CN105330630A - Benzofuran compound, preparation method and applications thereof - Google Patents
Benzofuran compound, preparation method and applications thereof Download PDFInfo
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- 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
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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Abstract
The present invention provides a benzofuran compound, a preparation method and applications thereof, wherein the structure is represented by a general formula (I-1) or (I-2), R1, R3 and R4 are any one selected from hydrogen, C1-C5 straight or branched chain alkyl, hydroxyl, an aldehyde group, an acetyl group, a carboxyl group, a cyano group, an amino group, a nitro group, fluorine, chlorine, bromine, an amide group, an ester group, an alkoxy group, an aromatic group, and a heteroaromatic group, R2 is any one selected from hydrogen, C1-C5 straight or branched chain alkyl group, a hydroxyl group, an aromatic group, and a heteroaromatic group, and m and n are integers of 0-5. According to the present invention, the Staphylococcus aureus protease Sortase A substrate polypeptide fragment -LPXTG- is adopted as the structural simulation object, the benzofuran structure is adopted as the simulation substrate proline, and the linked amide hydrophobic fragment segment is used to stimulate the substrate leucine residue to design the novel protease Sortase A inhibitor.
Description
Technical field
The present invention relates to a kind of benzofuran compounds and preparation method thereof, be specially a kind of 2,3-disubstituted benzofuran compounds and its preparation method and application.Belong to pharmaceutical chemistry technical field.
Background technology
In recent years, the phenomenon that China's microbiotic is seriously abused is on the rise.The tempo of the microbiotic multi-drug resistant bacteria caused thus is also more and more faster.Particularly Methicillin-resistant Staphylococcus aureus (methicilin-resistntstaphylococcusaureus, MRSA), since being found to global spread only ten years, has just become the Main Pathogenic Bacteria causing nosocomialtion.Resistance is existed to current most of microbiotic, even comprises and be considered to treat the best vancomycin of S. aureus L-forms effect.In order to tackle continuous variation and the evolution of bacterium, people have to actively find new antibacterial target and corresponding inhibitor, develop efficient, safe, stable novel antibacterial medicine, solve a bacterial drug resistance difficult problem, thus, bacterium evolve and new drug development competition in win the victory.
Tradition antibacterials are mostly to kill bacterium for target, and this is also the principal element causing bacterium to produce resistance.And bacteriological infection to produce a pathogenic prerequisite be the adhesion with host cell.Therefore, sorting enzyme (Sortase) just becomes the novel targets that scholars studies antibacterials very soon.SortaseA is present in nearly all gram-positive microorganism and part Gram-negative bacteria, and it has the function of proteolytic enzyme and transpeptidase concurrently, anchors to cell walls play a key effect at mediating bacterial surface protein and pili.After the SortaseA gene of bacterium is pounded out, to express and the surface protein anchoring to cell walls significantly reduces, it is pathogenic also significantly reduces, and does not even have infectivity.Therefore, with SortaseA enzyme for target Effect of Anti infection medicine will be a very promising direction.
Summary of the invention
The present invention is directed to the preparation method and application of the benzofuran compounds that the deficiencies in the prior art provide a class novel.Of the present invention 2,3-disubstituted benzofuran compounds, be design according to substrate pentapeptide fragment (LPXTG) constructional feature of proteolytic enzyme SortaseA, the fatty hydrophobic chain and Threonine (T) polar head that connect substrate fragment tail end leucine (L) using cumarone ring structure as simulation are aromatic ring center; Tested by preliminary protease inhibition SortaseA and confirm that the novel cpd prepared by the present invention has good SortaseA protease inhibiting activity, may be used for the medicine preparing treatment and prevention infection of staphylococcus aureus.
The present invention is achieved by the following technical solutions:
First aspect, the invention provides a kind of benzofuran compounds, and its structure is as general formula (I-1) or general formula (I-2)
Wherein, R
1, R
3, R
4for any one in hydrogen, C1-C5 straight or branched alkyl, hydroxyl, aldehyde radical, ethanoyl, carboxyl, cyano group, amino, nitro, fluorine, chlorine, bromine, amide group, ester group, alkoxyl group, aromatic base, assorted aromatic base;
R
2for hydrogen, C1-C5 straight or branched alkyl, hydroxyl, aromatic base, assorted aromatic base any one;
M, n are the integer of 0-5.
Preferably, described can equal, can not wait, also can be 0 simultaneously.
Preferably, described in
R
1for any one in hydrogen, methyl, hydroxyl, aldehyde radical, ethanoyl, cyano group, amino, nitro, fluorine, chlorine, bromine, amide group, ester group etc.;
R
2for hydrogen, C1-C5 straight or branched alkyl, hydroxyl;
R
3for any one in hydrogen, methyl, hydroxyl, aldehyde radical, ethanoyl, cyano group, amino, nitro, fluorine, chlorine, bromine, amide group, ester group etc.;
R
4for any one in hydrogen, methyl, hydroxyl, aldehyde radical, ethanoyl, cyano group, amino, nitro, fluorine, chlorine, bromine, amide group, ester group etc.
Preferably, described general formula (I-1) comprises following compound:
Described general formula (I-2) comprises following compound:
Second aspect, the invention provides a kind of preparation method showing compound as described in general formula (I-1), the method comprises the steps:
By the compound shown in formula II
with substituted benzoyl acid-like substance and salt of wormwood, at room temperature react, obtain showing compound described in formula (I-1).
Preferably, described benzoic acid analog is selected from any one in following compound:
The third aspect, the invention provides a kind of preparation method showing compound as described in general formula (I-2), the method comprises the steps:
Compound just shown in formula II
with fortified phenol analogue and salt of wormwood, react at 50 ~ 60 DEG C, obtain showing compound described in formula (I-2).
Preferably, described fortified phenol analogue is selected from any one in following compound:
Fourth aspect, present invention also offers a kind of preparation method such as formula compound (II) Suo Shi, comprises the steps:
Replacement is refluxed to methyl benzyl chlorine and triphenyl phosphorus at 85 ~ 90 DEG C, obtains the compound shown in formula (XII)
Compound shown in formula (XII) and replacement Benzaldehyde,2-hydroxy are refluxed at 85 ~ 90 DEG C, obtains the compound shown in formula (XI)
Compound shown in formula (XI) and iodine are at room temperature reacted, obtains the compound shown in formula (X)
By the compound shown in formula (X) and phosphorus oxychloride and N.N-dimethyl formamide, at 85 ~ 90 DEG C, carry out back flow reaction, obtain the compound shown in formula (IX)
Compound shown in formula (IX) and Textone are at room temperature reacted, obtains the compound shown in formula VIII
Compound formula (VIII) Suo Shi and methyl alcohol are carried out esterification, obtains the compound shown in formula (VII)
Compound shown in formula (VII) and N-bromo-succinimide are carried out back flow reaction at 80 ~ 85 DEG C, obtains the compound shown in formula (VI)
Compound shown in formula (VI) and sodium-acetate are reacted, obtains the compound shown in formula (V)
Compound shown in formula (V) is carried out alcoholysis in the basic conditions, obtains the compound shown in formula (IV)
Compound shown in formula (IV) and isobutylamine are reacted, obtains the compound shown in formula III
Compound shown in formula (III) and methylsulfonyl chloride are at room temperature reacted, obtains the compound shown in formula II
5th aspect, present invention also offers the purposes of a kind of benzofuran compounds as the aforementioned in anti-microbial infection.
