CN103588763B - 2-replaces-3-aryl ketone-6-(5-methyl-2-phenyl-4-ethyoxyl oxazole) benzofuran compound - Google Patents

Abstract

The present invention relates to a 2-substituted-3-aryl ketone-6-(5-methyl-2-phenyl-4-ethoxy oxazole) benzofuran compound; the 2-substituted-3- The structural formula of aryl ketone-6-(5-methyl-2-phenyl-4-ethoxy oxazole) benzofuran compound is: Compared with the prior art, the present invention takes the 3-methanone substituent benzofuran as the center of the aromatic ring, and introduces (5-methyl-2-phenyloxazol-4-yl)ethyl at the 6-position of the benzofuran. Oxygen, to obtain new compounds, and establish and optimize the preparation method of the compounds, and conduct antibacterial screening experiments on the prepared new compounds, and confirm that some of the prepared new compounds have excellent broad-spectrum antibacterial activity through preliminary in vitro antibacterial tests , can be used to prepare new antibacterial drugs.

Description

2-Substituted-3-arylmethanone-6-(5-methyl-2-phenyl-4-ethoxyoxazole)benzofuran compound

This application is a divisional application with the application number 201110292388.3, the filing date is 2011.9.29, and the invention name is "3-methanone-6-substituted benzofuran compounds and their preparation methods and uses".

technical field

The present invention relates to compounds in the field of medicine and chemical industry and their preparation and application methods, in particular to a 2-substituted-3-aryl ketone-6-(5-methyl-2-phenyl-4-ethoxyoxane Azole) benzofuran compounds.

Background technique

In recent years, infections caused by a large number of drug-resistant strains have become a medical problem worldwide, and methicillin-resistant Staphylococcus aureus is one of the important categories. Since most antibacterial drugs used clinically have serious side effects, the development of safe and efficient antibacterial compounds has become an important research direction for medicinal chemists.

Benzofuran derivatives are an important class of heterocyclic compounds, which have a very wide range of biological effects, such as antibacterial, antitumor, anti-inflammatory and so on. A large number of studies have found that the introduction of a ketone chain substituent at the 3-position of the benzofuran ring has an important impact on the antibacterial activity of this type of compound. For example, Xizhen Jiang et al published an article titled "Synthesis and antimicrobialevaluation of new benzofuranderivatives" on page 3526 of the 46th issue of "European Journal of Medicinal Chemistry". They designed a new class of 3-methanone-substituted benzofuran derivatives (structural formula shown in Figure 1), which are effective against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus Excellent broad-spectrum antibacterial activity, its MIC value is between 0.39-3.12ug/mL.

A further search found that Wei Zhang et al. published "Design, synthesis and antimicrobial activity of chiral2-(substituted-hydroxyl)-3-(benzo[d]oxazol-5-yl)propanoic acidderivatives" on "European Journal of Medicinal Chemistry" and mentioned a class of α-chiral Substituted propionic acid compounds (structural formula shown in Figure 2), this type of compound also has excellent broad-spectrum antibacterial activity against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus, and its MIC Values were between 1.56-6.25ug/mL. Based on the above literature research, we designed a new class of benzofuran compounds, introducing a hydrophobic (5-methyl-2-phenyloxazol-4-yl) ethoxy chain into the 6-position of the benzofuran ring , used to investigate the effect of substituents at positions other than the 2 and 3 positions of the benzofuran ring on the antibacterial activity of benzofuran compounds, in order to obtain a new class of benzofuran derivatives with excellent antibacterial activity.

Contents of the invention

The object of the present invention is to provide a kind of 2-substituted-3-aryl ketone-6-(5-methyl-2-phenyl-4-ethoxy oxazole) benzo furan compounds. Preliminary antibacterial tests confirm that some of the new compounds prepared by the present invention have excellent antibacterial activity, and the minimum inhibitory concentration is close to the positive control, and can be used to prepare new antibacterial drugs.

The purpose of the present invention is achieved through the following technical solutions:

The present invention relates to a kind of 2-substituted-3-aryl ketone-6-(5-methyl-2-phenyl-4-ethoxy oxazole) benzofuran compound, its structural formula is:

( ₁ ) R is a structure shown in formula (I) or formula (II):

Among them, Z is O, S or NH; R ₆ and R ₇ are hydrogen, C ₁ -C ₅ alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester, hydroxyl, amino, amido, alkoxy Any one of group, aldehyde group, aromatic group, heteroaryl group;

( ₂ ) R2 is the structure shown in formula (III), formula (IV), formula (V) or formula (VI):

Wherein, n ₂ is any one of the integers from 1 to 3, W is O, S or NH, R ₈ , R ₉ , R ₁₀ , and R ₁₁ are aryl or heteroaryl substituted by any group;

(3) R ₃ is hydrogen, C ₁ -C ₅ alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester, hydroxyl, amino, amido, alkoxy, aldehyde, aryl, heteroaromatic Any one of the bases; X, Y are O, S or NH; n ₁ is any one of the integers from 1 to 4;

(4) R ₄ is hydrogen, C ₁ -C ₅ linear or branched chain alkyl;

(5) R ₅ is hydrogen, C ₁ -C ₅ alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester, hydroxyl, amino, amido, alkoxy, aldehyde, aryl, heteroaromatic any of the bases.

