CN114262324A - Bixazole drug molecule capable of being used for hospital nursing sterilization and application thereof - Google Patents

Abstract

The invention discloses a bisoxazole medicine molecule for sterilization and disinfection in hospital care and a preparation method and application thereof, belonging to the technical field of antibacterial medicine synthesis. The technical scheme provided by the invention has the key points that: the bisoxazole drug molecule has a structure

R is a phenyl compound. The molecular structure of the obtained bisoxazole medicine is novel and has two oxazole ring structures, and the oxazole ring structures have N and O with good hydrophilicity and lipophilic property; triethyl orthoformate is used for providing a carbonyl structure and an amide structure to obtain an oxazole five-membered ring under the action of an activating reagent, and the reaction is simple and efficient; and has good inhibitory effect on staphylococcus aureus.

Description

Bixazole drug molecule capable of being used for hospital nursing sterilization and application thereof

Technical Field

The invention belongs to the technical field of synthesis of medical nursing disinfection drugs, and particularly relates to a bisoxazole drug molecule for sterilization and disinfection in hospital nursing, and a preparation method and application thereof.

Background

The hospital is a place for rescuing and bearing injuries, and the maintenance of the cleanness and the sanitation of the hospital is particularly important. Since there are many patients who come and go every day, the disease of the patient becomes more complicated if any patient is infected due to poor environment. Air microorganisms including many living particles such as bacteria, fungi, viruses and dust mites pollute air after breeding and breeding in a room, and also cause phenomena such as allergy, asthma, dermatitis and the like, and indoor microbial pollution becomes an important environmental sanitation problem. The hospital building has the characteristics of large personnel mobility and relatively centralized patients, and the indoor air contains a large amount of pathogenic and nonpathogenic microorganisms, so that the air environment quality of the hospital is influenced, nosocomial infection is caused, and the risk of the disease of medical care personnel, the patients and healthy people is increased; the air in the hospital room contains pathogenic and nonpathogenic microorganisms, and the pathogenic and nonpathogenic microorganisms enter the human body in the form of microbial aerosol, so nosocomial infection can be caused, and therefore, the air purification and disinfection of the hospital are very important. Researches show that the content of pseudomonas aeruginosa, salmonella, staphylococcus aureus and escherichia coli in medical instruments in hospitals is higher, and a disinfectant liquid needs to be sprayed while high-temperature disinfection is carried out, so that a general powerful disinfectant has a good effect in organic solvents such as ethanol, but the water solubility is not good, and if the ethanol and the like volatilize, the ethanol and the like can remain on the surfaces of the medical instruments and the like, so that the development of the disinfectant with both water solubility and fat solubility is necessary.

Oxazole antibacterial agents are a chemically synthesized antibiotic agent which has been developed gradually in the last 80 th century. Linezolid, for example, is the first oxazolidinone synthetic antibacterial drug approved by the U.S. food and drug administration in the market in 2000, and has excellent antibacterial activity against major gram-positive bacteria including methicillin-resistant staphylococcus aureus, vancomycin-resistant enterococcus coli, and penicillin-resistant streptococcus pneumoniae. Because oxazole has a unique nitrogen-containing and oxygen-containing structure, it has good hydrophilicity and can be used to develop a bactericidal drug which is easily soluble in water.

By means of a hospital biomolecule laboratory, a bisoxazole drug molecule with a novel structure is designed and synthesized, antibacterial activity research is carried out, work accumulation on antibacterial drug development already occurs for many years, and a plurality of patent achievements are obtained, so that the new drug molecule is found to have a certain inhibiting effect on staphylococcus aureus, and the bisoxazole drug molecule has two oxazole ring structures, has certain hydrophilicity, is convenient to clean by water after being sprayed, and is suitable for cleaning work of sterilization and disinfection of medical instruments by hospital medical care personnel.

Disclosure of Invention

The invention solves the technical problem of providing a preparation method of a novel bisoxazole medicine molecule with antibacterial activity, which has simple synthesis method, low raw material price and novel structure.

