CN109456998B - Method for synthesizing bishydroxycoumarin compound under catalysis of lipase - Google Patents
Method for synthesizing bishydroxycoumarin compound under catalysis of lipase Download PDFInfo
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Abstract
The invention discloses a method for synthesizing a dicoumarin compound under the catalysis of lipase, which comprises the following steps: 4-hydroxycoumarin is used as a substrate, and a Knoevenagel-Michael cascade reaction is carried out by utilizing lipase catalysis to generate the dicoumarin compound with a compound shown in a formula II. The dicoumarol compound can be used for treating thrombus, resisting HIV, treating asthma, skin cancer and snake venom, and can also be used for antibacterial treatment of some staphylococcus aureus and staphylococcus epidermidis and preparation of analytical reagents. The method provided by the invention has the advantages of mild reaction conditions, simple post-treatment, wide substrate spectrum and recyclable catalyst, and is an economic and environment-friendly novel method for synthesizing the bishydroxycoumarin compound.
Description
Technical Field
The invention belongs to the technical field of biocatalysis, and particularly relates to a method for synthesizing a bishydroxycoumarin compound by catalyzing aromatic aldehyde and 4-hydroxycoumarin to perform Knoevenagel-Michael cascade reaction by using lipase in a pure water phase.
Background
Dicoumarol compounds are widely used due to their active pharmacological and biological activities. It can be used as vitamin K antagonist, and has anticoagulant effect, and can be used for treating thrombosis; it has antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis, and can be used as antiinflammatory and antipyretic; it can be used for treating HIV, asthma, skin cancer and snake venom, and can also be used for preparing analytical reagent. The bishydroxycoumarin compound is generally obtained by Knoevenagel condensation-Michael addition of 4-hydroxycoumarin and aromatic aldehyde. At present, methods for synthesizing the dicoumarin compound are various. Such as TrBr/[ Fe ] with magnetic nano-particle catalyst3O4@SiO2@(CH2)3-ImSO3H]Cl (from J IRAN CHEM SOC, 2017, 14: 2187-2198), solid acid catalyst RHA-SO3H (from RSC Advances, 2013, 3 (46): 24046) and KF-montmorillonite (from JOURNAL OF CHEMICAL RESEARCH, 2007, 2007: 585-. These synthetic methods use DMF which is difficult to recover or volatile organic solvents, require high reaction temperature, are difficult to prepare or recycle catalysts, have narrow substrate spectra, and sometimes can only obtain products with moderate yield.
The enzyme is used as a special biocatalyst, has the characteristics of specificity, high efficiency, mild reaction conditions, environmental friendliness, adjustable catalytic activity and the like, and is widely applied to a plurality of fields of chemical industry, medicines, foods, environmental management and the like. In recent years, enzymes have been increasingly important in organic synthesis, and their applications to reactions of important C-C bond formation such as Aldol condensation, Mannich reaction, Henry reaction, Knoevenagel condensation, Michael addition, Baylis-Hillman reaction, and the like have been reported successively. In 2015, lipase LPL was used to catalyze Knoevenagel condensation reaction of aromatic aldehyde and active methylene compound in 35 ℃ anhydrous DMSO, and after 24-72h reaction, target product with Z configuration is generated; in 2016, lipase PPL is used for catalyzing Knoevenagel condensation reaction of aromatic aldehyde and heterocyclic active methylene compound-indol-2-ketone in DMSO (containing 20 percent of water) at 45 ℃, and after reaction for 10-20h, target products with E configuration and Z configuration are generated; at present, most of the enzymatic catalysis Knoevenagel condensation and Michael addition reactions are carried out in aqueous organic solvents or absolutely anhydrous organic solvents.