Preferably, its structural formula is the structure shown in formula (VII):

Among them, R ₁₂ , R ₁₃ , and R ₁₄ are hydrogen, C ₁ -C ₅ alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl group, amino group, amido group, alkoxy group, aldehyde group, Any of aryl and heteroaryl.

Preferably, its structural formula is the structure shown in formula (VIII):

Among them, R ₁₅ , R ₁₆ , R ₁₇ , and R ₁₈ are hydrogen, C ₁ -C ₅ alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester, hydroxyl, amino, amido, alkoxy, Any of an aldehyde group, an aromatic group, and a heteroaryl group.

The present invention also relates to a method for preparing the above-mentioned 2-substituted-3-aryl ketone-6-(5-methyl-2-phenyl-4-ethoxy oxazole) benzofuran compound, comprising the following steps step:

(1) get 1 molar equivalent of 2,4-dihydroxybenzaldehyde and 1.2 molar equivalents of benzyl chloride to reflux in acetonitrile to obtain 4-(benzyloxy)-2-hydroxybenzaldehyde;

(2) Take 1 molar equivalent of 4-(benzyloxy)-2-hydroxybenzaldehyde and 1.2 molar equivalents of substituted aldehydes to reflux in the zinc-titanium tetrachloride-tetrahydrofuran system to obtain (E)-5-(benzyloxy Base) -2-substituted vinylphenol;

(3) Take 1 molar equivalent of (E)-5-(benzyloxy)-2-substituted vinylphenol and stir at room temperature in 6 molar equivalents of potassium carbonate and 6 molar equivalents of iodine to obtain 6-(benzyloxy)-2 - substituted benzofurans;

(4) Dissolve 1 molar equivalent of 6-(benzyloxy)-2-substituted benzofuran in dichloromethane, and add 1.3 molar equivalent of titanium tetrachloride to obtain 6-hydroxyl-2-substituted benzofuran;

(5) Dissolve 1 molar equivalent of 6-hydroxy-2-substituted benzofuran in acetonitrile, add 1 molar equivalent of 2-(5-methyl-2-phenyloxazol-4-yl) methanesulfonic acid Ethyl ester and 2 molar equivalents of potassium carbonate are refluxed to obtain 5-methyl-2-phenyl-4-(2-(2-substituted benzofuran-6-oxyl group) ethyl) oxazole;

(6) Take 1 molar equivalent of 5-methyl-2-phenyl-4-(2-(2-substituted benzofuran-6-oxyl group) ethyl) oxazole and 1.5 molar equivalent of substituted acid chloride in In dichloromethane, add 1.2 molar equivalents of tin tetrachloride, and stir at room temperature for 12 hours to obtain 1-(2-substituted-6-(2-(5-methyl-2-phenyloxazol-4-yl) ethyl Oxy)benzofuran-3-yl) substituted ketone;

(7) Take 1 molar equivalent of 5-methyl-2-phenyl-4-(2-(2-substituted benzofuran-6-oxygen) ethyl) oxazole and 8 molar equivalents of phosphorus oxychloride and 8 molar equivalents of N,N-dimethylformamide in 1,2-dichloroethane to obtain 6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy Base)-2-phenylbenzofuran-3-carbaldehyde;

(8) Take 1 molar equivalent of 6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-phenylbenzofuran-3-carbaldehyde and 1 molar equivalent The 3,4,5-trimethoxyaniline is refluxed in toluene to obtain (E)-3,4,5-trimethoxy-N-((6-(2-(5-methyl-2-phenyloxa (Azol-4-yl)ethoxy)-2-phenylbenzofuran-3-yl)methylene)aniline;

(9) Take 1 molar equivalent of (E)-3,4,5-trimethoxy-N-((6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy Base)-2-phenylbenzofuran-3-yl)methylene)aniline and 1.5 molar equivalents of sodium borohydride are stirred in methanol to obtain 3,4,5-trimethoxy-N-((6-( 2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-phenylbenzofuran-3-yl)methyl)aniline.

The present invention also relates to a 2-substituted-3-aryl ketone-6-(5-methyl-2-phenyl-4-ethoxyl group having the structure shown in formula (VII) or formula (VIII) Oxazole) benzofuran compounds in the preparation of drugs for inhibiting the biological activity of microorganisms.

Preferably, said inhibiting the biological activity of microorganisms is specifically inhibiting the biological activity of one or more of Escherichia coli, Staphylococcus aureus, Staphylococcus aureus, Bacillus subtilis, and Pseudomonas aeruginosa.

Compared with the prior art, the present invention has the beneficial effects that: the present invention uses (5-methyl-2-phenyloxazol-4-yl) ethoxy hydrophobic tail as a flexible linking chain, and 3-methanone Substituting the benzofuran structure aromatic ring center, establishing and optimizing the preparation method of the compound, and conducting antibacterial screening experiments on the prepared new compound, and developed a new compound with excellent antibacterial activity.