Aforesaid purposes, carrys out infection control by suppressing streptococcus aureus sorting enzyme A.
This seminar by research SortaseA structure and with substrate LPXTG catalyst mechanism, the constructional feature of simulation substrate LPXTG, is devised a series of benzofuran compounds, and is tested by protein-active, set up structure activity relationship, further design goes out more efficiently enzyme inhibitors.
Compared with prior art, the present invention has following beneficial effect:
1, the present invention with the substrate polypeptide fragment-LPXTG-of SAP SortaseA for structural simulation object, using cumarone structure as simulation substrate proline, the amide group that it connects hydrophobic fragment simulation substrate leucine residue, designs novel proteolytic enzyme SortaseA inhibitor;
2 and centered by cumarone, set up and optimize the preparation method of compound, and the experiment of SAP SortaseA screening active ingredients is carried out to the novel benzofuran compounds of preparation, further confirmation benzofurans new compound, for the Inhibitory Mechanism of SortaseA, is expected for medicament for resisting gram-positive bacteria molecule provides new candidate compound.
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 of triphenyl-(4-methyl-benzyl) phosphonium chloride
By 4-methyl chloride benzyl (50g, 356mmol) with triphenylphosphine (93.3g, 356mmol) be dissolved in the acetonitrile of 200mL, reflux 6 hours, adularescent solid generates, be cooled to room temperature, filter, residue 30mL ether washes 3 times, collects residue, white powder triphenyl-(4-methyl-benzyl) phosphonium chloride (102g, yield:70%) is obtained after vacuum-drying.1HNMR(400MHz，DMSO-d
6)，8.00(d，J＝7.04Hz，1H)，7.89-7.97(m，J＝8.22Hz，2H)，7.65(d，J＝7.83Hz，1H)，7.41-7.49(m，J＝8.22Hz，2H)，7.36(quin，J＝6.85Hz，2H)，4.56(s，2H)。
embodiment 2
The synthesis of E-2-(4-vinyl toluene base) phenol
By triphenyl-(4-methyl-benzyl) phosphonium chloride (100g, 248.2mmol) be dissolved in 350mL acetonitrile with Benzaldehyde,2-hydroxy, stirring at room temperature also slowly drips DBU (91.3mL, 595.7mmol), after dropwising, heated and stirred backflow 12h reaction is complete, be cooled to room temperature, concentration of reaction solution, dilute hydrochloric acid is neutralized to neutrality, add 200mL water and be extracted with ethyl acetate 3 times, merge organic phase, the water washing of 200mL saturated common salt, anhydrous sodium sulfate drying, concentration of organic layers, through white solid powder E-2-(the 4-vinyl toluene base) phenol (31.8g of silica gel chromatography column separating purification, yield=61%).
1HNMR(400MHz，DMSO-d
6)9.67(s，1H)，7.52(d，J＝7.43Hz，1H)，7.40(d，J＝7.83Hz，2H)，7.32(d，J＝16.82Hz，1H)，7.09-7.17(m，3H)，7.01-7.08(m，1H)，6.83(d，J＝7.83Hz，1H)，6.77(t，J＝7.43Hz，1H)，2.27(s，3H)。
embodiment 3
The synthesis of 2-(4-aminomethyl phenyl) cumarone
By E-2-(4-vinyl toluene base) phenol and anhydrous K
2cO
3(21.2g, 154.2mmol) be dissolved in the tetrahydrofuran (THF) of 150mL, stirring at room temperature is disposable after 1 hour adds iodine powder (39.4g, 154.2mmol), thin layer plate detection reaction, 1h reacts completely, in reaction solution, drip thiosulfuric acid saturated aqueous solution of sodium remove unreacted iodine, be extracted with ethyl acetate 3 times, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, concentration of organic layers, obtains white powder compound 2-(4-aminomethyl phenyl) cumarone (5.03g, yield=94%) through silica gel chromatography column separating purification.1HNMR(400MHz，DMSO-d6)7.78(d，J＝8.22Hz，2H)，7.57(d，J＝8.61Hz，1H)，7.60(d，J＝7.43Hz，1H)，7.32(s，1H)，7.28(d，J＝8.22Hz，2H)，7.24(dd，J＝1.17，6.26Hz，1H)，7.19-7.22(m，1H)，2.32(s，3H)。
embodiment 4
The synthesis of 2-(4-aminomethyl phenyl) cumarone-3-aldehyde
Under condition of ice bath, in 1, the 2-dichloroethane solution of DMF (11.8mL, 153.6mmol), slowly drip P DEG C of Cl
3(23.5g, 153.6mmol), stirring at room temperature is after 1 hour, add 2-(4-aminomethyl phenyl) cumarone (4g, 19.2mmol), react 18 hours, the monitoring of TLC plate reacts completely, stopped reaction, be cooled to room temperature, reaction solution is slowly poured in frozen water and stirs 2h, dichloromethane extraction 3 times, merge organic interdependent secondary water, saturated sodium bicarbonate and saturated common salt water washing, anhydrous sodium sulfate drying, concentration of organic layers, obtains 2-(4-aminomethyl phenyl) cumarone-3-aldehyde (3.5g, yield=78%) through silica gel chromatography column separating purification.
1HNMR(400MHz，DMSO-d
6)10.23(s，1H)，8.10-8.14(m，1H)，7.87(d，J＝8.22Hz，2H)，7.71(d，J＝7.43Hz，1H)，7.36-7.46(m，4H)，2.39(s，3H)。
embodiment 5
The synthesis of 2-(4-aminomethyl phenyl) cumarone-3-formic acid
Under condition of ice bath, to 2-(4-aminomethyl phenyl) cumarone-3-aldehyde (3.5g, Textone (3.3g) is slowly added successively and thionamic acid (2.86g) constantly stirs in acetone soln 14.8mmol), room temperature reaction 4h, react completely, a large amount of yellow solid generates, and filters, namely vacuum-drying obtain 2-(4-aminomethyl phenyl) cumarone-3-formic acid (3.0g, yield=86%).
1HNMR(400MHz，DMSO-d
6)，7.95-8.02(m，1H)，7.88(d，J＝8.22Hz，2H)，7.64(d，J＝7.04Hz，1H)，7.28-7.41(m，4H)，2.36(s，3H)。
embodiment 6
The synthesis of 2-(4-aminomethyl phenyl) cumarone-3-methyl-formiate
2-(4-aminomethyl phenyl) cumarone-3-formic acid (3.0g) is dissolved completely in 50mL methanol solution, the slow dropping 5mL vitriol oil, reflux 12h, react completely, reduced vacuum is revolved and is steamed except desolventizing, and raffinate is dissolved in ethyl acetate, use water, saturated sodium bicarbonate and saturated common salt water washing successively, anhydrous sodium sulfate drying, concentrates to obtain crude product 2-(4-aminomethyl phenyl) cumarone-3-methyl-formiate (2.85g, yield=90%).
