CN104478836B - Benzofuran compounds and its preparation, purposes - Google Patents

Benzofuran compounds and its preparation, purposes Download PDF

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CN104478836B
CN104478836B CN201410753236.2A CN201410753236A CN104478836B CN 104478836 B CN104478836 B CN 104478836B CN 201410753236 A CN201410753236 A CN 201410753236A CN 104478836 B CN104478836 B CN 104478836B
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arh
benzofuran
benzyloxy
hydroxyls
phenyl
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CN104478836A (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

Abstract

The present invention relates to a kind of benzofuran compounds and its preparation, purposes, shown in its structural formula such as formula (I)：Wherein, R1、R2、R4It is respectively selected from hydrogen, C1‑C5Alkyl, nitro, halogen, ester group, hydroxyl, amino, amide groups or alkoxy；R3It is hydrogen, C1‑C5Alkyl, benzyl, aromatic radical or heteroaryl perfume base.The invention further relates to application of the benzofuran compound on gram-positive bacteria is suppressed.The present invention centered on 3 ketoximes substitution base benzofuran structure aromatic ring, set up and optimization compound preparation method, and new compound to preparing carries out antibacterial screening experiment, confirms that prepared compound has the bacteriostatic activity of wide spectrum by preliminary bacteriostatic test.

Description

Benzofuran compounds and its preparation, purposes
Technical field
The invention belongs to medicine and chemical field, and in particular to a kind of benzofuran compounds and its preparation, purposes.
Background technology
In recent years, the infection for being induced by a large amount of antibody-resistant bacterium has become a worldwide difficult medical problem, to first The staphylococcus aureus of oxygen XiLin tolerance is a wherein important class.Because the most of antimicrobial for clinically using has sternly The toxic and side effect of weight, therefore research and development have a safely and efficiently important research side of the antimicrobial compound as Pharmaceutical Chemist To.
Benzofuran derivative is the important heterocyclic compound of a class, with biological agent widely, such as antibacterial, Antitumor, anti-inflammatory etc..Substantial amounts of research finds that 3 in benzofuran ring introduce ketone base chain substituent to such compound Bacteriostatic activity there is important influence.As Xizhen Jiang et al. exist《European Journal of Medicinal Chemistry》Delivered on 46th phase page 3526《Synthesis and antimicrobial evaluation of new benzofuran derivatives》It is the experimental article of topic.Devise the new 3- ketones substitution benzofurans of a class Derivative, as shown in following formula A, such compound is to Escherichia coli, hay bacillus, staphylococcus aureus, methicillin-resistant gold Color staphylococcus has the bacteriostatic activity of outstanding wide spectrum, and its MIC value is between 0.39-3.12ug/mL.It should be noted that Compound obtained by introducing different substituents on benzofuran 3 is not all active, and the slight change of its structure is all The huge change of activity can be caused, such as compound B is to Escherichia coli, hay bacillus, Pseudomonas aeruginosa, staphylococcus aureus and resistance to Methicillin gold-coloured staphylococci has the bacteriostatic activity of outstanding wide spectrum, its MIC80It is worth between 0.78-6.25ug/mL, and The compound C having been surprisingly found that then optionally has outstanding bacteriostatic activity to staphylococcus aureus, its MIC80It is worth and is 3.12ug/mL。
The content of the invention
It is an object of the invention to provide a kind of benzofuran compounds and its preparation, purposes, tried by preliminary antibacterial Testing the noval chemical compound prepared by confirming has certain bacteriostatic activity, can be used for the new compound with outstanding antibacterial activity Research.It is also differ in that with prior art selection ketone base, the present invention have selected oxime substitution base, its object is to introduce One Michael acceptor, strengthens the disabled combination of amino acid in its some enzyme with bacterium, increases its targeting.
The purpose of the present invention is achieved through the following technical solutions：
The present invention relates to a kind of benzofuran compounds, shown in its structural formula such as formula (I)：
Wherein,
R1It is hydrogen, C1-C5Alkyl, nitro, halogen, ester group, hydroxyl, amino, amide groups or alkoxy；
R2It is hydrogen, C1-C5Alkyl, nitro, halogen, ester group, hydroxyl, amino, amide groups or alkoxy；
R3It is hydrogen, C1-C5Alkyl, benzyl, aromatic radical or heteroaryl perfume base；
R4It is hydrogen, C1-C5Alkyl, nitro, halogen, ester group, hydroxyl, amino, amide groups or alkoxy.
Preferably, shown in its structural formula such as formula (II)：
Wherein, R1, R2And R4It is selected from hydrogen, C1-C5Alkyl, nitro, fluorine, Any one in chlorine, bromine, ester group, hydroxyl, amino, amide groups, alkoxy.
The invention further relates to a kind of preparation method of benzofuran compounds shown in formula (II) of the invention, methods described Comprise the following steps：
A, 2, the 4- 4-dihydroxy benzaldehydes for taking 1 molar equivalent and the benzyl chloride of 1.2 molar equivalents flow back 12 small in acetonitrile When obtain 4- (benzyloxy)-Benzaldehyde,2-hydroxy；
B, 4- (the benzyloxy)-Benzaldehyde,2-hydroxy for taking 1 molar equivalent and 1.1 molar equivalentsIn toluene In be stirred at room temperature and obtain within 12 hours (E) -5- (benzyloxy) -2- substituted ethylene base phenol
C, (E) -5- (the benzyloxy) -2- substituted ethylene base phenol for taking 1 molar equivalent rub in 6 molar equivalent potassium carbonate and 6 It is stirred at room temperature in your equivalent iodine and obtains within 12 hours 6- (benzyloxy) -2- substitution benzofurans
D, take 1 molar equivalent 6- (benzyloxy) -2- substitution benzofuran be dissolved in 1,2- dichloroethanes, in 0 DEG C of ice Under bath, the POCl3 of 8 molar equivalents and the DMF of 8 molar equivalents are added, backflow overnight, obtains 6- benzyloxies Base -2- (4- benzyloxy-phenyls) benzofuran -3- formaldehyde
E, 6- benzyloxies -2- (4- benzyloxy-phenyls) benzofuran -3- formaldehyde for taking 1 molar equivalent are dissolved in dichloromethane In, add the titanium tetrachloride of 1.3 molar equivalents to obtain 6- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- formaldehyde
The 3 of F, 6- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- formaldehyde for taking 1 molar equivalent and 1.5 molar equivalents, 4,5- trimethoxy-anilines obtain (E) -3,4,5- trimethoxy-N- ((6- hydroxyls -2- (4- hydroxyls for 12 hours in reflux in toluene Phenyl) benzofuran -3- bases) methylene) aniline
Preferably, in step B, R1PPh3Cl is triphenyl (4- benzyloxy-benzyls) phosphonium chloride, and it is prepared includes following step Suddenly：
The benzyl chloride of the 4- salicylic alcohols and 1.2 molar equivalents that take 1 molar equivalent flows back in acetonitrile and obtains 4- benzyloxies Base phenmethylol；
The thionyl chloride of the 4- benzyloxybenzyl alcohols and 1.1 molar equivalents that take 1 molar equivalent is stirred in dichloromethane To 4- benzyloxy benzyl chlorides；
The triphenylphosphine of the 4- benzyloxies benzyl chloride and 1 molar equivalent that take 1 molar equivalent flows back in acetonitrile and obtains triphen Base (4- benzyloxy-benzyls) phosphonium chloride.