Description of drawings

Fig. 1 is a structural representation of a 3-methanone substituted benzofuran derivative;

Fig. 2 is a structural representation of a chiral propionic acid compound;

Figure 3 is a schematic diagram of the design of 3-methanone-substituted-6-substituted-benzofuran compounds;

Fig. 4 is a schematic diagram of the synthetic route of the preparation method of the benzofuran compound.

detailed description

The embodiments of the present invention are described in detail below. This embodiment is implemented on the premise of the technical solution of the present invention, and detailed implementation methods and specific operating procedures are provided, but the protection scope of the present invention is not limited to the following implementation example.

The present invention designs a kind of novel benzofuran compound on the basis of prior art, introduces hydrophobic (5-methyl-2-phenyloxazol-4-yl) ethoxy chain into benzofuran The 6-position of the furan ring is used to investigate the influence of substituents at positions other than the 2 and 3 positions of the benzofuran ring on the antibacterial activity of benzofuran compounds, in order to obtain a new type of benzofuran with excellent antibacterial activity derivatives; its design schematic diagram is shown in Figure 3.

Example 1

Synthesis of 4-(benzyloxy)-2-hydroxybenzaldehyde I (Figure 4): Dissolve 2,4-dihydroxybenzaldehyde (100 mg, 0.72 mmol) in acetonitrile (15 ml), then add potassium iodide (179.3 mg , 1.08mmol) and sodium bicarbonate (90.7mg, 1.08mmol), then slowly dropwise added benzyl chloride (100ul, 0.87mmol), and refluxed for 12 hours. After the reaction was completed, it was quenched with water, extracted with ethyl acetate, the organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10 : 1) 110 mg of 4-(benzyloxy)-2-hydroxybenzaldehyde was obtained (colorless solid, yield 67%). ¹ HNMR (CDCl ₃ ; 300MHz), δ5.12 (s, 2H, O CH ₂ Ph) 6.40-6.64 (m, 2H, ArH), 7.41-7.43 (m, 6H, ArH), 9.73 (s, 1H, CHO), 11.44 (brs, 1H, OH).

Example 2

Synthesis of (E)-5-(benzyloxy)-2-(4-methoxystyryl)phenol II ₁ (Figure 4): Zinc powder (1.4 g, 22 mmol) was added to In anhydrous tetrahydrofuran (20ml), then lower the temperature of the reaction system to -5～0°C, add titanium tetrachloride (1.2ml, 11mmol) dropwise at this temperature, and raise the temperature of the reaction system to room temperature after the addition , stirred for half an hour, and then refluxed for 2.5 hours. After the reflux, the temperature of the reaction system was lowered to -5～0°C again, and 4-(benzyloxy)-2-hydroxybenzaldehyde (1g, 4.4mmol) and p-methoxybenzaldehyde (721mg, 5.3mmol) of tetrahydrofuran solution, refluxed for 2 hours after dropping. After the reaction was completed, the reaction was quenched with 10% aqueous sodium bicarbonate solution, then extracted with dichloromethane, the organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (Petroleum ether:ethyl acetate=5:1) to obtain (E)-5-(benzyloxy)-2-(4-methoxystyryl)phenol 280mg (colorless solid, yield 20%). ¹ HNMR (CDCl ₃ ; 300MHz), δ3.84 (s, 3H, OCH3), 5.05 (s, 2H, O CH ₂ Ph), 6.48-6.49 (d, 1H, Ar, J=2.4Hz), 6.58- 6.62(dd, 1H, ArH, J=8.7Hz, 2.7Hz), 6.988-6.934(dd, 2H, ArH, J=3Hz, 8.7Hz), 6.951-6.989(d, 1H, CH, J=11.4Hz) , 7.133-7.155 (d, 1H, ArH, J=6.6Hz), 7.365-7.548 (m, 8H, ArH, CH).

Example 3

Synthesis of 6-(benzyloxy)-2-(4-methoxyphenyl)benzofuran III ₁ (Figure 4): (E)-5-(benzyloxy-2-(4-methoxy Styryl) phenol (280mg, 0.84mmol) was dissolved in tetrahydrofuran (15ml), anhydrous potassium carbonate (695mg, 5.04mmol) was added, after stirring for 10 minutes, iodine (1.28g, 5.04mmol) was added, and stirred at room temperature for 12 Hour. After the reaction finishes, quench the reaction with saturated aqueous sodium bicarbonate solution, then dropwise add saturated aqueous sodium bisulfite solution to remove residual iodine, then extract with ethyl acetate, combine the organic phases, and wash three times with saturated brine , dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 150 mg of 6-(benzyloxy)-2-methoxybenzofuran (yellow Solid, yield 54%). ¹ HNMR (CDCl ₃ ; 300MHz), δ3.87 (s, 3H, OCH ₃ ), 5.14 (s, 2H, O CH ₂ Ph), 6.826 (s, 1H, ArH), 6.889-6.918(d, 1H, ArH, J=8.7Hz), 6.968-6.991(d, 2H, ArH, J=6.9Hz), 7.132(s, 1H, CH), 7.350-7.503(m, 6H, ArH ), 7.739-7.768 (d, 2H, ArH, J=8.7Hz).