1HNMR(400MHz，DMSO-d
6)7.94-7.98(m，1H)，7.85(d，J＝8.22Hz，2H)，7.63-7.68(m，1H)，7.34-7.42(m，2H)，7.32(d，J＝7.83Hz，2H)，3.83(s，3H)，2.36(s，3H)。
embodiment 7
The synthesis of 2-(4-2-bromomethylphenyl) cumarone-3-methyl-formiate
By 2-(4-aminomethyl phenyl) cumarone-3-methyl-formiate (7g, 26.3mmol) be dissolved in the carbon tetrachloride solvent of 100mL, and add N-bromo-succinimide (5.14g successively, 28.9mmol) with azo isobutyl cyanogen (AIBN, 200mg), termination reaction after reflux 12h, be cooled to room temperature, filter, filtrate is extracted with ethyl acetate 3 times, organic phase is successively through water and saturated common salt water washing, anhydrous sodium sulfate drying, concentrated organic phase, 2-(4-2-bromomethylphenyl) cumarone-3-methyl-formiate (6.8g is obtained through chromatographic column separation and purification, yield=75%).
1HNMR(400MHz，DMSO-d
6)8.00(d，J＝5.48Hz，1H)，7.95(d，J＝8.61Hz，2H)，7.69(d，J＝7.43Hz，1H)，7.59(d，J＝8.22Hz，2H)，7.36-7.44(m，2H)，4.77(s，2H)，3.85(s，3H)。
embodiment 8
The synthesis of 2-(4-acetyl-o-methyl phenyl) cumarone-3-methyl-formiate
Get 2-(4-2-bromomethylphenyl) cumarone-3-methyl-formiate (1.5g, 4.3mmol) be dissolved in the N of 10mL, in dinethylformamide solvent, and add sodium acetate (1.78g, 21.5mmol), be heated to 120 DEG C of reaction 3h raw materials disappear, stopped reaction, put to room temperature, add frozen water 20mL, extraction into ethyl acetate 3 times, merge organic phase and use water successively, saturated common salt water washing, anhydrous sodium sulfate drying process, vacuum is revolved and is steamed except desolventizing, obtain pure 2-(4-acetyl-o-methyl phenyl) cumarone-3-methyl-formiate (1.2g, yield=86%).
1HNMR(400MHz，DMSO-d
6)7.93-7.98(m，3H)，7.66-7.70(m，1H)，7.50(d，J＝8.22Hz，2H)，7.37-7.42(m，2H)，5.14(s，2H)，3.84(s，3H)，2.08(s，3H)。
embodiment 9
The synthesis of 2-(4-hydroxymethyl phenyl) cumarone-3-formic acid
By 2-(4-acetyl-o-methyl phenyl) cumarone-3-methyl-formiate (2g, 6.17mmol) be dissolved in 10mL tetrahydrofuran solvent, add 3M aqueous sodium hydroxide solution 10mL, reflux 3 hours, react complete, put to room temperature, add 20mL frozen water, dilute hydrochloric acid is neutralized to pH and is about 4.0, solid is had to separate out, filtration under diminished pressure, obtains crude product 2-(4-hydroxymethyl phenyl) cumarone-3-formic acid (1.65g, yield=100%) after filtration cakes torrefaction.
1HNMR(400MHz，DMSO-d
6)8.00(d，J＝7.04Hz，1H)，7.91-7.97(m，J＝8.22Hz，2H)，7.65(d，J＝7.43Hz，1H)，7.41-7.47(m，J＝8.22Hz，2H)，7.31-7.41(m，2H)，4.56(s，2H)。
embodiment 10
The synthesis of 2-(4-hydroxymethyl phenyl) cumarone-3-formyl isobutylamine
By 2-(4-hydroxymethyl phenyl) cumarone-3-formic acid (1.0g, 3.7mmol) join in 20mL methylene dichloride, and slowly drip isobutylamine (0.54g successively to this turbid solution, 7.4mmol), HATU (2.1g, 5.6mmol) with triethylamine (754mg, 14.8mmol), stirring at room temperature reacts 2 hours, raw material disappears, add 10mL frozen water and dilute hydrochloric acid (1M) to pH about 5.0, dichloromethane extraction 3 times, merge organic phase and use saturated sodium bicarbonate water solvent and saturated common salt water washing successively, concentrated organic phase, 2-(4-hydroxymethyl phenyl) cumarone-3-formyl isobutylamine (1.2g is obtained through chromatographic column separation and purification, yield=90%).
1HNMR(400MHz，DMSO-d
6)8.56(t，J＝5.67Hz，1H)，7.79-7.88(m，J＝8.22Hz，2H)，7.64(d，J＝8.22Hz，1H)，7.57(d，J＝7.43Hz，1H)，7.39-7.45(m，J＝8.22Hz，2H)，7.27-7.39(m，2H)，5.30(br.s.，1H)，4.53(br.s.，2H)，3.11(t，J＝6.26Hz，2H)，1.83(tt，J＝6.65，13.30Hz，1H)，0.89(d，J＝6.65Hz，6H)。
embodiment 11
The synthesis of 4-(3-isobutylamine formyl benzofuran-2-base) benzyl methanesulfonates
By 2-(4-hydroxymethyl phenyl) cumarone-3-formyl isobutylamine (1g, 3.1mmol) be dissolved in methylene dichloride (20mL), triethylamine (1.3mL is slowly dripped successively under condition of ice bath, 9.3mmol), methylsulfonyl chloride (0.36mL, 4.6mmol), after dropwising, recover room temperature and continue stirring reaction 1h, thin layer plate detection reaction is complete, frozen water and 1M dilute hydrochloric acid is added to pH=5 to reaction solution, separatory collects organic phase, use saturated aqueous sodium carbonate and saturated common salt water washing more successively, vacuum revolves steaming, concentrated organic phase, 4-(3-isobutylamine formyl benzofuran-2-base) benzyl methanesulfonates (525mg is obtained through silica gel chromatography column separating purification, yield=40%).
1HNMR(400MHz，CDCl
3)8.01(d，J＝8.61Hz，2H)，7.78(d，J＝7.43Hz，1H)，7.49-7.55(m，3H)，7.29-7.39(m，2H)，5.27(s，2H)，3.31(t，J＝6.46Hz，2H)，2.97(s，3H)，1.87(td，J＝6.80，13.40Hz，1H)，0.95(d，J＝6.65Hz，6H)。
embodiment 12
4-(3-isobutylamine formyl benzofuran-2-base) benzyl benzoate (I-12)
By 4-(3-isobutylamine formyl benzofuran-2-base) benzyl methanesulfonates (200mg; 0.496mmol), Anhydrous potassium carbonate (342.4mg; 2.48mmol), phenylformic acid (302.6mg; 2.48mmol) be dissolved in the N of 10mL; in dinethylformamide; room temperature reaction is after 3 hours; stopped reaction; reaction solution is slowly poured in 20ml frozen water; stir; filtration obtains solid crude product, then obtains sterling Compound I-12 (150mg, yield=71%) through silica gel chromatography column separating purification.