The invention adopts the following technical scheme for solving the technical problems, and the preparation method of the bisoxazole medicine molecule for sterilization and disinfection in hospital care is characterized by comprising the following specific steps:

(1) 4-chloroaniline is subjected to alkylation and acylation substitution reaction to obtain 4- (dimethylamino) benzaldehyde;

(2) condensing 4- (dimethylamino) benzaldehyde and hydroxylamine hydrochloride, and then chlorinating to obtain 4- (dimethylamino) chlorobenzaldehyde oxime;

(3) reacting 4- (dimethylamino) chlorobenzaldehyde oxime with diethyl oxalate to obtain a single oxazole formate compound;

(4) reacting the single oxazole formic ether compound with phenethylamine derivative to obtain phenethyl-single oxazole formamide compound;

(5) and reacting the phenethyl-single oxazole formamide compound with an orthoformic acid triester compound to obtain a target compound with a double oxazole ring structure.

Further preferably, the specific process of step (1) is as follows: adding a certain amount of 4-chloroaniline, methyl iodide and potassium carbonate into toluene, heating to reflux under the protection of nitrogen, removing water in a reaction system through a water separation device in the reaction process, concentrating a reaction solution after reacting for a period of time, adding ethanol into a concentrate, stirring and dissolving the concentrate, transferring the concentrate into a high-pressure reaction kettle, adding triphenylphosphine, palladium acetate, ferrocene and triethylamine, replacing the inside of the high-pressure kettle for multiple times by using CO, introducing CO to ensure that the pressure in the kettle reaches a certain temperature, heating to a certain temperature, stirring for a period of time, carrying out vacuum concentration, and carrying out silica gel column chromatography separation and purification to obtain 4- (dimethylamino) benzaldehyde; the feeding amount molar ratio of the 4-chloroaniline to the methyl iodide to the potassium carbonate is 1: 2-2.5: 1 to 1.5; the feeding amount molar ratio of the 4-chloroaniline to the triphenylphosphine to the palladium acetate to the ferrocene and the triethylamine is 1: 0.1: 0.1: 0.05: 1; the pressure in the reaction kettle is 0.5-1 MPa; the reaction temperature was 80 ℃.

Further preferably, the specific process of step (2) is as follows: adding a certain amount of 4- (dimethylamino) benzaldehyde and hydroxylamine hydrochloride into N, N-dimethylformamide, stirring for dissolving, adding potassium carbonate, stirring uniformly, heating to 120 ℃, reacting for a period of time, adding N, N-dimethylformamide solution dissolved with N-chlorosuccinimide, keeping the reaction system in nitrogen atmosphere, continuously reacting for a period of time at 120 ℃, cooling to room temperature, filtering the reaction solution, adding saturated sodium chloride solution into the filtrate, stirring, extracting for multiple times by using dichloromethane, combining organic phases, washing by water, and concentrating the reaction solution to obtain 4- (dimethylamino) chlorobenzaldehyde oxime; the feeding amount molar ratio of the 4- (dimethylamino) benzaldehyde to the hydroxylamine hydrochloride to the potassium carbonate is 1: 2; the feeding amount molar ratio of the 4- (dimethylamino) benzaldehyde to the N-chlorosuccinimide is 1: 1 to 1.2.

Further preferably, the specific process of step (3) is as follows: adding a certain amount of 4- (dimethylamino) chlorobenzaldehyde oxime and an alkaline compound into 1, 2-dichloroethane; simultaneously adding a certain amount of sodium borohydride compound and diethyl oxalate into 1, 2-dichloroethane to prepare a mixed solution; then slowly dripping the mixed solution into a reaction system at 0 ℃, stirring after dripping, slowly heating to 45 ℃ under the protection of nitrogen for reaction for a period of time, cooling to room temperature, filtering the reaction solution, adding a saturated sodium chloride solution into the filtrate, then adjusting the pH to be neutral by using dilute hydrochloric acid under the stirring state, filtering the reaction solution again, separating out an organic phase, washing by using water, and concentrating the reaction solution to obtain a mono-oxazole formate compound; the alkaline compound is pyridine or piperidine; the feeding amount molar ratio of the 4- (dimethylamino) chlorobenzaldehyde oxime to the alkaline compound is 1: 1-2, preferably 1: 2; the sodium borohydride compound is sodium triacetoxyborohydride or sodium trimethoxyborohydride; the feeding amount molar ratio of the 4- (dimethylamino) chlorobenzaldehyde oxime to the sodium borohydride compound to the diethyl oxalate is 1: 1-1.1: 1.5.