Example 4

Synthesis of 2-(4-methoxyphenyl)-6-hydroxybenzofuran IV ₁ (Figure 4): 6-(benzyloxy)-2-(4-methoxyphenyl)benzofuran (50mg, 0.15ml) was dissolved in dichloromethane (10ml), and titanium tetrachloride (21.8ul, 0.20mmol) was added dropwise at room temperature, and stirred at room temperature for half an hour after dropping. After the reaction was completed, it was quenched with methanol, concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 23 mg of 2-methoxy-6-hydroxybenzofuran (colorless solid, recovered from Yield 63%). ¹ HNMR (CDCl ₃ ; 300MHz), δ3.968 (s, 3H, OCH ₃ ), 4.94 (brs, 1H, OH), 6.854-6.878 (d, 1H, ArH, J=7.2Hz) , 6.914(s, 1H, CH), 7.060-7.104(m, 3H, ArH), 7.470-7.498(d, 1H, ArH, J=8.4Hz), 7.836-7.864(d, 2H, ArH, J=8.4 Hz).

Example 5

Synthesis of methyl 2-(5-methyl-2-phenyloxazol-4-yl)acetate (Figure 4): Methyl 4-bromo-3-oxopentanoate (10 g, 45 mmol) was dissolved in toluene (200ml), then added benzamide (5.45g, 45mmol) in batches, and refluxed for 12 hours after the addition was complete. After the reaction was completed, it was filtered and concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain methyl 2-(5-methyl-2-phenyloxazol-4-yl)acetate 4.4 g (yellow oil, yield 40%). ¹ HNMR ((CD ₃ ) ₂ CO; 300MHz), δ2.378(s, 3H, CH ₃ ), 3.587(s, 2H, CH ₂ ), 3.665(s, 3H, OCH ₃ ), 7.473-7.499(m , 3H, ArH), 7.950-7.982 (m, 2H, ArH).

Example 6

Synthesis of 2-(5-methyl-2-phenyloxazol-4-yl)ethanol (Fig. 4): lithium aluminum hydride (207.1mg, 5.45mmol) was dissolved in anhydrous ether (20ml), in At -5°C, an ether solution of methyl 2-(5-methyl-2-phenyloxazol-4-yl)acetate (890 mg, 3.63 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for half an hour. After the reaction was completed, a saturated ammonium chloride aqueous solution was added dropwise to the reaction system to quench until white flocs appeared in the reaction system. Filter, wash the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated brine three times, and dry over anhydrous sodium sulfate. Concentration under reduced pressure gave 710 mg of 2-(5-methyl-2-phenyloxazol-4-yl)ethanol (colorless solid, yield 96%). ¹ HNMR (CDCl ₃ ; 300MHz), δ2.347(s, 3H, CH ₃ ), 2.754-2.792(t, 2H, CH ₂ CH ₂ , J=5.7Hz), 3.924-3.963(t, 2H, CH ₂ CH ₂ , J=5.8Hz), 6.0-6.5 (brs, 1H, OH), 7.431-7.450 (m, 3H, ArH), 7.989-8.021 (m, 2H, ArH).

Example 7

Synthesis of 2-(5-methyl-2-phenyloxazol-4-yl) ethyl methanesulfonate (Figure 4): 2-(5-methyl-2-phenyloxazol-4-yl ) ethanol (630mg, 3.1mmol) was dissolved in dichloromethane (15ml), triethylamine (0.64ml, 4.65mmol) was added dropwise, then methanesulfonyl chloride (0.37ml, 4.65mmol) was added dropwise to In the reaction system, after the dropwise addition was completed, it was stirred at room temperature for 4 hours. After the reaction was completed, saturated ammonium chloride aqueous solution was added dropwise to the reaction system to quench, the aqueous phase was washed with ethyl acetate, the organic phases were combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) gave 700 mg of ethyl 2-(5-methyl-2-phenyloxazol-4-yl) methanesulfonate (colorless Solid, yield 80%). ¹ HNMR (CDCl ₃ ; 300MHz), δ2.365 (s, 3H, CH ₃ ), 2.935-2.978 (m, 5H, CH ₂ CH ₂ , CH ₃ ), 4.509-4.553 (t, 2H, CH ₂ CH ₂ , J=6.6Hz), 7.423-7.446 (m, 3H, ArH), 7.957-7.990 (m, 2H, ArH).

Example 8

Synthesis of 4-(2-(2-(4-methoxybenzene)benzofuran-6-oxyl)ethyl)-5-methyl- ₂ -phenyloxazole V1 (Figure 4): the 2-(5-Methyl-2-phenyloxazol-4-yl) ethyl methanesulfonate (690mg, 2.45mmol), 2-methoxy-6-hydroxybenzofuran (588.2mg, 2.45mmol) Dissolve potassium carbonate (675.8mg, 4.9mmol) in acetonitrile (20ml) and reflux for 12 hours. After the reaction was completed, saturated ammonium chloride aqueous solution was added dropwise to the reaction system to quench, the aqueous phase was washed with ethyl acetate, the organic phases were combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate. After concentrated under reduced pressure, silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 4-(2-(2-(4-methoxybenzene)benzofuran-6-oxyl)ethyl) - 520 mg of 5-methyl-2-phenyloxazole (yellow solid, yield 50%). ¹ HNMR (CDCl ₃ ; 300MHz), δ2.415(s, 3H, CH ₃ ), 3.065-3.021(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 3.852(s, 3H, OCH ₃ ), 4.334-4.292(t, 2H, CH ₂ CH ₂ , J=6.3Hz), 6.802(s, 1H, CH), 6.830-6.859(d, 1H, ArH, J=8.7Hz), 6.951-6.980(d, 2H, ArH, J=8.7Hz), 7.065(s, 1H, ArH), 7.353-7.447(m, 4H, ArH), 7.723-7.748(d, 2H, ArH, J=7.5Hz), 8.001-8.025( m, 2H, ArH).

