CN111559985A - Oxazolone compound with bactericidal effect and preparation method thereof - Google Patents
Oxazolone compound with bactericidal effect and preparation method thereof Download PDFInfo
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
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Abstract
The invention discloses an oxazolone compound with bactericidal activity and a preparation method thereof, belonging to the technical field of synthesis of antibacterial drugs. The technical scheme provided by the invention has the key points that: the oxazolone compound has a structure
The 3-hydroxyacetophenone and 4-methylbenzaldehyde are used as starting materials, and an oxazolone compound with a novel structure is obtained through four-step reaction, so that the synthesis method is simple, and the reaction yield is high. Antibacterial activity tests are carried out by an oxford cup agar diffusion method, and the antibacterial activity tests show that the target compound has a far better inhibition effect on escherichia coli than that of oxacillin, has an inhibition effect on staphylococcus aureus close to that of oxacillin, and has potential as a broad-spectrum antibacterial drug.
Description
Technical Field
The invention belongs to the technical field of antibacterial drug synthesis, and particularly relates to an oxazolone compound with a bactericidal effect and a preparation method thereof.
Background
Since the discovery of penicillin in 1928, antibiotics become common medicines for treating various diseases in clinic. While the variety and the quantity of antibiotics are updated, the selection difficulty of the drugs and the situations of excessive drugs, abuse and the like are increased under the influence of various human and objective factors, and both gram-positive bacteria and gram-negative bacteria have serious drug resistance. In addition, the bacteria obtain exogenous drug-resistant genes through horizontal transfer, and the generation of drug-resistant strains is accelerated. In 2006 Science was reported that a staphylococcus aureus strain stored in the laboratory in 1930 was sensitive to currently clinically used antibiotics, while a staphylococcus aureus strain isolated from a patient was resistant to almost all antibiotics, and this resistance exhibited multiple resistance mechanisms to different classes of antibiotics in the same bacterium. According to the statistics of the world health organization, about 5 ten thousand patients die from infectious diseases every day in the world, and the human health and social development are seriously threatened, so that the high attention of people is attracted. Among them, the resistance problem of multi-resistant bacteria is particularly prominent, which brings great difficulty to clinical treatment. In the face of the vicious circle of 'drug resistance-new drug development-drug resistance', and the existing drugs are still difficult to effectively control the infection of novel drug-resistant bacteria, pharmaceutical chemists are struggling to develop novel drug-resistant bacteria resistant drugs, design and screen novel antibacterial drugs with brand new structures, unique action mechanisms or new action targets, or hybrid drugs with other drugs. The oxazolidinone antibacterial drug is a novel antibacterial drug developed in nearly 30 years, is a totally synthesized antibacterial drug on the market after sulfonamide and quinolone antibacterial drugs, has the efficacy of inhibiting multiple drug-resistant gram-positive bacteria, and has antibacterial activity on methicillin-resistant staphylococcus aureus, staphylococcus epidermidis, vancomycin-resistant enterococcus, penicillin-resistant streptococcus and anaerobic bacteria. The oxazolidinone antibacterial drug has a unique action mechanism, can inhibit the initial stage of protein synthesis, has no cross drug resistance with other antibacterial drugs, is concerned and has good prospects.
The oxazolone structure is a five-membered heterocyclic lactone compound, such as 2-oxazolidinone, does not need to be independently existed like oxazinone, and the unique and stable five-membered lactone structure enables the compound to have wide biological activity, for example, the compound can be used as a bacterial protein synthesis inhibitor and has a unique action mechanism different from other antibacterial drugs. By inhibiting the combination of ribosome and mRNA in the initial stage of bacterial protein synthesis, the upstream segment of the 3' end of the sequence combined with ribosome in mRNA can not be identified, and the initial translation process of bacterial protein synthesis is blocked to play a role in bacteriostasis. Oxazolidinones bind to the a site of the 50s subunit and do not bind to the fMet-tRNA to form a 70s functional initial complex, which is an important step in the bacterial translation process, thereby inhibiting bacterial protein synthesis and producing antibacterial effects. If the 70s complex has formed, binding to oxazolidinone inhibits movement of the peptide chain from the A site to the P site, thereby blocking bacterial protein synthesis.