further preferably, the specific process of step (4) is as follows: adding a certain amount of a mono-oxazole formate compound and a phenethylamine compound into diethyl ether for complete dissolution, placing at 0 ℃, sequentially adding a certain amount of dicyclohexylcarbodiimide and 4-dimethylaminopyridine under the protection of nitrogen, stirring for 30min after the addition is finished, slowly heating to room temperature, then reacting until the raw materials completely react, concentrating a reaction system, and then carrying out silica gel column chromatography separation to obtain a phenethyl-mono-oxazole formamide compound; the molar ratio of the single oxazole formate compound to the phenethylamine compound to the dicyclohexylcarbodiimide to the 4-dimethylamino pyridine is 1: 1: 1.2: 2

Further preferably, the specific process of step (5) is as follows: adding a certain amount of phenethyl-mono-oxazole carboxamide compound and hexamethyldisilazane based amino sodium into tetrahydrofuran solution, placing the tetrahydrofuran solution at-70 ℃, slowly dropwise adding the tetrahydrofuran solution dissolved with orthoformate triester compound under the protection of nitrogen, maintaining the reaction system at-40 ℃ after dropwise adding for reaction for a period of time to return to room temperature, slowly dropwise adding saturated sodium chloride solution into the reaction solution, then vacuum-concentrating the reaction system, adding ethyl acetate, separating out an organic phase, extracting the water phase with ethyl acetate for three times, combining the organic phases, and concentrating the organic phase under reduced pressure to obtain a bisoxazole cyclic compound; the orthoformate compound is triethyl orthoformate or trimethyl orthoformate; the molar ratio of the input amount of the phenethyl-single oxazole formamide compound to the hexamethyldisilazane sodium to the orthoformic acid triester compound is 1: 1: 2.

the invention has the technical advantages that: the target compound obtained by the invention contains two oxazole ring structures, wherein the oxazole ring structures have N and O with good hydrophilicity and lipophilic property; according to the invention, the carbonyl structure can be provided by using triethyl orthoformate, and the carbonyl structure and the amide structure can be used for obtaining the oxazole five-membered ring containing one N and one O under the action of an activating reagent, so that the reaction is simple and efficient, and the condition is mild; the method uses trimethoxy sodium borohydride to catalyze 4- (dimethylamino) chlorobenzaldehyde oxime and diethyl oxalate to cyclize to obtain the single oxazole formate compound, and the reaction is simple and the yield is high; the compound with the double oxazole ring structure obtained by the invention has good bactericidal activity, low toxicity to human body and obvious effect in practical application.

Drawings

FIG. 1 is a graph showing the bacteriostatic effect of the target compound prepared in example 9.

FIG. 2 is a general low resolution mass spectrum of the target compound prepared in example 9.

FIG. 3 is a general low resolution mass spectrum of the target compound prepared in example 10.

FIG. 4 is a liquid phase diagram of the objective compound prepared in example 9.

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 12.7g of 4-chloroaniline, 28.5g of methyl iodide and 14g of potassium carbonate into 500mL of toluene in a reaction bottle with a stirring device and a water distribution device, heating the mixture to reflux under the protection of nitrogen, removing water in a reaction system through the water distribution device in the reaction process, concentrating the reaction solution in vacuum after reacting for 5 hours, adding 600mL of ethanol into the concentrate, stirring and dissolving the concentrate, transferring the concentrate into a high-pressure reaction kettle, adding 2.6g of triphenylphosphine, 3.25g of palladium acetate, 0.93g of ferrocene and 10g of triethylamine, replacing the inside of the high-pressure kettle for multiple times by using CO, introducing CO to enable the pressure in the kettle to reach 1MPa, heating to 80 ℃, stirring for reaction for 9 hours, filtering reaction liquid, adjusting the pH to be neutral by using dilute hydrochloric acid, adding 300mL of dichloromethane for dissolution after vacuum concentration, washing with water, concentrating again, and separating and purifying by silica gel column chromatography to obtain 12.2g of 4- (dimethylamino) benzaldehyde; LC-MS (ESI) M/z 150[ M + H]⁺。

Example 2

Adding 12.7g of 4-chloroaniline, 35.2g of methyl iodide and 21g of potassium carbonate into 800mL of toluene in a reaction bottle with a stirring device and a water diversion device, heating the mixture to reflux under the protection of nitrogen, removing water in a reaction system through the water diversion device in the reaction process, concentrating a reaction solution after reacting for 3.5 hours, adding 900mL of ethanol into a concentrate, stirring and dissolving the concentrate, transferring the concentrate into a high-pressure reaction kettle, adding 2.6g of triphenylphosphine, 3.25g of palladium acetate, 0.93g of ferrocene and 10g of triethylamine, replacing the inside of the high-pressure kettle for multiple times by using CO, introducing CO to ensure that the pressure in the kettle reaches 1MPa, heating the kettle to 80 ℃, stirring and reacting for 9 hours, filtering the reaction solution, adjusting the pH to be neutral by using dilute hydrochloric acid, adding 300mL of dichloromethane after vacuum concentration, dissolving, washing the reaction solution by water and concentrating again,separating and purifying by silica gel column chromatography to obtain 14.3g of 4- (dimethylamino) benzaldehyde; LC-MS (ESI) M/z 150[ M + H]⁺。