Preferably, methods described comprises the following steps：
A, 2, the 4- 4-dihydroxy benzaldehydes for taking 1 molar equivalent and the benzyl chloride of 1.2 molar equivalents flow back 12 small in acetonitrile When obtain 4- (benzyloxy)-Benzaldehyde,2-hydroxy；
The benzyl chloride of B, the 4- salicylic alcohols for taking 1 molar equivalent and 1.2 molar equivalents flows back in acetonitrile and obtains 4- benzyls Epoxide phenmethylol；
The thionyl chloride of C, the 4- benzyloxybenzyl alcohols for taking 1 molar equivalent and 1.1 molar equivalents is stirred in dichloromethane Obtain 4- benzyloxy benzyl chlorides；
The triphenylphosphine of the 4- benzyloxies benzyl chloride and 1 molar equivalent that D. take 1 molar equivalent flows back in acetonitrile and obtains three Phenyl (4- benzyloxy-benzyls) phosphonium chloride；
E. 4- (the benzyloxy)-Benzaldehyde,2-hydroxy of 1 molar equivalent and triphenyl (the 4- benzyloxies of 1.1 molar equivalents are taken Benzyl) phosphonium chloride is stirred at room temperature in toluene and obtains within 12 hours (E) -5- (benzyloxy) -2- substituted ethylene base phenol；
F. (E) -5- (the benzyloxy) -2- substituted ethylene base phenol for taking 1 molar equivalent rubs in 6 molar equivalent potassium carbonate and 6 It is stirred at room temperature in your equivalent iodine and obtains within 12 hours 6- (benzyloxy) -2- substitution benzofurans；
G. 6- (the benzyloxy) -2- substitution benzofurans for taking 1 molar equivalent are dissolved in 1,2- dichloroethanes, in 0 DEG C of ice Under bath, the POCl3 of 8 molar equivalents and the DMF of 8 molar equivalents are added, backflow overnight, obtains 6- benzyloxies Base -2- (4- benzyloxy-phenyls) benzofuran -3- formaldehyde；
H. 6- benzyloxies -2- (4- benzyloxy-phenyls) benzofuran -3- formaldehyde for taking 1 molar equivalent is dissolved in dichloromethane In, add the titanium tetrachloride of 1.3 molar equivalents to obtain 6- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- formaldehyde；
L take 1 molar equivalent 6- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- formaldehyde and 1.5 molar equivalents 3,4, 5- trimethoxy-anilines obtain (E) -3,4,5- trimethoxy-N- ((6- hydroxyls -2- (4- hydroxy benzenes for 12 hours in reflux in toluene Base) benzofuran -3- bases) methylene) aniline；
J. 6- benzyloxies -2- (4- benzyloxy-phenyls) benzofuran -3- formaldehyde and 1.5 molar equivalents of 1 molar equivalent are taken 3,4,5- trimethoxy-anilines obtain within 12 hours (E) -3,4,5- trimethoxy-N- ((6- benzyloxies -2- in reflux in toluene (4- benzyloxy-phenyls) benzofuran -3- bases) methylene) aniline.
The invention further relates to a kind of benzofuran compounds, shown in its structural formula such as formula (III)：
Wherein R1、R4And R5It is selected from hydrogen, C1-C5Alkyl, nitro, fluorine, chlorine, Any one in bromine, ester group, hydroxyl, amino, amide groups, phenyl, alkoxy.
The invention further relates to a kind of preparation method of the benzofuran compounds as shown in formula (III) of the invention, institute The method of stating comprises the following steps：
A, 2, the 4- 4-dihydroxy benzaldehydes for taking 1 molar equivalent and the benzyl chloride of 1.2 molar equivalents flow back 12 small in acetonitrile When obtain 4- (benzyloxy)-Benzaldehyde,2-hydroxy；
B, 4- (the benzyloxy)-Benzaldehyde,2-hydroxy for taking 1 molar equivalent and 1.1 molar equivalentsIn toluene In be stirred at room temperature and obtain within 12 hours (E) -5- (benzyloxy) -2- substituted ethylene base phenol
C, (E) -5- (the benzyloxy) -2- substituted ethylene base phenol for taking 1 molar equivalent rub in 6 molar equivalent potassium carbonate and 6 It is stirred at room temperature in your equivalent iodine and obtains within 12 hours 6- (benzyloxy) -2- substitution benzofurans
D, the chloroacetic chloride of 6- (the benzyloxy) -2- substitution benzofurans for taking 1 molar equivalent and 1.5 molar equivalents and 1.3 are rubbed The butter of tin of your equivalent is stirred and obtains within 12 hours 2- (substituted-phenyl) -6- hydroxy benzo furans at room temperature in dichloromethane Mutter -3- ethyl ketones
The bioactivity medicine for suppressing microorganism is being prepared the invention further relates to a kind of benzofuran compounds of the invention Purposes in thing.
Preferably, the microorganism is gram-positive bacteria.
