CN112574215A - Preparation method and application of benzoxazole compound for hospital disinfection - Google Patents
Preparation method and application of benzoxazole compound for hospital disinfection Download PDFInfo
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Abstract
The invention discloses a preparation method and application of benzoxazole compounds for hospital disinfection, and belongs to the technical field of synthesis of antibacterial drugs. The technical scheme provided by the invention has the key points that: the benzoxazole compound has a structure
The 3, 4-dihydro-1 (2H) -naphthalenone is used as an initial raw material, and a benzoxazole compound with a novel structure is obtained through multi-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 inhibition effect of the target compound on escherichia coli and staphylococcus aureus is found to be superior to that of dicillin, so that the target compound 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 a preparation method and application of a benzoxazole compound for hospital disinfection.
Background
The disinfection supply center is an important department in the hospital, and is a department for cleaning, disinfecting, sterilizing and supplying sterile articles for all the reused medical instruments, instruments and articles in each department in the hospital. By strengthening the cleaning management of the multiplexing apparatus, the safety of the diagnosis and treatment activities of the hospital can be ensured, so that the disinfection supply center is the heart of the hospital. For various multiplexing instruments, proper cleaning technology must be selected to ensure the quality of medical instruments.
In order to reduce the chance of nosocomial infections, disinfection must be done. The disinfection supply center plays an important role in controlling nosocomial infections as a professional disinfection department of hospitals. Currently, with the wide application of new technologies and new instruments, the infection probability of hospitals is increased, and the harm is brought to the physical and mental health of medical care personnel and patients. Meanwhile, many disinfection supply centers still adopt the traditional management mode, cannot achieve thorough disinfection, and have great defects.
The disinfection medicine is the most commonly used and important material in disinfection supply centers, for example, the quaternary ammonium salt disinfectant commonly used in various hospitals at present is a surface active disinfectant, and the disinfection and sterilization mechanism of the disinfectant is that quaternary ammonium salt cations are gathered on cell walls under the action of electrostatic force, hydrogen bond force and surfactant molecules, so that important protein molecules and nutrient substances in thalli are leaked out, the respiration and sugar metabolism processes of bacteria are blocked, and then a chamber resistance effect is generated, so that mycoprotein is denatured, the growth of bacteria is inhibited, and bacteria are killed. The ammonium alkyl changes the permeability of bacterial cell membranes by combining with protein molecules on the surfaces of bacteria, and then the bacterial cell structures are damaged by lysis, so that the bacteria die, and the sterilization effect is achieved.
Heterocyclic compounds are the most bulky of organic compounds, and are widely distributed in nature, and the chemical structures of the heterocyclic compounds are also varied, and the heterocyclic compounds have unique properties and purposes. The nitrogen-containing heterocyclic compound has good biological activity and plays an important role in agricultural production such as pesticides and medicines and human health, and a plurality of nitrogen-containing heterocyclic compounds are developed into new pesticides and medical products at present. Benzoxazoles are heterocyclic compounds containing N and O heteroatoms, the heterocyclic compounds have wide application in pharmaceutical chemistry and wide application prospect in the pharmaceutical field, and the compounds have remarkable activities of resisting tumors, inflammation, HIV, bacteria, melatonin receptor antagonists and the like. The benzoxazole derivative not only has wide application in biology, medicine and other fields, but also has unique performance in optical material, high performance composite material and other fields.
A research team develops a benzoxazole disinfectant, and by means of a molecular biology laboratory in hospitals and a gulf stream organism in Henan, the compounds are found to have a certain inhibition effect on gram-positive bacteria and gram-negative bacteria, so that the benzoxazole disinfectant can be dissolved in ethanol and is convenient to use by a hospital disinfection center.
Disclosure of Invention
The invention solves the technical problem of providing a benzoxazole compound which is simple and easy to operate, cheap and easily available in raw materials, high in reaction efficiency and good in antibacterial effect, and a preparation method thereof.
The invention adopts the following technical scheme for solving the technical problems, and the benzoxazole compound for hospital disinfection is characterized by having the following structure:
the preparation method of the benzoxazole compound is characterized in that the compound
The specific preparation process comprises the following steps:
(1) condensing 3, 4-dihydro-1 (2H) -naphthalenone and diethyl oxalate under the action of sodium metal to obtain a compound 2;
(2) carrying out condensation reaction on the compound 2 and hydrazine hydrochloride under the action of alkalinity to obtain a compound 3;
(3) reacting the compound 3 with sodium dichloroisocyanurate under the action of a catalyst to obtain a compound 4;
(4) reacting the compound 4 with trifluoroethanol under the action of an alkaline environment to obtain a compound 5;
(5) carrying out substitution reaction on the compound 5 and hydrazine hydrochloride to obtain a compound 6;
(6) carrying out condensation reaction on the compound 6 and ethyl pyruvate to obtain a compound 7;
(7) carrying out intramolecular rearrangement cyclization on the compound 7 under the action of a catalyst, and then carrying out ester hydrolysis to obtain a compound 8;
(8) the compound 8 and [2- (1, 3-benzoxazol-2-yl) ethyl ] amine hydrochloride are condensed to obtain the target compound.