Example 3

Adding 15g of 4- (dimethylamino) benzaldehyde and 12g of hydroxylamine hydrochloride into 500mL of N, N-dimethylformamide in a reaction bottle, stirring to dissolve, adding 28g of potassium carbonate, stirring uniformly, heating to 120 ℃, reacting for 1h, then 150mL of N, N-dimethylformamide containing 16g of N-chlorosuccinimide dissolved therein is added through a constant pressure dropping funnel, the reaction system is maintained under the atmosphere of nitrogen, continuously reacting for 3h at 120 ℃, cooling to room temperature, filtering the reaction solution, concentrating the filtrate under vacuum to obtain partial solvent, then adding 300mL of saturated sodium chloride solution, stirring for 30min to enable the system to be in a uniform state, dissolving and extracting for 5 times by using 200mL of dichloromethane, combining organic phases, washing with water, concentrating reaction liquid, and finally separating by silica gel column chromatography to obtain 17.21g of 4- (dimethylamino) chlorobenzaldehyde oxime; LC-MS (ESI) M/z 199[ M + H]⁺(ii) a Calculated value of elemental analysis [ C₉H₁₁ClN₂O]C, 54.42; h, 5.58; n,14.10, found C, 54.49; h, 5.54; n, 14.12.

Example 4

In a reaction bottle with a stirring device, 20g of 4- (dimethylamino) chlorobenzaldehyde oxime, 16g of pyridine and 1.3g of nickel chloride are added into 400mL of 1, 2-dichloroethane; simultaneously adding 21.2g of sodium triacetoxyborohydride and 22g of diethyl oxalate into 400mL of 1, 2-dichloroethane to prepare a mixed solution, and stirring for 30 min; then slowly dripping the mixed solution into a reaction system through a constant pressure dropping funnel at the temperature of 0 ℃, stirring for 20min after dripping, slowly heating to 45 ℃ under the protection of nitrogen for reaction for 2.5h, reducing the temperature to room temperature after TLC monitors that the raw materials are completely reacted, filtering the reaction solution, and filtering the filtrateAdding 300mL of saturated sodium chloride solution, adding 5g of active carbon, adjusting the pH value to be neutral by using dilute hydrochloric acid under a stirring state, filtering the reaction solution again, separating out an organic phase, washing with water, and concentrating the reaction solution to obtain 19.3g of a mono-oxazole formate compound; LC-MS (ESI) M/z 265[ M + H]⁺(ii) a Calculated value of elemental analysis [ C₁₃H₁₆N₂O₄]C, 59.08; h, 6.10; n,10.60, found C, 59.01; h, 6.13; n, 10.64.

Example 5

In a reaction bottle with a stirring device, 20g of 4- (dimethylamino) chlorobenzaldehyde oxime, 17g of piperidine and 1.3g of nickel chloride are added into 500mL of 1, 2-dichloroethane; simultaneously adding 21.2g of sodium triacetoxyborohydride and 22g of diethyl oxalate into 400mL of 1, 2-dichloroethane to prepare a mixed solution, and stirring for 30 min; then slowly dropwise adding the mixed solution into a reaction system at 0 ℃, slowly heating to 45 ℃ under the protection of nitrogen for reaction for 1h, cooling to room temperature after the reaction is finished, filtering the reaction solution, adding 300mL of saturated sodium chloride solution into the filtrate, adding 5g of active carbon, adjusting the pH to be neutral by using dilute hydrochloric acid under a stirring state, filtering the reaction solution again, separating out an organic phase, washing by using water, and concentrating the reaction solution to obtain 24.9g of a mono-oxazole formate compound; LC-MS (ESI) M/z 265[ M + H]⁺(ii) a Calculated value of elemental analysis [ C₁₃H₁₆N₂O₄]C, 59.08; h, 6.10; n,10.60, found C, 59.01; h, 6.13; n, 10.64.