Example 9

1-(2-(4-methoxyphenyl)-6-(2-(5-methyl-2-phenyl-4-yl)ethoxy)benzofuran-3-yl)ethanone VI Synthesis of ₁ (Figure 4): 4-(2-(2-(4-methoxybenzene)benzofuran-6-oxyl)ethyl)-5-methyl-2-phenyloxazole ( 50mg, 0.12mmol) and acetyl chloride (12.7ul, 0.18mmol) were dissolved in dichloromethane (10ml), and tin tetrachloride (17.1ul, 0.144mmol) was added dropwise, and stirred at room temperature for 12 hours. After the reaction was completed, it was quenched with water, and then extracted with ethyl acetate. The organic phases were combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) gave 1-(2-(4-methoxyphenyl)-6-(2-(5-methyl-2- 28 mg of phenyl-4-yl)ethoxy)benzofuran-3-yl)ethanone (yellow solid, yield 51%). ¹ HNMR (CDCl ₃ ; 300MHz), δ2.051(s, 3H, CH 3 ), 2.415(s, 3H, CH ₃ ), 3.065-3.021(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 3.852(s, 3H, OCH ₃ ), 4.334-4.292(t, 2H, CH ₂ CH ₂ , J=6.3Hz), 6.830-6.859(d, 1H, ArH, J=8.7Hz), 6.951-6.980(d , 2H, ArH, J=8.7Hz), 7.065(s, 1H, ArH), 7.353-7.447(m, 4H, ArH), 7.723-7.748(d, 2H, ArH, J=7.5Hz), 8.001-8.025 (m, 2H, ArH).

Example 10

(E)-1-(2-(4-methoxyphenyl)-6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)benzofuran-3 -Synthesis of -3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one VI ₂ (Figure 4): 1-(2-(4-methoxybenzene yl)-6-(2-(5-methyl-2-phenyl-4-yl)ethoxy)benzofuran-3-yl)ethanone (28mg, 0.059mmol) and 3,4,5- Trimethoxybenzaldehyde (12mg, 0.059mmol) was dissolved in methanol (15ml), then potassium hydroxide (6.6mg, 0.118mmol) was added, and refluxed for 12 hours. After the reaction was completed, it was quenched with 1N hydrochloric acid, and the pH value of the solution was adjusted to 1. Then it was extracted with dichloromethane, and the organic phases were combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) gave (E)-1-(2-(4-methoxyphenyl)-6-(2-(5-methoxyphenyl) Base-2-phenyloxazol-4-yl)ethoxy)benzofuran-3-yl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 10 mg (solids, 25%). ¹ HNMR (CDCl ₃ ; 300MHz), δ2.586 (s, 3H, CH ₃ ), 3.035-3.079 (d, 2H, CH ₂ CH ₂ , J=6.6Hz), 3.853 (s, 12H, 4OCH ₃ ), 4.428-0.472(d, 2H, CH ₂ CH ₂ , J=6.6Hz), 6.510(s, 1H, ArH), 6.809-6.861(d, 1H, CH =CH, J=15.6Hz), 7.003-7.107( m, 5H, ArH), 7.429-7.443 (m, 2H, ArH), 7.654-7.743 (m, 4H, ArH), 7.992-8.021 (m, 2H, ArH).

Example 11

Synthesis of (E)-5-(benzyloxy)-2-(2-(5-methylfuran-2-yl)vinyl)phenol II ₂ (Figure 4): Referring to Example 2, the yield is 60% . ¹ HNMR (CDCl ₃ ; 300MHz), δ2.355 (s, 3H, CH ₃ ), 5.057 (s, 2H, CH ₂ ), 6.149-6.177 (d, 1H, CH CH , J=8.4Hz), 6.189- 6.200(d, 1H, CH CH, J=3.3Hz), 6.472-6.480(d, 1H, ArH, J=2.4Hz), 6.571-6.579(d, 1H, ArH, J=2.4Hz), 6.688(s , 1H, ArH), 6.765-6.819(d, 1H, CH =CH, J=16.2Hz), 7.073-7.128(d, 1H, CH= CH , J=16.5Hz), 7.372-7.426(m, 5H, ArH), 8.634-8.653 (brs, 1H, OH).

Example 12

Synthesis of (E)-5-(benzyloxy)-2-styrylphenol II ₃ (Figure 4): Referring to Example 2, the yield is 32%. ¹ HNMR (CDCl ₃ ; 300MHz), δ5.079 (s, 2H, CH ₂ ), 6.474-6.482 (d, 1H, ArH, J=2.4Hz), 6.523-6.531 (d, 1H, ArH, J=2.4 Hz), 6.608-6.644(d, 1H, CH= CH , J=10.8Hz), 6.993-7.048(d, 1H, CH =CH, J=16.5Hz), 7.138(s, 1H, ArH), 7.365- 7.534 (m, 5H, ArH), 8.105-8.133 (brs, 1H, OH).

