CN104478836A - Benzofuran compound as well as preparation method and application thereof - Google Patents

Benzofuran compound as well as preparation method and application thereof Download PDF

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CN104478836A
CN104478836A CN201410753236.2A CN201410753236A CN104478836A CN 104478836 A CN104478836 A CN 104478836A CN 201410753236 A CN201410753236 A CN 201410753236A CN 104478836 A CN104478836 A CN 104478836A
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benzyloxy
arh
cumarone
hydroxyl
phenyl
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CN104478836B (en
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傅磊
姜发琴
徐步哲
包健
何宛
张勇
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Shanghai Jiaotong University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/80—Radicals substituted by oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The invention relates to a benzofuran compound as well as a preparation method and application thereof. The structural formula of the benzofuran compound is as shown in formula (I) in the specification, wherein R1, R2 and R4 are respectively selected from hydrogen, C1-C5 alkyl, nitryl, halogen, ester group, hydroxyl, amino, acylamino or alkoxyl; R3 represents hydrogen, C1-C5 alkyl, benzyl, aryl or heteroaryl. The invention also relates to the application of the benzofuran compound in inhibition on gram-positive bacterium. According to the preparation method disclosed by the invention, an aromatic ring of a 3-ketoxime substituent benzofuran structure is taken as the center to build and optimize the compound; the prepared novel compound is subjected to an antibacterial screening experiment, and a primary antibacterial test proves that the prepared compound has broad-spectrum antibacterial activity.

Description

Benzofuran compounds and preparation thereof, purposes
Technical field
The invention belongs to medicine and chemical field, be specifically related to a kind of benzofuran compounds and preparation thereof, purposes.
Background technology
In recent years, the infection brought out by a large amount of Resistant strain has become a worldwide difficult medical problem, is a wherein important class to the streptococcus aureus of methicillin resistant.Because the most of antimicrobial drug used clinically has serious toxic side effect, therefore research and development have the important research direction that antimicrobial compounds safely and efficiently becomes Pharmaceutical Chemist.
Benzofuran derivative is the important heterogeneous ring compound of a class, has biological action widely, as antibacterial, antitumor, anti-inflammatory etc.Large quantifier elimination finds, has important impact at the bacteriostatic activity of 3 introducing ketone base chain substituents on this compounds of cumarone ring.As the people such as Xizhen Jiang have delivered at " European Journal of MedicinalChemistry " the experimental article that " Synthesis and antimicrobial evaluation of newbenzofuran derivatives " is topic the 46th phase 3526 pages.Devise the 3-ketone substituted benzene benzofuran derivatives that a class is novel, shown in A, this compounds has the bacteriostatic activity of outstanding wide spectrum to intestinal bacteria, Bacillus subtilus, streptococcus aureus, methicillin-resistant gold-coloured staphylococci, and its MIC value is between 0.39-3.12ug/mL.It should be noted that, introducing different substituents gained compound on cumarone 3 is not all have activity, the slight change of its structure can cause active huge change, as compd B to have the bacteriostatic activity of outstanding wide spectrum to intestinal bacteria, Bacillus subtilus, Pseudomonas aeruginosa, streptococcus aureus and methicillin-resistant gold-coloured staphylococci, its MIC 80value is between 0.78-6.25ug/mL, and the unexpected Compound C found then optionally has outstanding bacteriostatic activity to streptococcus aureus, its MIC 80value is 3.12ug/mL.
Summary of the invention
The object of the present invention is to provide a kind of benzofuran compounds and preparation thereof, purposes, the new compound prepared by being confirmed by preliminary antibacterial tests has certain bacteriostatic activity, may be used for the research of the novel cpd with outstanding anti-microbial activity.Select ketone base difference to be also with prior art, the present invention have selected oxime substituting group, its object is to introducing Michael acceptor, and the amino acid deformity strengthened in some enzymes of itself and bacterium combines, and increases its targeting.
The object of the invention is to be achieved through the following technical solutions:
The present invention relates to a kind of benzofuran compounds, its structural formula is such as formula shown in (I):
Wherein,
R 1for hydrogen, C 1-C 5alkyl, nitro, halogen, ester group, hydroxyl, amino, amide group or alkoxyl group;
R 2for hydrogen, C 1-C 5alkyl, nitro, halogen, ester group, hydroxyl, amino, amide group or alkoxyl group;
R 3for hydrogen, C 1-C 5alkyl, benzyl, aromatic base or assorted aromatic base;
R 4for hydrogen, C 1-C 5alkyl, nitro, halogen, ester group, hydroxyl, amino, amide group or alkoxyl group.
Preferably, its structural formula is such as formula shown in (II):
wherein, R 1, R 2and R 4all be selected from hydrogen, C 1-C 5alkyl, nitro, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, any one in alkoxyl group.
The invention still further relates to the preparation method of benzofuran compounds shown in a kind of formula of the present invention (II), described method comprises the steps:
A, the Benzyl Chloride of 2,4-Dihydroxy benzaldehydes and 1.2 molar equivalents getting 1 molar equivalent reflux and within 12 hours, obtain 4-(benzyloxy)-Benzaldehyde,2-hydroxy in acetonitrile;
B, 4-(the benzyloxy)-Benzaldehyde,2-hydroxy getting 1 molar equivalent and 1.1 molar equivalents in toluene, stirring at room temperature obtains (E)-5-(benzyloxy)-2-substituted ethylene base phenol for 12 hours
C, (E)-5-(benzyloxy)-2-substituted ethylene base phenol stirring at room temperature in 6 molar equivalent salt of wormwood and 6 molar equivalent iodine of getting 1 molar equivalent obtain 6-(benzyloxy)-2-for 12 hours and replace cumarone
D, get 1 molar equivalent 6-(benzyloxy)-2-replace cumarone be dissolved in 1, in 2-ethylene dichloride, under 0 DEG C of ice bath, add the phosphorus oxychloride of 8 molar equivalents and the N of 8 molar equivalents, dinethylformamide, backflow is spent the night, and obtains 6-benzyloxy-2-(4-benzyloxy-phenyl) cumarone-3-formaldehyde
E, 6-benzyloxy-2-(4-benzyloxy-phenyl) cumarone-3-formaldehyde getting 1 molar equivalent are dissolved in methylene dichloride, and the titanium tetrachloride adding 1.3 molar equivalents obtains 6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-formaldehyde
F, get 6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-formaldehyde of 1 molar equivalent and 3 of 1.5 molar equivalents, 4,5-trimethoxy-aniline obtains (E)-3 in 12 hours in reflux in toluene, 4,5-trimethoxy-N-((6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-base) methylene radical) aniline
Preferably, in step B, R 1pPh 3cl is triphenyl (4-benzyloxy-benzyl) phosphonium chloride, and its preparation comprises the steps:
The Benzyl Chloride of the 4-salicylic alcohol and 1.2 molar equivalents of getting 1 molar equivalent refluxes and obtains 4-benzyloxybenzyl alcohol in acetonitrile;
The thionyl chloride of the 4-benzyloxybenzyl alcohol and 1.1 molar equivalents of getting 1 molar equivalent stirs and obtains 4-benzyloxy Benzyl Chloride in methylene dichloride;
The triphenylphosphine of the 4-benzyloxy Benzyl Chloride and 1 molar equivalent of getting 1 molar equivalent refluxes and obtains triphenyl (4-benzyloxy-benzyl) phosphonium chloride in acetonitrile.