Therefore, the invention takes 2-hydroxyacetophenone and 4-methylbenzaldehyde as initial raw materials, an oxazolone compound with a novel structure is obtained through four-step reaction, antibacterial activity test is carried out on staphylococcus aureus, the method is simple and efficient, and the obtained drug molecules have better antibacterial effect.
Disclosure of Invention
The invention solves the technical problem of providing an oxazolone compound with bactericidal activity and a preparation method thereof.
The invention adopts the following technical scheme for solving the technical problems, and the oxazolone compound with bactericidal activity is characterized by having the following structure:
the invention adopts the following technical scheme for solving the technical problems, and the preparation method of the oxazolone compound with bactericidal activity is characterized by comprising the following specific steps:
(1) condensing 3-hydroxyacetophenone and 4-methylbenzaldehyde under an alkaline condition to obtain 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1 ketone;
(2) performing alkylation reaction on 1- (3-methoxybenzene) propyl-2-alkenyl-1-ketone and 4-methyliodibenzene under the action of a catalyst, and then demethylating to obtain 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1-ketone
(3) Epoxidizing the 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1 ketone under the action of peroxide to obtain (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) methanone;
(4) the (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) ketone and formamide are subjected to condensation addition reaction under the action of a catalyst to obtain 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -ketone;
(5) and reacting the 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -ketone with an isocyanate compound to obtain the target compound.
Further limiting, the specific process of step (1) is as follows: adding a certain amount of 3-hydroxyacetophenone into a certain amount of solvent, adding a certain amount of 4-methylbenzaldehyde and an alkaline compound, slowly heating to reflux, pouring the reaction liquid into water after reacting for a period of time, adjusting the pH of the reaction liquid to be neutral by using dilute hydrochloric acid, extracting for multiple times by using dichloromethane or ethyl acetate, combining organic phases, and separating and purifying by silica gel column chromatography to obtain 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1-ketone; the solvent is toluene or methanol; the alkaline compound is sodium methoxide or potassium hydroxide; the feeding amount molar ratio of the 3-hydroxyacetophenone, the 4-methylbenzaldehyde and the alkaline compound is 1:1.1: 1.1-2.
Further limiting, the specific process of step (2) is as follows: adding a certain amount of 1- (3-methoxybenzene) prop-2-alkenyl-1-one and triethylamine into N, N-dimethylformamide, adding a certain amount of catalyst, heating to a certain temperature under the protection of nitrogen, adding 4-methyl iodobenzene, filtering reaction liquid after complete reaction, pouring filtrate into water, adding dichloromethane for extraction for multiple times, combining organic phases, washing with saturated saline solution, concentrating, adding tetrahydrofuran, adding lithium bromide, heating to reflux, reacting for a period of time, filtering reaction liquid, concentrating, and separating by silica gel column chromatography to obtain a compound 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1-one; the catalyst is triphenylphosphine and palladium acetate; the reaction temperature is 60-90 ℃; the feeding amount molar ratio of the 1- (3-methoxy phenyl) propyl-2-alkenyl-1-ketone to the 4-methyl iodobenzene to the triethylamine is 1:1.1: 1.1; the feeding amount molar ratio of the 1- (3-methoxy phenyl) propyl-2-alkenyl-1-ketone to the triphenylphosphine to the palladium acetate is 1:0.1: 0.1; the mass ratio of the 1- (3-methoxybenzene) prop-2-enyl-1-one to the lithium bromide is 1: 1-1.5.
Further limiting, the specific process of step (3) is as follows: adding a certain amount of 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1 ketone into a certain solvent, adding a certain amount of alkaline compound, peroxide and manganese dioxide, stirring and reacting at a certain temperature under an oxygen atmosphere, concentrating the reaction solution under a vacuum condition after the reaction is finished, adding water for washing, extracting for multiple times by using ethyl acetate, combining organic phases, washing by using saturated saline solution, concentrating, and performing chromatographic separation and purification by using a silica gel column to obtain (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) methanone; the solvent is methanol or dichloromethane; the alkaline compound is sodium hydroxide or sodium bicarbonate; the peroxide is m-chloroperoxybenzoic acid or peroxytrifluoroacetic acid; the certain temperature is 0-25 ℃; the feeding amount molar ratio of the 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1 ketone to the alkaline compound to the peroxide is 1: 2-3: 1-5, and the feeding amount mass ratio of the 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1 ketone to the manganese dioxide is 10: 1-2.