Disclosure of Invention
In the prior art, Knoevenagel condensation and Michael addition reactions are basically carried out by a chemical catalysis method, the invention provides a method for preparing a bishydroxycoumarin compound by taking lipase as a catalyst and aromatic aldehyde and 4-hydroxycoumarin as substrates through Knoevenagel-Michael cascade reaction, the method can be carried out in a water phase, the reaction condition is mild, the yield is high, and the catalyst can be recovered.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing a bishydroxycoumarin compound under lipase catalysis comprises the following steps: taking 4-hydroxycoumarin (a compound shown in a formula I) as a substrate, carrying out Knoevenagel-Michael cascade reaction under catalysis of lipase, and generating a dicoumarin compound (shown in a formula III) with a compound shown in a formula II, wherein the reaction equation is as follows:
wherein Ar is 4-ClC6H4，2-NO2C6H4，3-NO2C6H4，4-NO2C6H4，4-OHC6H4，2-OHC6H4，4-CNC6H4，4-FC6H4，C6H5，4-CH3C6H4，4-OCH3C6H4，2-OH-3-OCH3C6H3，2,6-Cl2C6H3，4-C4H9C6H4，2-SC4H3，2-NC5H4，3-NC8H6，2-OH-4-OCH3C6H3，C5H11Or C3H7。
The lipase is a lipase in the general meaning, namely lipase (e.c. 3.1.1.3), which can catalyze the hydrolysis of triglyceride to generate fatty acid, glycerol and monoglyceride or diglyceride, is derived from animals and plants or microorganisms, and is generally used for carrying out reactions such as catalytic hydrolysis, esterification, transesterification, ammonolysis and the like.
Preferably, the selected Lipase is selected from the group consisting of Candida antarctica Lipase B (Amano Lipase PS from Burkholderiaceae), Novozym435 Lipase (Lipase B from Candida antarctica, immobilized on a macroperomatous acid resin), Lipase from Thermomyces lanuginosus (Lipase from Thermomyces lanuginosus), Candida rugosa Lipase (Candida rugosa Lipase), Lipase DF, Lipase RMIM (Lipase from Rhizomucormidis) Lipase, Porcine pancreatic Lipase (Porcine pancreas Lipase), one of the bovine serum proteins, preferably Lipase RMIM (Lipase from Rhizomucormidis).
The solvent for the reaction is one of water, isopropanol, toluene, dichloromethane, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide or N-hexane, and preferably water.
The molar ratio of the compound shown in the formula II to the 4-hydroxycoumarin is 1: 0.5-4, and 1:2 is preferred.
The total volume concentration of the lipase in the reaction is c, wherein c is more than 0 and less than or equal to 30mg/mL, and the preferred total volume concentration of the lipase is 10 mg/mL.
The reaction temperature of the reaction is 25-65 ℃, and the preferable reaction temperature is 45 ℃.
The reaction time is 2-48 h.
The method for synthesizing the dicoumarin compound under the catalysis of lipase comprises the following steps: adding lipase into the mixed solution of the compound of formula II and 4-hydroxycoumarin, and carrying out catalytic reaction to generate the dicoumarin compound.
Further, the method for synthesizing the dicoumarin compound under the catalysis of lipase also comprises the steps of filtering and recovering the solvent or recovering the enzyme after the reaction is finished.
The recovery enzyme comprises: filtering the reaction system, adding 1, 4-epoxy hexacyclic ring into the filter residue to dissolve and filtering to recover enzyme.
Further, the method for synthesizing the dicoumarin compound under the catalysis of lipase also comprises a post-treatment step after the reaction is finished, and the post-treatment step comprises the following steps:
(1) filtering the reaction mixed liquid after the reaction is finished;
(2) adding 1, 4-epoxy hexacyclic ring into the filter residue, and then filtering;
(3) and (3) evaporating the filtrate obtained in the step (2) to remove the solvent, and washing the residual solid product to obtain the catalyst.
And (4) washing in the step (3) is washing by adopting ethanol.
The step (3) further comprises a step of recrystallizing the washed product with ethanol.
The invention has the beneficial effects that:
(1) novel synthesis methods for the products are provided. The method for synthesizing the dicoumarol compound has the advantages of mild reaction conditions, simple operation, low production cost, high yield, few byproducts, wide substrate application range and small environmental pollution.
(2) Develops the new application of lipase, in particular to Knoevenagel-Michael cascade reaction using 4-hydroxycoumarin as a substrate.