Further limiting, the specific process of step (1) is as follows: adding a certain amount of metal sodium into dry ethanol, heating to reflux under the protection of nitrogen gas, observing the gradual dissolution of the metal sodium, maintaining the nitrogen atmosphere, under the condition of 50 ℃, slowly adding a certain amount of diethyl oxalate into the reaction system through a constant pressure dropping funnel, cooling to room temperature after the dropwise addition is finished, slowly dropwise adding an ethanol solution dissolved with 3, 4-dihydro-1 (2H) -naphthalenone through the constant pressure dropping funnel, reducing the temperature of the reaction system to 0 ℃ after the reaction system reacts for a period of time at room temperature, adding a certain amount of dichloromethane into the reaction system, slowly dropwise adding a 2N hydrochloric acid solution at the temperature of 0 ℃ to adjust the pH value of the reaction system to 6-7, concentrating the reaction solution, adding dichloromethane into the concentrate to completely dissolve the dichloromethane, washing the concentrate for multiple times with water, separating an organic phase, concentrating, and performing silica gel column chromatography separation to obtain a compound 2; the feeding amount molar ratio of the 3, 4-dihydro-1 (2H) -naphthalenone to the diethyl oxalate to the metal sodium is 1:1: 2.
Further limiting, the specific process of step (2) is as follows: adding a certain amount of compound 2 into a dry solvent in a reaction bottle with a water separator, adding a certain amount of piperidine, carbonate and hydrazine hydrochloride, stirring uniformly, adding zeolite, slowly heating to reflux, removing water generated in the reaction process through the water separator, uniformly dividing the water separator into equal parts, filtering the reaction solution while hot after continuously reacting for a period of time, concentrating the filtrate under a vacuum condition, adding dichloromethane, slowly dropwise adding 2N hydrochloric acid solution at 0 ℃ to adjust the pH value of the reaction system to 8-9, separating out an organic phase, and concentrating to obtain a compound 3; the mass ratio of the compound 2 to the piperidine is 1: 1; the feeding amount molar ratio of the compound 2 to the carbonate to the hydrazine hydrochloride is 1:1: 1.5; the carbonate is potassium carbonate or sodium carbonate or cesium carbonate; the reaction time is 2-8 h.
Further limiting, the specific process of step (3) is as follows: adding a certain amount of a compound 3 into a mixed solution of dichloromethane and trifluoroacetic acid in a reaction bottle with a nitrogen protection device, uniformly stirring at room temperature for a period of time, concentrating a reaction solution, then adding dichloromethane and silver trifluoromethanesulfonate, slowly dropwise adding an acetonitrile solution dissolved with sodium dichloroisocyanurate under the protection of nitrogen, slowly heating to a certain temperature under the protection of nitrogen after dropwise adding, keeping the temperature, stirring for reacting for a period of time, adding a certain amount of phosphate, cooling to 0-10 ℃ after the reaction is finished, slowly dropwise adding water under the protection of nitrogen, controlling the temperature of a reaction system to be not more than 20 ℃, filtering the reaction solution after dropwise adding, adding activated carbon into the reaction solution, filtering the reaction solution while heating, then adjusting the pH of the reaction solution to 4-5 with dilute hydrochloric acid, adding chloroform, stirring for extraction, and then separating an organic phase; washing the organic phase twice with water, washing once with saturated sodium chloride solution, drying with anhydrous magnesium sulfate, filtering, and concentrating to obtain compound 4; the feeding amount molar ratio of the compound 3 to the sodium dichloroisocyanurate is 1: 0.6-1; the volume ratio of the mixed solution of the dichloromethane and the trifluoroacetic acid is VMethylene dichloride:VTrifluoroacetic acid2: 1; the feeding amount molar ratio of the compound 3 to the silver trifluoromethanesulfonate to the phosphate is 10:1: 1-1.5; the phosphate is potassium phosphate or magnesium phosphate; the reaction temperature is 60-80 ℃.
Further limiting, the specific process of step (4) is as follows: adding a certain amount of compound 4 and a certain amount of metal alkoxide and trifluoroethanol into tetrahydrofuran, slowly heating to reflux, monitoring the complete reaction of the raw material compound 4 by TLC, concentrating the reaction solution, adding dichloromethane, washing with water for multiple times, concentrating, and recrystallizing in a mixed solution of acetone and normal hexane to obtain a compound 5; the metal alkoxide is potassium tert-butoxide or sodium tert-butoxide; the feeding amount molar ratio of the compound 4 to the metal alkoxide to the trifluoroethanol is 1: 1-1.5: 1.5.