1H-NMR(400MHz，CDCl
3)δ8.07(m，2H)，7.94(d，J＝8.3Hz，2H)，7.81(m，1H)7.54(m，4H)，7.44(dd，J＝7.7Hz，J＝7.7Hz，2H)，7.32(m，2H)，5.94(br.s.，1H)，5.41(s，2H)，3.28(t，J＝6.46Hz，2H)，1.82(tt，J＝6.70，13.45Hz，1H)，0.91(d，J＝6.65Hz，6H)。
embodiment 13
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-2 hydroxybenzoic acid ester (I-13)
With reference to embodiment 12, yield 55%.
1HNMR(400MHz，CDCl
3)10.70(s，1H)，7.97(d，J＝8.22Hz，2H)，7.88(dd，J＝1.57，8.22Hz，1H)，7.77-7.82(m，1H)，7.49-7.56(m，3H)，7.43-7.49(m，1H)，7.27-7.37(m，2H)，6.98(d，J＝8.61Hz，1H)，6.88(t，J＝7.63Hz，1H)，5.96(br.s.，1H)，5.41(s，2H)，3.28(t，J＝6.46Hz，2H)，1.84(tt，J＝6.70，13.45Hz，1H)，0.92(d，J＝6.65Hz，6H)。
embodiment 14
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-3-hydroxybenzoate (I-14)
With reference to embodiment 12, yield 64%.
1HNMR(400MHz，DMSO-d
6)9.81(s，1H)，8.60(t，J＝5.67Hz，1H)，7.89(d，J＝8.22Hz，2H)，7.65(d，J＝7.83Hz，1H)，7.54-7.59(m，3H)，7.24-7.45(m，5H)，7.01(d，J＝8.61Hz，1H)，5.32(s，2H)，3.11(t，J＝6.26Hz，2H)，1.83(tt，J＝6.70，13.60Hz，1H)，0.88(d，J＝6.65Hz，6H)。
embodiment 15
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-4-HBA ester (I-11)
With reference to embodiment 12, yield 52%.
1HNMR(400MHz，DMSO-d
6)10.34(s，1H)，8.57(t，J＝5.67Hz，1H)，7.89(d，J＝8.22Hz，2H)，7.84(d，J＝9.00Hz，2H)，7.65(d，J＝7.83Hz，1H)，7.54-7.59(m，3H)，7.35-7.38(m，1H)，7.31-7.34(m，1H)，6.84(d，J＝8.61Hz，2H)，5.32(s，2H)，3.11(t，J＝6.26Hz，2H)，1.82(tt，J＝6.70，13.60Hz，1H)，0.88(d，J＝6.65Hz，6H)。
embodiment 16
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-3,5-resorcylic acid ester (I-15)
With reference to embodiment 12, yield 45%.
1HNMR(400MHz，DMSO-d
6)9.61(s，2H)，8.57(t，J＝5.87Hz，1H)，7.90(d，J＝8.22Hz，2H)，7.65(d，J＝8.22Hz，1H)，7.53-7.60(m，3H)，7.35-7.40(m，1H)，7.29-7.35(m，1H)，6.85(d，J＝1.96Hz，2H)，6.43(t，J＝2.15Hz，1H)，5.32(s，2H)，3.12(t，J＝6.26Hz，2H)，1.83(tt，J＝6.65，13.30Hz，1H)，0.89(d，J＝6.65Hz，6H)。
embodiment 17
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-3,5-dimethoxybenzoic acid ester (I-16)
With reference to embodiment 12, yield 54%.
1HNMR(400MHz，DMSO-d
6)8.56(t，J＝5.87Hz，1H)，7.90(d，J＝8.61Hz，2H)，7.65(d，J＝8.22Hz，1H)，7.55-7.60(m，3H)，7.35-7.40(m，1H)，7.29-7.34(m，1H)，7.09(d，J＝2.35Hz，2H)，6.77(t，J＝2.35Hz，1H)，5.38(s，2H)，3.77(s，6H)，3.11(t，J＝6.26Hz，2H)，1.83(tt，J＝6.69，13.55Hz，1H)，0.88(d，J＝6.65Hz，6H)。
embodiment 18
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-PCA ester (I-17)
With reference to embodiment 12, yield 34%.
1HNMR(400MHz，DMSO-d
6)9.81(s，1H)，9.38(s，1H)，8.59(t，J＝5.67Hz，1H)，7.87-7.93(m，2H)，7.65(d，J＝7.83Hz，1H)，7.52-7.60(m，3H)，7.29-7.40(m，4H)，6.80(d，J＝8.22Hz，1H)，5.30(s，2H)，3.12(t，J＝6.26Hz，2H)，1.83(tt，J＝6.80，13.35Hz，1H)，0.89(d，J＝6.65Hz，6H)。
embodiment 19
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-3,4,5-TMB (I-18)
With reference to embodiment 12, yield 28%.
1HNMR(400MHz，DMSO-d
6)8.57(t，J＝5.67Hz，1H)，7.90(d，J＝8.22Hz，2H)，7.65(d，J＝7.83Hz，1H)，7.54-7.61(m，3H)，7.35-7.40(m，1H)，7.29-7.34(m，1H)，7.27(s，2H)，5.39(s，2H)，3.81(s，6H)，3.71(s，3H)，3.11(t，J＝6.26Hz，2H)，1.82(tt，J＝6.65，13.30Hz，1H)，0.88(d，J＝6.65Hz，6H)。
embodiment 20
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-3-hydroxybenzoate (I-19)
With reference to embodiment 12, yield 65%.
1HNMR(400MHz，DMSO-d
6)8.57(br.s.，1H)，7.89(d，J＝7.83Hz，2H)，7.77-7.83(m，J＝9.00Hz，2H)，7.65(d，J＝7.83Hz，1H)，7.52-7.61(m，3H)，7.37(t，J＝7.43Hz，1H)，7.32(t，J＝7.24Hz，1H)，6.67-6.74(m，J＝8.61Hz，2H)，5.30(s，2H)，3.12(t，J＝6.06Hz，2H)，2.97(s，6H)，1.83(td，J＝6.36，13.11Hz，1H)，0.89(d，J＝6.65Hz，6H)。
embodiment 21
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-2,4-resorcylic acid ester (I-110)
With reference to embodiment 12, yield 27%.
1HNMR(400MHz，DMSO-d
6)10.64(s，1H)，10.48(s，1H)，8.58(t，J＝5.67Hz，1H)，7.90(d，J＝8.22Hz，2H)，7.65(d，J＝8.22Hz，1H)，7.68(d，J＝9.00Hz，1H)，7.54-7.60(m，3H)，7.37(t，J＝7.43Hz，1H)，7.32(t，J＝7.24Hz，1H)，6.36(dd，J＝1.76，8.80Hz，1H)，6.29(d，J＝1.96Hz，1H)，5.37(s，2H)，3.11(t，J＝6.26Hz，2H)，1.83(tt，J＝6.95，13.40Hz，1H)，0.88(d，J＝6.65Hz，6H)。
embodiment 22
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-2-nitrobenzoyl acid esters (I-111)
With reference to embodiment 12, yield 68%.