(3) The method has the product yield of 70-98%, and has stronger competitive advantages compared with other synthesis methods.
(4) The lipase can be repeatedly used, and still has higher catalytic activity after being repeatedly used for 5 times.
Drawings
FIG. 1 shows the NMR spectrum of 4 (bis (4-hydroxy-2-oxo-2H-chromen-3-yl) methyl) benzonitrile obtained in example 8.
FIG. 2 shows the NMR spectrum of 3,3' - ((4 (tert-butyl) phenyl) methylene) bis (4-hydroxy-2H-chromen-2-one) prepared in example 4.
FIG. 3 is a NMR hydrogen spectrum of 3,3' - (thiophene-2-methylene) bis (4-hydroxy-2H-chromen-2-one) prepared in example 6.
FIG. 4 is a NMR hydrogen spectrum of 3,3' - (butane-1, 1-diyl) bis (4-hydroxy-2H-pyran-2-one) obtained in example 7.
Detailed Description
The present invention will be further described with reference to the following examples. The present embodiments are to be considered as illustrative and not restrictive, and the spirit and scope of the invention is not to be limited to the details and modifications thereof.
The biological enzyme and other reagents related to the invention are purchased in the market, wherein the reagents are not further purified; nuclear magnetic resonance hydrogen spectrum (1HNMR) was measured with a Bruker Advance 2B 400 nmr spectrometer at a frequency of 400MHz, in deuterated DMSO as solvent and Tetramethylsilicon (TMS) as internal standard.
Example 1:
1mmol of p-chlorobenzaldehyde and 2mmol of 4-hydroxycoumarin were charged into a 10mL reaction flask, followed by addition of 50mg of lipase RMIM, 5mL of water, stirring at 45 ℃ for reaction, and monitoring of the progress of the reaction by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 20h, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filtrate to recover the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 93%, and mp:257 and 258 ℃;1H NMR(400MHz,DMSO-d6)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)。
example 2:
1mmol benzaldehyde and 2mmol 4-hydroxycoumarin were added to a 10mL reaction flask, followed by addition of 150mg lipase RMIM, 5mL water, stirring at 65 ℃ and monitoring of the progress of the reaction by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 2h, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filter liquor and recovering the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 89%, and m.p. is 231.9-232.3 ℃;1H NMR(400MHz,DMSO-d6)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)。
example 3:
1mmol p-methoxybenzaldehyde and 2mmol 4-hydroxycoumarin were added to a 10mL reaction flask, followed by 5mg lipase RMIM, 5mL water, stirring reaction at 25 deg.C, and reaction progress monitored by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 48 hours, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and steaming the filter liquor to recover the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 96%, and the m.p. is 249-mangnolia acid at 250 ℃;1H NMR(400MHz,DMSO-d6)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)。
example 4:
1mmol of p-tert-butylbenzaldehyde and 2mmol of 4-hydroxycoumarin were charged to a 10mL reaction flask, followed by addition of 50mg of lipase RMIM, 5mL of water, stirring at 55 deg.C and monitoring of the progress of the reaction by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 24 hours, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary steaming the filtrate to recover 1, 4-epoxy hexacyclic ring, filteringWashing slag with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 88%, and the m.p. is 250-251 ℃;1H NMR(400MHz,DMSO-d6)δ10.81(s,2H),7.90(d,J＝7.9Hz,2H),7.64–7.53(m,2H),7.44–7.27(m,4H),7.24(d,J＝8.4Hz,2H),7.06(d,J＝8.1Hz,2H),6.31(s,1H),1.24(s,9H)。
example 5:
1mmol of o-nitrobenzaldehyde and 2mmol of 4-hydroxycoumarin were added to a 10mL reaction flask, followed by 50mg of lipase RMIM, 5mL of water, stirring at 45 ℃ and monitoring of the progress of the reaction by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 8 hours, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filter liquor and recovering the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is yellow solid, the yield is 90%, and m.p. is 235-;1H NMR(400MHz,DMSO-d6)δ10.30(s,2H),8.01(d,J＝8.0Hz,1H),7.91(s,1H),7.88–7.82(m,2H),7.65–7.48(m,4H),7.29(dd,J＝17.1,8.2Hz,4H),6.38(s,1H)。