Preferably, the gram-positive bacteria is Escherichia coli, gold-coloured staphylococci, gold-coloured staphylococci, withered Careless bacillus or Pseudomonas aeruginosa.
Through seminar where the present invention further study show that, the benzofuran compounds that 6 bit strips have free hydroxyl have There are outstanding, wide spectrum antibacterial activity, MIC80Value is between 0.78-6.25ug/mL.In addition, present inventors have unexpectedly found that 3 bit strips have The benzofuran compounds of imine structure have outstanding antibacterial activity, MIC for staphylococcus aureus80It is worth and is 3.12ug/mL, and positive control CTX and Benzylpenicillin sodium salt bacteriostatic activity it is close.According to above result of study, the present invention The new benzofuran compound of a class is designed, as shown in Fig. 2 hydroxyl is incorporated into 6 of benzofuran ring, by imine structure 3 of benzofuran ring are introduced, for investigating 2,3, benzofuran ring with the substitution base on external position to benzofurans chemical combination The influence of thing bacteriostatic activity, is desirably to obtain the new benzofuran derivative with outstanding bacteriostatic activity of a class.
Compared with prior art, the present invention possesses following beneficial effect：Hydroxyl is incorporated into the present invention the 6 of benzofuran ring Position, 3 of benzofuran ring are introduced by imine structure, set up and optimize the preparation method of compound, and the newcooperative medical system to preparing Compound carries out antibacterial screening experiment, to develop the new compound of outstanding antibacterial activity.
Brief description of the drawings
The detailed description made to non-limiting example with reference to the following drawings by reading, further feature of the invention, Objects and advantages will become more apparent upon：
Fig. 1 is the preparation method synthetic route schematic diagram of benzofuran compound；
Fig. 2 is the design principle figure of 3- ketoxime -6- substitution-benzofuran compounds.
Specific embodiment
With reference to specific embodiment, the present invention is described in detail.Following examples will be helpful to the technology of this area Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that to the ordinary skill of this area For personnel, without departing from the inventive concept of the premise, various modifications and improvements can be made.These belong to the present invention Protection domain.
Embodiment 1
The synthesis (Fig. 1) of 4- (benzyloxy)-Benzaldehyde,2-hydroxy I：By 2,4- 4-dihydroxy benzaldehydes (5.00g, 36mmol) Be dissolved in acetonitrile (500mL), be subsequently adding KI (9.00g, 54mmol) and sodium acid carbonate (4.50g, 54mmol), add with Afterwards, benzyl chloride (5.50g, 43.5mmol) is slowly added dropwise, flow back 12h.After the completion of reaction, add water and be quenched, be extracted with ethyl acetate, Merge organic phase, with saturated common salt water washing three times, after anhydrous sodium sulfate drying, be concentrated under reduced pressure, (stone is purified through silica gel chromatographic column Oily ether: ethyl acetate=10: 1) obtains 4- (benzyloxy)-Benzaldehyde,2-hydroxy 5.25g (white solid, yield 64%).
1H NMR(CDCl3；300MHz), δ 5.11 (s, 2H, OCH2Ph) 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：By benzyl chloride (2.88g, 31.6mmol) and triphenylphosphine (8.57g, 32.7mmo) it is dissolved in 20mL acetonitriles, heated overnight at reflux.After the completion of reaction, room temperature is cooled to, filtered, obtain triphenylbenzylphosphonium Phosphonium chloride 7.5g (white solid, yield 61%).
1H NMR(DMSO；300MHz), δ 5.25-5.30 (d, 2H, J=15.9Hz, CH2P), 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 alcohols：4- salicylic alcohols (10.00g, 80.55mmol) are dissolved in 150mL acetonitriles, Potassium carbonate (22.27g, 161.1mmol) is subsequently adding, then is slowly added dropwise benzyl chloride (12.24g, 96.66mmol), flow back 12h. After the completion of reaction, add water and be quenched, be extracted with ethyl acetate, merge organic phase, use saturated common salt water washing, anhydrous sodium sulfate is done It is dry, it is concentrated under reduced pressure, through silica gel chromatographic column purifying, (petroleum ether: ethyl acetate=3: 1) obtains 4- benzyloxybenzyl alcohols 15g (whites Solid, yield 87%).
1H NMR(DMSO；300MHz), δ 4.39-4.41 (d, 2H, CH2OH), 5.00-5.04 (t, 1H, CH2OH), 5.06 (s, 2H, OCH2Ph), 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 chlorides：4- benzyloxybenzyl alcohols (15.00g, 70.02mmol) are dissolved in 100mL dichloros In methane, cool to 0 DEG C, be slowly added dropwise thionyl chloride (5.60ml, 77.02mmol), after completion of dropping, be stirred at room temperature 1h until Raw material reaction is finished.Concentrated under reduced pressure, through silica gel chromatographic column purifying, (petroleum ether: ethyl acetate=10: 1) obtains 4- benzyloxy chlorinations Benzyl 12g (white solid, yield 74%).
1H NMR(DMSO；300MHz), δ 4.71 (s, 2H, CH2Cl), 5.11 (s, 2H, OCH2Ph), 6.99-7.02 (d, 2H, ArH), 7.32-7.45 (m, 7H, ArH).
Embodiment 5
The synthesis of triphenyl (4- benzyloxy-benzyls) phosphonium chloride：By 4- benzyloxies benzyl chloride (11.8g, 50.70mmol) and Triphenylphosphine (13.70g, 52.22mmol) is dissolved in 100mL acetonitriles, heated overnight at reflux.After the completion of reaction, room temperature is cooled to, Filtering, obtains triphenyl (4- benzyloxy-benzyls) phosphonium chloride 20.8g (white solid, yield 83%).
1H NMR(DMSO；300MHz), δ 5.04 (s, 2H, OCH2Ph), 5.11-5.16 (d, 2H, J=15Hz, CH2P), 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 II1Synthesis (Fig. 1)：Under the atmosphere of nitrogen, by 4- (benzyls Epoxide)-Benzaldehyde,2-hydroxy (1.70g, 7.45mmol) and triphenylbenzylphosphonium chloride phosphine (2.89g, 7.45mmol) be dissolved in 12mL In acetonitrile, DBU (1.17g, 7.70mmol), heated overnight at reflux is added dropwise.After question response is finished, solvent is spin-dried for, and use dichloromethane Alkane dissolution residual substance, respectively with water, 1N HCl solutions and saturated common salt water washing, with anhydrous sodium sulfate drying, are concentrated under reduced pressure, warp (petroleum ether: ethyl acetate=5: 1) obtains (E) -5- (benzyloxy) -2- (styryl) phenol 1.78g for silica gel chromatographic column purifying (white solid, yield 79%).