1HNMR(400MHz，DMSO-d
6)8.61(t，J＝5.87Hz，1H)，8.03-8.08(m，1H)，7.88-7.93(m，3H)，7.80-7.85(m，2H)，7.66(d，J＝8.22Hz，1H)，7.52-7.60(m，3H)，7.35-7.40(m，1H)，7.32(t，J＝7.43Hz，1H)，5.38(s，2H)，3.12(t，J＝6.26Hz，2H)，1.77-1.89(tt，1H)，0.89(d，J＝6.65Hz，6H)。
embodiment 23
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-4-fluorobenzoate (I-112)
With reference to embodiment 12, yield 55%.
1HNMR(400MHz，DMSO-d
6)8.59(t，J＝5.28Hz，1H)，8.06(dd，J＝5.87，8.22Hz，2H)，7.90(d，J＝7.83Hz，2H)，7.65(d，J＝7.83Hz，1H)，7.58(d，J＝8.22Hz，3H)，7.29-7.41(m，4H)，5.38(s，2H)，3.11(t，J＝6.26Hz，2H)，1.82(td，J＝6.65，13.30Hz，1H)，0.88(d，J＝6.65Hz，7H)。
embodiment 24
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-4-thiol group benzoic ether (I-113)
With reference to embodiment 12, yield 18%.
1HNMR(400MHz，DMSO-d
6)8.58(t，J＝5.67Hz，1H)，7.71-7.86(m，4H)，7.62(d，J＝7.83Hz，1H)，7.55(d，J＝7.43Hz，1H)，7.47(d，J＝8.22Hz，2H)，7.27-7.38(m，2H)，7.23(d，J＝7.83Hz，2H)，4.28(s，2H)，3.09(br.s.，2H)，1.81(td，J＝6.65，13.30Hz，1H)，0.87(dJ＝6.26Hz，6H)。
embodiment 25
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-3-hydroxyl-4-nitrobenzoyl acid esters (I-114)
With reference to embodiment 12, yield 38%.
1HNMR(400MHz，DMSO-d
6)8.60(t，J＝5.67Hz，1H)，7.87-7.97(m，3H)，7.68-7.72(m，1H)，7.66(d，J＝8.22Hz，1H)，7.55-7.62(m，3H)，7.48-7.53(m，1H)，7.38(t，J＝7.83Hz，1H)，7.32(t，J＝7.24Hz，1H)，5.39(s，2H)，3.12(t，J＝6.26Hz，2H)，1.83(tt，J＝6.65，13.30Hz，1H)，0.89(d，J＝6.65Hz，6H)。
embodiment 26
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-PABA ester (I-115)
With reference to embodiment 12, yield 45%.
1HNMR(400MHz，DMSO-d
6)8.61(t，J＝5.67Hz，1H)，7.85-7.92(m，J＝8.22Hz，2H)，7.63-7.72(m，3H)，7.59(d，J＝7.43Hz，1H)，7.51-7.57(m，J＝8.22Hz，2H)，7.38(t，J＝7.83Hz，1H)，7.33(t，J＝7.43Hz，1H)，6.56(d，J＝8.61Hz，2H)，6.02(s，2H)，5.28(s，2H)，3.12(t，J＝6.26Hz，2H)，1.83(tt，J＝6.50，13.25Hz，1H)，0.89(d，J＝6.65Hz，6H)。
embodiment 27
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-2-Hydroxyphenyl Acetic Acid ester (I-116)
With reference to embodiment 12, yield 42%.
1HNMR(400MHz，CDCl
3)7.87(d，J＝8.22Hz，2H)，7.77(d，J＝7.43Hz，1H)，7.49(d，J＝7.83Hz，1H)，7.40(d，J＝8.22Hz，2H)，7.26-7.36(m，2H)，7.15(t，J＝7.63Hz，1H)，7.10(d，J＝7.43Hz，1H)，6.81-6.94(m，2H)，6.01(br.s.，1H)，5.17(s，2H)，3.71(s，2H)，3.27(t，J＝6.26Hz，2H)，1.84(tt，J＝6.80，13.35Hz，1H)，0.92(d，J＝6.65Hz，6H)。
embodiment 28
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-3-hydroxyl phenylacetic acid ester (I-117)
With reference to embodiment 12, yield 39%.
1HNMR(400MHz，DMSO-d
6)9.40(br.s.，1H)，8.59(t，J＝5.67Hz，1H)，7.80-7.90(m，J＝8.22Hz，2H)，7.65(d，J＝8.22Hz，1H)，7.58(d，J＝7.83Hz，1H)，7.41-7.48(m，J＝7.83Hz，2H)，7.37(t，J＝7.63Hz，1H)，7.32(t，J＝7.24Hz，1H)，7.08(t，J＝7.83Hz，1H)，6.57-6.74(m，3H)，5.14(s，2H)，3.63(s，2H)，3.12(t，J＝6.26Hz，2H)，1.83(tt，J＝6.36，13.21Hz，1H)，0.89(d，J＝6.65Hz，6H)。
embodiment 29
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-4-hydroxyl phenylacetic acid ester (I-118)
With reference to embodiment 12, yield 33%.
1HNMR(400MHz，DMSO-d
6)9.28(s，1H)，8.55(t，J＝5.87Hz，1H)，7.81-7.89(m，J＝8.22Hz，2H)，7.65(d，J＝8.22Hz，1H)，7.55-7.61(m，1H)，7.40-7.46(m，J＝8.22Hz，2H)，7.35-7.40(m，1H)，7.28-7.34(m，1H)，7.02-7.08(m，J＝8.61Hz，2H)，6.65-6.72(m，J＝8.61Hz，2H)，5.13(s，2H)，3.59(s，2H)，3.12(t，J＝6.46Hz，2H)，1.83(tt，J＝6.70，13.45Hz，1H)，0.90(d，J＝6.65Hz，6H)。
embodiment 30
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-4-nitrophenyl-acetic acid ester (I-119)
With reference to embodiment 12, yield 42%.
1HNMR(400MHz，DMSO-d
6)8.56(t，J＝5.67Hz，1H)，8.13-8.22(m，2H)，7.83-7.89(m，J＝8.61Hz，2H)，7.65(d，J＝8.22Hz，1H)，7.57(d，J＝9.00Hz，3H)，7.42-7.48(m，J＝8.22Hz，2H)，7.38(dt，J＝1.56，7.63Hz，1H)，7.29-7.35(m，1H)，5.17(s，2H)，3.97(s，2H)，3.11(t，J＝6.26Hz，2H)，1.83(tt，J＝6.65，13.50Hz，1H)，0.89(d，J＝6.65Hz，6H)。
embodiment 31
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-3-trifluoromethyl phenylacetic acid ester (I-120)
With reference to embodiment 12, yield 61%.
1HNMR(400MHz，CDCl
3)7.86-7.96(m，J＝8.22Hz，2H)，7.78(d，J＝7.43Hz，1H)，7.43-7.57(m，5H)，7.36-7.41(m，J＝7.83Hz，2H)，7.26-7.36(m，2H)，5.99(br.s.，1H)，5.17(s，2H)，3.74(s，2H)，3.27(t，J＝6.26Hz，2H)，1.83(tt，J＝6.85，13.50Hz，1H)，0.92(d，J＝6.65Hz，6H)。
embodiment 32
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-4-trifluoromethyl phenylacetic acid ester (I-121)
With reference to embodiment 12, yield 56%.