Example 13

Synthesis of 6-(benzyloxy)-2-(5-methylfuran-2-yl)benzofuran III ₂ (Figure 4): Referring to Example 3, the yield is 15%. ¹ HNMR (CDCl ₃ ; 300MHz), δ2.385 (s, 3H, CH ₃ ), 5.112 (s, 2H, CH ₂ ), 6.085-6.093 (d, 1H, CHCH, J=2.4Hz), 6.611-6.600 (d, 1H, CHCH, J=3.3Hz), 6.754(s, 1H, ArH), 6.923-6.931(d, 1H, ArH, J=2.4Hz), 6.952-6.959(d, 1H, ArH, J= 2.1 Hz), 7.256 (s, 1H, CH), 7.375-7.452 (m, 5H, ArH).

Example 14

Synthesis of 6-(benzyloxy)-2-phenylbenzofuran III ₃ (Figure 4): Referring to Example 3, the yield is 54%. ¹ HNMR (CDCl ₃ ; 300MHz), δ5.134 (s, 2H, CH ₂ ), 6.937-6.972 (m, 2H, ArH), 7.116-7.141 (m, 1H, ArH), 7.257-7.465 (m, 10H , ArH), 7.822 (s, 1H, CH).

Example 15

Synthesis of 2-phenyl-6-hydroxybenzofuran IV ₂ (Figure 4): Referring to Example 4, the yield is 90%. ¹ HNMR (CDCl ₃ ; 300MHz), δ4.5-5.0 (brs, 1H, OH), 6.957-7.025 (m, 2H, ArH), 7.269-7.302 (m, 1H, ArH), 7.405-7.441 (m, 5H, ArH), 7.839 (s, 1H, CH).

Example 16

Synthesis of 2-(5-methylfuran-2-yl)-6-hydroxybenzofuran IV ₃ (Figure 4): Referring to Example 4, the yield is 60%. ¹ HNMR (CDCl ₃ ; 300MHz), δ2.478 (s, 3H, CH ₃ ), 6.864-6.893 (d, 1H, CHCH, J=8.7Hz), 6.955-6.984 (d, 1H, CHCH, J=8.7 Hz), 7.066 (s, 1H, CH), 7.523 (s, 1H, ArH), 7.872-7.892 (m, 2H, ArH), 9.843 (brs, 1H, OH).

Example 17

5-methyl-4-(2-(2-(5-methylfuran-2-yl)benzofuran-6-oxyl)ethyl)-2-phenyloxazole V ₃ (Figure 4): Referring to Example 8, the yield is 66%. ¹ HNMR (CDCl ₃ ; 300MHz), δ2.058(s, 3H, CH ₃ ), 2.389(s, 3H, CH ₃ ), 3.014-3.058(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 4.283-4.327(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 6.089-6.097(d, 1H, CH CH , J=2.4Hz), 6.602-6.613(d, 1H, CH CH , J=3.3 Hz), 6.749(s, 1H, CH), 6.868-6.875(d, 1H, ArH, J=2.1Hz), 7.050-7.054(d, 1H, ArH, J=1.2Hz), 7.270-7.292(m, 2H, ArH), 7.431-7.450 (m, 3H, ArH), 7.998-8.030 (m, 2H, ArH).

Example 18

(6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-(5-methylfuran-2-yl)benzofuran-3-yl)( Synthesis of 3,4,5-trimethoxyphenyl)methanone VI ₃ (Figure 4): Referring to Example 9, the yield is 35%. ¹ HNMR (CDCl ₃ ; 300MHz), δ2.056 (s, 3H, CH ₃ ), 2.436 (s, 3H, CH ₃ ), 3.075-3.119 (t, 2H, CH ₂ CH ₂ , J=6.6Hz), 3.993(s, 9H, 3OCH ₃ ), 4.223-4.367(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 6.863-6.874(d, 1H, CH CH, J=3.3Hz), 6.892-6.912( d, 1H, CHCH, J=2.4Hz), 7.102-7.116 (m, 3H, ArH), 7.378-7.462 (m, 3H, ArH), 7.463-7.472 (m, 2H, ArH).

Example 19

1-(6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-(5-methylfuran-2-yl)benzofuran-3-yl ) Synthesis of acetone VI ₄ (Figure 4): Referring to Example 9, the yield is 33%. ¹ HNMR (CDCl ₃ ; 300MHz), δ2.413(s, 3H, CH ₃ ), 2.453(s, 3H, CH ₃ ), 2.677(s, 3H, CH ₃ ), 3.029-3.073(t, 2H, CH 3 ₂ CH ₂ , J=6.6Hz), 4.298-4.342(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 6.213-6.224(d, 1H, CH CH, J=3.3Hz), 6.947-6.658( d, 1H, CH CH , J=3.3Hz), 7.137-7.144(d, 1H, ArH, J=2.1Hz), 7.147-7.159(d, 1H, ArH, J=3.6Hz), 7.430-7.485(m , 3H, ArH), 7.834 (s, 1H, ArH), 8.003-8.024 (m, 2H, ArH).