Further limiting, the specific process of step (5) is as follows: adding a certain amount of compound 5 and triethylamine into dimethyl sulfoxide, adding the mixture into the dimethyl sulfoxide at room temperature, uniformly stirring, slowly dropwise adding a dimethyl sulfoxide solution in which hydrazine hydrochloride is dissolved, heating to 80 ℃ after dropwise adding, cooling to room temperature after TLC (thin layer chromatography) monitoring of raw materials completely reacts, filtering reaction liquid, adding water into filtrate, adding ethyl acetate into the filtrate after stirring for extraction for multiple times, combining organic phases, concentrating under a vacuum condition, and separating a concentrate by silica gel column chromatography to obtain a compound 6; the feeding amount molar ratio of the compound 5 to the triethylamine to the hydrazine hydrochloride is 1:1.5: 1.1.
Further limiting, the specific process of step (6) is as follows: adding a certain amount of compound 6 and ethyl pyruvate into toluene, stirring uniformly at room temperature, adding sodium p-toluenesulfonate, gradually heating to reflux, removing water generated in the reaction process in time, dropwise adding trifluoroacetic acid into the reaction solution under the protection of nitrogen after approximately refluxing for a period of time, stopping heating after continuously refluxing for a period of time, slowly adding a methanol solution dissolved with barium hydroxide into the reaction solution under the protection of nitrogen, continuously refluxing and stirring for a period of time after dropwise adding, pouring water into the filtrate, 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, combining organic phases, drying by using anhydrous magnesium sulfate, concentrating, and performing silica gel column chromatography to obtain a compound 7; the feeding amount molar ratio of the compound 6 to the ethyl pyruvate to the sodium p-toluenesulfonate is 1: 1-1.1: 1; the feeding amount molar ratio of the compound 6 to the trifluoroacetic acid to the barium hydroxide is 1:1: 2-3.
Further limiting, the specific process of step (7) is as follows: adding a certain amount of compound 7 and a catalyst into nitromethane, adding a certain amount of lithium bromide, heating to a certain temperature, stirring for reaction, starting vacuum, and evaporating out the nitromethaneAdding ice water into methyl hydride, stirring, filtering the reaction solution, recrystallizing a filter cake by acetone, adding the filter cake into tetrahydrofuran, adding a certain amount of lithium hydroxide, heating to reflux, cooling to room temperature after the reaction is finished, adjusting the pH of the reaction solution to 4-5 by using dilute hydrochloric acid, separating out an organic phase, extracting a water phase by using dichloromethane for multiple times, combining the organic phases, concentrating and drying to obtain a compound 8; the catalyst is Bi (OTf)3-LiClO4(ii) a The mass ratio of the compound 7 to the catalyst is 5: 1-2; the reaction temperature is 60-80 ℃; the feeding amount molar ratio of the compound 7 to the lithium hydroxide is 1: 1-2.
Further limiting, the specific process of step (8) is as follows: adding a certain amount of compound 8 and [2- (1, 3-benzoxazol-2-yl) ethyl ] amine hydrochloride into N, N-dimethylformamide, adding a certain amount of HATU and DIPEA, heating to 45 ℃, stirring for reacting overnight, monitoring the reaction of raw materials by TLC (thin layer chromatography), concentrating in vacuum, adding dichloromethane, washing with water for multiple times, concentrating an organic phase, and recrystallizing a concentrate by N-hexane to obtain a target compound; the charging amount molar ratio of the compound 8 to the [2- (1, 3-benzoxazol-2-yl) ethyl ] amine hydrochloride to the HATU to the DIPEA is 1:1:1.5: 3.
The invention creatively obtains a benzoxazole compound with a novel structure by taking 3, 4-dihydro-1 (2H) -naphthalenone with low price as an initial raw material through seven-step conventional synthesis reaction, and the compound has a certain inhibition effect on gram-positive bacteria and gram-negative bacteria.