1H NMR(DMSO；300MHz), δ 5.07 (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- benzyloxies styryl) phenol II2Synthesis (Fig. 1)：Under the atmosphere of nitrogen, By 4- (benzyloxy)-Benzaldehyde,2-hydroxy (0.20g, 0.88mmol) and triphenyl (4- benzyloxy-benzyls) phosphonium chloride (0.48g, 0.96mmol) it is dissolved in 10mL toluene, adds KOH (0.06g, 1.06mmol), 12h is stirred at room temperature, to after completion of the reaction, distinguishes With water, 1N HCl solutions and saturated aqueous common salt washing reaction liquid use anhydrous sodium sulfate drying organic phase, are concentrated under reduced pressure, through silica gel (petroleum ether: ethyl acetate=5: 1) obtains (E) -5- (benzyloxy) -2- (4- benzyloxies styryl) phenol to chromatography 0.1g (white solid, yield 28%).
1H NMR(DMSO；300MHz), δ 5.063 (s, 2H, OCH2Ph), 5.11 (s, 2H, OCH2Ph), 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) benzofurans III1Synthesis (Fig. 1)：By (E) -5- (benzyloxy) -2- (styrene Base) phenol (1.00g, 3.31mmol) is dissolved in tetrahydrofuran (20ml), adds Anhydrous potassium carbonate (2.74g, 19.85mmol), After stirring 10min, iodine (5.04g, 19.85mmol) is added, 2h is stirred at room temperature.After reaction terminates, with the sodium bicarbonate water of saturation Solution is quenched reaction, and the aqueous solution of sodium bisulfite that saturation is then added dropwise removes the iodine of residual, then is extracted with ethyl acetate, and merges Organic phase, with saturated common salt water washing three times, after anhydrous sodium sulfate drying, is concentrated under reduced pressure, and (petroleum ether is purified through silica gel chromatographic column : ethyl acetate=5: 1), obtain 6- (benzyloxy) -2- (phenyl) benzofurans 0.18g (yellow solid, yield 18%).
1H NMR(CDCl3；300MHz), δ 5.137 (s, 2H, OCH2Ph), 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-phenyls) benzofuran III2Synthesis (Fig. 1)：By (E) -5- (benzyloxy) - 2- (4- benzyloxies styryl) phenol (0.50g, 1.22mmol) is dissolved in tetrahydrofuran (10mL), adds Anhydrous potassium carbonate (1.02g, 7.35mmol), after stirring 30min, adds iodine (1.87g, 7.35mmol), and 2h is stirred at room temperature.After reaction terminates, use The sodium bicarbonate aqueous solution of saturation is quenched reaction, and the aqueous solution of sodium bisulfite that saturation is then added dropwise removes the iodine of residual, then uses Ethyl acetate is extracted, and merges organic phase, with saturated common salt water washing three times, after anhydrous sodium sulfate drying, is concentrated under reduced pressure, through silica gel (petroleum ether: ethyl acetate=5: 1), obtains 6- (benzyloxy) -2- (4- benzyloxy-phenyls) benzofuran 0.32g to chromatography (light yellow solid, yield 64%).
1H NMR(DMSO；300MHz), δ 5.152 (s, 4H, OCH2Ph, OCH2Ph), 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) benzofuran -3- formaldehyde IV1Synthesis (Fig. 1)：At 0~5 DEG C by POCl3 (1.5mL, 16.0mmol) is added drop-wise in DMF (1.3mL, 16.0mmol) and 1,2- dichloroethanes (20mL), After stirring 10min, 6- (benzyloxy) -2- (phenyl) benzofuran (0.6g, 2.0mmol) is added in mixture solution, returned Stream 12h.After reaction terminates, reaction solution is poured into frozen water, extracted with dichloromethane, it is molten with water, saturated sodium bicarbonate water successively Liquid and saturated common salt water washing, then use anhydrous sodium sulfate drying.After concentrated under reduced pressure (petroleum ether: acetic acid is purified through silica gel chromatographic column Ethyl ester=10: 1) obtain 6- (benzyloxy) -2- (phenyl) benzofuran -3- formaldehyde 0.45g (yellow solid, yield 69%).
1H NMR(CDCl3；300MHz), δ 5.149 (s, 2H, OCH2Ph), 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-phenyls) benzofuran -3- formaldehyde IV2Synthesis (Fig. 1)：With reference to embodiment 10, POCl3 (1.5mL, 16.0mmol) is added drop-wise to DMF (1.3mL, 16.0mmol) at 0~5 DEG C In 1,2- dichloroethanes (20mL), after stirring 10min, by 6- (benzyloxy) -2- (4- benzyloxy-phenyls) benzofuran (2.0mmol) is added in mixture solution, and flow back 12h.After reaction terminates, reaction solution is poured into frozen water, use dichloromethane Extraction, successively with water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing, then uses anhydrous sodium sulfate drying.It is concentrated under reduced pressure By silica gel chromatographic column purifying, (petroleum ether: ethyl acetate=10: 1) obtains 6- (benzyloxy) -2- (4- benzyloxy-phenyls) benzo Furans -3- formaldehyde 0.53g, (yellow solid, yield 65%.)
1H NMR(DMSO；300MHz), δ 5.176 (s, 2H, OCH2Ph), 5.214 (s, 2H, OCH2Ph), 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) benzofuran -3- bases) methylene) aniline V1 Synthesis (Fig. 1)：By 6- (benzyloxy) -2- (phenyl) benzofuran -3- formaldehyde (50mg, 0.152mmol) and 3,4,5- front threes Epoxide aniline (28mg, 0.152mmol) is dissolved in toluene (10mL), and flow back 12hrs.After reaction terminates, it is concentrated under reduced pressure, through silica gel (petroleum ether: ethyl acetate=5: 1) obtains (E) -3,4,5- trimethoxy-N- ((6- (benzyloxy) -2- (benzene to chromatography Base) benzofuran -3- bases) methylene) aniline 45mg (yellow solid, yield 60%).