Preferably, described method comprises the steps:
A, the Benzyl Chloride of 2,4-Dihydroxy benzaldehydes and 1.2 molar equivalents getting 1 molar equivalent reflux and within 12 hours, obtain 4-(benzyloxy)-Benzaldehyde,2-hydroxy in acetonitrile;
B, the Benzyl Chloride of 4-salicylic alcohol and 1.2 molar equivalents getting 1 molar equivalent reflux and obtain 4-benzyloxybenzyl alcohol in acetonitrile;
C, the thionyl chloride of 4-benzyloxybenzyl alcohol and 1.1 molar equivalents getting 1 molar equivalent stir and obtain 4-benzyloxy Benzyl Chloride in methylene dichloride;
The triphenylphosphine of the 4-benzyloxy Benzyl Chloride and 1 molar equivalent of D. getting 1 molar equivalent refluxes and obtains triphenyl (4-benzyloxy-benzyl) phosphonium chloride in acetonitrile;
Triphenyl (4-benzyloxy-benzyl) phosphonium chloride stirring at room temperature in toluene of 4-(the benzyloxy)-Benzaldehyde,2-hydroxy and 1.1 molar equivalents of E. getting 1 molar equivalent obtains (E)-5-(benzyloxy)-2-substituted ethylene base phenol for 12 hours;
(E)-5-(benzyloxy)-2-substituted ethylene base phenol stirring at room temperature in 6 molar equivalent salt of wormwood and 6 molar equivalent iodine of F. getting 1 molar equivalent obtains 6-(benzyloxy)-2-for 12 hours and replaces cumarone;
G. 6-(the benzyloxy)-2-getting 1 molar equivalent replaces cumarone and is dissolved in 1, in 2-ethylene dichloride, under 0 DEG C of ice bath, add the phosphorus oxychloride of 8 molar equivalents and the N of 8 molar equivalents, dinethylformamide, backflow is spent the night, and obtains 6-benzyloxy-2-(4-benzyloxy-phenyl) cumarone-3-formaldehyde;
H. 6-benzyloxy-2-(4-benzyloxy-phenyl) cumarone-3-formaldehyde getting 1 molar equivalent is dissolved in methylene dichloride, and the titanium tetrachloride adding 1.3 molar equivalents obtains 6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-formaldehyde;
L gets 6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-formaldehyde of 1 molar equivalent and 3 of 1.5 molar equivalents, 4,5-trimethoxy-aniline obtains (E)-3 in 12 hours in reflux in toluene, 4,5-trimethoxy-N-((6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-base) methylene radical) aniline;
J. 6-benzyloxy-2-(4-benzyloxy-phenyl) cumarone-3-formaldehyde of 1 molar equivalent and 3 of 1.5 molar equivalents are got, 4,5-trimethoxy-aniline obtains (E)-3 in 12 hours in reflux in toluene, 4,5-trimethoxy-N-((6-benzyloxy-2-(4-benzyloxy-phenyl) cumarone-3-base) methylene radical) aniline.
The invention still further relates to a kind of benzofuran compounds, its structural formula is such as formula shown in (III):
wherein R 1, R 4and R 5all be selected from hydrogen, C 1-C 5alkyl, nitro, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, phenyl, any one in alkoxyl group.
The invention still further relates to a kind of preparation method such as formula the benzofuran compounds shown in (III) of the present invention, described method comprises the steps:
A, the Benzyl Chloride of 2,4-Dihydroxy benzaldehydes and 1.2 molar equivalents getting 1 molar equivalent reflux and within 12 hours, obtain 4-(benzyloxy)-Benzaldehyde,2-hydroxy in acetonitrile;
B, 4-(the benzyloxy)-Benzaldehyde,2-hydroxy getting 1 molar equivalent and 1.1 molar equivalents in toluene, stirring at room temperature obtains (E)-5-(benzyloxy)-2-substituted ethylene base phenol for 12 hours
C, (E)-5-(benzyloxy)-2-substituted ethylene base phenol stirring at room temperature in 6 molar equivalent salt of wormwood and 6 molar equivalent iodine of getting 1 molar equivalent obtain 6-(benzyloxy)-2-for 12 hours and replace cumarone
D, 6-(the benzyloxy)-2-replacement cumarone getting 1 molar equivalent and the Acetyl Chloride 98Min. of 1.5 molar equivalents and the tin tetrachloride of 1.3 molar equivalents obtain 2-(substituted-phenyl)-6-hydroxyl benzofuran-3-ethyl ketone for 12 hours in stirred at ambient temperature in methylene dichloride
The invention still further relates to the purposes of a kind of benzofuran compounds of the present invention in the biologically active drug of preparation suppression microorganism.
Preferably, described microorganism is gram-positive microorganism.
Preferably, described gram-positive microorganism is intestinal bacteria, gold-coloured staphylococci, gold-coloured staphylococci, subtilis or Pseudomonas aeruginosa.
Study discovery further through place seminar of the present invention, 6 bit strips have the benzofuran compounds of free hydroxyl to have anti-microbial activity that is outstanding, wide spectrum, MIC 80value is between 0.78-6.25ug/mL.In addition, the present invention surprisingly finds that 3 bit strips have the benzofuran compounds of imine structure to have outstanding anti-microbial activity for streptococcus aureus, MIC 80value is 3.12ug/mL, close with benzylpenicillin sodium bacteriostatic activity with positive control cefotaxime.According to above result of study, the present invention designs the novel benzofuran compound of a class, as shown in Figure 2, hydroxyl is incorporated into 6 of cumarone ring, 3 that imine structure are introduced cumarone ring, for investigating cumarone ring prosposition with the impact of the substituting group on external position on benzofuran compounds bacteriostatic activity, to obtaining the novel benzofuran derivative with outstanding bacteriostatic activity of a class.
Compared with prior art, the present invention possesses following beneficial effect: hydroxyl is incorporated into 6 of cumarone ring by the present invention, 3 that imine structure are introduced cumarone ring, set up and optimize the preparation method of compound, and antibacterial screening experiment is carried out, to developing the novel cpd of outstanding anti-microbial activity to the novel cpd of preparation.
Accompanying drawing explanation
By reading the detailed description done non-limiting example with reference to the following drawings, other features, objects and advantages of the present invention will become more obvious:
Fig. 1 is preparation method's synthetic route schematic diagram of benzofuran compound;
Fig. 2 is the principle of design figure of 3-ketoxime-6-replacement-benzofuran compounds.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.Following examples will contribute to those skilled in the art and understand the present invention further, but not limit the present invention in any form.It should be pointed out that to those skilled in the art, without departing from the inventive concept of the premise, some distortion and improvement can also be made.These all belong to protection scope of the present invention.
embodiment 1
The synthesis (Fig. 1) of 4-(benzyloxy)-Benzaldehyde,2-hydroxy I: by 2,4-Dihydroxy benzaldehyde (5.00g, 36mmol) be dissolved in acetonitrile (500mL), then potassiumiodide (9.00g, 54mmol) and sodium bicarbonate (4.50g, 54mmol) is added, after adding, slow dropping Benzyl Chloride (5.50g, 43.5mmol), backflow 12h.After having reacted, add water cancellation, be extracted with ethyl acetate, merge organic phase, with saturated common salt water washing three times, after anhydrous sodium sulfate drying, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=10: 1) obtain 4-(benzyloxy)-Benzaldehyde,2-hydroxy 5.25g (white solid, yield 64%).
1H NMR(CDCl 3；300MHz)，δ5.11(s，2H，OCH 2Ph)6.51-6.52(d，1H，ArH)，6.60-6.63(dd，1H，ArH)，7.36-7.46(m，6H，ArH)，9.72(s，1H，OH)，11.48(s，1H，OH)。
embodiment 2
The synthesis of triphenylbenzylphosphonium chloride phosphine: Benzyl Chloride (2.88g, 31.6mmol) and triphenylphosphine (8.57g, 32.7mmo) are dissolved in 20mL acetonitrile, heated overnight at reflux.After having reacted, be cooled to room temperature, filter, obtain triphenylbenzylphosphonium chloride phosphine 7.5g (white solid, yield 61%).