example 6:
1mmol 2-thiophenecarboxaldehyde and 2mmol 4-hydroxycoumarin were added to a 10mL reaction flask, followed by 2.5mg lipase RMIM, 5mL water, stirring the reaction at 45 deg.C, and the progress of the reaction was monitored by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 20h, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filter liquor to recover 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a cyan solid, the yield is 81%, and m.p. is 215-215.6 ℃;1H NMR(400MHz,DMSO-d6)δ12.48(s,2H),7.88(dd,J＝7.8,1.2Hz,2H),7.60–7.51(m,2H),7.28(td,J＝8.4,2.2Hz,4H),7.19(d,J＝5.1Hz,1H),6.82(dd,J＝5.0,3.6Hz,1H),6.65(dd,J＝3.1,1.5Hz,1H),6.46(s,1H)。
example 7:
1mmol butyraldehyde and 2mmol 4-hydroxycoumarin were added to a 10mL reaction flask, followed by 50mg of lipidThe reaction was stirred at 45 ℃ with lipase RMIM, 5mL of water, and the progress of the reaction was monitored by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 48 hours, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filter liquor to recover the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 87%, and m.p. is 123-;1H NMR(400MHz,DMSO-d6)δ7.97–7.86(m,2H),7.55(t,J＝7.6Hz,2H),7.40–7.21(m,4H),4.90(td,J＝8.2,2.6Hz,1H),2.11–2.03(m,2H),1.20(t,J＝10.8Hz,2H),0.85(td,J＝7.2,2.0Hz,3H)。
example 8:
1mmol of 4-cyanobenzaldehyde and 2mmol of 4-hydroxycoumarin were introduced into a 10mL reaction flask, followed by addition of 50mg of lipase RMIM, 5mL of water, stirring at 45 ℃ and monitoring of the progress of the reaction by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 20h, filtering to recover water, adding 1, 4-epoxy hexacyclic ring into filter residue to dissolve and filtering to recover enzyme, decompressing and rotary-steaming the filtrate to recover 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 94%, and m.p.: 281-282 ℃;1H NMR(400MHz,DMSO-d6)δ12.48(s,2H),7.86(d,J＝7.8Hz,2H),7.66(d,J＝8.3Hz,2H),7.56(t,J＝8.2Hz,2H),7.33(s,2H),7.31(s,2H),7.27(d,J＝7.4Hz,2H),6.35(s,1H)。
example 9:
1mmol of 2-hydroxy-3-methoxybenzaldehyde and 2mmol of 4-hydroxycoumarin were charged into a 10mL reaction flask, followed by addition of 50mg of lipase RMIM, 5mL of water, stirring the reaction at 45 ℃ and monitoring the progress of the reaction by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 20h, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filter liquor and recovering the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 86%, and m.p. is 273-;1H NMR(400MHz,DMSO-d6)δ12.18(s,2H),8.00(d,J＝7.5Hz,2H),7.70(t,J＝7.4Hz,1H),7.60(t,J＝7.6Hz,1H),7.51(t,J＝7.5Hz,2H),7.45(d,J＝8.2Hz,1H),7.36(s,1H),7.33(d,J＝7.9Hz,1H),7.08(t,J＝7.9Hz,1H),7.02(d,J＝7.9Hz,1H),6.76(d,J＝7.5Hz,1H),5.72(s,1H),3.94(s,3H)。
example 10:
1mmol of pyridine-2-carbaldehyde and 2mmol of 4-hydroxycoumarin were charged into a 10mL reaction flask, 50mg of lipase RMIM, 5mL of water were added, the reaction was stirred at 45 ℃ and the progress of the reaction was monitored by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 20h, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filter liquor and recovering the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 93%, and m.p. is 278 and 281 ℃;1H NMR(400MHz,DMSO-d6)δ8.64(d,J＝5.1Hz,1H),8.50–8.41(m,1H),7.92–7.86(m,2H),7.82(d,J＝1.5Hz,1H),7.80(d,J＝1.5Hz,1H),7.61–7.55(m,2H),7.34(d,J＝7.9Hz,2H),7.29–7.25(m,2H),6.52(s,1H)。
example 11:
1mmol of 2, 6-dichlorobenzaldehyde and 2mmol of 4-hydroxycoumarin were added to a 10mL reaction flask, followed by addition of 50mg of lipase RMIM, 5mL of water, stirring at 45 ℃ and monitoring of the progress of the reaction by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 24 hours, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filter liquor to recover the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 85%, and m.p. is 226-;1H NMR(400MHz,DMSO-d6)δ7.95(d,J＝7.9Hz,2H),7.66–7.52(m,2H),7.41–7.26(m,6H),7.18(dd,J＝8.6,7.3Hz,1H),6.23(s,1H)。