1H NMR(CDCl3；300MHz), δ 3.892 (s, 3H, OCH3), 3.919 (s, 6H, OCH3, OCH3), 5.185 (s, 2H, OCH2Ph), 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 groups-N- ((6- (benzyloxy) -2- (phenyl) benzofuran -3- bases) methylene) aniline V2Synthesis (Fig. 1)：With reference to embodiment 12, by 6- (benzyloxy) -2- (phenyl) benzofuran -3- formaldehyde (50mg, 0.152mmol) and 4- first Epoxide aniline (0.152mmol) is dissolved in toluene (10mL), and flow back 12hrs.After reaction terminates, it is concentrated under reduced pressure, through silica gel chromatograph Post purifying (petroleum ether: ethyl acetate=5: 1) obtain (E) -4- methoxyl groups-N- ((6- (benzyloxy) -2- (phenyl) benzofuran - 3- yls) methylene) aniline, yellow solid, yield 66%.
1H NMR(DMSO；300MHz), δ 3.78 (s, 3H, OCH3), 5.21 (s, 2H, OCH2Ph), 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-ns-((6- (benzyloxy) -2- (phenyl) benzofuran -3- bases) methylene) aniline V3Synthesis (Fig. 1)：With reference to embodiment 12, by 6- (benzyloxy) -2- (phenyl) benzofuran -3- formaldehyde (50mg, 0.152mmol) and 4- hydroxyls Base aniline (0.152mmol) is dissolved in toluene (10mL), and flow back 12hrs.After reaction terminates, it is concentrated under reduced pressure, through silica gel chromatographic column (petroleum ether: ethyl acetate=5: 1) obtains (E) -4- hydroxy-ns-((6- (benzyloxy) -2- (phenyl) benzofurans -3- for purifying Base) methylene) aniline, yellow solid, yield 40%.
1H NMR(DMSO；300MHz), δ 5.209 (s, 2H, OCH2Ph), 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- hydroxyls -4- methoxyl groups-N- ((6- (benzyloxy) -2- (phenyl) benzofuran -3- bases) methylene) aniline V4Synthesis (Fig. 1)：With reference to embodiment 12, by 6- (benzyloxy) -2- (phenyl) benzofuran -3- formaldehyde (50mg, 0.152mmol) it is dissolved in toluene (10mL) with 3- hydroxyl -4- aminoanisoles (0.152mmol), flow back 12hrs.Reaction terminates Afterwards, it is concentrated under reduced pressure, through silica gel chromatographic column purifying, (petroleum ether: ethyl acetate=5: 1) obtains (E) -3- hydroxyl -4- methoxyl groups-N- ((6- (benzyloxy) -2- (phenyl) benzofuran -3- bases) methylene) aniline, yellow solid, yield 65%.
1H NMR(DMSO；300MHz), δ 3.789 (s, 3H, OCH3), 5.215 (s, 2H, OCH2Ph), 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) benzofuran -3- bases) methylene) aniline V5Synthesis (figure 1)：With reference to embodiment 12, by 6- (benzyloxy) -2- (phenyl) benzofuran -3- formaldehyde (50mg, 0.152mmol) and 4- fluorobenzene Amine (0.152mmol) is dissolved in toluene (10mL), and flow back 12hrs.After reaction terminates, it is concentrated under reduced pressure, is purified through silica gel chromatographic column (petroleum ether: ethyl acetate=5: 1) obtains the fluoro- N- of (E) -4- ((6- (benzyloxy) -2- (phenyl) benzofuran -3- bases) methylenes Base) aniline, yellow solid, yield 55%.
1H NMR(DMSO；300MHz), δ 5.196 (s, 2H, OCH2Ph), 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-hydroxyls-N- ((6- (benzyloxy) -2- (phenyl) benzofuran -3- bases) methylene) aniline V6's Synthesis (Fig. 1)：With reference to embodiment 12, by 6- (benzyloxy) -2- (phenyl) benzofuran -3- formaldehyde (50mg, 0.152mmol) and 3- chloro-4-hydroxyls aniline (0.152mmol) are dissolved in toluene (10mL), and flow back 12hrs.After reaction terminates, it is concentrated under reduced pressure, through silicon (petroleum ether: ethyl acetate=5: 1) obtains (E) -3- chloro-4-hydroxyls-N- ((6- (benzyloxy) -2- (phenyl) to glue chromatography Benzofuran -3- bases) methylene) aniline, yellow solid, yield 54%.
1H NMR(DMSO；300MHz), δ 5.206 (s, 2H, OCH2Ph), 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-styrenes) benzofuran V7Synthesis (Fig. 1)： Under nitrogen environment, zinc powder (0.2g, 3.05mmol) is added in anhydrous tetrahydro furan (20mL), then by the temperature of reaction system - 5~0 DEG C is dropped to, titanium tetrachloride (0.17mL, 1.53mmol) is added dropwise at this temperature, by the temperature liter of reaction system after adding To room temperature, half an hour is stirred, then flow back 2.5h again.After backflow terminates, the temperature of reaction system is dropped to -5~0 DEG C again, It is added dropwise over 6- (benzyloxy) -2- (phenyl) benzofuran -3- formaldehyde (0.2g, 0.61mmol) and P-methoxybenzal-dehyde The tetrahydrofuran solution of (0.1g, 0.73mmol), flow back 2h after dripping off.After reaction terminates, with 10% sodium bicarbonate aqueous solution Reaction is quenched, is then extracted with dichloromethane, merge organic phase, with saturated common salt water washing three times, after anhydrous sodium sulfate drying, Concentrated under reduced pressure, through silica gel chromatographic column purifying, (petroleum ether: ethyl acetate=5: 1) obtains (E) -6- (benzyloxy) -2- (phenyl) -3- (4- methoxyl-styrenes) benzofuran 18mg (light yellow solid, yield 7%).
