CN110878061B - 2-aryl substituted benzoxazoline compound and synthesis method and application thereof - Google Patents

2-aryl substituted benzoxazoline compound and synthesis method and application thereof Download PDF

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CN110878061B
CN110878061B CN201911299077.2A CN201911299077A CN110878061B CN 110878061 B CN110878061 B CN 110878061B CN 201911299077 A CN201911299077 A CN 201911299077A CN 110878061 B CN110878061 B CN 110878061B
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compound
formula
pharmaceutical composition
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otf
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CN110878061A (en
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陈丽萍
周慧
单丹
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Shenzhen Guangxi biological science and Technology Co.,Ltd.
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Yangzhou Polytechnic Institute
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57Aryl or substituted aryl radicals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
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Abstract

The invention relates to aThe 2-aryl substituted benzoxazoline compound has a structure shown in formula I:
Figure DDA0002319338220000011
wherein R is1、R2Each independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and the like; m and n are each independently selected from integers of 0 to 4. The preparation method comprises the following steps:

Description

2-aryl substituted benzoxazoline compound and synthesis method and application thereof
Technical Field
The invention belongs to the field of drug design and synthesis, and particularly relates to a 2-aryl substituted benzoxazoline compound and a synthesis method and application thereof.
Background
Benzoxazole, oxazolone, oxazoline and oxazolidine structures are important structural units in medicines, pesticides, dyes and organic synthesis, and the compounds show various biological activities and are widely concerned by chemists. The invention provides a construction method of a novel and efficient benzoxazoline skeleton, and a series of 2-aryl substituted benzoxazoline antibacterial compounds are obtained simultaneously.
Disclosure of Invention
The invention provides a 2-aryl substituted benzoxazoline compound with a structure shown in formula I or a pharmaceutically acceptable salt thereof, which is characterized in that the structure shown in formula I is as follows:
Figure BDA0002319338210000011
wherein R is1、R2Each independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, and the like; m and n are each independently selected from integers of 0 to 4.
Another embodiment of the present invention provides that the 2-aryl substituted benzoxazolines of the structure of formula I above are selected from the following compounds 1-3:
Figure BDA0002319338210000012
another embodiment of the present invention provides a method for preparing a 2-aryl substituted benzoxazoline compound having the structure of formula I, characterized by comprising the following steps:
Figure BDA0002319338210000013
reacting a compound of formula II with a compound of formula III in an organic solvent under the action of a catalyst to obtain a compound of formula I, wherein R1、R2M and n are as defined above.
The organic solvent is preferably one or more of DMF, acetonitrile, dioxane, toluene, methanol, tert-butanol, chloroform and 1, 2-dichloroethane; the catalyst is selected from the group consisting of trifluoromethanesulfonate, preferably AgOTf, Cu (OTf)2、Zn(OTf)2、Mg(OTf)2、Fe(OTf)3、Al(OTf)3One or more of the above; the reaction temperature is preferably from 60 ℃ to reflux temperature; the molar ratio of the compound of formula II to the compound of formula III is preferably 1-4:1, and the amount of catalyst used is 2% to 15%, preferably 5% to 10%, of the molar amount of the compound of formula III.
In another embodiment, the present invention provides the use of the 2-aryl substituted benzoxazolines of formula I or pharmaceutically acceptable salts thereof as described above for the preparation of antibacterial agents. The antibacterial agent is preferably against gram-positive bacteria including bacillus subtilis ATCC9372, sensitive staphylococcus aureus (s.aureus ATCC 25923); the gram-negative bacteria are bacterial infections such as Escherichia coli (E.coli ATCC 25922).
Another embodiment of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition comprises the 2-aryl substituted benzoxazoline compound with the structure of formula I or its pharmaceutically acceptable salt as an active ingredient. The pharmaceutical composition may optionally further comprise other antibacterial agents. The pharmaceutical composition also comprises pharmaceutically acceptable auxiliary materials. The dosage form of the pharmaceutical composition is selected from tablets, capsules or injections.
Detailed Description
In order to facilitate a further understanding of the invention, the following examples are provided to illustrate it in more detail. However, these examples are only for better understanding of the present invention and are not intended to limit the scope or the principle of the present invention, and the embodiments of the present invention are not limited to the following.
Example 1
Figure BDA0002319338210000021
Dissolving compound 11(1mmol) and compound 12(3mmol) in 1, 2-dichloroethane (50mL), adding Cu (OTf)2(0.15mmol), heating to 70 ℃, stirring for reaction overnight, detecting by TLC that the compound 11 completely disappears, concentrating the reaction solution, and performing silica gel column chromatography (ethyl acetate/petroleum ether: 1/30-1/15) to obtain 203mg of yellow solid, namely the compound 1, with the yield of about 87.1%, and ESI-MS M/z 256.1[ M + Na 256.1 ]]+1H NMR(CDCl3,400MHz)δ:6.96-6.91(m,2H),6.85(t,J=8.3Hz,2H),6.65(d,J=9.1Hz,3H),4.68(s,1H).13C NMR(CDCl3,100MHz)δ:164.5,159.2,144.7,134.2,129.6,125.2,115.8,114.6,114.3,108.2,107.9,103.5,86.4.
Example 2
Figure BDA0002319338210000031
Dissolving compound 13(1mmol) and compound 14(2mmol) in dioxane (40mL), adding Zn (OTf)2(0.2mmol), heating to reflux temperature for 8 hours, detecting by TLC that compound 13 completely disappears, concentrating the reaction solution, and performing silica gel column chromatography (ethyl acetate/petroleum ether: 1/30-1/20) to obtain 191mg of yellow solid, namely compound 2, with yield of about 82.4%, ESI-MS M/z 254.0[ M + Na + 1/30-1/20 ]]+1H NMR(CDCl3,400MHz)δ:7.26(dd,J=4.5,12.0Hz,1H),7.10(t,J=7.9Hz,2H),6.92(d,J=7.7Hz,2H),6.82(s,2H),6.71(s,1H),4.82(s,1H).13C NMR(CDCl3,100MHz)δ:142.6,138.3,130.6,129.3,127.6,127.5,126.2,120.8,116.8,115.3,85.7.
Example 3
Figure BDA0002319338210000032
Compound 15(1mmol) and compound 14(4mmol) were dissolved in chloroform (50mL), and Fe (OTf) was added3(0.08mmol), heating to 60 deg.C for 12 hr, detecting by TLC that compound 15 completely disappears, concentrating the reaction solution, and performing silica gel column chromatography (ethyl acetate/petroleum ether 1/30-1/20) to obtain yellow solid 167mg, i.e. compound 3, with yield of about 79.0%, ESI-MS M/z 234.1[ M + Na + ].]+1H NMR(CDCl3,400MHz)δ:7.23(d,J=7.0Hz,1H),7.09(t,J=7.4Hz,2H),7.00(d,J=7.5Hz,2H),6.80(d,J=8.0Hz,1H),6.66(d,J=8.0Hz,1H),6.55(s,1H),4.72(s,1H),2.29(s,3H).13C NMR(CDCl3,100MHz)δ:146.5,142.2,139.6,130.9,129.1,127.9,127.5,121.6,116.2,115.6,85.9,21.2.
Example 4 antimicrobial Activity test
The test strains were: gram-positive bacteria include bacillus subtilis ATCC9372, sensitive staphylococcus aureus (s. aureus ATCC 25923); the gram-negative bacterium is escherichia coli (e.coli ATCC 25922).
The experimental principle is as follows: adding a proper amount of bacterial culture solution into a 96-well plate by adopting a trace broth two-fold dilution method, then adding a drug mother solution with a certain concentration into a first hole, uniformly mixing, sucking a half volume of the culture solution from the first hole, adding the culture solution into a second hole, uniformly mixing, diluting till a tenth hole in such a way, decreasing the drug concentration from one hole to the tenth hole by two times, finally adding bacterial solution into the first hole to the eleventh hole, and only adding a liquid culture medium into the twelfth hole as a blank control. After the 96-well plate is placed in a 37 ℃ incubator to be cultured for 24 hours, the growth condition of bacteria in each well is observed, and the drug concentration of the non-growth bacteria well is taken as the Minimum Inhibitory Concentration (MIC).
The MICs of compounds 1-3 of the present invention, as measured by the above method, are shown in the following Table.
Figure BDA0002319338210000041