example 12:
1mmol of p-chlorobenzaldehyde and 4mmol of 4-hydroxycoumarin were added to a 10mL reaction flask, followed by addition of 50mg of bovine serum albumin BSA, 5mL of water, stirring at 35 ℃ for reaction, and progress of the reaction was monitored by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 48 hours, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recoveringPerforming reduced pressure rotary evaporation on the filtrate to recover 1, 4-epoxy hexacyclic ring, washing filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 70 percent, and mp is 257-;1H NMR(400MHz,DMSO-d6)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)。
example 13:
1mmol of p-chlorobenzaldehyde and 4mmol of 4-hydroxycoumarin were added to a 10mL reaction flask, 50mg of lipase DF and 5mL of water were added, the reaction was stirred at 35 ℃ and the progress of the reaction was monitored by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 40h, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and steaming the filter liquor to recover the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 72%, and m.p. is 257 and 258 ℃;1H NMR(400MHz,DMSO-d6)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)。
example 14:
1mmol of p-chlorobenzaldehyde and 2mmol of 4-hydroxycoumarin were added to a 10mL reaction flask, followed by addition of 50mg of lipase TLIM, 5mL of n-hexane, stirring at 35 ℃ for reaction, and monitoring of the progress of the reaction by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 14h, filtering and recovering n-hexane, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filtrate to recover 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 82%, and m.p. is 257 and 258 ℃;1H NMR(400MHz,DMSO-d6)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)。
example 15:
1mmol of p-chlorobenzaldehyde and 2mmol of 4-hydroxycoumarin were added to a 10mL reaction flask, followed by addition of 50mg of lipase TLIM, 5mL of water, stirring at 35 ℃ and monitoring of the progress of the reaction by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 14h, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filter liquor to recover the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 78%, and m.p. is 257 and 258 ℃;1H NMR(400MHz,DMSO-d6)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)。
example 16:
1mmol of p-chlorobenzaldehyde and 2mmol of 4-hydroxycoumarin were charged into a 10mL reaction flask, followed by addition of 50mg of lipase RMIM, 5mL of acetonitrile, stirring at 35 ℃ and monitoring of the progress of the reaction by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 14h, filtering and recovering acetonitrile, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filtrate to recover 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 80%, and m.p. is 257 and 258 ℃;1H NMR(400MHz,DMSO-d6)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)。
example 17:
1mmol of p-chlorobenzaldehyde and 3mmol of 4-hydroxycoumarin were put in a 10mL reaction flask, 50mg of lipase RMIM and 5mL of n-hexane were added, the reaction was stirred at 35 ℃ and the progress of the reaction was monitored by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 24 hours, filtering and recovering normal hexane, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filter liquor and recovering 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is white solidThe yield is 85 percent, mp is 257-258 ℃;1H NMR(400MHz,DMSO-d6)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)。
example 18:
1mmol of p-chlorobenzaldehyde and 2mmol of 4-hydroxycoumarin were charged into a 10mL reaction flask, 50mg of lipase RMIM and 5mL of water were added, the reaction was stirred at 30 ℃ and the progress of the reaction was monitored by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 14h, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filtrate to recover 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 78%, and mp:257 and 258 ℃;1H NMR(400MHz,DMSO-d6)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)。