Example 6

In a reaction bottle, 20g of 4- (dimethylamino) chlorobenzaldehyde oxime, 8.5g of piperidine and 1.3g of nickel chloride are added into 400mL of 1, 2-dichloroethane; simultaneously adding 14g of trimethoxy sodium borohydride and 22g of diethyl oxalate into 400mL of 1, 2-dichloroethane to prepare a mixed solution, and stirring for 30 min; however, the device is not suitable for use in a kitchenThen slowly dropwise adding the mixed solution into a reaction system at 0 ℃, slowly heating to 45 ℃ under the protection of nitrogen for reaction for 1.5h, monitoring by TLC that the raw materials are completely reacted, cooling to room temperature, filtering the reaction solution, adding 300mL of saturated sodium chloride solution into the filtrate, adding 5g of active carbon, adjusting the pH to be neutral by using dilute hydrochloric acid under the stirring state, filtering the reaction solution again, separating out an organic phase, washing by water, and concentrating the reaction solution to obtain 23.1g of a mono-oxazole formate compound; LC-MS (ESI) M/z 265[ M + H]⁺(ii) a Calculated value of elemental analysis [ C₁₃H₁₆N₂O₄]C, 59.08; h, 6.10; n,10.60, found C, 59.01; h, 6.13; n, 10.64.

Example 7

Adding 2.65g of mono-oxazole formate compound and 1.7g of 2-nitrophenylethylamine into 200mL of diethyl ether for complete dissolution, placing at 0 ℃, sequentially adding 2.4g of dicyclohexylcarbodiimide and 2.5g of 4-dimethylaminopyridine under the protection of nitrogen, stirring for 30min after the addition is finished, slowly raising to reflux, then reacting for 9h, monitoring by TLC (thin layer chromatography) that raw materials are completely reacted, concentrating a reaction system, adding 100mL of water and 100mL of dichloromethane, stirring, separating out an organic phase, extracting a water phase for multiple times by 50mL of dichloromethane, combining the organic phases, drying, concentrating, and then carrying out silica gel column chromatography to obtain 3.66g of 2-nitrophenylethyl-mono-oxazole carboxamide compound; LC-MS (ESI) M/z 385M + H]⁺；¹H NMR(400MHz,DMSO-d₆):9.49(s,1H),7.93(d,J＝4.0Hz,1H),7.47-7.41(m,3H),7.14(dd,J₁＝4.0Hz,J₂＝4.0Hz,2H),7.01-6.98(m,2H),6.47(s,1H),3.16-3.12(m,2H),3.07(s,6H),2.78(dd,J₁＝4.0Hz,J₂4.0Hz, 2H); calculated value of elemental analysis [ C₁₉H₂₀N₄O₅]C, 59.37; h, 5.24; n,14.58, found C, 59.30; h, 5.27; n, 14.52.

Example 8

Adding 2.65g of mono-oxazole formate compound and 1.8g of 2, 4-difluorophenylethylamine into 200mL of diethyl ether for complete dissolution, placing at 0 ℃, sequentially adding 2.4g of dicyclohexylcarbodiimide and 2.5g of 4-dimethylaminopyridine under the protection of nitrogen, stirring for 30min after the addition is finished, slowly raising the temperature to reflux, reacting for 3.2h, monitoring the reaction of raw materials by TLC (thin layer chromatography), concentrating a reaction system, adding 100mL of water and 100mL of dichloromethane, stirring, separating out an organic phase, extracting a water phase with 50mL of dichloromethane for multiple times, combining the organic phases, drying, concentrating, and carrying out silica gel column chromatography to obtain 3.61g of 2, 4-difluorophenylethyl-mono-oxazole carboxamide compound; LC-MS (ESI) M/z 376[ M + H]⁺；¹H NMR(400MHz,DMSO-d₆):9.52(s,1H),7.46(d,J＝8.0Hz,2H),7.17-7.13(m,2H),7.06(d,J＝4.0Hz,1H),6.99-6.94(m,2H),6.45(s,1H),3.17-3.12(m,2H),3.05(s,6H),2.77(dd,J₁＝4.0Hz,J₂4.0Hz, 2H); calculated value of elemental analysis [ C₁₉H₁₉F₂N₃O₃]C, 60.79; h, 5.10; n,11.19, found C, 60.71; h, 5.13; n, 11.17.