1H NMR(DMSO；300MHz)，δ5.25-5.30(d，2H，J＝15.9Hz，CH 2P)，6.98-7.01(m，2H，ArH)，7.19-7.29(m，3H，ArH)，7.65-7.77(m，12H，Ph)，7.87-7.93(m，3H，Ph)。
embodiment 3
The synthesis of 4-benzyloxybenzyl alcohol: 4-salicylic alcohol (10.00g, 80.55mmol) is dissolved in 150mL acetonitrile, then adds salt of wormwood (22.27g, 161.1mmol), slowly drip Benzyl Chloride (12.24g, 96.66mmol) again, backflow 12h.After having reacted, add water cancellation, be extracted with ethyl acetate, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=3: 1) obtain 4-benzyloxybenzyl alcohol 15g (white solid, yield 87%).
1H NMR(DMSO；300MHz)，δ4.39-4.41(d，2H，CH 2OH)，5.00-5.04(t，1H，CH 2OH)，5.06(s，2H，OCH 2Ph)，6.94-6.97(d，2H，ArH)，7.20-7.23(d，2H，ArH)，7.31-7.45(m，5H，ArH)。
embodiment 4
The synthesis of 4-benzyloxy Benzyl Chloride: be dissolved in 100mL methylene dichloride by 4-benzyloxybenzyl alcohol (15.00g, 70.02mmol), cools to 0 DEG C, slow dropping thionyl chloride (5.60ml, 77.02mmol), after dropwising, stirring at room temperature 1h is until raw material reaction is complete.Concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=10: 1) obtain 4-benzyloxy Benzyl Chloride 12g (white solid, yield 74%).
1H NMR(DMSO；300MHz)，δ4.71(s，2H，CH 2Cl)，5.11(s，2H，OCH 2Ph)，6.99-7.02(d，2H，ArH)，7.32-7.45(m，7H，ArH)。
embodiment 5
The synthesis of triphenyl (4-benzyloxy-benzyl) phosphonium chloride: 4-benzyloxy Benzyl Chloride (11.8g, 50.70mmol) and triphenylphosphine (13.70g, 52.22mmol) are dissolved in 100mL acetonitrile, heated overnight at reflux.After having reacted, be cooled to room temperature, filter, obtain triphenyl (4-benzyloxy-benzyl) phosphonium chloride 20.8g (white solid, yield 83%).
1H NMR(DMSO；300MHz)，δ5.04(s，2H，OCH 2Ph)，5.11-5.16(d，2H，J＝15Hz，CH 2P)，6.88(s，4H，ArH)，7.36-7.40(m，5H，ArH)，7.63-7.77(m，12H，ArH)，7.87-7.90(m，3H，ArH)。
embodiment 6
(E)-5-(benzyloxy)-2-(styryl) phenol II 1synthesis (Fig. 1): under the atmosphere of nitrogen, by 4-(benzyloxy)-Benzaldehyde,2-hydroxy (1.70g, 7.45mmol) with triphenylbenzylphosphonium chloride phosphine (2.89g, 7.45mmol) be dissolved in 12mL acetonitrile, drip DBU (1.17g, 7.70mmol), heated overnight at reflux.After question response, be spin-dried for solvent, and use methylene dichloride dissolution residual substance, use water respectively, 1N HCl solution and saturated common salt water washing, with anhydrous sodium sulfate drying, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1) obtain (E)-5-(benzyloxy)-2-(styryl) phenol 1.78g (white solid, yield 79%).
1H NMR(DMSO；300MHz)，δ5.07(s，2H，OCH2Ph)，6.51-6.53(m，2H，ArH)，7.04-7.09(d，1H，J＝16.5，CH＝CH)，7.181-7.245(q，1H，J＝7.5，J＝4.5，ArH)，7.299-7.51(m，11H，ArH)，9.829(s，1H，OH)。
embodiment 7
(E)-5-(benzyloxy)-2-(4-benzyloxy styryl) phenol II 2synthesis (Fig. 1): under the atmosphere of nitrogen, by 4-(benzyloxy)-Benzaldehyde,2-hydroxy (0.20g, 0.88mmol) with triphenyl (4-benzyloxy-benzyl) phosphonium chloride (0.48g, 0.96mmol) be dissolved in 10mL toluene, add KOH (0.06g, 1.06mmol), stirring at room temperature 12h, extremely after completion of the reaction, use water respectively, 1N HCl solution and saturated aqueous common salt washing reaction liquid, use anhydrous sodium sulfate drying organic phase, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1) obtain (E)-5-(benzyloxy)-2-(4-benzyloxy styryl) phenol 0.1g (white solid, yield 28%).
1H NMR(DMSO；300MHz)，δ5.063(s，2H，OCH 2Ph)，5.11(s，2H，OCH 2Ph)，6.491-6.509(m，2H，ArH)，6.977-7.021(m，3H，ArH)，7.144-7.199(d，1H，J＝16.5，CH＝CH)，7.327-7.468(m，13H，ArH)，9.736(s，1H，OH)。
embodiment 8
6-(benzyloxy)-2-(phenyl) cumarone III 1synthesis (Fig. 1): by (E)-5-(benzyloxy)-2-(styryl) phenol (1.00g, 3.31mmol) be dissolved in tetrahydrofuran (THF) (20ml), add Anhydrous potassium carbonate (2.74g, 19.85mmol), after stirring 10min, add iodine (5.04g, 19.85mmol), stirring at room temperature 2h.After reaction terminates, react with saturated sodium bicarbonate aqueous solution cancellation, then drip saturated aqueous solution of sodium bisulfite and remove residual iodine, then be extracted with ethyl acetate, merge organic phase, with saturated common salt water washing three times, after anhydrous sodium sulfate drying, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1), obtain 6-(benzyloxy)-2-(phenyl) cumarone 0.18g (yellow solid, yield 18%).
1H NMR(CDCl 3；300MHz)，δ5.137(s，2H，OCH 2Ph)，6.94-6.974(m，2H，ArH)，7.138-7.143(d，1H，J＝2.1，ArH)，7.318-7.493(m，9H，ArH)，7.799-7.824(d，2H，J＝7.5，ArH)。
embodiment 9
6-(benzyloxy)-2-(4-benzyloxy-phenyl) cumarone III 2synthesis (Fig. 1): by (E)-5-(benzyloxy)-2-(4-benzyloxy styryl) phenol (0.50g, 1.22mmol) be dissolved in tetrahydrofuran (THF) (10mL), add Anhydrous potassium carbonate (1.02g, 7.35mmol), after stirring 30min, add iodine (1.87g, 7.35mmol), stirring at room temperature 2h.After reaction terminates, react with saturated sodium bicarbonate aqueous solution cancellation, then drip saturated aqueous solution of sodium bisulfite and remove residual iodine, be extracted with ethyl acetate again, merge organic phase, with saturated common salt water washing three times, after anhydrous sodium sulfate drying, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1), obtain 6-(benzyloxy)-2-(4-benzyloxy-phenyl) cumarone 0.32g (light yellow solid, yield 64%).
1H NMR(DMSO；300MHz)，δ5.152(s，4H，OCH 2Ph，OCH 2Ph)，6.915-6.95(dd，1H，J＝8.4，J＝2.1，ArH)，7.095-7.158(t，3H，J＝9，ArH)，7.288-7.486(m，12H，ArH)，7.754-7.783(d，2H，J＝8.7，ArH)。
embodiment 10
6-(benzyloxy)-2-(phenyl) cumarone-3-formaldehyde IV 1synthesis (Fig. 1): by phosphorus oxychloride (1.5mL 0 ~ 5 DEG C time, 16.0mmol) be added drop-wise to N, dinethylformamide (1.3mL, 16.0mmol) He 1, in 2-ethylene dichloride (20mL), after stirring 10min, by 6-(benzyloxy)-2-(phenyl) cumarone (0.6g, 2.0mmol) join in mixture solution, backflow 12h.After reaction terminates, reaction solution is poured in frozen water, with dichloromethane extraction, use water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively, then use anhydrous sodium sulfate drying.Through silica gel chromatography column purification (sherwood oil: ethyl acetate=10: 1) obtain 6-(benzyloxy)-2-(phenyl) cumarone-3-formaldehyde 0.45g (yellow solid, yield 69%) after concentrating under reduced pressure.