example 19:
1mmol of p-chlorobenzaldehyde and 2mmol of 4-hydroxycoumarin were charged into a 10mL reaction flask, then 100mg of lipase RMIM, 5mL of water were added, the reaction was stirred at 45 ℃ and the progress of the reaction was monitored by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 14h, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filtrate to recover 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 89%, and mp:257 and 258 ℃;1H NMR(400MHz,DMSO-d6)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)。
example 20:
adding 1mmol p-chlorobenzaldehyde and 2mmol 4-hydroxycoumarin into 10mL reaction flask, adding 20mg lipase RMIM, 5mL water, stirring at 45 deg.C, and performing TLC (n-hexane/ethyl acetate)1/2, v/v) monitor the progress of the reaction. After 14h, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filtrate to recover 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 75%, and mp:257 and 258 ℃;1H NMR(400MHz,DMSO-d6)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)。
example 21:
1mmol of p-chlorobenzaldehyde and 2mmol of 4-hydroxycoumarin were charged into a 10mL reaction flask, 50mg of lipase RMIM after 4-fold reuse and 5mL of water were added, the reaction was stirred at 45 ℃ and the progress of the reaction was monitored by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 14h, filtering and recovering water, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filtrate to recover 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, the yield is 81%, and mp:257 and 258 ℃;1H NMR(400MHz,DMSO-d6)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)。
example 22:
2mmol of m-nitrobenzaldehyde and 1mmol of 4-hydroxycoumarin were added to a 10mL reaction flask, followed by 0.5mg of Candida antarctica lipase B, 5mL of isopropanol, the reaction was stirred at 45 ℃ and the progress of the reaction was monitored by TLC (n-hexane/ethyl acetate, 1/2, v/v). And after 48 hours, filtering and recovering the solvent, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filtrate to recover the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, and recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the yield is 66%. m.p. 235-;1H NMR(400MHz,DMSO-d6)δ10.30(s,2H),8.01(d,J＝8.0Hz,1H),7.91(s,1H),7.88–7.82(m,2H),7.65–7.48(m,4H),7.29(dd,J＝17.1,8.2Hz,4H),6.38(s,1H)。
example 23:
1mmol of p-nitrobenzaldehyde and 1mmol of 4-hydroxycoumarin were added to a 10mL reaction flask, followed by addition of 75mg of Novozym435 lipase and 5mL of toluene, stirring the reaction at 45 ℃ and monitoring the progress of the reaction by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 18h, filtering and recovering the solvent, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filtrate to recover 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, and recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the yield is 82%. 236.6-237 ℃ in m.p.;1H NMR(400MHz,DMSO-d6)δ8.08(d,J＝8.8Hz,2H),7.84(dd,J＝7.9,1.4Hz,2H),7.57–7.54(m,2H),7.39(d,J＝8.8Hz,2H),7.32(d,J＝8.2Hz,2H),7.27(t,J＝7.5Hz,2H),6.37(s,1H)。
example 24:
1mmol of p-hydroxybenzaldehyde and 1.5mmol of 4-hydroxycoumarin were added to a 10mL reaction flask, followed by 50mg of the enzyme Candida rugosa lipase, 5mL of dichloromethane, stirring the reaction at 45 ℃ and monitoring the progress of the reaction by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 36 hours, filtering and recovering the solvent, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filtrate to recover 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, and recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the yield is 81%. m.p. 211-212 ℃;1H NMR(400MHz,DMSO-d6)δ9.23(s,3H),7.89(d,J＝7.9Hz,2H),7.65–7.52(m,2H),7.33(dd,J＝14.4,7.7Hz,4H),6.93(d,J＝8.3Hz,2H),6.62(d,J＝8.5Hz,2H),6.24(s,1H)。
example 25:
1mmol of o-hydroxybenzaldehyde and 2.5mmol of 4-hydroxycoumarin were added to a 10mL reaction flask, then 50mg of porcine pancreatic lipase and 5mL of tetrahydrofuran were added, the reaction was stirred at 45 ℃ and the progress of the reaction was monitored by TLC (n-hexane/ethyl acetate, 1/2, v/v). After 14h, filtering and recovering the solvent, adding 1, 4-epoxy hexacyclic ring into the filter residue for dissolving, filtering and recovering the enzyme, decompressing and rotary-steaming the filter liquor and recovering the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product,the yield thereof was found to be 56%. m.p. 160-;1H NMR(400MHz,DMSO-d6)δ17.07(s,2H),7.78(dd,J＝7.4,2.0Hz,2H),7.29(td,J＝7.3,1.7Hz,2H),7.22(s,1H),7.15–7.07(m,2H),7.04(td,J＝7.6,2.1Hz,2H),6.99(dd,J＝7.5,2.0Hz,2H),6.86(td,J＝7.6,1.9Hz,1H),6.80(dd,J＝7.3,1.9Hz,1H),5.82(s,1H)。
example 26:
1mmol p-fluorobenzaldehyde and 3mmol 4-hydroxycoumarin were added to a 10mL reaction flask, followed by addition of 50mg lipase RMIM, 5mL dimethyl sulfoxide, stirring at 45 ℃ and reaction progress monitored by TLC (n-hexane/ethyl acetate, 1/2, v/v). And after 14h, filtering and recovering the solvent, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filtrate to recover the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, and recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the yield is 94%. m.p. 215.5-215.7 ℃;1H NMR(400MHz,DMSO-d6)δ10.66(s,2H),8.01–7.83(m,2H),7.69–7.51(m,2H),7.40–7.23(m,4H),7.16(dd,J＝8.0,5.7Hz,2H),7.02(t,J＝8.8Hz,2H),6.30(s,1H)。
example 27:
1mmol of p-tolualdehyde and 3.5mmol of 4-hydroxycoumarin were charged into a 10mL reaction flask, followed by addition of 50mg of lipase RMIM, 5mLN, N-dimethylformamide, and the reaction was stirred at 45 ℃ and monitored by TLC (N-hexane/ethyl acetate, 1/2, v/v). And after 14h, filtering and recovering the solvent, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filtrate to recover the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, and recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the yield is 88%. 273: 274 ℃ m.p.;1H NMR(400MHz,DMSO-d6)δ11.33(s,2H),7.89(dd,J＝7.9,1.2Hz,2H),7.70–7.49(m,2H),7.49–7.14(m,4H),7.02(s,4H),6.30(s,1H),2.24(s,3H)。
example 28:
1mmol 3-indolecarboxaldehyde and 4mmol 4-hydroxycoumarin were added to a 10mL reaction flask, followed by addition of 50mg lipase RMIM, 5mL water, stirring the reaction at 45 deg.C, and monitoring the progress of the reaction by TLC (n-hexane/ethyl acetate, 1/2, v/v). And after 14h, filtering and recovering the solvent, adding 1, 4-epoxy hexacyclic ring into filter residue for dissolving, filtering and recovering enzyme, decompressing and rotary-steaming the filtrate to recover the 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, and recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the yield is 81%.
Example 29:
1mmol of 2-hydroxy-4-methoxybenzaldehyde and 2mmol of 4-hydroxycoumarin were charged into a 10mL reaction flask, followed by addition of 50mg of lipase RMIM, 5mL of water, stirring the reaction at 45 ℃ and monitoring the progress of the reaction by TLC (n-hexane/ethyl acetate, 1/2, v/v). And after 20h, filtering to recover water, adding 1, 4-epoxy hexacyclic ring into filter residue to dissolve and filtering to recover enzyme, decompressing and rotary-steaming the filtrate to recover 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, and the yield is 90%.
Example 30:
1mmol of n-hexanal and 2mmol of 4-hydroxycoumarin were added to a 10mL reaction flask, 50mg of lipase RMIM and 5mL of water were added, the reaction was stirred at 45 ℃ and the progress of the reaction was monitored by TLC (n-hexane/ethyl acetate, 1/2, v/v). And after 20h, filtering to recover water, adding 1, 4-epoxy hexacyclic ring into filter residue to dissolve and filtering to recover enzyme, decompressing and rotary-steaming the filtrate to recover 1, 4-epoxy hexacyclic ring, washing the filter residue with cold ethanol to obtain a crude product, recrystallizing the crude product with hot ethanol to obtain a purified target product, wherein the target product is a white solid, and the yield is 90%.
