CN105272952A - Benzofuran compounds intermediates, and preparation method and application thereof - Google Patents
Benzofuran compounds intermediates, and preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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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 invention provides a kind of benzofuran compounds intermediates, and a preparation method and application thereof, and the structure of the intermediates is shown as a general formula (I) in the specification. In the general formula (I), R1 and R3 are any one of hydrogen, C1-C5 linear or branched alkyl, hydroxyl, aldehyde group, acetyl, carboxyl, cyano, amino, nitro, fluorine, chlorine, bromine, amide, ester group, alkyloxy, aryl and heteroaryl; R2 is any one of hydrogen, C1-C5 linear or branched alkyl, hydroxyl, aryl and heteroaryl; and R4 is any one of hydroxyl, amino, bromine, chlorine, cyano and methanesulfonyloxy. By researching Sortase A structure and the catalysis mechanism of Sortase A structure and a substrate LPXTG and simulating the structure characteristics of the substrate LPXTG, a series of benzofuran compounds are designed, the structure function relationship is established through protein activity test, and helps to further guide and design relatively effective enzyme inhibitors.
Description
Technical field
The present invention relates to a kind of benzofuran compounds intermediate and preparation method thereof, be specially a kind of 2,3-disubstituted benzofuran compounds intermediate 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 intermediate, 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 benzofuran compounds intermediate, and its structure is as shown in general formula (I):
Wherein, R
1, R
3for hydrogen, C
1-C
5any one in 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, C
1-C
5straight or branched alkyl, hydroxyl, aromatic base, assorted aromatic base any one;
R
4for in hydroxyl, amino, bromine, chlorine, cyano group, mesyloxy any one.
Preferably, wherein, R is worked as
4during for amino, get rid of R
1for isopropoxy, R
2for methyl, R
3for the simultaneous situation of hydrogen three.
Preferably, aforesaid benzofuran compounds intermediate, is selected from the one in following general formula:
Preferably, R is worked as
4during for amino, get rid of R
1for isopropoxy, R
2for methyl, R
3for the simultaneous situation of hydrogen three.
Wherein, the preparation method of the compound of formula (I-1) comprises the steps:
Replacement is refluxed to methyl benzyl chlorine and triphenyl phosphorus at 85 ~ 90 DEG C, obtains the compound shown in formula (X):
Compound shown in formula (X) and replacement Benzaldehyde,2-hydroxy are refluxed at 85 ~ 90 DEG C, obtain the compound shown in formula (IX):
Compound shown in formula (IX) and iodine are at room temperature reacted, obtains the compound shown in formula (VIII);
By the compound shown in formula (VIII) and phosphorus oxychloride and N.N-dimethyl formamide, at 85 ~ 90 DEG C, carry out back flow reaction, obtain the compound shown in formula (VII):
Compound shown in formula (VII) and Textone are at room temperature reacted, obtain the compound shown in formula (VI):
Compound formula (VI) Suo Shi and methyl alcohol are carried out esterification, obtains the compound shown in formula (V)
Compound shown in formula (V) and N-bromo-succinimide are carried out back flow reaction at 80 ~ 85 DEG C, obtain the compound shown in formula (IV):
Compound shown in formula (IV) and sodium-acetate are reacted, obtain the compound shown in formula (III):
Compound shown in formula (III) is hydrolyzed in the basic conditions, obtains the compound shown in formula (II)
Compound shown in formula (II) and isobutylamine are reacted, obtains the compound shown in formula (I-1)
Preferably, the preparation method of the compound of formula (I-2) comprises the steps:
The compound of formula (I-1) and methyl-sulphoxide are at room temperature reacted, obtains the compound of formula (I-2).
Preferably, the preparation method of the compound of formula (I-3) comprises the steps:
The compound of formula (I-1) and phosphorus tribromide are at room temperature reacted, the compound of the formula (I-3) obtained.
Preferably, the preparation method of the compound of formula (I-4) comprises the steps:
The compound of formula (I-1) and methylsulfonyl chloride are at room temperature reacted, obtains the compound of formula (I-4).