Further limiting, the specific process of step (4) is as follows: adding a certain amount of (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) ketone and zeolite into formamide and toluene, adding a cerium catalyst and 1, 8-diazabicycloundec-7-ene, slowly heating to a certain reaction temperature under a nitrogen atmosphere, continuously carrying out toluene reflux to remove water generated by the reaction, adding water into a reaction solution after the reaction is finished, slowly cooling to room temperature, adding ethyl acetate into the reaction solution, stirring for a period of time, separating an organic phase, extracting the water phase with ethyl acetate for multiple times, combining the organic phases, concentrating, and recrystallizing with methanol and cyclohexane to obtain 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -one; the cerium catalyst is cerium chloride, cerium acetate or cerium aluminate; the feeding amount molar ratio of the (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) ketone to the cerium catalyst is 1: 0.1-0.3; the reaction temperature is 80-100 ℃; the charging amount molar ratio of the (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) ketone to the 1, 8-diazabicycloundec-7-ene is 10: 1-5.
Further limiting, the specific process of step (5) is as follows: under the protection of nitrogen, adding a certain amount of 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -ketone and triethylamine into a solvent, adding dichloromethane solution dissolved with 3, 4-dimethoxyphenyl isocyanate at a reverse room temperature, reacting for a period of time at a certain temperature, adding the solution into water, adjusting the pH of the reaction solution to be neutral by using dilute hydrochloric acid, extracting the reaction solution for multiple times by using dichloromethane after stirring at the room temperature, combining organic phases, filtering the reaction solution, drying by using anhydrous magnesium sulfate, and concentrating to obtain a target compound; the charging amount molar ratio of the 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -ketone to the triethylamine to the 3, 4-dimethoxyphenyl isocyanate is 1:2: 1.1; the solvent is dichloromethane or toluene; the reaction temperature is 20-50 ℃.
The invention has the following beneficial effects: the invention synthesizes an oxazolone compound with a novel structure through a new method, designs a method for efficiently synthesizing a five-membered lactone oxazolone ring, and finds that a target compound has good antibacterial effect through an oxford cup method for antibacterial activity test.
Drawings
FIG. 1 nuclear magnetic hydrogen spectrum of oxazolone compounds
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
Adding 13.5g of 3-hydroxyacetophenone into 150mL of toluene in a reaction bottle with a water separator, stirring and dissolving, then adding 12g of 4-methylbenzaldehyde and 11g of sodium methoxide, slowly heating to reflux, discharging water generated in the reaction process through the water separator in the reflux reaction process, after reacting for 3h, monitoring the complete reaction of raw materials by TLC (thin layer chromatography), evaporating to remove 50mL of toluene under reduced pressure under vacuum condition, then pouring the reaction liquid into 200mL of water, adjusting the pH of the reaction liquid to be neutral by using dilute hydrochloric acid, then extracting for 3 times by using 100mL of dichloromethane, merging organic phases, and then carrying out silica gel column chromatography separation and purification to obtain 18.1g of 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1 ketone; LC-MS (ESI) M/z 239[ M + H]+。
Example 2
Adding 13.5g of 3-hydroxyacetophenone into 150mL of toluene in a reaction bottle with a water separator, stirring and dissolving, adding 12g of 4-methylbenzaldehyde and 5.5g of sodium methoxide, slowly heating to reflux, discharging water generated in the reaction process through the water separator in the reflux reaction process, keeping the reflux reaction for 11h, evaporating 50mL of toluene under reduced pressure under a vacuum condition, pouring the reaction liquid into 200mL of water, adjusting the pH of the reaction liquid to be neutral by using dilute hydrochloric acid, extracting for 3 times by using 100mL of dichloromethane, combining organic phases, and performing silica gel column chromatography separation and purification to obtain 9.4g of 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1 ketone; LC-MS (ESI) M/z 239[ M + H]+。