1HNMR(400MHz，CDCl
3)7.92(d，J＝8.22Hz，2H)，7.79(d，J＝7.43Hz，1H)，7.58(d，J＝7.83Hz，2H)，7.51(d，J＝7.83Hz，1H)，7.26-7.45(m，6H)，5.96(br.s.，1H)，5.17(s，2H)，3.74(s，2H)，3.28(t，J＝6.26Hz，2H)，1.84(tt，J＝6.31，13.06Hz，1H)，0.92(d，J＝6.65Hz，6H)。
embodiment 33
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-DOPAC ester (I-122)
With reference to embodiment 12, yield 23%.
1HNMR(400MHz，DMSO-d
6)8.87(s，1H)，8.78(s，1H)，8.60(t，J＝5.67Hz，1H)，7.81-7.89(m，J＝8.22Hz，2H)，7.66(d，J＝8.22Hz，1H)，7.58(d，J＝7.43Hz，1H)，7.40-7.47(m，J＝8.22Hz，2H)，7.37(t，J＝7.43Hz，1H)，7.32(t，J＝7.43Hz，1H)，6.66(br.s.，1H)，6.64(d，J＝8.22Hz，1H)，6.50(d，J＝7.83Hz，1H)，5.12(s，2H)，3.52(s，2H)，3.12(t，J＝6.06Hz，2H)，1.83(tt，J＝6.65，13.30Hz，1H)，0.89(d，J＝6.65Hz，6H)。
embodiment 34
4-(3-isobutylamine formyl benzofuran-2-base) benzyl-4-hydroxy-cinnamic acid ester (I-123)
With reference to embodiment 12, yield 37%.
1HNMR(400MHz，DMSO-d
6)10.02(s，1H)，8.60(t，J＝5.87Hz，1H)，7.85-7.91(m，J＝8.22Hz，2H)，7.60-7.69(m，2H)，7.57(d，J＝8.61Hz，2H)，7.54(d，J＝2.35Hz，2H)，7.51(s，1H)，7.37(t，J＝7.24Hz，1H)，7.32(t，J＝7.43Hz，1H)，6.74-6.79(m，J＝8.61Hz，2H)，6.46(d，J＝15.65Hz，1H)，5.23(s，2H)，3.11(t，J＝6.26Hz，2H)，1.83(tt，J＝6.70，13.45Hz，1H)，0.89(d，J＝6.65Hz，6H)。
embodiment 35
4-(cumarone-3-formyl isobutylamine-2-base) benzyl-4-HBA ester (I-124)
With reference to embodiment 12, yield 49%.
1HNMR(400MHz，DMSO-d
6)10.37(br.s.，1H)，8.55(t，J＝5.67Hz，1H)，7.85(d，J＝9.00Hz，2H)，7.88(d，J＝8.22Hz，2H)，7.65(d，J＝7.83Hz，1H)，7.53-7.61(m，3H)，7.34-7.40(m，1H)，7.28-7.34(m，1H)，6.84(d，J＝9.00Hz，2H)，5.33(s，2H)，3.24-3.31(m，2H)，1.49(quin，J＝7.24Hz，2H)，1.31(qd，J＝7.32，14.82Hz，2H)，0.87(t，J＝7.24Hz，3H)。
embodiment 36
4-(cumarone-3-formyl isobutylamine-2-base) benzyl-PCA ester (I-125)
With reference to embodiment 12, yield 32%.
1HNMR(400MHz，DMSO-d
6)9.83(br.s.，1H)，9.39(br.s.，1H)，8.55(t，J＝5.28Hz，1H)，7.89(d，J＝7.83Hz，2H)，7.65(d，J＝8.22Hz，1H)，7.52-7.61(m，3H)，7.28-7.41(m，4H)，6.80(d，J＝8.22Hz，1H)，5.30(s，2H)，3.28(q，J＝6.39Hz，2H)，1.50(quin，J＝7.14Hz，2H)，1.31(qd，J＝7.21，14.77Hz，2H)，0.87(t，J＝7.24Hz，3H)。
embodiment 37
3-(4-(cumarone-3-formyl isobutylamine-2-base) benzyloxy) phenol (I-22)
Get 4-(3-isobutylamine formyl benzofuran-2-base) benzyl methanesulfonates (250mg, 0.62mmol), Resorcinol (68.2mg, 0.62mmol) with Anhydrous potassium carbonate (171.12mg, 1.24mmol) to join in 10mL acetonitrile reflux 12 hours, thin layer plate detection reaction is complete, be cooled to room temperature and add the stirring of 15mL water, solid is had to separate out, filtration obtains product crude product, pure product 3-(4-(cumarone-3-formyl isobutylamine-2-base) benzyloxy) phenol (210mg is obtained through recrystallizing methanol or silica gel column chromatogram separating purification, yield=57%).
1hNMR (400MHz, DMSO-d
6) 9.39 (s, 1H), 8.59 (br.s., 1H), 7.89 (d, J=7.43Hz, 2H), 7.65 (d, J=7.83Hz, 1H), 7.49-7.61 (m, 3H), 7.28-7.42 (m, 2H), 7.03 (t, J=7.83Hz, 1H), 6.30-6.48 (m, 3H), 5.08 (br.s., 2H), 3.12 (br.s., 2H), 1.83 (tt, J=6.65,13.11Hz, 1H), 0.89 (d, J=6.26Hz, 6H).
embodiment 38
4-(4-(cumarone-3-formyl isobutylamine-2-base) benzyloxy) toluene (I-23)
With reference to embodiment 37, yield 80%.
1HNMR(400MHz，DMSO-d
6)8.60(t，J＝5.87Hz，1H)，7.88(d，J＝8.22Hz，2H)，7.65(d，J＝8.22Hz，1H)，7.50-7.60(m，3H)，7.35-7.40(m，1H)，7.29-7.34(m，1H)，7.02-7.10(m，J＝8.61Hz，2H)，6.85-6.92(m，J＝8.61Hz，2H)，5.10(s，2H)，3.12(t，J＝6.26Hz，2H)，2.19(s，3H)，1.83(td，J＝6.65，13.30Hz，1H)，0.89(d，J＝6.65Hz，6H)。
embodiment 39
4-(4-(cumarone-3-formyl isobutylamine-2-base) benzyloxy) chlorobenzene (I-24)
With reference to embodiment 37, yield 76%.
1HNMR(400MHz，DMSO-d
6)8.59(t，J＝5.87Hz，1H)，7.86-7.92(m，J＝8.22Hz，2H)，7.65(d，J＝8.22Hz，1H)，7.58(d，J＝7.43Hz，1H)，7.55(d，J＝8.22Hz，2H)，7.35-7.40(m，1H)，7.28-7.35(m，3H)，7.00-7.05(m，J＝9.00Hz，2H)，5.14(s，2H)，3.11(t，J＝6.26Hz，2H)，1.82(tt，J＝6.70，13.45Hz，1H)，0.88(d，J＝6.26Hz，6H)。
embodiment 40
4-(4-(cumarone-3-formyl isobutylamine-2-base) benzyloxy) phenylcarbinol (I-25)
With reference to embodiment 37, yield 33%.