Example 9

Adding 200mL of tetrahydrofuran solution containing 3.9g of 2-nitrophenylethyl-monooxazole carboxamide compound and 1.85g of sodium hexamethyldisilazide into a multi-mouth bottle with a stirrer, placing at-70 ℃, slowly dripping 100mL of tetrahydrofuran solution dissolved with 3g of triethyl orthoformate through a constant-pressure dropping funnel under the protection of nitrogen, slowly heating after dripping, maintaining a reaction system at-40 ℃ for reaction for 4 hours, returning to room temperature, slowly dripping 200mL of saturated sodium chloride solution into the reaction solution, then concentrating the reaction system in vacuum, adding 200mL of ethyl acetate, separating out an organic phase, extracting the water phase for three times by using 50mL of ethyl acetate, combining the organic phases, drying by using 10g of anhydrous magnesium sulfate, concentrating the organic phase under reduced pressure, and finally separating by using silica gel column chromatography (PE: EA ═ 10: 1) to obtain the 2-nitrobenzyl-bis-oxazole cyclization.Compound 3.57 g; the purity is 99.4% by liquid phase detection; LC-MS (ESI) M/z 395[ M + H]⁺；¹H NMR(400MHz,DMSO-d₆) 7.95(d, J ═ 4.0Hz,1H),7.90(s,1H),7.67-7.54(m,3H),7.42(d, J ═ 8.0Hz,1H),7.09-7.07(m,1H),7.00-6.96(m,2H),6.45(s,1H),3.78(s,2H),3.02(s, 6H); calculated value of elemental analysis [ C₂₀H₁₈N₄O₅]C, 60.91; h, 4.60; n,14.21, found C, 60.97; h, 4.63; n, 14.26.

Example 10

Adding 250mL of tetrahydrofuran solution containing 3.8g of 2, 4-difluorophenethyl-single oxazole carboxamide compound and 2.75g of hexamethyldisilazane based amino sodium into a multi-mouth bottle with a stirring device, placing the bottle at-70 ℃, slowly dripping 100mL of tetrahydrofuran solution dissolved with 2.2g of trimethyl orthoformate into a constant-pressure dropping funnel under the protection of nitrogen, slowly heating after dripping, keeping a reaction system at-40 ℃ for reaction for 7.5h, returning to room temperature, slowly dripping 250mL of saturated sodium chloride solution into the reaction solution, then concentrating the reaction system in vacuum, adding 200mL of ethyl acetate, separating out an organic phase, extracting the water phase for three times by using 100mL of ethyl acetate, combining the organic phases, drying by using 15g of anhydrous magnesium sulfate, concentrating the organic phase under reduced pressure, and finally separating by using silica gel column chromatography (PE: EA is 10: 1) to obtain 3.17g of a 2, 4-difluorobenzyl-bis-oxazole cyclic compound; the purity is 98.6 percent through liquid phase detection; LC-MS (ESI) M/z 386[ M + H]⁺；¹H NMR(400MHz,DMSO-d₆):7.91(s,1H),7.61-7.57(m,2H),7.14(t,J₁＝4.0Hz,J₂4.0Hz,1H),7.07-7.02(m,3H),6.96(d, J ═ 8.0Hz,1H),6.45(s,1H),3.79(s,2H),3.05(s, 6H); calculated value of elemental analysis [ C₂₀H₁₇F₂N₃O₃]C, 62.33; h, 4.45; n,10.90, found C, 62.25; h, 4.47; n, 10.94.

Example 11

Staphylococcus aureus (gram positive bacterium) was selected as the test object for antibacterial activity. The radius of the inhibition zone of the two synthesized compounds on staphylococcus aureus is determined by adopting a paper diffusion method. The culture medium is composed of 200mL of water, 2g of casein tryptone, 1g of yeast extract powder, 4g of nutrient agar, 2g of sodium chloride and other nutrient components, and is sterilized by autoclaving for 30 min. Then 10mL of the medium was added to a sterile petri dish (90 mm. times.15 mm). Dipping a bacteria solution (108cfu/mL) obtained by adjusting the turbidity to 0.5 McLeod by a Merrier electron turbidimeter by using a sterile cotton swab, uniformly coating the bacteria solution on a culture medium, soaking the bacteria solution in a dimethyl sulfoxide solution with the compound concentration of 1.0mg/mL by using sterile filter paper, and taking minocycline as a positive control; the filter paper containing the sample is placed on the culture medium and incubated at 37 ℃ for 24h, and the transparent area around the paper is the area to be measured for inhibiting bacteria (the radius of the transparent area is detected in the experiment).