Example 3
Adding 13.5g of 3-hydroxyacetophenone into 200mL of methanol in a reaction flask, stirring to dissolve, adding 12g of 4-methylphenylacetal and 11.5g of potassium hydroxide, slowly heating to reflux, carrying out reflux reaction for 15h, concentrating the reaction solution, adding 250mL of water, extracting with 50mL of ethyl acetate for multiple times, combining organic phases, washing with saturated saline, concentrating, and carrying out silica gel column chromatography to obtain 14.5g of a compound 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1-one; LC-MS (ESI) M/z 239[ M + H]+。
Example 4
In a reaction flask, 3-hydroxy is putAdding 13.5 of acetophenone into 200mL of methanol, stirring for dissolving, adding 12g of 4-methylphenylacetal and 8g of potassium hydroxide, slowly heating to reflux, concentrating the reaction solution after reflux reaction for 19h, adding 250mL of water, extracting for multiple times by using 50mL of ethyl acetate, merging organic phases, washing by using saturated saline solution, concentrating, and carrying out silica gel column chromatography to obtain 16.6g of a compound 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1-one; LC-MS (ESI) M/z 239[ M + H]+。
Example 5
Adding 16.5g of 1- (3-methoxybenzene) prop-2-alkenyl-1-ketone and 10g of triethylamine into 150mL of N, N-dimethylformamide, adding 2.6g of triphenylphosphine and 2.2g of palladium acetate at 0 ℃, slowly heating to 60 ℃ under the protection of nitrogen, raising the temperature for 2 hours, stirring for 1 hour, adding 170mL of N, N-dimethylformamide solution dissolved with 22g of p-iodotoluene, continuously stirring for reaction for 4 hours, monitoring the reaction completion of raw materials by TLC, filtering the reaction solution, pouring the filtrate into water, adding dichloromethane for extraction for multiple times, mixing organic phases, washing with saturated saline solution, concentrating, adding 200mL of tetrahydrofuran, adding 16.5g of lithium bromide, heating to reflux, reacting for 6 hours, filtering the reaction solution, concentrating, and separating by silica gel column chromatography to obtain 1- (3-hydroxyphenyl) -3- (tolyl) -2-ketone -alkenyl-1-one 17.5 g; LC-MS (ESI) M/z 239[ M + H]+。
Example 6
Adding 16.5g of 1- (3-methoxybenzene) prop-2-alkenyl-1-ketone and 10g of triethylamine into 150mL of N, N-dimethylformamide in a reaction bottle, adding 2.6g of triphenylphosphine and 2.2g of palladium acetate at 0 ℃, heating to 90 ℃ under the protection of nitrogen, raising the temperature for 3h, stirring for 1h, adding 170mL of N, N-dimethylformamide solution dissolved with 22g of p-iodotoluene, continuously stirring for reaction for 3.5h, filtering the reaction solution, pouring the filtrate into water, adding 100mL of dichloromethane for extraction for multiple times, mixing organic phases, washing with saturated saline solution, concentrating, adding 200mL of tetrahydrofuran, adding 16.5g of lithium bromide, heating to reflux, reacting for 4h, filtering, reacting, and filteringConcentrating, and separating by silica gel column chromatography to obtain 19.9g of 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1-ketone; LC-MS (ESI) M/z 239[ M + H]+。
Example 7
In a reaction apparatus equipped with a cooler, 24g of 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1-one was charged into 300mL of methylene chloride, 17g of sodium hydrogencarbonate and 2.4g of manganese dioxide were further added, stirring evenly at 0 ℃, quickly adding 200mL of dichloromethane solution dissolved with 20g of m-chloroperoxybenzoic acid into a reaction system under the protection of oxygen, keeping the temperature at 0-10 ℃, reacting for 15h, monitoring the complete reaction of raw materials by TLC, adding 150mL of water, then heating to 50 ℃, stirring for 30min, cooling, filtering reaction liquid, removing dichloromethane by vacuum concentration, extracting for multiple times by using 50mL of ethyl acetate, merging organic phases, then adding 3g of activated carbon, stirring at 50 deg.C for 20min, filtering, washing with saturated saline, and concentrating to obtain (3-hydroxyphenyl) (3- (tolyl) oxyethylene-2-yl) methanone 12.6 g; LC-MS (ESI) M/z 255[ M + H]+；1H NMR(400MHz,DMSO-d6):7.81-7.78(m,2H),7.59(s,1H),7.45(dd,J1＝4.0Hz,J2＝4.0Hz,2H),7.27(dd,J1＝4.0Hz,J2＝4.0Hz,2H),7.09(d,J＝8.0Hz,1H),6.07(s,1H),4.66(d,J＝12.0Hz,1H),4.59(d,J＝12.0Hz,1H),2.31(s,3H)。