1HNMR(400MHz，DMSO-d
6)8.60(t，J＝5.87Hz，1H)，7.88(d，J＝8.22Hz，2H)，7.65(d，J＝7.83Hz，1H)，7.52-7.60(m，3H)，7.37(dt，J＝1.37，7.73Hz，1H)，7.32(dt，J＝1.17，7.43Hz，1H)，7.18-7.23(m，J＝8.61Hz，2H)，6.93-6.97(m，2H)，5.13(s，2H)，5.03(t，J＝5.67Hz，1H)，4.38(d，J＝5.48Hz，2H)，3.11(t，J＝6.46Hz，2H)，1.83(quind，J＝6.69，13.55Hz，1H)，0.89(d，J＝7.04Hz，6H)。
embodiment 41
3-(4-(cumarone-3-formyl isobutylamine-2-base) benzyloxy) phenyl aldehyde (I-26)
With reference to embodiment 37, yield 42%.
1HNMR(400MHz，DMSO-d
6)9.95(s，1H)，8.60(t，J＝5.67Hz，1H)，7.90(d，J＝8.22Hz，2H)，7.65(d，J＝8.22Hz，1H)，7.58(d，J＝8.61Hz，3H)，7.49-7.54(m，3H)，7.31-7.39(m，3H)，5.24(s，2H)，3.11(t，J＝6.26Hz，2H)，1.82(quind，J＝6.69，13.55Hz，1H)，0.88(d，J＝7.04Hz，6H)。
embodiment 42
3-(4-(cumarone-3-formyl isobutylamine-2-base) benzyloxy) methyl phenyl ketone (I-21)
With reference to embodiment 37, yield 47%.
1HNMR(400MHz，DMSO-d
6)8.60(t，J＝5.87Hz，1H)，7.90(d，J＝8.61Hz，2H)，7.65(d，J＝8.22Hz，1H)，7.58(d，J＝8.61Hz，3H)，7.52-7.56(m，2H)，7.43(t，J＝7.83Hz，1H)，7.35-7.40(m，1H)，7.33(dd，J＝0.98，7.63Hz，1H)，7.26-7.31(m，1H)，5.23(s，2H)，3.11(t，J＝6.26Hz，2H)，2.55(s，3H)，1.82(tt，J＝6.65，13.50Hz，1H)，0.88(d，J＝6.65Hz，6H)。
embodiment 43
1-cyano group-4-(4-(cumarone-3-formyl isobutylamine-2-base) benzyloxy) benzene (I-27)
With reference to embodiment 37, yield 51%.
1HNMR(400MHz，DMSO-d
6)8.60(t，J＝5.87Hz，1H)，7.90(d，J＝8.61Hz，2H)，7.74-7.79(m，2H)，7.65(d，J＝8.22Hz，1H)，7.54-7.60(m，3H)，7.38(dt，J＝1.37，7.73Hz，1H)，7.29-7.35(m，1H)，7.15-7.20(m，2H)，5.25(s，2H)，3.11(t，J＝6.46Hz，2H)，1.82(quind，J＝6.69，13.55Hz，1H)，0.88(d，J＝6.65Hz，7H)。
embodiment 44
1-methylsulfonic acid base-4-(4-(cumarone-3-formyl isobutylamine-2-base) benzyloxy) benzene (I-28)
With reference to embodiment 37, yield 60%.
1HNMR(400MHz，DMSO-d
6)8.60(t，J＝5.67Hz，1H)，7.90(d，J＝8.22Hz，2H)，7.80-7.86(m，J＝9.00Hz，2H)，7.65(d，J＝8.22Hz，1H)，7.58(d，J＝7.83Hz，3H)，7.38(t，J＝7.43Hz，1H)，7.32(t，J＝7.43Hz，1H)，7.20-7.26(m，J＝8.61Hz，2H)，5.27(s，2H)，3.13(s，3H)，1.83(tt，J＝6.65，13.30Hz，1H)，0.89(d，J＝6.65Hz，6H)。
embodiment 45
1-acetylaminohydroxyphenylarsonic acid 3-(4-(cumarone-3-formyl isobutylamine-2-base) benzyloxy) benzene (I-29)
With reference to embodiment 37, yield 45%.
1HNMR(400MHz，DMSO-d
6)9.91(s，1H)，8.60(t，J＝5.67Hz，1H)，7.89(d，J＝8.61Hz，2H)，7.65(d，J＝7.83Hz，1H)，7.52-7.60(m，3H)，7.29-7.40(m，3H)，7.17(t，J＝8.22Hz，1H)，7.08(d，J＝8.22Hz，1H)，6.68(dd，J＝1.96，7.83Hz，1H)，5.10(s，2H)，3.12(t，J＝6.26Hz，2H)，2.00(s，3H)，1.83(tt，J＝6.70，13.45Hz，1H)，0.89(d，J＝6.65Hz，6H)。
embodiment 46
1-acetylaminohydroxyphenylarsonic acid 4-(4-(cumarone-3-formyl isobutylamine-2-base) benzyloxy) benzene (I-210)
With reference to embodiment 37, yield 49%.
1HNMR(400MHz，DMSO-d
6)9.90(br.s.，1H)，8.60(br.s.，1H)，7.89(d，J＝8.22Hz，2H)，7.65(d，J＝7.83Hz，1H)，7.49-7.61(m，3H)，7.28-7.41(m，3H)，7.16(t，J＝8.02Hz，1H)，7.07(d，J＝7.83Hz，1H)，6.68(d，J＝7.43Hz，1H)，5.10(s，2H)，3.12(t，J＝6.06Hz，2H)，2.00(s，3H)，1.83(tt，J＝6.65，13.11Hz，1H)，0.89(d，J＝6.26Hz，6H)。
embodiment 47
4-(4-(cumarone-3-formyl isobutylamine-2-base) benzyloxy) methyl benzoate (I-211)
With reference to embodiment 37, yield 37%.
1HNMR(400MHz，DMSO-d
6)8.60(t，J＝5.48Hz，1H)，7.90(d，J＝8.22Hz，4H)，7.65(d，J＝7.83Hz，1H)，7.53-7.61(m，3H)，7.28-7.42(m，2H)，7.12(d，J＝8.61Hz，2H)，5.23(s，2H)，3.78(s，3H)，3.12(t，J＝6.26Hz，2H)，1.83(tt，J＝6.50，13.25Hz，1H)，0.88(d，J＝6.65Hz，6H)。
embodiment 48
1-methylsulfonic acid base-4-(4-(cumarone-3-formyl n-Butyl Amine 99-2-base) benzyloxy) benzene (I-212)
With reference to embodiment 37, yield 61%.