Example 20

(6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-(5-methylfuran-2-yl)benzofuran-3-yl)( Synthesis of 4-(trifluoromethyl)phenyl)methanone VI ₅ (Figure 4): Referring to Example 9, the yield is 14%. ¹ HNMR (CDCl ₃ ; 300MHz), δ2.287(s, 3H, CH ₃ ), 2.265(s, 3H, CH ₃ ), 2.967-3.011(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 4.253-4.297(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 6.213-6.224(d, 1H, CH CH, J=3.3Hz), 6.947-6.658(d, 1H, CH CH , J=3.3 Hz), 7.039-7.061(d, 2H, ArH, J=6.6Hz), 7.137-7.144(d, 1H, ArH, J=2.1Hz), 7.147-7.159(d, 1H, ArH, J=3.6Hz) , 7.393-7.402 (m, 5H, ArH), 7.834 (s, 1H, ArH), 7.997-8.010 (m, 2H, ArH).

Example 21

Synthesis of 1-(6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-phenylbenzofuran-3-yl)ethanone VI ₆ (Fig. 4): With reference to Example 9, the yield is 61%. ¹ HNMR (CDCl ₃ ; 300MHz), δ2.223(s, 3H, CH ₃ ), 2.532(s, 3H, CH ₃ ), 3.006-3.050(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 4.206-4.250(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 7.137-7.144(d, 1H, ArH, J=2.1Hz), 7.147-7.159(d, 1H, ArH, J=3.6Hz) , 7.376-7.627 (m, 10H, ArH), 7.834 (s, 1H, ArH).

Example 22

(E)-1-(6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-phenylbenzofuran-3-yl)-3-( Synthesis of 4-(trifluoromethyl)phenyl)prop-2-en-1-one VI ₇ (Figure 4): Referring to Example 10, the yield is 35%. ¹ HNMR (CDCl ₃ ; 300MHz), δ2.435(s, 3H, CH ₃ ), 3.011-3.055(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 4.483-4.527(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 6.610-6.637(d, 2H, ArH, J=8.1Hz), 6.983-6.997(d, 1H, ArH, J=4.2Hz), 7.060-7.079(d, 1H, ArH , J=5.7Hz), 7.393-7.605 (m, 13H, ArH, CH =CH), 7.743 (s, 1H, ArH).

Example 23

Synthesis of (6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-phenylbenzofuran-3-yl)methanol VI ₉ (Figure 4): Dissolve 6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-phenylbenzofuran-3-carbaldehyde (60mg, 0.14mmol) in methanol (10ml ), after adding sodium borohydride (8.1mg, 0.21mmol), stir at room temperature for 45 minutes. After the reaction, the reaction liquid was poured into ice water, extracted with dichloromethane, the organic phases were combined, washed three times with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, it was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain (6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)- 12 mg of 2-phenylbenzofuran-3-yl)methanol (yellow solid, yield 20%). ¹ HNMR (CDCl ₃ ; 300MHz), δ2.390(s, 3H, CH ₃ ), 2.977-3.021(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 4.234-4.278(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 4.936(s, 2H, CH ₂ OH), 6.861-6.889(d, 2H, ArH, J=8.4Hz), 7.043(s, 1H, ArH), 7.376-7.470(m , 10H, ArH).

Example 24

(E)-3,4,5-trimethoxy-N-((6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-phenylbenzene Synthesis of furan-3-yl)methylene)aniline VI ₁₀ (Figure 4): 6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2 -Phenylbenzofuran-3-carbaldehyde (50mg, 0.118mmol) and 3,4,5-trimethoxyaniline (21.6mg, 0.118mmol) were dissolved in toluene (10ml) and refluxed for 12 hours. After the reaction was completed, it was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain (E)-3,4,5-trimethoxy-N-((6-(2-( 23 mg of 5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-phenylbenzofuran-3-yl)methylene)aniline (yellow solid, yield 33%). ¹ HNMR (CDCl ₃ ; 300MHz), δ2.416 (s, 3H, CH ₃ ), 3.022-3.067 (t, 2H, CH ₂ CH ₂ , J=6.6Hz), 3.906 (s, 9H, 3OCH ₃ ), 4.327-4.371(t, 2H, CH ₂ CH ₂ , J=6.6Hz), 6.462-6.497(d, 2H, ArH, J=10.5Hz), 6.982(s, 1H, ArH), 6.989-7.145(m, 2H, ArH), 7.425-7.505 (m, 6H, ArH), 7.751-7.769 (m, 2H, ArH), 7.990-8.011 (m, 2H, ArH), 8.784 (s, 1H, CH =N).