Example 8
Adding 24g of 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1 ketone into 300mL of dichloromethane in a reaction device with cooling, adding 17g of sodium bicarbonate and 2.4g of manganese dioxide, stirring uniformly at 0 ℃, quickly adding 200mL of dichloromethane solution dissolved with 26g of peroxytrifluoroacetic acid into a reaction system under the protection of oxygen, reacting for 11h while maintaining the temperature of 0-10 ℃, adding 150mL of water, heating to 50 ℃, stirring for 30min, cooling, filtering the reaction solution, concentrating under vacuum to remove dichloromethane, extracting for multiple times by using 50mL of ethyl acetate, combining organic phases, adding 3g of activated carbon, stirring for 20min at 50 ℃, washing with saturated saline after filtering, concentrating, and performing silica gel column chromatographyChromatographic separation and purification to obtain 7.7g of (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) methanone; LC-MS (ESI) M/z 255[ M + H]+；1H NMR(400MHz,DMSO-d6):7.81-7.78(m,2H),7.59(s,1H),7.45(dd,J1＝4.0Hz,J2＝4.0Hz,2H),7.27(dd,J1＝4.0Hz,J2＝4.0Hz,2H),7.09(d,J＝8.0Hz,1H),6.07(s,1H),4.66(d,J＝12.0Hz,1H),4.59(d,J＝12.0Hz,1H),2.31(s,3H)。
Example 9
In a reaction apparatus equipped with a cooler, 24g of 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1-one was charged into 300mL of methylene chloride, and 17g of sodium hydrogencarbonate and 4.8g of manganese dioxide were further added, stirring evenly at 0 ℃, quickly adding 200mL of dichloromethane solution dissolved with 26g of peroxytrifluoroacetic acid into a reaction system under the protection of oxygen, keeping the temperature at 0-10 ℃, reacting for 11h, adding 150mL of water, then heating to 50 ℃, stirring for 30min, cooling, filtering reaction liquid, removing dichloromethane by vacuum concentration, extracting for multiple times by using 50mL of ethyl acetate, merging organic phases, then adding 3g of activated carbon, stirring at 50 deg.C for 20min, filtering, washing with saturated saline, concentrating, separating and purifying by silica gel column chromatography to obtain 11.4g of (3-hydroxyphenyl) (3- (tolyl) oxyethylene-2-yl) methanone; LC-MS (ESI) M/z 255[ M + H]+；1H NMR(400MHz,DMSO-d6):7.81-7.78(m,2H),7.59(s,1H),7.45(dd,J1＝4.0Hz,J2＝4.0Hz,2H),7.27(dd,J1＝4.0Hz,J2＝4.0Hz,2H),7.09(d,J＝8.0Hz,1H),6.07(s,1H),4.66(d,J＝12.0Hz,1H),4.59(d,J＝12.0Hz,1H),2.31(s,3H)。
Example 10
In a reaction bottle with a water separator, 25g of (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) methanone and 2.5g of porous zeolite were added to 150mL of formamide and 150mL of toluene, and the mixture was heated to reflux to separate water in the reaction system, then 7.5g of cerium chloride and 7.5g of 1, 8-diazabicycloundecen-7-ene were added, and the reaction was carried out by continuing toluene reflux under a nitrogen atmosphereReacting generated water for 5 hours, monitoring the reaction completion of raw materials by TLC, filtering reaction liquid, concentrating the reaction liquid, cooling to room temperature, adding 200mL of ethyl acetate and 180mL of water into the reaction liquid, stirring for 1 hour at 40 ℃, then separating out an organic phase, extracting a water phase for multiple times by using 20mL of ethyl acetate, combining the organic phases, concentrating, placing the concentrated organic phase into 80mL of methanol and 40mL of cyclohexane, stirring at 0 ℃ to separate out solids, and performing suction filtration to obtain 17.4g of 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -ketone with a stable five-membered heterocyclic ring 2-oxazolone structure;1H NMR(400MHz,DMSO-d6):8.42(s,1H),7.68(t,J1＝4.0Hz,J2＝4.0Hz,1H),7.55(d,J＝8.0Hz,1H),7.39-7.35(m,2H),7.24(dd,J1＝8.0Hz,J2＝4.0Hz,2H),7.02-6.98(m,2H),5.58(s,1H),3.73(s,2H),2.34(s,3H)。
example 11