Claims (13)
1. A method for synthesizing a bishydroxycoumarin compound under the catalysis of lipase is characterized by comprising the following steps: taking 4-hydroxycoumarin as a substrate, and carrying out Knoevenagel-Michael cascade reaction under the catalysis of lipase or bovine serum albumin to generate a dicoumarin compound with a compound shown in a formula II, wherein the reaction equation is as follows:
wherein Ar is 4-ClC6H4，2-NO2C6H4，3-NO2C6H4，4-NO2C6H4，4-OHC6H4，2-OHC6H4，4-CNC6H4，4-FC6H4，C6H5，4-CH3C6H4，4-OCH3C6H4，2-OH-3-OCH3C6H3，2,6-Cl2C6H3，4-C4H9C6H4，2-SC4H3，2-NC5H4，3-NC8H6，2-OH-4-OCH3C6H3，C5H11Or C3H7；
The selected lipase is selected from one of Candida antarctica lipase B, Novozym435 lipase, lipase from Thermomyces lanuginosus, enzyme Candida rugosa lipase, lipase DF, lipase RMIM or porcine pancreatic lipase.
2. The method according to claim 1, wherein the selected lipase is lipase RMIM.
3. The method of claim 1, wherein the solvent of the reaction is one of water, isopropanol, toluene, dichloromethane, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide or N-hexane.
4. The process according to claim 3, wherein the solvent of the reaction is water.
5. The method according to claim 1, wherein the molar ratio of the compound of formula II to 4-hydroxycoumarin is 1: 0.5-4.
6. The process of claim 5, wherein the molar ratio of the compound of formula II to 4-hydroxycoumarin is 1: 2.
7. The method of claim 1, wherein the lipase is present in the reaction at a total volume concentration of c, wherein 0 < c.ltoreq.30 mg/mL.
8. The method of claim 7, wherein the lipase is present in the reaction at a total volume concentration of 10 mg/mL.
9. The method according to claim 1, wherein the reaction temperature of the reaction is 25 to 65 ℃.
10. The process according to claim 9, characterized in that the reaction temperature is 45 ℃.
11. The method according to claim 1, wherein the reaction time is 2-48 h.
12. The process of claim 1, wherein the lipase catalyzed synthesis of bishydroxycoumarin further comprises the step of filtering and recovering the solvent or recovering the enzyme after the reaction is complete.
13. The process according to claim 1, wherein the lipase catalyzed synthesis of bishydroxycoumarin compounds further comprises a post-treatment step after completion of the reaction, comprising:
(1) filtering the reaction mixed liquid after the reaction is finished;
(2) adding 1, 4-epoxy hexacyclic ring into the filter residue, and then filtering;
(3) and (3) evaporating the filtrate obtained in the step (2) to remove the solvent, and washing the residual solid product to obtain the catalyst.
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| CN102492749A (en) * | 2011-12-30 | 2012-06-13 | 西南大学 | Application of porcine pancreas lipase as catalyst for Michael addition reaction |
| CN102558049A (en) * | 2010-12-17 | 2012-07-11 | 中国科学院上海药物研究所 | Dicoumarol compound, as well as preparation method and application thereof |
| CN104193718A (en) * | 2014-08-14 | 2014-12-10 | 安徽工业大学 | Catalytic preparation method of bishydroxycoumarin derivatives |
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| CN102558049A (en) * | 2010-12-17 | 2012-07-11 | 中国科学院上海药物研究所 | Dicoumarol compound, as well as preparation method and application thereof |
| CN102492749A (en) * | 2011-12-30 | 2012-06-13 | 西南大学 | Application of porcine pancreas lipase as catalyst for Michael addition reaction |
| CN104193718A (en) * | 2014-08-14 | 2014-12-10 | 安徽工业大学 | Catalytic preparation method of bishydroxycoumarin derivatives |
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