vitamin K antagonist, anticoagulant, and used to treat thrombosis; it has antibacterial activity against certain Staphylococcus aureus and Staphylococcus epidermidis, and can be used as an anti-inflammatory and antipyretic; it can be used to treat HIV, asthma, skin cancer and snake venom can also be used to make analytical reagents. Dicoumarins are generally obtained from 4-hydroxycoumarin and aromatic aldehydes through Knoevenagel condensation-Michael addition. At present, there are various methods for synthesizing dicoumarin compounds. For exa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/06
CPCC12P17/06Y02P20/584
Inventor 胡燚傅雅洁鲁泽平王莹
Owner NANJING UNIV OF TECH
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