1H NMR(CDCl 3；300MHz)，δ5.149(s，2H，OCH 2Ph)，7.074-7.109(dd，1H，J＝8.7，J＝2.1，ArH)，7.141-7.147(d，1H，J＝2.1，ArH)，7.343-7.565(m，8H，ArH)，7.809-7.840(m，2H，ArH)，8.128-8.157(d，1H，J＝8.7，ArH)，10.310(s，1H，CHO)。
embodiment 11
6-(benzyloxy)-2-(4-benzyloxy-phenyl) cumarone-3-formaldehyde IV 2synthesis (Fig. 1): with reference to embodiment 10, by phosphorus oxychloride (1.5mL 0 ~ 5 DEG C time, 16.0mmol) be added drop-wise to N, dinethylformamide (1.3mL, 16.0mmol) with in 1,2-ethylene dichloride (20mL), after stirring 10min, 6-(benzyloxy)-2-(4-benzyloxy-phenyl) cumarone (2.0mmol) is joined in mixture solution, backflow 12h.After reaction terminates, reaction solution is poured in frozen water, with dichloromethane extraction, use water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively, then use anhydrous sodium sulfate drying.Through silica gel chromatography column purification (sherwood oil: ethyl acetate=10: 1) obtain 6-(benzyloxy)-2-(4-benzyloxy-phenyl) cumarone-3-formaldehyde 0.53g, (yellow solid, yield 65% after concentrating under reduced pressure.)
1H NMR(DMSO；300MHz)，δ5.176(s，2H，OCH 2Ph)，5.214(s，2H，OCH 2Ph)，7.066-7.102(dd，1H，J＝8.7，J＝2.1，ArH)，7.210-7.239(d，2H，J＝8.7，ArH)，7.322-7.457(m，11H，ArH)，7.891-7.92(d，2H，J＝8.7，ArH)，7.959-7.988(d，1H，J＝8.7，ArH)，10.182(s，1H，CHO)。
embodiment 12
(E)-3,4,5-trimethoxy-N-((6-(benzyloxy)-2-(phenyl) cumarone-3-base) methylene radical) aniline V 1synthesis (Fig. 1): by 6-(benzyloxy)-2-(phenyl) cumarone-3-formaldehyde (50mg, 0.152mmol) He 3,4,5-trimethoxy-aniline (28mg, 0.152mmol) be dissolved in toluene (10mL), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1) obtain (E)-3,4,5-trimethoxy-N-((6-(benzyloxy)-2-(phenyl) cumarone-3-base) methylene radical) aniline 45mg (yellow solid, yield 60%).
1H NMR(CDCl 3；300MHz)，δ3.892(s，3H，OCH 3)，3.919(s，6H，OCH 3，OCH 3)，5.185(s，2H，OCH 2Ph)，6.514(s，2H，ArH)，7.083-7.12(dd，1H，J＝8.7，J＝2.4，ArH)，7.173-7.18(d，1H，J＝2.1，ArH)，7.361-7.578(m，8H，ArH)，7.786-7.818(dd，2H，J＝8.4，J＝1.8，ArH)，8.39-8.419(d，1H，J＝8.7，ArH)，8.801(s，1H，CH＝N)。
embodiment 13
(E)-4-methoxyl group-N-((6-(benzyloxy)-2-(phenyl) cumarone-3-base) methylene radical) aniline V 2synthesis (Fig. 1): with reference to embodiment 12, by 6-(benzyloxy)-2-(phenyl) cumarone-3-formaldehyde (50mg, 0.152mmol) be dissolved in toluene (10mL) with 4-anisidine (0.152mmol), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1) obtain (E)-4-methoxyl group-N-((6-(benzyloxy)-2-(phenyl) cumarone-3-base) methylene radical) aniline, yellow solid, yield 66%.
1H NMR(DMSO；300MHz)，δ3.78(s，3H，OCH 3)，5.21(s，2H，OCH 2Ph)，6.971-7.00(d，2H，J＝8.7，ArH)，7.087-7.123(dd，1H，J＝8.7，J＝2.4，ArH)，7.329-7.628(m，11H，ArH)，7.869-7.896(m，2H，ArH)，8.329-8.358(d，1H，J＝8.7，ArH)，8.831(s，1H，CH＝N)。
embodiment 14
(E)-4-hydroxy-n-((6-(benzyloxy)-2-(phenyl) cumarone-3-base) methylene radical) aniline V 3synthesis (Fig. 1): with reference to embodiment 12, by 6-(benzyloxy)-2-(phenyl) cumarone-3-formaldehyde (50mg, 0.152mmol) be dissolved in toluene (10mL) with 4-hydroxyanilines (0.152mmol), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1) obtain (E)-4-hydroxy-n-((6-(benzyloxy)-2-(phenyl) cumarone-3-base) methylene radical) aniline, yellow solid, yield 40%.
1H NMR(DMSO；300MHz)，δ5.209(s，2H，OCH 2Ph)，6.802-6.831(d，2H，J＝8.7，ArH)，7.082-7.118(dd，1H，J＝8.7，J＝2.1，ArH)，7.234-7.263(d，2H，J＝8.7，ArH)，7.345-7.627(m，9H，ArH)，7.86-7.888(m，2H，ArH)，8.327-8.356(d，1H，J＝8.7，ArH)，8.822(s，1H，CH＝N)，9.486(s，1H，OH)。
embodiment 15
(E)-3-hydroxyl-4-methoxyl group-N-((6-(benzyloxy)-2-(phenyl) cumarone-3-base) methylene radical) aniline V 4synthesis (Fig. 1): with reference to embodiment 12, by 6-(benzyloxy)-2-(phenyl) cumarone-3-formaldehyde (50mg, 0.152mmol) be dissolved in toluene (10mL) with 3-hydroxyl-4-anisidine (0.152mmol), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1) obtain (E)-3-hydroxyl-4-methoxyl group-N-((6-(benzyloxy)-2-(phenyl) cumarone-3-base) methylene radical) aniline, yellow solid, yield 65%.
1H NMR(DMSO；300MHz)，δ3.789(s，3H，OCH 3)，5.215(s，2H，OCH 2Ph)，6.783-6.84(m，2H，ArH)，6.94-6.968(d，1H，J＝8.4，ArH)，7.093-7.129(dd，1H，J＝8.7，J＝2.1，ArH)，7.347-7.635(m，9H，ArH)，7.857-7.884(m，2H，ArH)，8.303-8.332(d，1H，J＝8.7，ArH)，8.776(s，1H，CH＝N)，9.103(s，1H，OH)。
embodiment 16
(E) the fluoro-N-of-4-((6-(benzyloxy)-2-(phenyl) cumarone-3-base) methylene radical) aniline V 5synthesis (Fig. 1): with reference to embodiment 12, by 6-(benzyloxy)-2-(phenyl) cumarone-3-formaldehyde (50mg, 0.152mmol) be dissolved in toluene (10mL) with 4-fluoroaniline (0.152mmol), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1) obtain the fluoro-N-of (E)-4-((6-(benzyloxy)-2-(phenyl) cumarone-3-base) methylene radical) aniline, yellow solid, yield 55%.
1H NMR(DMSO；300MHz)，δ5.196(s，2H，OCH 2Ph)，7.076-7.113(dd，1H，J＝8.7，J＝2.4，ArH)，7.197-7.256(m，2H，ArH)，7.328-7.613(m，11H，ArH)，7.865-7.896(m，2H，ArH)，8.29-8.318(d，1H，J＝8.4，ArH)，8.792(s，1H，CH＝N)。
embodiment 17
(E)-3-chloro-4-hydroxyl-N-((6-(benzyloxy)-2-(phenyl) cumarone-3-base) methylene radical) aniline V 6synthesis (Fig. 1): with reference to embodiment 12, by 6-(benzyloxy)-2-(phenyl) cumarone-3-formaldehyde (50mg, 0.152mmol) be dissolved in toluene (10mL) with 3-chloro-4-hydroxyl aniline (0.152mmol), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1) obtain (E)-3-chloro-4-hydroxyl-N-((6-(benzyloxy)-2-(phenyl) cumarone-3-base) methylene radical) aniline, yellow solid, yield 54%.