Preferably, the preparation method of the compound of formula (I-5) comprises the steps:
By the compound of formula (I-4) and sodiumazide room temperature reaction 12 hours, then with triphenylphosphine 70 ~ 80 DEG C of conditions under react, obtain compound shown in formula (I-5).
Preferably, the preparation method of the compound of formula (I-6) comprises the steps:
The compound of formula (I-4) and trimethylammonium cyanoalkysilane are reacted at 85 ~ 90 DEG C, obtains compound shown in formula (I-6).
Second aspect, present invention also offers the purposes of a kind of benzofuran compounds intermediate as the aforementioned in anti-microbial infection.
The purposes of aforesaid anti-microbial infection aspect, by suppressing streptococcus aureus sorting enzyme A to carry out infection control, specifically utilize described benzofuran compounds Intermediate Preparation to have the benzofuran compounds of antibiont infection activity, the structure of described benzofuran compounds is as shown in general formula (X) or general formula (Y):
The present invention 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
The synthesis of 2-(4-chloromethyl phenyl) cumarone-3-formyl isobutylamine
By 2-(4-hydroxymethyl phenyl) cumarone-3-formyl isobutylamine
At room temperature react with thionyl chloride, obtain 2-(4-chloromethyl phenyl) cumarone-3-formyl isobutylamine
embodiment 13
The synthesis of 2-(4-2-bromomethylphenyl) cumarone-3-formyl isobutylamine
By 2-(4-hydroxymethyl phenyl) cumarone-3-formyl isobutylamine
at room temperature react with phosphorus tribromide, obtain 2-(4-2-bromomethylphenyl) cumarone-3-formyl isobutylamine
embodiment 14
The synthesis of 2-(4-Methanesulfonvloxvmethvl phenyl) cumarone-3-formyl isobutylamine
By 2-(4-hydroxymethyl phenyl) cumarone-3-formyl isobutylamine
at room temperature react with methylsulfonyl chloride, obtain 2-(4-Methanesulfonvloxvmethvl phenyl) cumarone-3-formyl isobutylamine,
embodiment 15
The synthesis of 2-(4-aminomethyl phenyl) cumarone-3-formyl isobutylamine
By 2-(4-Methanesulfonvloxvmethvl phenyl) cumarone-3-formyl isobutylamine
with sodiumazide room temperature reaction 12h, the crude product obtained reacts 12 hours again and with triphenylphosphine 70 ~ 80 DEG C, obtains 2-(4-aminomethyl phenyl) cumarone-3-formyl isobutylamine
embodiment 16
The synthesis of 2-(4-cyanogen aminomethyl phenyl) cumarone-3-formyl isobutylamine
By 2-(4-Methanesulfonvloxvmethvl phenyl) cumarone-3-formyl isobutylamine
react with at trimethylammonium cyanoalkysilane 85 ~ 90 DEG C, obtain 2-(4-cyanogen aminomethyl phenyl) cumarone-3-formyl isobutylamine
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 (12)
1. benzofuran compounds intermediate, its structure is as shown in general formula (I):
Wherein, R
1, R
3for hydrogen, C
1-C
5any one in 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, C
1-C
5straight or branched alkyl, hydroxyl, aromatic base, assorted aromatic base any one;
R
4for in hydroxyl, amino, bromine, chlorine, cyano group, mesyloxy any one.
2. benzofuran compounds intermediate as claimed in claim 1, wherein, works as R
4during for amino, get rid of R
1for isopropoxy, R
2for methyl, R
3for the simultaneous situation of hydrogen three.