The bacteriostatic effect of the compounds obtained in example 9 and example 10 on staphylococcus aureus, with the radius of the zone of inhibition being 18.47mm and 5.73mm respectively, is found by averaging five parallel experiments, and the result shows that the compound obtained in example 9 shows a certain bacteriostatic sensitivity on staphylococcus aureus, which is close to the level equivalent to minocycline (1.0mg/mL) (the radius of the zone of inhibition is 19.08 mm).

Example 12

The CCK-8 method is used for detecting the influence of different concentrations of target compounds on the cytotoxicity of 293T of human renal epithelial cells: 293T cells in the growth phase are collected, 0.25% trypsin digestion solution is taken to ensure that adherent cells fall off to prepare cell suspension, and the cells in the logarithmic growth phase are inoculated to a 96-well plate according to 2500 cells/well. After plating and incubation in a carbon dioxide incubator for 8h, cells were treated with different concentrations of drug (1 μ M, 4 μ M, 16 μ M, 64 μ M, 256 μ M) for 48 h, with 0.1% DMSO as a negative control. Finally, CCK-8 reagent is added for incubation for 3-4 hours, and the absorbance (OD value) of each well is measured at the wavelength of 450 nm. The cell viability of the negative control group was taken as 100%, and compound IC was calculated using non-linear regression with the aid of Graph Pad Prism 8.0 software₅₀The value is obtained. The results showed that the half inhibitory concentration IC of the target compounds obtained in example 9 and example 10 on 293T cells₅₀The concentration reaches 138 +/-6.7 mu M and 164 +/-4.1 mu M, which indicates that the toxicity is lower.

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 bisoxazole medicine molecule for sterilization and disinfection in hospital care and a preparation method and application thereof are characterized in that the structure of the bisoxazole medicine molecule is as follows:

r is an aryl compound.

2. The bisoxazole medicine molecule for hospital nursing sterilization and disinfection and the preparation method thereof according to claim 1 are characterized in that the specific process is as follows:

(1) 4-chloroaniline is subjected to alkylation and acylation substitution reaction to obtain 4- (dimethylamino) benzaldehyde;

(2) condensing 4- (dimethylamino) benzaldehyde and hydroxylamine hydrochloride, and performing chlorination reaction to obtain 4- (dimethylamino) chlorobenzaldehyde oxime;

(3) 4- (dimethylamino) chlorobenzaldehyde oxime and diethyl oxalate to obtain

(mono-oxazole formate compounds);

(4) the single oxazole formic ether compound and phenethylamine derivative are subjected to amide condensation reaction to obtain

(phenethyl-mono-oxazole carboxamides);

(5) and reacting the phenethyl-single oxazole formamide compound with an orthoformic acid triester compound to obtain a target compound with a double oxazole ring structure.

3. The preparation method of the bisoxazole drug molecule used for sterilization and disinfection in hospital care according to claim 2 is characterized in that the specific process of the step (1) is as follows: adding a certain amount of 4-chloroaniline, methyl iodide and potassium carbonate into toluene, heating to reflux under the protection of nitrogen, removing water in a reaction system through a water separation device in the reaction process, concentrating a reaction solution after reacting for a period of time, adding ethanol into a concentrate, stirring and dissolving the concentrate, transferring the concentrate into a high-pressure reaction kettle, adding triphenylphosphine, palladium acetate, ferrocene and triethylamine, replacing the inside of the high-pressure kettle for multiple times by using CO, introducing CO to ensure that the pressure in the kettle reaches a certain temperature, heating to a certain temperature, stirring for a period of time, carrying out vacuum concentration, and carrying out chromatographic separation and purification by using a silica gel column to obtain 4- (dimethylamino) benzaldehyde; the feeding amount molar ratio of the 4-chloroaniline to the methyl iodide to the potassium carbonate is 1: 2-2.5: 1 to 1.5, preferably 1: 2.5: 1.5; the feeding amount molar ratio of the 4-chloroaniline to the triphenylphosphine to the palladium acetate to the ferrocene and the triethylamine is 1: 0.1: 0.1: 0.05: 1; the pressure in the reaction kettle is 0.5-1 MPa, preferably 1 MPa; the reaction temperature was 80 ℃.