1H NMR(DMSO；300MHz)，δ5.206(s，2H，OCH 2Ph)，6.996-7.024(d，1H，J＝8.4，ArH)，7.077-7.113(dd，1H，J＝8.7，J＝2.1，ArH)，7.209-7.246(dd，1H，J＝8.7，J＝2.7，ArH)，7.343-7.623(m，10H，ArH)，7.88-7.903(d，2H，J＝6.9，ArH)，8.309-8.337(d，1H，J＝8.4，ArH)，8.811(s，1H，CH＝N)，10.209(s，1H，OH)。
embodiment 18
(E)-6-(benzyloxy)-2-(phenyl)-3-(4-methoxyl-styrene) cumarone V 7synthesis (Fig. 1): in a nitrogen environment, by zinc powder (0.2g, 3.05mmol) be added in anhydrous tetrahydro furan (20mL), then the temperature of reaction system is dropped to-5 ~ 0 DEG C, drip titanium tetrachloride (0.17mL, 1.53mmol) at this temperature, after adding, the temperature of reaction system is risen to room temperature, stir half an hour, and then the 2.5h that refluxes.After backflow terminates, the temperature of reaction system is dropped to-5 ~ 0 DEG C again, dropwise add 6-(benzyloxy)-2-(phenyl) cumarone-3-formaldehyde (0.2g, 0.61mmol) with aubepine (0.1g, tetrahydrofuran solution 0.73mmol), drips off rear backflow 2h.After reaction terminates, with the sodium bicarbonate aqueous solution cancellation reaction of 10%, then dichloromethane extraction is used, merge organic phase, with saturated common salt water washing three times, after anhydrous sodium sulfate drying, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1) obtain (E)-6-(benzyloxy)-2-(phenyl)-3-(4-methoxyl-styrene) cumarone 18mg (light yellow solid, yield 7%).
1H NMR(DMSO；300MHz)，δ3.765(s，3H，OCH 3)，5.197(s，2H，OCH 2Ph)，6.933-6.962(d，2H，J＝8.7，ArH)，7.027-7.064(dd，1H，J＝8.7，J＝2.4，ArH)，7.196-7.251(d，1H，J＝16.5，CH＝CH)，7.331-7.603(m，12H，CH＝CH，ArH)，7.747-7.772(d，2H，J＝7.5，ArH)，7.967-7.996(d，1H，J＝8.7，ArH)。
embodiment 19
(E)-6-(benzyloxy)-2-(phenyl)-3-(4-benzyloxy styryl) cumarone V 8synthesis (Fig. 1): under the atmosphere of nitrogen, by 6-(benzyloxy)-2-(phenyl) cumarone-3-formaldehyde (0.20g, 0.61mmol) with triphenyl (4-benzyloxy-benzyl) phosphonium chloride (0.33g, 0.67mmol) be dissolved in 10mL toluene, add KOH (0.04g, 0.73mmol), stirring at room temperature 12h, extremely after completion of the reaction, use water respectively, 1N HCl solution and saturated aqueous common salt washing reaction liquid, use anhydrous sodium sulfate drying organic phase, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=30: 1) obtain (E)-6-(benzyloxy)-2-(phenyl)-3-(4-benzyloxy styryl) cumarone 121mg (white solid, yield 39%).
1H NMR(DMSO；300MHz)，δ5.124(s，2H，OCH 2Ph)，5.194(s，2H，OCH 2Ph)，7.009-7.037(d，2H，J＝8.4，ArH)，7.057-7.064(d，1H，J＝2.1，ArH)，7.198-7.253(d，1H，J＝16.5，CH＝CH)，7.327-7.598(m，17H，CH＝CH，ArH)，7.747-7.772(d，2H，J＝7.5，ArH)，7.961-7.991(d，1H，J＝9.0，ArH)。
embodiment 20
2-(phenyl)-6-hydroxyl benzofuran-3-formaldehyde VI 1synthesis (Fig. 1): by 6-(benzyloxy)-2-(phenyl) cumarone-3-formaldehyde (100mg, 0.31mL) be dissolved in methylene dichloride (10mL), titanium tetrachloride (47uL is dripped under room temperature, 0.43mmol), rear stirring at room temperature 0.5h is dripped off.After reaction terminates, use methyl alcohol cancellation, through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1) obtain 2-(phenyl)-6-hydroxyl benzofuran-3-formaldehyde 65mg (yellow solid, yield 90%) after concentrating under reduced pressure.
1H NMR(DMSO；300MHz)，δ6.887-6.922(dd，1H，J＝8.7，J＝2.1，ArH)，7.065-7.072(d，1H，J＝2.1，ArH)，7.60-7.621(m，3H，ArH)，7.913-7.964(m，3H，ArH)，9.920(s，1H，OH)，10.221(s，1H，CHO)。
embodiment 21
2-(phenyl)-6-hydroxyl benzofuran-3-ethyl ketone VI 2synthesis (Fig. 1): by 6-(benzyloxy)-2-(phenyl) cumarone (1.00g, 3.33mmol) with Acetyl Chloride 98Min. (354uL, 5.00mmol) be dissolved in methylene dichloride (20mL), tin tetrachloride (493uL is dripped in reaction system, 4.00mmol), rear stirring at room temperature 12h is dripped off.After reaction terminates, reactant is poured in ice, then use methylene dichloride (20mL) to extract three times, merge organic phase, use saturated sodium bicarbonate solution and saturated common salt water washing successively, use anhydrous sodium sulfate drying.Through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1) obtain 2-(phenyl)-6-hydroxyl benzofuran-3-ethyl ketone 0.89g (yellow solid, yield 88%) after filtration concentrating under reduced pressure.
1H NMR(DMSO；300MHz)，δ2.289(s，3H，O＝CH 3)，7.018-7.052(dd，1H，J＝8.4，J＝1.8，ArH)，7.376-7.523(m，5H，ArH，OH)，7.634-7.662(d，1H，J＝8.4，ArH)，7.885-7.91(d，2H，J＝7.5，ArH)。
embodiment 22
2-(phenyl)-6-hydroxyl benzofuran-3-benzophenone VI 3synthesis (Fig. 1): with reference to embodiment 21, by 6-(benzyloxy)-2-(phenyl) cumarone (1.00g, 3.33mmol) be dissolved in methylene dichloride (20mL) with Benzoyl chloride (5.00mmol), tin tetrachloride (493uL is dripped in reaction system, 4.00mmol), rear stirring at room temperature 12h is dripped off.After reaction terminates, reactant is poured in ice, then use methylene dichloride (20mL) to extract three times, merge organic phase, use saturated sodium bicarbonate solution and saturated common salt water washing successively, use anhydrous sodium sulfate drying.Through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1) obtain 2-(phenyl)-6-hydroxyl benzofuran-3-benzophenone, yellow solid, yield 41% after filtration concentrating under reduced pressure.
1H NMR(DMSO；300MHz)，δ7.185-7.219(dd，1H，J＝8.4，J＝1.8，ArH)，7.41-7.434(d，1H，J＝8.4，ArH)，7.482-7.534(m，3H，ArH)，7.594-7.783(m，5H，ArH，OH)，7.905-7.929(d，2H，J＝8.4，ArH)，8.150-8.174(d，2H，J＝8.4，ArH)。
embodiment 23
2-(4-hydroxy phenyl)-6-hydroxyl benzofuran-3-formaldehyde VI 4synthesis (Fig. 1): with reference to embodiment 20,6-(benzyloxy)-2-(4-hydroxy phenyl) cumarone-3-formaldehyde (0.31mL) is dissolved in methylene dichloride (10mL), titanium tetrachloride (47uL is dripped under room temperature, 0.43mmol), rear stirring at room temperature 0.5h is dripped off.After reaction terminates, use methyl alcohol cancellation, through silica gel chromatography column purification (sherwood oil: ethyl acetate=5: 1) obtain 2-(4-hydroxy phenyl)-6-hydroxyl benzofuran-3-formaldehyde, yellow solid, yield 78% after concentrating under reduced pressure.