1HNMR(400MHz，DMSO-d
6)8.56(t，J＝5.67Hz，1H)，7.90(d，J＝8.22Hz，2H)，7.81-7.86(m，J＝9.00Hz，2H)，7.65(d，J＝7.83Hz，1H)，7.58(d，J＝8.22Hz，3H)，7.34-7.40(m，1H)，7.29-7.34(m，1H)，7.20-7.26(m，J＝8.61Hz，2H)，5.28(s，2H)，3.28(q，J＝6.65Hz，2H)，3.13(s，3H)，1.50(quin，J＝7.24Hz，2H)，1.26-1.38(m，2H)，0.88(t，J＝7.43Hz，3H)。
embodiment 49
SortaseA inhibit activities is tested
First this experiment clones SortaseA enzyme gene from the genome of streptococcus aureus, builds plasmid, goes out SortaseA enzyme at expression in escherichia coli.The change in fluorescence rate of the Segment A bz-LPET (excitatin λ=320nm, emissin λ=420nm) after utilizing substrate A bz-LPETG-Dap (Dnp) to be cut off by SortaseA enzyme represents that SortaseA Enzyme activities and compound are to the suppression situation of enzyme.
SortaseA enzymic activity test system: at assay buffer (5mMCaCl
2, 150mMNaCl, 50mMTris-HCl, 2mMpentaglycine (BACHEM, Torrance, CA), 0.05%Tween20, pH7.5) monomer SortaseA (ultimate density 5 μMs) is added in successively, testing compound and substrate (Abz-LPETG-Dap (Dnp), ultimate density 20 μMs), after dropping terminates, 96 orifice plates are put into microplate reader detects each hole fluorescent value rapidly, the temperature of microplate reader is set to 37 DEG C, every 5mins detects the fluorescent value in the 96 each holes of orifice plate, computerized compound is to the inhibiting rate of SortaseA albumen, result is as shown in table 1.
(1) experimental result
Table 1. benzofuran compounds protein inhibiting activity is tested
As can be seen from Table 1:
(1) this is tested all compounds and is consistent with negative and positive experiment condition.
(2) SortaseA protease inhibiting activity test-results explanation, compounds main involved by present method shows obvious inhibit activities to SortaseA, as Compound I-14, I-11, I-15, I-17, I-18, I-115, I-122, I-123, I-27, I-29 are to SortaseA protease inhibiting activity IC
50be about about 50 μMs.In further his-and-hers watches, data analysis finds, on cumarone ring, the activity of substituted radical to compound of side chain R2 is most important, when replace be isobutylamine time, there is certain activity, activity as Compound I-11 is 49 μMs, but when being become n-Butyl Amine 99, loss of activity, the activity as Compound I-124 is 200 μMs.When substituent R 1 is the aromatic hydrocarbon with electron-donating group or conjugation group, compound has certain activity, and the activity as I-123 is 42 μMs, otherwise, if R
1for with the aromatic hydrocarbon of electron-withdrawing group as nitro, halogen, the activity of compound is lost substantially, and the activity as I-112 is more than 200 μMs.
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 (10)
1. benzofuran compounds, its structure is as shown in general formula (I-1) or general formula (I-2):
Wherein, R
1, R
3, R
4for any one in hydrogen, C1-C5 straight or branched alkyl, hydroxyl, aldehyde radical, ethanoyl, carboxyl, cyano group, amino, nitro, fluorine, chlorine, bromine, amide group, ester group, alkoxyl group, aromatic base, assorted aromatic base;
R
2for hydrogen, C1-C5 straight or branched alkyl, hydroxyl, aromatic base, assorted aromatic base any one;
M, n are the integer of 0-5.
2. benzofuran compounds as claimed in claim 1, wherein: described in
R
1for any one in hydrogen, methyl, hydroxyl, aldehyde radical, ethanoyl, cyano group, amino, nitro, fluorine, chlorine, bromine, amide group, ester group etc.;
R
2for hydrogen, C1-C5 straight or branched alkyl, hydroxyl;
R
3for any one in hydrogen, methyl, hydroxyl, aldehyde radical, ethanoyl, cyano group, amino, nitro, fluorine, chlorine, bromine, amide group, ester group etc.;
R
4for any one in hydrogen, methyl, hydroxyl, aldehyde radical, ethanoyl, cyano group, amino, nitro, fluorine, chlorine, bromine, amide group, ester group etc.
3. Benzofurans compound as claimed in claim 1 or 2, wherein, described general formula (I-1) comprises following compound:
Described general formula (I-2) comprises following compound:
4. one kind is shown compound as described in general formula (I-1)
preparation method, comprise the steps:
By the compound shown in formula II
with substituted benzoyl acid-like substance and salt of wormwood, at room temperature react, obtain showing compound described in formula (I-1)
5. preparation method as claimed in claim 4, wherein, described benzoic acid analog be selected from following compound any one:
6. one kind is shown compound as described in general formula (I-2)
preparation method, comprise the steps:
By the compound shown in formula II
with fortified phenol analogue and salt of wormwood, react at 50 ~ 60 DEG C, obtain showing compound described in formula (I-2).
7. preparation method as claimed in claim 6, wherein, described fortified phenol analogue be selected from following compound any one:
8., such as formula a preparation method for compound (II) Suo Shi, comprise the steps:
Replacement is refluxed to methyl benzyl chlorine and triphenyl phosphorus at 85 ~ 90 DEG C, obtains the compound shown in formula (XII)
Compound shown in formula (XII) and replacement Benzaldehyde,2-hydroxy are refluxed at 85 ~ 90 DEG C, obtains the compound shown in formula (XI)
Compound shown in formula (XI) and iodine are at room temperature reacted, obtains the compound shown in formula (X)
By the compound shown in formula (X) and phosphorus oxychloride and N.N-dimethyl formamide, at 85 ~ 90 DEG C, carry out back flow reaction, obtain the compound shown in formula (IX)
Compound shown in formula (IX) and Textone are at room temperature reacted, obtains the compound shown in formula VIII
Compound formula (VIII) Suo Shi and methyl alcohol are carried out esterification, obtains the compound shown in formula (VII)
Compound shown in formula (VII) and N-bromo-succinimide are carried out back flow reaction at 80 ~ 85 DEG C, obtains the compound shown in formula (VI)
Compound shown in formula (VI) and sodium-acetate are reacted, obtains the compound shown in formula (V)
Compound shown in formula (V) is carried out alcoholysis in the basic conditions, obtains the compound shown in formula (IV)
Compound shown in formula (IV) and isobutylamine are reacted, obtains the compound shown in formula III
Compound shown in formula (III) and methylsulfonyl chloride are at room temperature reacted, obtains the compound shown in formula II
9. the purposes of a benzofuran compounds as claimed in claim 1 in anti-microbial infection.
10. purposes as claimed in claim 9 is by suppressing streptococcus aureus sorting enzyme A to carry out infection control.
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| CN104478836A (en) * | 2014-12-09 | 2015-04-01 | 上海交通大学 | Benzofuran compound as well as preparation method and application thereof |
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| CN109574965A (en) * | 2018-12-18 | 2019-04-05 | 上海交通大学 | The preparation and application of 2- (4- substituent group phenyl) -3- formamide benzofuran alkene cyanides |
| CN109574965B (en) * | 2018-12-18 | 2022-12-30 | 上海交通大学 | Preparation and application of 2- (4-substituent phenyl) -3-formamide benzofuran alkene cyanide compound |
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