Adding 25g of (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) ketone and 2.5g of porous zeolite into 150mL of formamide and 150mL of toluene in a reaction bottle with a water separator, heating to reflux to separate water in a reaction system, then adding 3.2g of cerium acetate and 7.5g of 1, 8-diazabicycloundecen-7-ene, continuously carrying out toluene reflux under a nitrogen atmosphere to carry out water generated by the reaction, reacting for 9h, monitoring the completion of the raw material reaction by TLC, filtering the reaction solution, concentrating the reaction solution, cooling to room temperature, adding 200mL of ethyl acetate and 180mL of water into the reaction solution, stirring for 1h at 40 ℃, then separating an organic phase, extracting the aqueous phase with 20mL of ethyl acetate for multiple times, combining the organic phases, concentrating, placing into 80mL of methanol and 40mL of cyclohexane, stirring at 0 ℃ to separate out a solid, and performing suction filtration to obtain 21.9g of 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -ketone;1H NMR(400MHz,DMSO-d6):8.42(s,1H),7.68(t,J1＝4.0Hz,J2＝4.0Hz,1H),7.55(d,J＝8.0Hz,1H),7.39-7.35(m,2H),7.24(dd,J1＝8.0Hz,J2＝4.0Hz,2H),7.02-6.98(m,2H),5.58(s,1H),3.73(s,2H),2.34(s,3H)。
example 12
In a reaction flask equipped with a water trap, 25g of (3-hydroxyphenyl) (3- (tolyl) oxyethylene-2-yl) methanone and porous zeolite 2 were placedAdding 5g of the mixture into 150mL of formamide and 150mL of toluene, heating to reflux, separating water in a reaction system, then adding 2.2g of cerium aluminate and 7.5g of 1, 8-diazabicycloundecen-7-ene, continuously carrying out toluene reflux under the nitrogen atmosphere to take out water generated by the reaction, reacting for 3h, monitoring the complete reaction of the raw materials by TLC, filtering the reaction solution, concentrating the reaction solution, cooling to room temperature, adding 200mL of ethyl acetate and 180mL of water into the reaction solution, stirring for 1h at 40 ℃, then separating out an organic phase, extracting the water phase for multiple times by using 20mL of ethyl acetate, combining the organic phases, concentrating, placing into 80mL of methanol and 40mL of cyclohexane, stirring at 0 ℃ to separate out a solid, and performing suction filtration to obtain 25.4g of 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -ketone;1H NMR(400MHz,DMSO-d6):8.42(s,1H),7.68(t,J1＝4.0Hz,J2＝4.0Hz,1H),7.55(d,J＝8.0Hz,1H),7.39-7.35(m,2H),7.24(dd,J1＝8.0Hz,J2＝4.0Hz,2H),7.02-6.98(m,2H),5.58(s,1H),3.73(s,2H),2.34(s,3H)。
example 13
Adding 28g of 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -ketone, 10g of triethylamine and 300mL of dichloromethane into a four-necked bottle under the protection of nitrogen, stirring at room temperature for 30min, then adding 150mL of dichloromethane solution dissolved with 18g of 3, 4-dimethoxyphenyl isocyanate, continuing to stir at room temperature for 8H, then adding the mixture into 500mL of water, adjusting the pH of the reaction solution to be neutral by using diluted hydrochloric acid, stirring at room temperature for 30min, separating out an organic phase, extracting the reaction solution for 5 times by using 200mL of dichloromethane, combining the organic phases, drying by using anhydrous magnesium sulfate, and concentrating to obtain 31.6g of oxazolone compound; LC-MS (ESI) M/z 461[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.82(s,1H),8.44(s,1H),8.15(s,1H),7.53-7.41(m,3H),7.26-7.12(m,5H),6.83(d,J＝8.0Hz,2H),4.26(s,2H),3.77-3.69(m,6H)“3.77(s,3H),3.69(s,3H)”,2.28(s,3H)。
Example 14
Under the protection of nitrogen, toAdding 28g of 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -ketone, 10g of triethylamine and 150mL of toluene into a four-mouth bottle, adding 150mL of toluene solution dissolved with 18g of 3, 4-dimethoxyphenyl isocyanate under the protection of nitrogen at room temperature, slowly heating to 50 ℃, stirring for reaction for 1H, heating in vacuum to concentrate partial toluene, adding the partial toluene into 500mL of water, adjusting the pH of a reaction solution to be neutral by using diluted hydrochloric acid, stirring for 30min at room temperature, extracting the reaction solution for 5 times by using 200mL of dichloromethane, combining organic phases, drying by using anhydrous magnesium sulfate, and concentrating to obtain 40.2g of oxazolone compound; LC-MS (ESI) M/z 461[ M + H ]]+；1H NMR(400MHz,DMSO-d6):8.82(s,1H),8.44(s,1H),8.15(s,1H),7.53-7.41(m,3H),7.26-7.12(m,5H),6.83(d,J＝8.0Hz,2H),4.26(s,2H),3.77-3.69(m,6H)“3.77(s,3H),3.69(s,3H)”,2.28(s,3H)。