1H NMR(DMSO；300MHz)，δ6.826-6.861(dd，1H，J＝8.4，J＝2.1，ArH)，6.94-6.969(d，2H，J＝8.7，ArH)，7.000-7.006(d，1H，J＝1.8，ArH)，7.757-7.786(d，2H，J＝8.7，ArH)，7.847-7.876(d，1H，J＝8.7，ArH)，9.802(s，1H，OH)，10.15(s，1H，OH)，10.228(s，1H，CHO)。
embodiment 24
2-(4-hydroxy phenyl)-6-hydroxyl benzofuran VI 5synthesis (Fig. 1): with reference to embodiment 20, yield 90%.
1H NMR(DMSO；300MHz)，δ6.70-6.726(dd，1H，J＝6，J＝1.5，ArH)，6.836-6.866(m，2H，ArH)，7.01(s，1H，ArH)，7.338-7.359(d，1H，J＝8.7，ArH)，7.513-7.515(dd，1H，J＝6.6，J＝2.1，ArH)，7.634-7.656(d，2H，J＝6.6，ArH)，9.492(s，1H，OH)，9.739(s，1H，OH)。
embodiment 25
(E)-3,4,5-trimethoxy-N-((6-hydroxyl-2-(phenyl) cumarone-3-base) methylene radical) aniline VII 1synthesis (Fig. 1): by 6-hydroxyl-2-(phenyl) cumarone-3-formaldehyde (50mg, 0.21mmol) with 3,4,5-trimethoxy-aniline (38mg, 0.21mmol) be dissolved in toluene (10mL), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=3: 1) obtain (E)-3,4,5-trimethoxy-N-((6-hydroxyl-2-(phenyl) cumarone-3-base) methylene radical) aniline 52mg (yellow solid, yield 62%).
1H NMR(DMSO；300MHz)，δ3.666(s，3H，OCH 3)，3.819(s，6H，2OCH 3)，6.637(s，2H，ArH)，6.873-6.918(m，1H，ArH)，7.038-7.045(d，1H，J＝2.1，ArH)，7.554-7.591(m，3H，ArH)，7.864-7.892(m，2H，ArH)，8.199-8.228(d，1H，J＝8.7，ArH)，8.804(s，1H，CH＝N)，9.819(s，1H，OH)。
embodiment 26
(E)-4-methoxyl group-N-((6-hydroxyl-2-(phenyl) cumarone-3-base) methylene radical) aniline VII 2synthesis (Fig. 1): with reference to embodiment 25, by 6-hydroxyl-2-(phenyl) cumarone-3-formaldehyde (50mg, 0.21mmol) be dissolved in toluene (10mL) with 4-anisidine (0.21mmol), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=3: 1) obtain (E)-4-methoxyl group-N-((6-hydroxyl-2-(phenyl) cumarone-3-base) methylene radical) aniline, yellow solid, yield 60%.
1H NMR(DMSO；300MHz)，δ3.781(s，3H，OCH 3)，6.872-6.906(m，1H，ArH)，6.97-7.032(m，3H，ArH)，7.316-7.345(d，2H，J＝8.7，ArH)，7.525-7.611(m，3H，ArH)，7.853-7.877(d，2H，J＝7.2，ArH)，8.232-8.26(d，1H，J＝8.4，ArH)，8.815(s，1H，CH＝N)，9.796(s，1H，OH)。
embodiment 27
(E)-4-hydroxy-n-((6-hydroxyl-2-(phenyl) cumarone-3-base) methylene radical) aniline VII 3synthesis (Fig. 1): with reference to embodiment 25, by 6-hydroxyl-2-(phenyl) cumarone-3-formaldehyde (50mg, 0.21mmol) be dissolved in toluene (10mL) with 4-hydroxyanilines (0.21mmol), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=3: 1) obtain (E)-4-hydroxy-n-((6-hydroxyl-2-(phenyl) cumarone-3-base) methylene radical) aniline.Yellow solid, yield 80%.
1H NMR(DMSO；300MHz)，δ6.796-6.825(d，2H，J＝8.7，ArH)，6.861-6.896(dd，1H，J＝8.7，J＝2.1，ArH)，7.02-7.026(d，1H，J＝1.8，ArH)，7.217-7.246(d，2H，J＝8.7，ArH)，7.521-7.615(m，3H，ArH)，7.837-7.87(dd，2H，J＝8.4，J＝1.5，ArH)，8.226-8.255(d，1H，J＝8.7，ArH)，8.803(s，1H，CH＝N)，9.465(s，1H，OH)，9.779(s，1H，OH)。
embodiment 28
(E)-3-hydroxyl-4-methoxyl group-N-((6-hydroxyl-2-(phenyl) cumarone-3-base) methylene radical) aniline VII 4synthesis (Fig. 1): with reference to embodiment 25, by 6-hydroxyl-2-(phenyl) cumarone-3-formaldehyde (50mg, 0.21mmol) with 3-hydroxyl, 4-anisidine (0.21mmol) is dissolved in toluene (10mL), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=3: 1) obtain (E)-3-hydroxyl-4-methoxyl group-N-((6-hydroxyl-2-(phenyl) cumarone-3-base) methylene radical) aniline, yellow solid, yield 80%.
1H NMR(DMSO；300MHz)，δ7.387(s，3H，OCH 3)，6.764-6.822(m，2H，ArH)，6.867-6.902(dd，1H，J＝8.4，J＝1.8，ArH)，6.936-6.964(d，1H，J＝8.4，ArH)，7.025-7.031(d，1H，J＝1.8，ArH)，7.53-7.623(m，3H，ArH)，7.837-7.864(m，2H，ArH)，8.201-8.23(d，1H，J＝8.7，ArH)，8.754(s，1H，CH＝N)，9.095(s，1H，OH)，9.794(s，1H，OH)。
embodiment 29
(E) the fluoro-N-of-4-((6-hydroxyl-2-(phenyl) cumarone-3-base) methylene radical) aniline VII ssynthesis (Fig. 1): with reference to embodiment 25, by 6-hydroxyl-2-(phenyl) cumarone-3-formaldehyde (50mg, 0.21mmol) be dissolved in toluene (10mL) with 4-fluoroaniline (0.21mmol), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=3: 1) obtain the fluoro-N-of (E)-4-((6-hydroxyl-2-(phenyl) cumarone-3-base) methylene radical) aniline, yellow solid, yield 53%.
1H NMR(DMSO；300MHz)，δ6.857-6.892(dd，1H，J＝8.4，J＝2.1，ArH)，7.022-7.028(d，1H，J＝1.8，ArH)，7.193-7.252(m，2H，ArH)，7.343-7.39(m，2H，ArH)，7.514-7.60(m，3H，ArH)，7.847-7.878(dd，2H，J＝7.8，J＝1.8，ArH)，8.192-8.22(d，1H，J＝8.4，ArH)，8.772(s，1H，CH＝N)，9.804(s，1H，OH)。
embodiment 30
(E)-3-chloro-4-hydroxyl-N-((6-hydroxyl-2-(phenyl) cumarone-3-base) methylene radical) aniline VII 6synthesis (Fig. 1): with reference to embodiment 25, by 6-hydroxyl-2-(phenyl) cumarone-3-formaldehyde (50mg, 0.21mmol) be dissolved in toluene (10mL) with 3-chloro-4-hydroxyl aniline (0.21mmol), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=3: 1) obtain (E)-3-chloro-4-hydroxyl-N-((6-hydroxyl-2-(phenyl) cumarone-3-base) methylene radical) aniline, yellow solid, yield 67%.