Drawings
FIG. 1 nuclear magnetic hydrogen spectrum of the object compound
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 metal sodium (4.5g) into 200mL of dry ethanol, heating to reflux under the protection of nitrogen, observing that the metal sodium is gradually dissolved, keeping the nitrogen atmosphere, slowly adding diethyl oxalate (15g) into a reaction system through a constant-pressure dropping funnel under the condition of 50 ℃, reacting for a period of time after the dropping is finished, cooling the reaction system to room temperature, slowly dropping 200mL of ethanol solution dissolved with 3, 4-dihydro-1 (2H) -naphthalenone (compound 1, 15g) through the constant-pressure dropping funnel, reacting for 7 hours under the condition of room temperature, cooling to 0 ℃, adding certain dichloromethane into the reaction system, slowly dropping 2N hydrochloric acid solution under the condition of 0 ℃ to adjust the pH of the reaction system to 6-7, concentrating the reaction solution, adding dichloromethane into the concentrate to completely dissolve the concentrate, washing with water for several times, separating organic phase, concentrating, and separating by silica gel column chromatography to obtain compound 2(20.8g), LC-MS (ESI) with M/z 247[ M + H ]]+。
Example 2
Adding a compound 2(25g) into 300mL of dry toluene in a reaction bottle with a water separator, adding 25g of piperidine, 14g of potassium carbonate and 15g of hydrazine hydrochloride, stirring uniformly, adding 2.5g of zeolite, slowly heating to reflux, removing water generated in the reaction process through the water separator, continuously reacting for 2H when no water exists in a water separator, filtering the reaction solution while hot, concentrating the filtrate under vacuum condition, adding 500mL of dichloromethane, slowly dropwise adding 2N hydrochloric acid solution at 0 ℃ to adjust the pH of the reaction system to 8-9, separating an organic phase, and concentrating to obtain a compound 3(18.6g), LC-MS (ESI)]+。
Example 3
In a reaction flask with a water separatorAdding a compound 2(25g) into 600mL of dried tetrahydrofuran, adding 25g of piperidine, 32g of cesium carbonate and 15g of hydrazine hydrochloride, stirring uniformly, adding 2.5g of zeolite, slowly heating to reflux, removing water generated in the reaction process through a water separator, dividing a water separator into equal parts, continuing to react for 6 hours, filtering the reaction solution while hot, concentrating the filtrate under a vacuum condition, adding 500mL of dichloromethane, slowly dropwise adding a 2N hydrochloric acid solution at 0 ℃ to adjust the pH of the reaction system to 8-9, separating an organic phase, and concentrating to obtain a compound 3(21.1g), LC-MS (ESI) M/z 243[ M + H + ESI ]]+。
Example 4
Adding a compound 2(25g) into 300mL of dry toluene in a reaction bottle with a water separator, adding 25g of piperidine, 10g of sodium carbonate and 15g of hydrazine hydrochloride, stirring uniformly, adding 2.5g of zeolite, slowly heating to reflux, removing water generated in the reaction process through the water separator, continuously reacting for 7.5H when no water exists in a water separator, filtering the reaction solution while hot, concentrating the filtrate under vacuum condition, adding 500mL of dichloromethane, slowly dropwise adding a 2N hydrochloric acid solution at 0 ℃ to adjust the pH of the reaction system to 8-9, separating an organic phase, concentrating, and separating and purifying by silica gel column chromatography to obtain a compound 3(11.9g), LC-MS (ESI) M/z 243[ M + H ], (11.]+。
Example 5
Adding compound 3(24g) into a mixed solution of 400mL of dichloromethane and 200mL of trifluoroacetic acid in a reaction bottle with a nitrogen protection device, uniformly stirring at room temperature for 7h, concentrating the reaction solution, then adding 500mL of dichloromethane and 2.6g of silver trifluoromethanesulfonate, slowly dropwise adding 250mL of acetonitrile solution dissolved with 22g of sodium dichloroisocyanurate under the protection of nitrogen, slowly heating to 60 ℃ under the protection of nitrogen after dropwise adding, and keeping the temperatureStirring the mixture at the temperature for reaction for 3 hours, adding potassium phosphate (2g), wherein the reaction system gradually becomes slightly turbid, and monitoring by TLC that the compound 3 is completely reacted; then cooling to 0-10 ℃, slowly dripping 120mL of water under the protection of nitrogen, controlling the temperature of a reaction system not to exceed 20 ℃, filtering the reaction solution after dripping, adding 10g of activated carbon into the reaction solution, heating to 40 ℃, stirring for 20min, filtering the reaction solution while the reaction solution is hot, then adjusting the pH of the reaction solution to 4-5 by using dilute hydrochloric acid, adding 300mL of chloroform, stirring and extracting, and then separating an organic phase; washing the organic phase twice with 20mL of water, washing once with 80mL of saturated sodium chloride solution, drying with anhydrous magnesium sulfate, filtering, and concentrating to obtain compound 4(15.7 g); LC-MS (ESI) M/z 205[ M + H]+；1H NMR(400MHz,DMSO-d6):δ12.31(s,1H),7.74-7.71(m,1H),7.29-7.25(m,2H),7.13(d,J＝8.0Hz,1H),2.92-2.85(m,4H)。