Example 15
And (3) testing antibacterial activity: the antibacterial activity of the oxazolone compounds on escherichia coli and staphylococcus aureus is tested by an oxford cup agar diffusion method; a dimethyl sulfoxide solution with the compound concentration of 1mg/mL, penicillin with the concentration of 1mg/mL is used as a positive control, and a dimethyl sulfoxide solvent is used as a blank control; each sample is cultured for 24h at 37 ℃ in a repeated way for 5 times, in the culture process, on one hand, the test bacteria start to grow, on the other hand, the antibiotics are diffused in a spherical shape, and the closer to the cup, the higher the antibiotic concentration is, and the farther from the cup, the smaller the antibiotic concentration is. As the concentration of the antibiotic is reduced, a minimum inhibitory concentration zone exists, bacteria cannot grow in the zone range and are in a transparent circle, namely an 'inhibitory zone', and the inhibitory diameter is taken as the average value.
As can be seen from the table above, the inhibition effect of the oxazolone target compound on escherichia coli is far better than that of oxacillin, the inhibition effect on staphylococcus aureus is close to that of oxacillin, and the oxazolone target compound has the potential of being used as a broad-spectrum antibacterial drug.
The foregoing embodiments illustrate the principles, principal features and advantages of the invention, and it will be understood by those skilled in the art that the invention is not limited to the foregoing embodiments, which are merely illustrative of the principles of the invention, and that various changes and modifications may be made therein without departing from the scope of the principles of the invention.
Claims (8)
1. A preparation method of oxazolone compounds with bactericidal activity is characterized in that the oxazolone compounds have the following structures:
2. the oxazolone compound with bactericidal activity according to claim 1, characterized in that the oxazolone compound is prepared by the following steps:
(1) condensing 3-hydroxyacetophenone and 4-methylbenzaldehyde under an alkaline condition to obtain 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1 ketone;
(2) performing alkylation reaction on the 1- (3-methoxybenzene) propyl-2-alkenyl-1-ketone and 4-methyliodibenzene under the action of a catalyst, and then performing demethylation to obtain 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1-ketone;
(3) epoxidizing the 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1 ketone under the action of peroxide to obtain (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) methanone;
(4) the (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) ketone and formamide are subjected to condensation addition reaction under the action of a catalyst to obtain 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -ketone;
(5) and reacting 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -ketone with 3, 4-dimethoxyphenyl isocyanate to obtain the target compound.
3. The method for producing oxazolone compounds according to claim 2, characterized in that: the step (1) is as follows: adding a certain amount of 3-hydroxyacetophenone into a certain amount of solvent, adding a certain amount of 4-methylbenzaldehyde and an alkaline compound, slowly heating to reflux, pouring the reaction liquid into water after reacting for a period of time, adjusting the pH of the reaction liquid to be neutral by using dilute hydrochloric acid, extracting for multiple times by using dichloromethane or ethyl acetate, combining organic phases, and separating and purifying by silica gel column chromatography to obtain 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1-ketone; the solvent is toluene or methanol; the alkaline compound is sodium methoxide or potassium hydroxide; the feeding amount molar ratio of the 3-hydroxyacetophenone, the 4-methylbenzaldehyde and the alkaline compound is 1:1.1: 1.1-2.