1H NMR(DMSO；300MHz)，δ6.857-6.892(dd，1H，J＝8.4，J＝2.1，ArH)，6.992-7.021(d，2H，J＝8.7，ArH)，7.193-7.23(dd，1H，J＝8.7，J＝2.4，ArH)，7.409-7.417(d，1H，J＝2.4，ArH)，7.501-7.616(m，3H，ArH)，7.861-7.883(d，2H，J＝6.6，ArH)，8.209-8.237(d，1H，J＝8.4，ArH)，8.791(s，1H，CH＝N)，9.797(s，1H，OH)，10.188(s，1H，OH)。
embodiment 31
(E)-3,4,5-trimethoxy-N-((6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-base) methylene radical) aniline VII 7synthesis (Fig. 1): with reference to embodiment 25, by 6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-formaldehyde (0.21mmol) and 3,4,5-trimethoxy-aniline (38mg, 0.21mmol) be dissolved in toluene (10mL), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=3: 1) obtain (E)-3,4,5-trimethoxy-N-((6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-base) methylene radical) aniline, yellow solid, yield 61%.
1H NMR(DMSO；300MHz)，δ3.647(s，3H，OCH 3)，3.801(s，6H，2OCH 3)，6.587(s，2H，ArH)，6.824-6.852(d，1H，J＝8.4，ArH)，6.928-6.977(m，3H，ArH)，7.667-7.694(d，2H，J＝8.4，ArH)，8.13-8.158(d，1H，J＝8.4，ArH)，8.719(s，1H，CH＝N)，9.7-9.74(brs，1H，OH)，10.02-10.08(brs，1H，OH)。
Get 6-benzyloxy-2-(4-benzyloxy-phenyl) cumarone-3-formaldehyde of 1 molar equivalent and 3 of 1.5 molar equivalents, 4,5-trimethoxy-aniline obtains (E)-3 in 12 hours in reflux in toluene, 4,5-trimethoxy-N-((6-benzyloxy-2-(4-benzyloxy-phenyl) cumarone-3-base) methylene radical) aniline.
embodiment 32
(E)-4-methoxyl group-N-((6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-base) methylene radical) aniline VII 8synthesis (Fig. 1): with reference to embodiment 25,6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-formaldehyde (0.21mmol) and 4-anisidine (0.21mmol) are dissolved in toluene (10mL), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=3: 1) obtain (E)-4-methoxyl group-N-((6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-base) methylene radical) aniline, yellow solid, yield 70%.
1H NMR(DMSO；300MHz)，δ3.76(s，3H，OCH 3)，6.814-6.849(dd，1H，J＝8.7，J＝1.8，ArH)，6.929-6.972(m，5H，ArH)，7.271-7.30(d，2H，J＝8.7，ArH)，7.657-7.685(d，2H，J＝8.4，ArH)，8.162-8.19(d，1H，J＝8.4，ArH)，8.732(s，1H，CH＝N)，9.691(s，1H，OH)，10.042(s，1H，OH)。
embodiment 33
(E)-3-hydroxyl-4-methoxyl group-N-((6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-base) methylene radical) aniline VII 9synthesis (Fig. 1): with reference to embodiment 25,6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-formaldehyde (0.21mmol) and 3-hydroxyl-4-anisidine (0.21mmol) is dissolved in toluene (10mL), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=3: 1) obtain (E)-3-hydroxyl-4-methoxyl group-N-((6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-base) methylene radical) aniline, yellow solid, yield 50%.
1H NMR(DMSO；300MHz)，δ3.783(s，3H，OCH 3)，6.74-6.767(dd，1H，J＝6.3，J＝1.8，ArH)，6.786-6.792(d，1H，J＝1.8，ArH)，6.832-6.858(dd，1H，J＝8.7，J＝1.5，ArH)，6.93-6.986(m，4H，ArH)，7.658-7.68(d，2H，J＝6.6，ArH)，8.151-8.172(d，1H，J＝6.3，ArH)，8.689(s，1H，CH＝N)，9.092(s，1H，OH)，9.71(s，1H，OH)，10.071(s，1H，OH)。
embodiment 34
(E) the fluoro-N-of-4-((6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-base) methylene radical) aniline VII 10synthesis (Fig. 1): with reference to embodiment 25,6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-formaldehyde (0.21mmol) and 4-fluoroaniline (0.21mmol) are dissolved in toluene (10mL), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=3: 1) obtain the fluoro-N-of (E)-4-((6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-base) methylene radical) aniline, yellow solid, yield 55%.
1H NMR(DMSO；300MHz)，δ6.848-6.868(m，1H，ArH)，6.953-7.004(m，3H，ArH)，7.235-7.256(d，2H，J＝6.3，ArH)，7.357-7.362(m，2H，ArH)，7.70-7.718(d，2H，J＝5.4，ArH)，8.166-8.186(d，1H，J＝6.0，ArH)，8.732(s，1H，CH＝N)，9.74(s，1H，OH)，10.089(s，1H，OH)。
embodiment 35
(E)-3-chloro-4-hydroxyl-N-((6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-base) methylene radical) aniline VII 11synthesis (Fig. 1): with reference to embodiment 25,6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-formaldehyde (0.21mmol) and 3-chloro-4-hydroxyl aniline (0.21mmol) are dissolved in toluene (10mL), backflow 12hrs.After reaction terminates, concentrating under reduced pressure, through silica gel chromatography column purification (sherwood oil: ethyl acetate=3: 1) obtain (E)-3-chloro-4-hydroxyl-N-((6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-base) methylene radical) aniline, yellow solid, yield 68%.
1H NMR(DMSO；300MHz)，δ6.805-6.839(dd，1H，J＝8.7，J＝1.8，ArH)，6.93-7.00(m，4H，ArH)，7.152-7.186(dd，1H，J＝8.4，J＝1.8，ArH)，7.358-7.365(d，1H，J＝2.1，ArH)，7.667-7.696(d，2H，J＝8.7，ArH)，8.142-8.171(d，1H，J＝8.7，ArH)，8.71(s，1H，CH＝N)，9.687(s，1H，OH)，10.045(s，1H，OH)，10.134(s，1H，OH)。
embodiment 36, antibacterial activity in vitro research
For investigating the anti-microbial activity of the new compound involved by present method, carry out the evaluation of microorganism growth inhibit activities by preliminary antibacterial pharmacological testing.
Adopt the U.S. clinical laboratory standard council (NCCLs) to the concrete regulation M7-A6 of each genus bacteria drug sensitivity test, concrete testing sequence:
(1) microbial culture
Pseudomonas aeruginosa, intestinal bacteria, gold-coloured staphylococci, subtilis, gold-coloured staphylococci (resistance), all use nutrient broth medium to cultivate;
Get the test tube slant that pseudomonas putida, intestinal bacteria, gold-coloured staphylococci, subtilis, the gold-coloured staphylococci (resistance) preserved in refrigerator are inoculated in nutrient broth medium, hatch in the bacteriological incubator of 37 DEG C, go down to posterity, needed for experiment in good time.
(2) medicine ordinance
All compounds are mixed with the DMSO solution that concentration is 4mg/mL.In the 2nd row sky of 96 orifice plates, add liquid 10 μ L, each compound repeats 1 time, and 96 orifice plates are placed in-20 DEG C of preservations.
(3) antibacterial tests
The desired microorganisms of taking the logarithm vegetative period, use Maxwell opacity tube 0.5 than turbid, adjustment microorganism concn is 1*10 8cfu/mL, with substratum dilution 10 4obtain 1*10 4the bacterium liquid of cfu/mL.96 orifice plate first rows add the bacterium liquid not adding 100 μ L containing the substratum of bacterium liquid, 3-12 row hole, in the 2nd row, add 200 μ L bacterium liquid, draw 100 μ L and add the 3rd and arrange after blow and beat 6-8 time, and 2 times are diluted to the 11st and arrange successively.And the microbiological incubator that 96 well culture plates after administration are placed in 37 DEG C is respectively cultivated 24hrs.