1H NMR(DMSO；300MHz), δ 3.765 (s, 3H, OCH3), 5.197 (s, 2H, OCH2Ph), 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- benzyloxies styryl) benzofuran V8Synthesis (Fig. 1)： Under the atmosphere of nitrogen, by 6- (benzyloxy) -2- (phenyl) benzofuran -3- formaldehyde (0.20g, 0.61mmol) and triphenyl (4- Benzyloxy-benzyl) phosphonium chloride (0.33g, 0.67mmol) is dissolved in 10mL toluene, adds KOH (0.04g, 0.73mmol), room temperature Stirring 12h, to after completion of the reaction, respectively with water, 1N HCl solutions and saturated aqueous common salt washing reaction liquid are dry with anhydrous sodium sulfate Dry organic phase, be concentrated under reduced pressure, through silica gel chromatographic column purifying (petroleum ether: ethyl acetate=30: 1) obtain (E) -6- (benzyloxy) - 2- (phenyl) -3- (4- benzyloxies styryl) benzofuran 121mg (white solid, yield 39%).
1H NMR(DMSO；300MHz), δ 5.124 (s, 2H, OCH2Ph), 5.194 (s, 2H, OCH2Ph), 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 VI1Synthesis (Fig. 1)：By 6- (benzyloxy) -2- (phenyl) benzene And furans -3- formaldehyde (100mg, 0.31mL) is dissolved in dichloromethane (10mL), at room temperature be added dropwise titanium tetrachloride (47uL, 0.43mmol), 0.5h is stirred at room temperature after dripping off.After reaction terminates, it is quenched with methyl alcohol, is purified through silica gel chromatographic column after being concentrated under reduced pressure (petroleum ether: ethyl acetate=5: 1) obtains 2- (phenyl) -6- hydroxyl benzofuran -3- formaldehyde 65mg (yellow solid, yield 90%).
1H NMR(DMSO；300MHz), δ 6.887-6.922 (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 ketones VI2Synthesis (Fig. 1)：By 6- (benzyloxy) -2- (phenyl) benzene And furans (1.00g, 3.33mmol) and chloroacetic chloride (354uL, 5.00mmol) are dissolved in dichloromethane (20mL), to reaction system Middle dropwise addition butter of tin (493uL, 4.00mmol), 12h is stirred at room temperature after dripping off.After reaction terminates, reactant is poured into ice, Then extracted three times with dichloromethane (20mL), merge organic phase, washed with saturated sodium bicarbonate solution and saturated common salt successively Wash, use anhydrous sodium sulfate drying.Through silica gel chromatographic column purifying, (petroleum ether: ethyl acetate=5: 1) obtains after filtering is concentrated under reduced pressure 2- (phenyl) -6- hydroxyl benzofuran -3- ethyl ketones 0.89g (yellow solid, yield 88%).
1H NMR(DMSO；300MHz), δ 2.289 (s, 3H, O=CH3), 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- Benzophenones VI3Synthesis (Fig. 1)：With reference to embodiment 21, by 6- (benzyloxies Base) -2- (phenyl) benzofuran (1.00g, 3.33mmol) and chlorobenzoyl chloride (5.00mmol) be dissolved in dichloromethane (20mL), To butter of tin (493uL, 4.00mmol) is added dropwise in reaction system, 12h is stirred at room temperature after dripping off.After reaction terminates, will react Thing is poured into ice, is then extracted three times with dichloromethane (20mL), merges organic phase, saturated sodium bicarbonate solution is used successively and is satisfied And brine It, use anhydrous sodium sulfate drying.After filtering is concentrated under reduced pressure (petroleum ether: ethyl acetate is purified through silica gel chromatographic column =5: 1) obtain 2- (phenyl) -6- hydroxyl benzofuran -3- Benzophenones, yellow solid, yield 41%.
1H NMR(DMSO；300MHz), δ 7.185-7.219 (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 phenyls) -6- hydroxyl benzofuran -3- formaldehyde VI4Synthesis (Fig. 1)：With reference to embodiment 20, by 6- (benzyloxy) -2- (4- hydroxy phenyls) benzofuran -3- formaldehyde (0.31mL) is dissolved in dichloromethane (10mL), is added dropwise at room temperature Titanium tetrachloride (47uL, 0.43mmol), 0.5h is stirred at room temperature after dripping off.After reaction terminates, it is quenched with methyl alcohol, is passed through after being concentrated under reduced pressure Silica gel chromatographic column purifying (petroleum ether: ethyl acetate=5: 2- (4- hydroxy phenyls) -6- hydroxyl benzofuran -3- formaldehyde 1) is obtained, Yellow solid, yield 78%.
1H NMR(DMSO；300MHz), δ 6.826-6.861 (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 phenyls) -6- hydroxyl benzofurans VI5Synthesis (Fig. 1)：With reference to embodiment 20, yield 90%.
1H NMR(DMSO；300MHz), δ 6.70-6.726 (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- hydroxyls -2- (phenyl) benzofuran -3- bases) methylene) aniline VII1's Synthesis (Fig. 1)：By 6- hydroxyls -2- (phenyl) benzofuran -3- formaldehyde (50mg, 0.21mmol) and 3,4,5- trimethoxy-anilines (38mg, 0.21mmol) is dissolved in toluene (10mL), and flow back 12hrs.After reaction terminates, it is concentrated under reduced pressure, it is pure through silica gel chromatographic column (petroleum ether: ethyl acetate=3: 1) obtains (E) -3,4,5- trimethoxy-N- ((6- hydroxyls -2- (phenyl) benzofurans -3- for change Base) methylene) aniline 52mg (yellow solid, yield 62%).
1H NMR(DMSO；300MHz), δ 3.666 (s, 3H, OCH3), 3.819 (s, 6H, 2OCH3), 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 groups-N- ((6- hydroxyls -2- (phenyl) benzofuran -3- bases) methylene) aniline VII2Synthesis (Fig. 1)：With reference to embodiment 25, by 6- hydroxyls -2- (phenyl) benzofuran -3- formaldehyde (50mg, 0.21mmol) and 4- methoxyl groups Aniline (0.21mmol) is dissolved in toluene (10mL), and flow back 12hrs.After reaction terminates, it is concentrated under reduced pressure, is purified through silica gel chromatographic column (petroleum ether: ethyl acetate=3: 1) obtains (E) -4- methoxyl groups-N- ((6- hydroxyls -2- (phenyl) benzofuran -3- bases) methylenes Base) aniline, yellow solid, yield 60%.