Claims (7)

1. Compound 1-3 or a pharmaceutically acceptable salt thereof, characterized in that compound 1-3 has the structure:
Figure FDA0003157998160000011
2. a preparation method of a 2-aryl substituted benzoxazoline compound with a structure shown in formula I is characterized by comprising the following steps:
Figure FDA0003157998160000012
reacting a compound of formula II with a compound of formula III in an organic solvent under the action of a catalyst to obtain a compound of formula I, wherein R1、R2Each independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen; m and n are each independently selected from integers of 0 to 4; the organic solvent is one or more selected from DMF, acetonitrile, dioxane, toluene, methanol, tert-butanol, chloroform and 1, 2-dichloroethane; the catalyst is selected from Cu (OTf)2、Zn(OTf)2、Fe(OTf)3One or more of the above; the reaction temperature is preferably from 60 ℃ to reflux temperature; the molar ratio of the compound of the formula II to the compound of the formula III is 1-4:1, and the amount of the catalyst is 2-15% of the molar amount of the compound of the formula III.
3. The use of compounds 1-3 according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of an antibacterial medicament.
4. A pharmaceutical composition characterized by comprising the compound 1-3 according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition further comprises an additional antibacterial agent.
6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is in a dosage form selected from the group consisting of tablets, capsules, and injections.
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