3. benzofuran compounds intermediate as claimed in claim 1 or 2, is selected from the one in following general formula:
4. benzofuran compounds intermediate as claimed in claim 3, wherein, the preparation method of the compound of formula (I-1) comprises the steps:
Replacement is refluxed to methyl benzyl chlorine and triphenyl phosphorus at 85 ~ 90 DEG C, obtains the compound shown in formula (X):
Compound shown in formula (X) and replacement Benzaldehyde,2-hydroxy are refluxed at 85 ~ 90 DEG C, obtain the compound shown in formula (IX):
Compound shown in formula (IX) and iodine are at room temperature reacted, obtains the compound shown in formula (VIII);
By the compound shown in formula (VIII) and phosphorus oxychloride and N.N-dimethyl formamide, at 85 ~ 90 DEG C, carry out back flow reaction, obtain the compound shown in formula (VII):
Compound shown in formula (VII) and Textone are at room temperature reacted, obtain the compound shown in formula (VI):
Compound formula (VI) Suo Shi and methyl alcohol are carried out esterification, obtains the compound shown in formula (V)
Compound shown in formula (V) and N-bromo-succinimide are carried out back flow reaction at 80 ~ 85 DEG C, obtain the compound shown in formula (IV):
Compound shown in formula (IV) and sodium-acetate are reacted, obtain the compound shown in formula (III):
Compound shown in formula (III) is hydrolyzed in the basic conditions, obtains the compound shown in formula (II)
Compound shown in formula (II) and isobutylamine room temperature are reacted, obtains the compound shown in formula (I-1)
5. benzofuran compounds intermediate as claimed in claim 3, wherein, the preparation method of the compound of formula (I-2) comprises the steps:
The compound of formula (I-1) and methyl-sulphoxide are at room temperature reacted, obtains the compound of formula (I-2).
6. benzofuran compounds intermediate as claimed in claim 3, wherein, the preparation method of the compound of formula (I-3) comprises the steps:
The compound of formula (I-1) and phosphorus tribromide are at room temperature reacted, the compound of the formula (I-3) obtained.
7. benzofuran compounds intermediate as claimed in claim 3, wherein, the preparation method of the compound of formula (I-4) comprises the steps:
The compound of formula (I-1) and methylsulfonyl chloride are at room temperature reacted, obtains the compound of formula (I-4).
8. benzofuran compounds intermediate as claimed in claim 3, wherein, the preparation method of the compound of formula (I-5) comprises the steps:
By the compound of formula (I-4) and sodiumazide room temperature reaction 12 hours, then react under 70 ~ 80 DEG C of conditions with triphenylphosphine, obtain compound shown in formula (I-5).
9. benzofuran compounds intermediate as claimed in claim 3, wherein, the preparation method of the compound of formula (I-6) comprises the steps:
The compound of formula (I-4) and trimethylammonium cyanoalkysilane are reacted at 85 ~ 90 DEG C, obtains compound shown in formula (I-6).
10. the purposes of a benzofuran compounds intermediate as claimed in claim 1 in anti-microbial infection.
The purposes of 11. anti-microbial infection aspects as claimed in claim 10 is by suppressing streptococcus aureus sorting enzyme A to carry out infection control.
12. purposes in anti-microbial infection as described in claim 10 or 11, be utilize described benzofuran compounds Intermediate Preparation to have the benzofuran compounds of antibiont infection activity, the structure of described benzofuran compounds is as shown in general formula (X) or general formula (Y):
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084125A (en) * | 2016-11-23 | 2018-05-29 | 华东理工大学 | Benzheterocycle alkyl amine compound and application thereof |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101914080A (en) * | 2010-08-05 | 2010-12-15 | 上海交通大学 | Benzofuran-3-ketone substitute phenyl compound as well as preparation method and application |
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| CN101914080A (en) * | 2010-08-05 | 2010-12-15 | 上海交通大学 | Benzofuran-3-ketone substitute phenyl compound as well as preparation method and application |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108084125A (en) * | 2016-11-23 | 2018-05-29 | 华东理工大学 | Benzheterocycle alkyl amine compound and application thereof |
| WO2018095287A1 (en) * | 2016-11-23 | 2018-05-31 | 华东理工大学 | Benzoheterocyclyl alkylamine compound and use thereof |
| US20190315703A1 (en) * | 2016-11-23 | 2019-10-17 | East China University Of Science And Technology | Benzoheterocyclic alkylamine compounds and use thereof |
| CN108084125B (en) * | 2016-11-23 | 2020-08-18 | 华东理工大学 | Benzoheterocyclylalkylamines and their use |
| US10829464B2 (en) * | 2016-11-23 | 2020-11-10 | East China University Of Science And Technology | Benzoheterocyclic alkylamine compounds and use thereof |
| 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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