1H NMR(DMSO；300MHz), δ 3.781 (s, 3H, OCH3), 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-ns-((6- hydroxyls -2- (phenyl) benzofuran -3- bases) methylene) aniline VII3Synthesis (figure 1)：With reference to embodiment 25, by 6- hydroxyls -2- (phenyl) benzofuran -3- formaldehyde (50mg, 0.21mmol) and 4- hydroxyanilines (0.21mmol) is dissolved in toluene (10mL), and flow back 12hrs.After reaction terminates, it is concentrated under reduced pressure, (stone is purified through silica gel chromatographic column Oily ether: ethyl acetate=3: 1) obtains (E) -4- hydroxy-ns-((6- hydroxyls -2- (phenyl) benzofuran -3- bases) methylene) benzene Amine.Yellow solid, yield 80%.
1H NMR(DMSO；300MHz), δ 6.796-6.825 (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- hydroxyls -4- methoxyl groups-N- ((6- hydroxyls -2- (phenyl) benzofuran -3- bases) methylene) aniline VII4 Synthesis (Fig. 1)：With reference to embodiment 25, by 6- hydroxyls -2- (phenyl) benzofuran -3- formaldehyde (50mg, 0.21mmol) and 3- Hydroxyl, 4- aminoanisoles (0.21mmol) are dissolved in toluene (10mL), and flow back 12hrs.After reaction terminates, it is concentrated under reduced pressure, warp (petroleum ether: ethyl acetate=3: 1) obtains (E) -3- hydroxyl -4- methoxyl groups-N- ((6- hydroxyl -2- (benzene for silica gel chromatographic column purifying Base) benzofuran -3- bases) methylene) aniline, yellow solid, yield 80%.
1H NMR(DMSO；300MHz), δ 7.387 (s, 3H, OCH3), 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- hydroxyls -2- (phenyl) benzofuran -3- bases) methylene) aniline VIIsSynthesis (Fig. 1)： With reference to embodiment 25, by 6- hydroxyls -2- (phenyl) benzofuran -3- formaldehyde (50mg, 0.21mmol) and 4- fluoroanilines (0.21mmol) is dissolved in toluene (10mL), and flow back 12hrs.After reaction terminates, it is concentrated under reduced pressure, (stone is purified through silica gel chromatographic column Oily ether: ethyl acetate=3: the fluoro- N- of (E) -4- ((6- hydroxyls -2- (phenyl) benzofuran -3- bases) methylene) aniline 1) is obtained, Yellow solid, yield 53%.
1H NMR(DMSO；300MHz), δ 6.857-6.892 (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-hydroxyls-N- ((6- hydroxyls -2- (phenyl) benzofuran -3- bases) methylene) aniline VII6Conjunction Into (Fig. 1)：With reference to embodiment 25, by 6- hydroxyls -2- (phenyl) benzofuran -3- formaldehyde (50mg, 0.21mmol) and the chloro- 4- of 3- Hydroxyanilines (0.21mmol) are dissolved in toluene (10mL), and flow back 12hrs.After reaction terminates, it is concentrated under reduced pressure, through silica gel chromatographic column (petroleum ether: ethyl acetate=3: 1) obtains (E) -3- chloro-4-hydroxyls-N- ((6- hydroxyls -2- (phenyl) benzofurans -3- for purifying Base) methylene) aniline, yellow solid, yield 67%.
1H NMR(DMSO；300MHz), δ 6.857-6.892 (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- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- bases) methylene) aniline VII7Synthesis (Fig. 1)：With reference to embodiment 25, by 6- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- formaldehyde (0.21mmol) With 3,4,5- trimethoxy-anilines (38mg, 0.21mmol) are dissolved in toluene (10mL), and flow back 12hrs.After reaction terminates, decompression Concentration, through silica gel chromatographic column purifying (petroleum ether: ethyl acetate=3: 1) obtain (E) -3,4,5- trimethoxy-N- ((6- hydroxyls - 2- (4- hydroxy phenyls) benzofuran -3- bases) methylene) aniline, yellow solid, yield 61%.
1H NMR(DMSO；300MHz), δ 3.647 (s, 3H, OCH3), 3.801 (s, 6H, 2OCH3), 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).
Take 6- benzyloxies -2- (4- benzyloxy-phenyls) benzofuran -3- formaldehyde and 1.5 molar equivalents of 1 molar equivalent 3,4,5- trimethoxy-anilines obtain (E) -3,4,5- trimethoxy-N- ((6- benzyloxy -2- (4- for 12 hours in reflux in toluene Benzyloxy-phenyl) benzofuran -3- bases) methylene) aniline.
Embodiment 32
(E) -4- methoxyl groups-N- ((6- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- bases) methylene) aniline VII8's Synthesis (Fig. 1)：With reference to embodiment 25, by 6- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- formaldehyde (0.21mmol) and 4- first Epoxide aniline (0.21mmol) is dissolved in toluene (10mL), and flow back 12hrs.After reaction terminates, it is concentrated under reduced pressure, through silica gel chromatographic column Purifying (petroleum ether: ethyl acetate=3: 1) obtain (E) -4- methoxyl groups-N- ((6- hydroxyls -2- (4- hydroxy phenyls) benzofuran - 3- yls) methylene) aniline, yellow solid, yield 70%.
1H NMR(DMSO；300MHz), δ 3.76 (s, 3H, OCH3), 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- hydroxyls -4- methoxyl groups-N- ((6- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- bases) methylene) benzene Amine VII9Synthesis (Fig. 1)：With reference to embodiment 25, by 6- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- formaldehyde (0.21mmol) and 3- hydroxyl -4- aminoanisoles (0.21mmol) are dissolved in toluene (10mL), and flow back 12hrs.Reaction terminates Afterwards, it is concentrated under reduced pressure, through silica gel chromatographic column purifying, (petroleum ether: ethyl acetate=3: 1) obtains (E) -3- hydroxyl -4- methoxyl groups-N- ((6- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- bases) methylene) aniline, yellow solid, yield 50%.