4. The method for producing oxazolone compounds according to claim 2, characterized in that: the step (2) is as follows: adding a certain amount of 1- (3-methoxybenzene) prop-2-alkenyl-1-ketone and triethylamine into N, N-dimethylformamide, adding a certain amount of catalyst, heating to a certain temperature under the protection of nitrogen, adding 4-methyl iodobenzene, filtering reaction liquid after complete reaction, pouring filtrate into water, adding dichloromethane for extraction for multiple times, combining organic phases, washing with saturated saline solution, concentrating, adding tetrahydrofuran, adding lithium bromide, heating to reflux, reacting for a period of time, filtering reaction liquid, concentrating, and performing chromatographic separation by using a silica gel column to obtain 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1-ketone; the catalyst is triphenylphosphine and palladium acetate; the reaction temperature is 60-80 ℃; the feeding amount molar ratio of the 1- (3-methoxy phenyl) propyl-2-alkenyl-1-ketone to the 4-methyl iodobenzene to the triethylamine is 1:1.1: 1.1; the feeding amount molar ratio of the 1- (3-methoxy phenyl) propyl-2-alkenyl-1-ketone to the triphenylphosphine to the palladium acetate is 1:0.1: 0.1; the mass ratio of the 1- (3-methoxybenzene) prop-2-enyl-1-one to the lithium bromide is 1: 1-1.5.
5. The method for producing oxazolone compounds according to claim 2, characterized in that: the step (3) is as follows: adding a certain amount of 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1 ketone into a certain solvent, adding a certain amount of alkaline compound, peroxide and manganese dioxide, stirring and reacting at a certain temperature under an oxygen atmosphere, concentrating the reaction solution under a vacuum condition after the reaction is finished, adding water for washing, extracting for multiple times by using ethyl acetate, combining organic phases, washing by using saturated saline solution, concentrating, and performing chromatographic separation and purification by using a silica gel column to obtain (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) methanone; the solvent is methanol or dichloromethane; the alkaline compound is sodium hydroxide or sodium bicarbonate; the peroxide is m-chloroperoxybenzoic acid or peroxytrifluoroacetic acid; the certain temperature is 0-25 ℃; the feeding amount molar ratio of the 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1 ketone to the alkaline compound to the peroxide is 1: 2-3: 1-5; the charging amount mass ratio of the 1- (3-hydroxyphenyl) -3- (tolyl) -2-alkenyl-1 ketone to the manganese dioxide is 10: 1-2.
6. The method for producing oxazolone compounds according to claim 2, characterized in that: the step (4) is as follows: adding a certain amount of (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) ketone and zeolite into formamide and toluene, adding a cerium catalyst and 1, 8-diazabicycloundec-7-ene, slowly heating to a certain reaction temperature under a nitrogen atmosphere, continuously carrying out toluene reflux to remove water generated by the reaction, adding water into a reaction solution after the reaction is finished, slowly cooling to room temperature, adding ethyl acetate into the reaction solution, stirring for a period of time, separating an organic phase, extracting the water phase with ethyl acetate for multiple times, combining the organic phases, concentrating, and recrystallizing with methanol and cyclohexane to obtain 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -one; the cerium catalyst is cerium chloride, cerium acetate or cerium aluminate; the feeding amount molar ratio of the (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) ketone to the cerium catalyst is 1: 0.1-0.3; the reaction temperature is 80-100 ℃; the charging amount molar ratio of the (3-hydroxyphenyl) (3- (tolyl) ethylene oxide-2-yl) ketone to the 1, 8-diazabicycloundec-7-ene is 10: 1-5.
7. The method for producing oxazolone compounds according to claim 2, characterized in that: the step (5) is as follows: under the protection of nitrogen, adding a certain amount of 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -ketone and triethylamine into a solvent, adding dichloromethane solution dissolved with 3, 4-dimethoxyphenyl isocyanate at a reverse room temperature, reacting for a period of time at a certain temperature, adding the solution into water, adjusting the pH of the reaction solution to be neutral by using dilute hydrochloric acid, extracting the reaction solution for multiple times by using dichloromethane after stirring at the room temperature, combining organic phases, filtering the reaction solution, drying by using anhydrous magnesium sulfate, and concentrating to obtain a target compound; the feeding amount molar ratio of the 4- (3-hydroxyphenyl) -5- (4-methylbenzyl) oxazole-2 (3H) -ketone to triethylamine to the 3, 4-dimethoxyphenyl isocyanate is 1: 1-2: 1-1.1; the solvent is dichloromethane or toluene; the reaction temperature is 20-50 ℃.
8. The oxazolone compound of claim 1 has antibacterial effect.
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