Example 6
Adding a compound 3(24g) into a mixed solution of 400mL of dichloromethane and 200mL of trifluoroacetic acid in a reaction bottle with a nitrogen protection device, uniformly stirring at room temperature for 7h, concentrating the reaction solution, then adding 500mL of dichloromethane and 2.6g of silver trifluoromethanesulfonate, slowly dropwise adding 250mL of acetonitrile solution dissolved with 22g of sodium dichloroisocyanurate under the protection of nitrogen, slowly heating to 60 ℃ under the protection of nitrogen after dropwise adding, keeping the temperature, stirring for reaction for 3h, adding 4g of magnesium phosphate, showing that the reaction system gradually presents slight turbidity, and monitoring by TLC that the compound 3 is completely reacted; then cooling to 0-10 ℃, slowly dripping 200mL of water under the protection of nitrogen, controlling the temperature of a reaction system not to exceed 20 ℃, filtering the reaction solution after dripping, adding 10g of activated carbon into the reaction solution, heating to 40 ℃, stirring for 20min, filtering the reaction solution while the reaction solution is hot, then adjusting the pH of the reaction solution to 4-5 by using dilute hydrochloric acid, adding 300mL of chloroform, stirring and extracting, and then separating an organic phase; washing the organic phase twice with 20mL of water, washing once with 80mL of saturated sodium chloride solution, drying with anhydrous magnesium sulfate, filtering, and concentratingTo give compound 4(17.1 g); LC-MS (ESI) M/z 205[ M + H]+；1H NMR(400MHz,DMSO-d6):δ12.31(s,1H),7.74-7.71(m,1H),7.29-7.25(m,2H),7.13(d,J＝8.0Hz,1H),2.92-2.85(m,4H)。
Example 7
Adding a compound 3(24g) into a mixed solution of 400mL of dichloromethane and 200mL of trifluoroacetic acid in a reaction bottle with a nitrogen protection device, uniformly stirring at room temperature for 7h, concentrating the reaction solution, then adding 500mL of dichloromethane and 2.6g of silver trifluoromethanesulfonate, slowly dropwise adding 150mL of acetonitrile solution dissolved with 13.5g of sodium dichloroisocyanurate under the protection of nitrogen, slowly heating to 80 ℃ under the protection of nitrogen after dropwise adding, keeping the temperature, stirring for reaction for 3h, and then adding potassium phosphate (2g) and continuing to react for 5 h; then cooling to 0-10 ℃, slowly dripping 120mL of water under the protection of nitrogen, controlling the temperature of a reaction system not to exceed 20 ℃, filtering the reaction solution after dripping, adding 10g of activated carbon into the reaction solution, heating to 40 ℃, stirring for 20min, filtering the reaction solution while the reaction solution is hot, then adjusting the pH of the reaction solution to 4-5 by using dilute hydrochloric acid, adding 300mL of chloroform, stirring and extracting, and then separating an organic phase; washing the organic phase twice with 20mL of water, washing once with 80mL of saturated sodium chloride solution, drying with anhydrous magnesium sulfate, filtering, concentrating, and purifying by column chromatography to obtain compound 4(9.2 g); LC-MS (ESI) M/z 205[ M + H]+；1H NMR(400MHz,DMSO-d6):δ12.31(s,1H),7.74-7.71(m,1H),7.29-7.25(m,2H),7.13(d,J＝8.0Hz,1H),2.92-2.85(m,4H)。
Example 8
In a reaction flask, compound 4(20g), potassium tert-butoxide (11g) and trifluoroethanol (15g) were added to tetrahydrofuran 300mL, slowly warmed to reflux, reacted for 1h, and TLC monitored the starting compound4, concentrating the reaction solution after completion of the reaction, adding 300mL of dichloromethane, washing with 50mL of water for a large amount, concentrating, and recrystallizing in 300mL of a mixture of acetone and n-hexane (V acetone: V n-hexane ═ 3:1) to obtain compound 5(24.1 g); LC-MS (ESI) M/z 269[ M + H]+；1H NMR(400MHz,CDCl3) Delta 12.63(s,1H),7.69-7.66(m,1H),7.31-7.28(m,2H),7.17-7.15(m,1H),4.62(s,2H),2.87-2.81(m, 4H); calculated value of elemental analysis [ C13H11F3N2O]C, 58.21; h, 4.13; n,10.44, found C, 58.12; h, 4.16; n, 10.38.
Example 9
In a reaction flask, adding compound 4(20g) and a certain amount of sodium tert-butoxide (14.5g) and trifluoroethanol (15g) into 500mL of tetrahydrofuran, slowly heating to reflux, reacting for 2.5h, monitoring by TLC that the reaction of the raw material compound 4 is complete, concentrating the reaction solution, adding 300mL of dichloromethane, washing with 50mL of water for a while, concentrating, then pulping in a mixed solution of acetone and n-hexane (V acetone: V n-hexane ═ 3:1)300mL, recrystallizing and washing to obtain compound 5(19.3 g); LC-MS (ESI) M/z 269[ M + H]+；1H NMR(400MHz,CDCl3) Delta 12.63(s,1H),7.69-7.66(m,1H),7.31-7.28(m,2H),7.17-7.15(m,1H),4.62(s,2H),2.87-2.81(m, 4H); calculated value of elemental analysis [ C13H11F3N2O]C, 58.21; h, 4.13; n,10.44, found C, 58.12; h, 4.16; n, 10.38.