1H NMR(DMSO；300MHz), δ 3.783 (s, 3H, OCH3), 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- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- bases) methylene) aniline VII10Synthesis (Fig. 1)：With reference to embodiment 25, by 6- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- formaldehyde (0.21mmol) and 4- fluoroanilines (0.21mmol) is dissolved in toluene (10mL), and flow back 12hrs.After reaction terminates, it is concentrated under reduced pressure, (stone is purified through silica gel chromatographic column Oily ether: ethyl acetate=3: 1) obtains the fluoro- N- of (E) -4- ((6- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- bases) methylenes Base) aniline, yellow solid, yield 55%.
1H NMR(DMSO；300MHz), δ 6.848-6.868 (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-hydroxyls-N- ((6- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- bases) methylene) aniline VII11Synthesis (Fig. 1)：With reference to embodiment 25, by 6- hydroxyls -2- (4- hydroxy phenyls) benzofuran -3- formaldehyde (0.21mmol) It is dissolved in toluene (10mL) with 3- chloro-4-hydroxyls aniline (0.21mmol), flow back 12hrs.After reaction terminates, it is concentrated under reduced pressure, warp (petroleum ether: ethyl acetate=3: 1) obtains (E) -3- chloro-4-hydroxyls-N- ((6- hydroxyls -2- (4- hydroxyls for silica gel chromatographic column purifying Phenyl) benzofuran -3- bases) methylene) aniline, yellow solid, yield 68%.
1H NMR(DMSO；300MHz), δ 6.805-6.839 (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
To investigate the antibacterial activity of the noval chemical compound involved by this method, micro- life is carried out by preliminary antibacterial pharmacological testing Thing GIA is evaluated.
Using the U.S. clinical laboratory standard committee (NCCLs) to each concrete regulation M7-A6 for belonging to bacteria drug sensitivity test, Specific test procedure：
(1) Bacteria Culture
Pseudomonas aeruginosa, Escherichia coli, gold-coloured staphylococci, bacillus subtilis, gold-coloured staphylococci (resistance), Cultivated using nutrient broth medium；
Take pseudomonas putida, Escherichia coli, gold-coloured staphylococci, bacillus subtilis, the golden Portugal preserved in refrigerator Grape coccus (resistance) is inoculated in the test tube slant of nutrient broth medium, is incubated in 37 DEG C of bacteriological incubator, in good time passage, In case needed for experiment.
(2) medicine ordinance
All compounds are configured to the DMSO solution that concentration is 4mg/mL.The μ of liquid 10 is added in the 2nd row of 96 orifice plates are empty L, each compound is repeated 1 times, and 96 orifice plates are placed in -20 DEG C of preservations.
(3) antibacterial tests
Take the logarithm the required microorganism in growth period, using Maxwell opacity tube 0.5 than turbid, adjustment microorganism concn is 1* 108Cfu/mL, 10 are diluted with culture medium4Obtain 1*104The bacterium solution of cfu/mL.Culture medium of the 96 orifice plate first rows addition without bacterium solution, 3-12 row hole adds the bacterium solution of 100 μ L, and 200 μ L bacterium solutions are added in being arranged the 2nd, and drawing 100 μ L after blowing and beating 6-8 times adds the 3rd Row, 2 times are diluted to the 11st row successively.And 96 well culture plates after by administration are trained in being respectively placed in 37 DEG C of microbiological incubator Support 24hrs.
Each hole A530 values are detected using ELIASA, inhibiting rate is calculated, inhibition concentration MIC value is calculated using SPSS softwares.
Table 1.3- ketoxime -6- substitution-benzofuran compounds antibiotic bioactive is tested
Table 1 is illustrated：
(1) positive control medicine of antibacterial activity in vitro experiment is tetracycline and Benzylpenicillin sodium salt.
(2) explanation of microbial inhibition assays result, compound (compound VI involved by this method1, VI4, VI5With VII1-VII11) bacteriostatic activity substantially all between 12.5-50ug/mL, and with certain selectivity, to Gram-positive Bacterium has preferable fungistatic effect.As can be seen from the table, 6 exposed hydroxyls of benzofuran ring press down to such compound Bacterium activity has very important influence, and after working as hydroxyl by benzyl or hydrophobic chain shielding, the compound for obtaining is not antibacterial Activity.The bit substituent of benzofuran ring 3 equally has important decisive action for the antibacterial activity of such compound, when 3 When substitution base lipophilicity increases, the compound for obtaining is without antibacterial activity.Meanwhile, when on 2 of benzofuran ring or 3 Substituted aroma ring on polarized substitution base when, the antibacterial activity of resulting compound has some improvement.
Specific embodiment of the invention is described above.It is to be appreciated that the invention is not limited in above-mentioned Particular implementation, those skilled in the art can within the scope of the claims make various deformations or amendments, this not shadow Sound substance of the invention.

Claims (4)

1. a kind of benzofuran compounds, it is characterised in that shown in its structural formula such as formula (I)：
Wherein, R1It is hydrogen, R2It is 3,4,5- trimethoxies, 4- methoxyl groups, 4- hydroxyls, 3- hydroxyl -4- methoxyl groups, 4- fluorine or 3- are chloro- 4- hydroxyls, R3It is hydrogen, R4It is hydrogen；
Or, R1It is 4- hydroxyls, R2It is 3,4,5- trimethoxies, 4- methoxyl groups, 3- hydroxyl -4- methoxyl groups, 4- fluorine or the chloro- 4- hydroxyls of 3- Base, R3It is hydrogen, R4It is hydrogen.
2. a kind of benzofuran compounds as claimed in claim 1 are in the biologically active drug for suppressing microorganism is prepared Purposes.
3. purposes as claimed in claim 2, it is characterised in that the microorganism is gram-positive bacteria.
4. purposes as claimed in claim 3, it is characterised in that the gram-positive bacteria is gold-coloured staphylococci or withered grass bud Spore bacillus.
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CN108676029B (en) * 2018-05-22 2020-08-04 河南大学 Benzyl triphenyl phosphonium bis (trifluoromethane) sulfonyl imide ionic liquid, synthetic method and application thereof as metal corrosion inhibitor
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
CN110590722B (en) * 2019-10-22 2022-11-04 温州大学 Synthesis method of 2-trifluoromethyl benzofuran derivative
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