Example 25

3,4,5-Trimethoxy-N-((6-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)-2-phenylbenzofuran-3 Synthesis of -yl)methyl)aniline VI ₁₁ (Figure 4): (E)-3,4,5-trimethoxy-N-((6-(2-(5-methyl-2-phenyl Oxazol-4-yl)ethoxy)-2-phenylbenzofuran-3-yl)methylene)aniline (17mg, 0.0289mmol) was dissolved in methanol (5ml) and sodium borohydride (1.65mg , 0.0433mmol) and acetic acid (catalytic amount), stirred at room temperature for 12 hours. After the reaction, the reaction solution was poured into ice water, extracted with dichloromethane, and the organic phases were combined, washed three times with saturated brine, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, it was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain 3,4,5-trimethoxy-N-((6-(2-(5-methyl-2-benzene (oxazol-4-yl)ethoxy)-2-phenylbenzofuran-3-yl)methyl)aniline 17 mg (yellow solid, yield 100%). ¹ HNMR (CDCl ₃ ; 300MHz), δ2.411 (s, 3H, CH ₃ ), 3.016-3.060 (d, 2H, CH ₂ CH ₂ , J=6.6Hz), 3.789 (s, 9H, 3OCH ₃ ), 4.299-4.343(d, 2H, CH ₂ CH ₂ , J=6.6Hz), 5.917(s, 2H, CH), 7.094-7.172(m, 3H, ArH), 7.421-7.476(m, 8H, ArH), 7.774-7.800 (m, 2H, ArH), 7.979-7.994 (m, 2H, ArH).

Embodiment 26, in vitro antibacterial activity research

In order to investigate the antibacterial activity of the new compounds involved in the method, the microbial growth inhibitory activity was evaluated through preliminary antibacterial pharmacological tests.

The specific regulations M7-A6 of the National Committee for Clinical Laboratory Standards (NCCLs) on the drug susceptibility test of each genus of bacteria are adopted, and the specific test steps are as follows:

(1) Bacterial culture

Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, Staphylococcus aureus (drug-resistant), are all cultured using nutrient broth medium;

Inoculate Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, and Staphylococcus aureus (drug-resistant) stored in the refrigerator on the slant of the test tube of the nutrient broth medium, incubate in a bacterial incubator at 37°C, and passage in time , for experimental needs.

(2) Drug configuration

All compounds were dissolved in DMSO to prepare a stock solution with a concentration of 4 mg/ml. 10 μl of the drug solution was added to a 96-well plate, each compound was repeated once, and the 96-well plate was stored at -20°C until use.

(3) Antibacterial test

Take the required microorganisms in the logarithmic growth phase, use McFarland 0.5 turbidimetric tube, adjust the microbial concentration to 1×10 ⁸ cfu/ml, dilute 10 ⁴ times with the culture medium to obtain the concentration of 1×10 ⁴ cfu/ml bacteria liquid. Each compound was dosed at 10 serial concentrations from high to low, and the 96-well culture plates were placed in a microbial incubator at 37°C for 24 hours.

Use a microplate reader to detect the A530 value of each well, calculate the inhibition rate, and use SPSS software to calculate the inhibitory concentration MIC value, the results are shown in Table 1:

Table 1.3-substituted-6-substituted-benzofuran compound antibacterial biological activity test

^a E.coli-Escherichia coli, S.aureus-Staphylococcus aureus, MRSA-Methicillin-resistant Staphylococcus aureus, B.subtilis-Bacillus subtilis, P.aeruginosa-Pseudomonas aeruginosa.

In table 1, (1) "-" means that this antibacterial test has not been done; 2) the positive control drugs of bacteria are cephradine, ceftazidime, cefotaxime sodium and penicillin sodium; the microbial inhibition test results in table 1 are explained : the antibacterial activity of some compounds involved in this method is between 0.78～6.25ug/mL, and has broad-spectrum antibacterial activity, and some activities are better than positive controls ceftazidime, cefotaxime sodium and penicillin sodium; It can be seen from the data in the table that the exposed hydroxyl group at the 6-position of the benzofuran ring has a very important impact on the antibacterial activity of this type of compound, and when the hydroxyl group is shielded by benzyl or hydrophobic chains, the obtained compounds have no antibacterial activity; The 3-position substituent of the benzofuran ring has a decisive effect on the antibacterial selectivity of the benzofuran ring.

Claims (2)

1. the purposes of a kind of 6-(5-methyl-2-substituted phenyl-4-ethoxy oxazole) benzofuran compound in the medicine that is used to inhibit the biological activity of microorganism, it is characterized in that, The structural formula of described benzofuran compound is the structure shown in formula (Ⅷ): Wherein, R ₁₅ is the structure shown in formula (I) or formula (II): When the R ₁₅ is a structure shown in formula (I), Z is O, and R ₆ is hydrogen or a C ₁ -C ₅ alkyl group; when R ₁₅ is a structure shown in formula (II), R ₇ is hydrogen , hydroxyl, alkoxy or aldehyde; R ₁₆ is hydrogen, an aldehyde group or a structure shown in any one of formula (X), formula (XI), and formula (XII): R ₁₇ is hydrogen, R ₁₈ is hydrogen; The said inhibiting the biological activity of microorganisms is specifically inhibiting the biological activity of one or more of Escherichia coli, Staphylococcus aureus, Staphylococcus aureus, Bacillus subtilis and Pseudomonas aeruginosa. 2. The use according to claim 1, characterized in that, the R ₁₅ is a phenyl group, and the R ₁₆ is hydrogen or an aldehyde group.