4. The preparation method of the bisoxazole drug molecule used for sterilization and disinfection in hospital care according to claim 2 is characterized in that the specific process of the step (2) is as follows: adding a certain amount of 4- (dimethylamino) benzaldehyde and hydroxylamine hydrochloride into N, N-dimethylformamide, stirring for dissolving, adding potassium carbonate, stirring uniformly, heating to 120 ℃, reacting for a period of time, adding N, N-dimethylformamide solution dissolved with N-chlorosuccinimide, keeping the reaction system in nitrogen atmosphere, continuously reacting for a period of time at 120 ℃, cooling to room temperature, filtering the reaction solution, adding saturated sodium chloride solution into the filtrate, stirring, extracting for multiple times by using dichloromethane, combining organic phases, washing by water, and concentrating the reaction solution to obtain 4- (dimethylamino) chlorobenzaldehyde oxime; the feeding amount molar ratio of the 4- (dimethylamino) benzaldehyde to the hydroxylamine hydrochloride to the potassium carbonate is 1: 2; the feeding amount molar ratio of the 4- (dimethylamino) benzaldehyde to the N-chlorosuccinimide is 1: 1 to 1.2.

5. The preparation method of the bisoxazole drug molecule used for sterilization and disinfection in hospital care according to claim 2 is characterized in that the specific process of the step (3) is as follows: adding a certain amount of 4- (dimethylamino) chlorobenzaldehyde oxime, an alkaline compound and nickel chloride into 1, 2-dichloroethane; simultaneously adding a certain amount of sodium borohydride compound and diethyl oxalate into 1, 2-dichloroethane to prepare a mixed solution; then slowly dripping the mixed solution into a reaction system at 0 ℃, stirring after dripping, slowly heating to 45 ℃ under the protection of nitrogen for reaction for a period of time, cooling to room temperature, filtering the reaction solution, adding a saturated sodium chloride solution into the filtrate, then adjusting the pH to be neutral by using dilute hydrochloric acid under the stirring state, filtering the reaction solution again, separating out an organic phase, washing by using water, and concentrating the reaction solution to obtain a mono-oxazole formate compound; the alkaline compound is pyridine or piperidine; the feeding amount molar ratio of the 4- (dimethylamino) chlorobenzaldehyde oxime to the alkaline compound to the nickel chloride is 1: 1-2: 0.1; the sodium borohydride compound is sodium triacetoxyborohydride or sodium trimethoxyborohydride; the feeding amount molar ratio of the 4- (dimethylamino) chlorobenzaldehyde oxime to the sodium borohydride compound to the diethyl oxalate is 1: 1-1.1: 1.5.

6. the preparation method of the bisoxazole drug molecule used for sterilization and disinfection in hospital care according to claim 2 is characterized in that the specific process of the step (4) is as follows: adding a certain amount of a mono-oxazole formate compound and a phenethylamine compound into diethyl ether for complete dissolution, placing at 0 ℃, sequentially adding a certain amount of dicyclohexylcarbodiimide and 4-dimethylaminopyridine under the protection of nitrogen, stirring for a period of time after the addition till reflux, then reacting until the raw materials react completely, concentrating a reaction system, and then carrying out silica gel column chromatographic separation to obtain a phenethyl-mono-oxazole formamide compound; the molar ratio of the single oxazole formate compound to the phenethylamine compound to the dicyclohexylcarbodiimide to the 4-dimethylamino pyridine is 1: 1-1.1: 1.2: 2.

7. the preparation method of the bisoxazole drug molecule used for sterilization and disinfection in hospital care according to claim 2 is characterized in that the specific process of the step (5) is as follows: adding a certain amount of phenethyl-mono-oxazole carboxamide compound and hexamethyldisilazane based amino sodium into tetrahydrofuran solution, placing the tetrahydrofuran solution at-70 ℃, slowly dropwise adding the tetrahydrofuran solution dissolved with orthoformate triester compound under the protection of nitrogen, maintaining the reaction system at-40 ℃ after dropwise adding for reaction for a period of time to return to room temperature, slowly dropwise adding saturated sodium chloride solution into the reaction solution, then vacuum-concentrating the reaction system, adding ethyl acetate, separating out an organic phase, extracting the water phase with ethyl acetate for three times, combining the organic phases, and concentrating the organic phase under reduced pressure to obtain a bisoxazole cyclic compound; the orthoformate compound is triethyl orthoformate or trimethyl orthoformate; the molar ratio of the input amount of the phenethyl-single oxazole formamide compound to the hexamethyldisilazane sodium to the orthoformic acid triester compound is 1: 1-1.5: 2.

8. the effect of piribazole drug molecules of claim 1 in antibacterial aspects.

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