Example 10
In a reaction bottle, adding compound 5(26g) and triethylamine (15g) into 300mL of dimethyl sulfoxide, adding and stirring uniformly at room temperature, then slowly dropwise adding 150mL of dimethyl sulfoxide solution dissolved with hydrazine hydrochloride (11g), heating to 80 ℃ after dropwise adding, and monitoring by TLC that the raw materials completely reactThen, cooling to room temperature, filtering the reaction solution, adding 500mL of water into the filtrate, stirring, adding 100mL of ethyl acetate, extracting for 5 times, combining organic phases, concentrating under vacuum (vacuum is realized by an oil pump), and separating the concentrate by silica gel column chromatography to obtain a compound 6(17.4 g); LC-MS (ESI) M/z 201[ M + H]+。
Example 11
In a reaction flask, compound 6(20g) and ethylpyruvate (13g) were added to 300mL of toluene, under the condition of room temperature, after being stirred evenly, sodium p-toluenesulfonate (2g) is added, then the temperature is gradually increased to reflux, water generated in the reaction process is removed in time, the reflux reaction is carried out for about 3 hours, trifluoroacetic acid (1.2g) is dripped into the reaction liquid under the protection of nitrogen, the heating is stopped after the reflux reaction is continued for 1h, then, under the protection of nitrogen, 100mL of methanol solution dissolved with barium hydroxide (5.0g) is slowly added into the reaction solution, after the dropwise addition is finished, the reflux stirring reaction is continued for 3 hours, then, 200mL of water was added to the filtrate, the pH of the reaction solution was adjusted to neutral with dilute hydrochloric acid, then extracting the reaction solution for multiple times by using 50mL of dichloromethane, combining organic phases, drying by using anhydrous magnesium sulfate, concentrating, and performing silica gel column chromatography to obtain a compound 7(24.8 g); LC-MS (ESI) M/z 299[ M + H [)]+。
Example 12
In a reaction flask, compound 7(30g) and Bi (OTf)3-LiClO4Adding 6g of the mixture into 600mL of nitromethane, adding 50mL of nitromethane solution dissolved with 0.9g of lithium bromide, heating to 75 ℃, stirring for reaction for 1h, filtering the reaction solution while the reaction solution is hot, starting vacuum evaporation to remove nitromethane, adding 1000mL of ice water, stirring for 10min, filtering the reaction solution, recrystallizing and washing a filter cake with 350mL of acetone, adding 500mL of tetrahydrofuran, adding 4.8g of lithium hydroxide, heating to reflux, reacting for 3h, cooling to room temperatureAdjusting the pH of the reaction solution to 4-5 with dilute hydrochloric acid, separating out an organic phase, extracting a water phase with 50mL of dichloromethane for multiple times, combining the organic phases, concentrating, and drying to obtain a compound 8(17.4 g);1H NMR(400MHz,CDCl3):δ12.79(s,1H),8.36(s,1H),7.69(d,J＝12.0Hz,1H),7.25-7.19(m,2H),7.11(d,J＝4.0Hz,1H),2.94-2.87(m,4H)。
example 13
In a reaction flask, compound 7(30g) and Bi (OTf)3-LiClO4Adding 12g of the mixture into 800mL of nitromethane, adding 50mL of nitromethane solution dissolved with 0.9g of lithium bromide, heating to 80 ℃, stirring for reaction for 1h, filtering the reaction solution while the reaction solution is hot, starting vacuum evaporation to remove nitromethane, adding 1000mL of ice water, stirring for 10min, then carrying out suction filtration on the reaction solution, recrystallizing and washing a filter cake with 400mL of acetone, adding 500mL of tetrahydrofuran, adding 4.8g of lithium hydroxide, heating to reflux, reacting for 3h, cooling to room temperature, adjusting the pH of the reaction solution to 4-5 with dilute hydrochloric acid, separating out an organic phase, extracting a water phase with 50mL of dichloromethane for multiple times, combining the organic phases, concentrating and drying to obtain a compound 8(22.7 g);1H NMR(400MHz,CDCl3):δ12.79(s,1H),8.36(s,1H),7.69(d,J＝12.0Hz,1H),7.25-7.19(m,2H),7.11(d,J＝4.0Hz,1H),2.94-2.87(m,4H)。
example 14
In a reaction flask, compound 8(25g) and [2- (1, 3-benzoxazol-2-yl) ethyl ] ethyl]Adding amine hydrochloride (20g) into 1200mL of N, N-dimethylformamide, then adding HATU (57g) and DIPEA (40g), heating to 45 ℃, stirring for reacting overnight, monitoring the reaction completion of raw materials by TLC, concentrating in vacuum, then adding 1000mL of dichloromethane, washing for multiple times by 200mL of water, separating out an organic phase, concentrating, and recrystallizing the concentrate by N-hexane to obtain 34g of a target compound; LC-MS (ESI) M/z 398[ M + H]+；1H NMR(400MHz,DMSO-d6):δ13.51(s,1H),12.22(s,1H),8.43(s,1H),7.64(d,J＝8.0Hz,1H),7.47(s,2H),7.29-7.16(m,3H),7.13-7.10(m,2H),3.69(d,J＝4.0Hz,2H),3.08(t,J1＝8.0Hz,J2＝8.0Hz,2H),2.89-2.78(m,4H)。
Example 15
And (3) testing antibacterial activity: the antibacterial activity of the benzoxazole compounds on escherichia coli and staphylococcus aureus is tested by an oxford cup agar diffusion method; preparing a dimethyl sulfoxide solution with the concentration of benzoxazole compounds being 1mg/mL, taking the dimethyl sulfoxide solution of penicillin with the concentration of 1mg/mL as a positive control, and taking a solvent dimethyl sulfoxide 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.