Use microplate reader to detect each hole A530 value, calculate inhibiting rate, use SPSS computed in software inhibition concentration MIC value.
The test of table 1.3-ketoxime-6-replacement-benzofuran compound antibiotic bioactive
Table 1 illustrates:
(1) the positive control medicine of antibacterial activity in vitro experiment is tsiklomitsin and benzylpenicillin sodium.
(2) microbial inhibition assays result illustrates, compound (compound VI involved by present method 1, VI 4, VI 5and VII 1-VII 11) bacteriostatic activity substantially all between 12.5-50ug/mL, and there is certain selectivity, to gram-positive microorganism, there is good fungistatic effect.As can be seen from the table, the hydroxyl that 6, cumarone ring is exposed has very important impact to this compounds bacteriostatic activity, and after hydroxyl is by benzyl or hydrophobic chain shielding, the compound obtained all does not have bacteriostatic activity.Cumarone ring 3 bit substituent has important decisive action equally for the anti-microbial activity of this compounds, and when 3 bit substituent lipotropys increase, the compound obtained all does not have anti-microbial activity.Meanwhile, when the substituted aroma ring on 2 or 3 of cumarone ring having polar substituent, the anti-microbial activity of the compound obtained has some improvement.
Above specific embodiments of the invention are described.It is to be appreciated that the present invention is not limited to above-mentioned particular implementation, those skilled in the art can make various distortion or amendment within the scope of the claims, and this does not affect flesh and blood of the present invention.

Claims (8)

1. a benzofuran compounds, is characterized in that, its structural formula is such as formula shown in (I):
Wherein,
R 1for hydrogen, C 1-C 5alkyl, nitro, halogen, ester group, hydroxyl, amino, amide group or alkoxyl group;
R 2for hydrogen, C 1-C 5alkyl, nitro, halogen, ester group, hydroxyl, amino, amide group or alkoxyl group;
R 3for hydrogen, C 1-C 5alkyl, benzyl, aromatic base or assorted aromatic base;
R 4for hydrogen, C 1-C 5alkyl, nitro, halogen, ester group, hydroxyl, amino, amide group or alkoxyl group.
2. benzofuran compounds as claimed in claim 1, it is characterized in that, its structural formula is such as formula shown in (II):
(II); Wherein, R 1, R 2and R 4all be selected from hydrogen, C 1-C 5alkyl, nitro, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, any one in alkoxyl group.
3. a preparation method for benzofuran compounds as claimed in claim 2, is characterized in that, described method comprises the steps:
A, the Benzyl Chloride of 2,4-Dihydroxy benzaldehydes and 1.2 molar equivalents getting 1 molar equivalent reflux and within 12 hours, obtain 4-(benzyloxy)-Benzaldehyde,2-hydroxy in acetonitrile;
B, 4-(the benzyloxy)-Benzaldehyde,2-hydroxy getting 1 molar equivalent and 1.1 molar equivalents in toluene, stirring at room temperature obtains (E)-5-(benzyloxy)-2-substituted ethylene base phenol for 12 hours
C, (E)-5-(benzyloxy)-2-substituted ethylene base phenol stirring at room temperature in 6 molar equivalent salt of wormwood and 6 molar equivalent iodine of getting 1 molar equivalent obtain 6-(benzyloxy)-2-for 12 hours and replace cumarone
D, get 1 molar equivalent 6-(benzyloxy)-2-replace cumarone be dissolved in 1, in 2-ethylene dichloride, under 0 DEG C of ice bath, add the phosphorus oxychloride of 8 molar equivalents and the N of 8 molar equivalents, dinethylformamide, backflow is spent the night, and obtains 6-benzyloxy-2-(4-benzyloxy-phenyl) cumarone-3-formaldehyde
E, 6-benzyloxy-2-(4-benzyloxy-phenyl) cumarone-3-formaldehyde getting 1 molar equivalent are dissolved in methylene dichloride, and the titanium tetrachloride adding 1.3 molar equivalents obtains 6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-formaldehyde
F, get 6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-formaldehyde of 1 molar equivalent and 3 of 1.5 molar equivalents, 4,5-trimethoxy-aniline obtains (E)-3 in 12 hours in reflux in toluene, 4,5-trimethoxy-N-((6-hydroxyl-2-(4-hydroxy phenyl) cumarone-3-base) methylene radical) aniline
4. a benzofuran compounds, is characterized in that, its structural formula is such as formula shown in (III):
(III), wherein R 1, R 4and R 5all be selected from hydrogen, C 1-C 5alkyl, nitro, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, phenyl, any one in alkoxyl group.
5. a preparation method for benzofuran compounds as claimed in claim 4, is characterized in that, described method comprises the steps:
A, the Benzyl Chloride of 2,4-Dihydroxy benzaldehydes and 1.2 molar equivalents getting 1 molar equivalent reflux and within 12 hours, obtain 4-(benzyloxy)-Benzaldehyde,2-hydroxy in acetonitrile;
B, 4-(the benzyloxy)-Benzaldehyde,2-hydroxy getting 1 molar equivalent and 1.1 molar equivalents in toluene, stirring at room temperature obtains (E)-5-(benzyloxy)-2-substituted ethylene base phenol for 12 hours
C, (E)-5-(benzyloxy)-2-substituted ethylene base phenol stirring at room temperature in 6 molar equivalent salt of wormwood and 6 molar equivalent iodine of getting 1 molar equivalent obtain 6-(benzyloxy)-2-for 12 hours and replace cumarone
D, 6-(the benzyloxy)-2-replacement cumarone getting 1 molar equivalent and the Acetyl Chloride 98Min. of 1.5 molar equivalents and the tin tetrachloride of 1.3 molar equivalents obtain 2-(substituted-phenyl)-6-hydroxyl benzofuran-3-ethyl ketone for 12 hours in stirred at ambient temperature in methylene dichloride
6. the purposes of the benzofuran compounds as described in claim 1,2 or 3 in the biologically active drug of preparation suppression microorganism.
7. purposes as claimed in claim 6, it is characterized in that, described microorganism is gram-positive microorganism.
8. purposes as claimed in claim 7, it is characterized in that, described gram-positive microorganism is intestinal bacteria, gold-coloured staphylococci, gold-coloured staphylococci, subtilis or Pseudomonas aeruginosa.
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CN108676029A (en) * 2018-05-22 2018-10-19 河南大学 The double trifluoromethanesulfonimide ionic liquids of Bian bases triphenyl phosphonium, synthetic method and its application as metal inhibitor
CN110590722A (en) * 2019-10-22 2019-12-20 温州大学 Synthesis method of 2-trifluoromethyl benzofuran derivative
CN107805232B (en) * 2017-10-31 2020-01-07 沅江华龙催化科技有限公司 Synthetic method of derivative containing methylthio furan
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CN105330630A (en) * 2015-10-13 2016-02-17 上海交通大学 Benzofuran compound, preparation method and applications thereof
CN107805232B (en) * 2017-10-31 2020-01-07 沅江华龙催化科技有限公司 Synthetic method of derivative containing methylthio furan
CN108676029A (en) * 2018-05-22 2018-10-19 河南大学 The double trifluoromethanesulfonimide ionic liquids of Bian bases triphenyl phosphonium, synthetic method and its application as metal inhibitor
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CN108586401A (en) * 2018-05-27 2018-09-28 扬州工业职业技术学院 A kind of preparation method of 2- substitutions-benzofuran compounds
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CN113683769A (en) * 2020-05-19 2021-11-23 上海交通大学 Compound responding to endocytosis release and application thereof

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