After five times of experiments, the diameter of the inhibition zone of the benzoxazole compound on escherichia coli is 22.97mm, the diameter of the inhibition zone on staphylococcus aureus is 24.72mm, and the inhibition zones are superior to those of dicillin (14.7mm and 22.5 mm).
The above embodiments are only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and any modifications made on the basis of the technical scheme according to the technical idea of the present invention fall within the protection scope of the present invention.
Claims (10)
1. A preparation method and application of benzoxazole compounds for hospital disinfection are characterized in that the benzoxazole compounds have the following structure:
2. according to claim 2The preparation method of the benzoxazole compound for hospital disinfection is characterized by comprising the following specific steps: adding a certain amount of metal sodium into dry ethanol, heating to reflux under the protection of nitrogen gas, observing the gradual dissolution of the metal sodium, maintaining the nitrogen atmosphere, under the condition of 50 ℃, slowly adding a certain amount of diethyl oxalate into the reaction system through a constant pressure dropping funnel, cooling to room temperature after the dropwise addition is finished, slowly dropwise adding an ethanol solution dissolved with 3, 4-dihydro-1 (2H) -naphthalenone through the constant pressure dropping funnel, reducing the temperature of the reaction system to 0 ℃ after the reaction system reacts for a period of time at room temperature, adding a certain amount of dichloromethane into the reaction system, and then slowly dropwise adding a 2N hydrochloric acid solution at the temperature of 0 ℃ to adjust the pH value of the reaction system to 6-7, concentrating the reaction solution, adding dichloromethane into the concentrate to completely dissolve the dichloromethane, washing the concentrate for multiple times with water, separating an organic phase, concentrating, and performing silica gel column chromatography separation to obtain the compound.
The feeding amount molar ratio of the 3, 4-dihydro-1 (2H) -naphthalenone to the diethyl oxalate to the metal sodium is 1:1: 2.
3. The preparation method of benzoxazole compound for hospital sterilization according to claim 2, characterized by comprising the following steps: in a reaction bottle with a water separator, a certain amount of
Adding the mixture into a dry solvent, adding a certain amount of piperidine, carbonate and hydrazine hydrochloride, stirring uniformly, adding zeolite, slowly heating to reflux, removing water generated in the reaction process through a water separator, uniformly dividing the water into equal parts, no water appears in a water separator, continuously reacting for a period of time, filtering the reaction solution while the reaction solution is hot, concentrating the filtrate under vacuum condition, adding dichloromethane, slowly dropwise adding 2N hydrochloric acid solution at 0 ℃ to adjust the pH of the reaction system to 8-9, separating an organic phase, and concentrating to obtain the product
Said
The mass ratio of the material to the piperidine is 1: 1; said
The feeding amount of the carbonate and the hydrazine hydrochloride is 1:1:1.5 in a molar ratio; the carbonate is potassium carbonate or sodium carbonate or cesium carbonate; the reaction time is 2-8 h.
4. The preparation method of benzoxazole compound for hospital sterilization according to claim 2, characterized by comprising the following steps: in a reaction flask with nitrogen protection device, adding a certain amount of
Adding the mixture into a mixed solution of dichloromethane and trifluoroacetic acid, uniformly stirring at room temperature for a period of time, concentrating a reaction solution, then adding dichloromethane and silver trifluoromethanesulfonate, slowly dropwise adding an acetonitrile solution in which sodium dichloroisocyanurate is dissolved under the protection of nitrogen, slowly heating to a certain temperature under the protection of nitrogen after dropwise adding, keeping the temperature, stirring, reacting for a period of time, adding a certain amount of phosphate, cooling to 0-10 ℃ after reaction, slowly dropwise adding water under the protection of nitrogen, controlling the temperature of a reaction system to be not more than 20 ℃, filtering the reaction solution after dropwise adding, adding activated carbon into the reaction solution, filtering the reaction solution while hot after heating, then adjusting the pH of the reaction solution to 4-5 by using dilute hydrochloric acid, adding chloroform, stirring and extracting, and then separating an organic phase; washing the organic phase twice with water, washing with saturated sodium chloride solution once, drying with anhydrous magnesium sulfate, vacuum filtering, and concentrating to obtain the final product
Said
The feeding amount of the sodium dichloroisocyanurate is 1: 0.6-1 in molar ratio; the volume ratio of the mixed solution of the dichloromethane and the trifluoroacetic acid is VMethylene dichloride:VTrifluoroacetic acid2: 1; said
The feeding amount of the silver trifluoromethanesulfonate to the phosphate is 10:1: 1-1.5 in molar ratio; the phosphate is potassium phosphate or magnesium phosphate; the reaction temperature is 60-80 ℃.
5. The preparation method of benzoxazole compound for hospital sterilization according to claim 2, characterized by comprising the following steps: a certain amount of
Adding a certain amount of metal alkoxide and trifluoroethanol into tetrahydrofuran, slowly heating to reflux, concentrating the reaction solution after the reaction is finished, adding dichloromethane, washing with water for multiple times, concentrating, and recrystallizing in a mixed solution of acetone and n-hexane to obtain the product
The metal alkoxide is potassium tert-butoxide or sodium tert-butoxide; said
The molar ratio of the metal alkoxide to the feeding amount of the trifluoroethanol is 1: 1-1.5: 1.5.
6. The preparation method of benzoxazole compound for hospital sterilization according to claim 2, characterized by comprising the following steps: a certain amount of
And triethylamine is added to dimethyl sulfoxide inAdding into dimethyl sulfoxide solution dissolved with hydrazine hydrochloride, stirring at room temperature, slowly adding dropwise dimethyl sulfoxide solution dissolved with hydrazine hydrochloride, heating to 80 deg.C, reacting, cooling to room temperature, filtering the reaction solution, adding water into the filtrate, stirring, extracting with ethyl acetate for several times, mixing organic phases, concentrating under vacuum, and separating the concentrate by silica gel column chromatography to obtain the final product
Said
The feeding amount of the triethylamine and the hydrazine hydrochloride is 1:1.5:1.1 in molar ratio.
7. The preparation method of benzoxazole compound for hospital sterilization according to claim 2, characterized by comprising the following steps: a certain amount of
Adding ethyl pyruvate and ethyl pyruvate into toluene, stirring uniformly at room temperature, adding sodium p-toluenesulfonate, gradually heating to reflux, removing water generated in the reaction process in time, carrying out reflux reaction for a period of time, dropwise adding trifluoroacetic acid into the reaction solution under the protection of nitrogen, continuing reflux reaction for a period of time, stopping heating, slowly adding a methanol solution dissolved with barium hydroxide into the reaction solution under the protection of nitrogen, after dropwise adding, continuing reflux stirring reaction for a period of time, pouring water into the filtrate, 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, combining organic phases, drying by using anhydrous magnesium sulfate, concentrating, and carrying out silica gel column chromatography to obtain the sodium p-toluenesulfonate-ethyl pyruvate
Said
With pyruvic acid ethyl esterThe feeding amount of the sodium p-toluenesulfonate is 1: 1-1.1: 1 in a molar ratio; said
The feeding amount of the sodium trifluoroacetate and the barium hydroxide is 1:1: 2-3 in molar ratio.
8. The preparation method of benzoxazole compound for hospital sterilization according to claim 2, characterized by comprising the following steps: a certain amount of
Adding a catalyst into nitromethane, adding a certain amount of lithium bromide, heating to a certain temperature, filtering a reaction solution while the reaction solution is hot after stirring reaction, then evaporating the nitromethane in vacuum, adding ice water, filtering the reaction solution after stirring, recrystallizing a filter cake by acetone, adding the filter cake into tetrahydrofuran, adding a certain amount of lithium hydroxide, heating to reflux, cooling to room temperature after the reaction is finished, adjusting the pH of the reaction solution to 4-5 by using dilute hydrochloric acid, separating an organic phase, extracting a water phase by using dichloromethane for multiple times, combining the organic phases, concentrating, and drying to obtain the lithium bromide-free nitromethane
The catalyst is Bi (OTf)3-LiClO4(ii) a Said
The mass ratio of the catalyst to the feeding amount of the catalyst is 5: 1-2; the reaction temperature is 60-80 ℃; said
The feeding amount of the lithium hydroxide is 1: 1-2 in molar ratio.
9. The preparation method of benzoxazole compound for hospital sterilization according to claim 2, characterized by comprising the following steps:a certain amount of
And [2- (1, 3-benzoxazol-2-yl) ethyl]Adding amine hydrochloride into N, N-dimethylformamide, adding a certain amount of HATU and DIPEA, heating to 45 deg.C, stirring for reaction overnight, vacuum concentrating after reaction, adding dichloromethane, washing with water for several times, vacuum concentrating organic phase, and recrystallizing with N-hexane
Said
With [2- (1, 3-benzooxazol-2-yl) ethyl]The feeding amount molar ratio of the amine hydrochloride to the HATU to the DIPEA is 1:1:1.5: 3.
10. The benzoxazole compound of claim 1 that has antibacterial effect.
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