An Osthole 8-position Structural Modification Product, Its Preparation Method and Application

Abstract

This solution discloses osthole 8-position structure modifiers shown by general formula Ⅰ in the field of organic chemistry technology, wherein, R is a hydrocarbon group with 1 to 6 carbon atoms; or R is phenyl or substituted phenyl; or R is benzyl or substituted benzyl; or R is thiophenemethyl or substituted thiophenemethyl. The compound shown by the general formula Ⅰ has strong antibacterial activity and can be used as a drug against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), methicillin-resistant Staphylococcus aureus (MRSA) and fluoroquinolone-resistant Escherichia coli (FREC); meanwhile, it can also be used in combination with other antibacterial active substances.

Description

Technical Field

[0001] The present invention belongs to the field of organic chemistry, and particularly relates to an osthole 8-position structural modification, a preparation method thereof, and an application thereof. Background Art

[0002] Antibacterial drugs are one of the great discoveries in the 20th century. However, the abuse of antibacterial drugs has led to the rapid emergence of clinically multi-drug resistant bacteria, seriously affecting people's daily production and life. At present, the drug resistance of antibiotics has become a major global health problem. The successive emergence of different drug-resistant bacteria has continuously increased the morbidity and mortality of patients with various infectious diseases, and brought great challenges to clinical treatment. Therefore, there is an urgent need for new antibacterial drugs to overcome these worrying drug resistance problems. Summary of the Invention

[0003] The present invention uses the natural product osthole as a raw material, applies relevant drug design and synthesis theories to modify the structure at the 8-position, and obtains a series of 8-position structural modifications. The research results show that: some compounds have significant antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) and fluoroquinolone-resistant Escherichia coli (FREC), far superior to the control drugs oxacillin and norfloxacin.

[0004] An osthole 8-position structural modification in the present scheme has a chemical structure as shown in general formula I:

[0005]

[0006] Wherein, R is a hydrocarbon group with 1 to 6 carbon atoms; or R is a phenyl group or a substituted phenyl group; or R is a benzyl group or a substituted benzyl group; or R is a thiophenemethyl group or a substituted thiophenemethyl group.

[0007] The osthole 8-position structural modification described by general formula I of the present invention can be used for treating and / or preventing Staphylococcus aureus (S. aureus).

[0008] The osthole 8-position structural modification described by general formula I of the present invention can be used for treating and / or preventing Escherichia coli (E. coli).

[0009] The osthole 8-position structural modification described by general formula I of the present invention can be used for treating and / or preventing methicillin-resistant Staphylococcus aureus (MRSA).

[0010] The osthole 8-position structural modification described by general formula I of the present invention can be used for treating and / or preventing fluoroquinolone-resistant Escherichia coli (FREC).

[0011] Preferably, any of the following compounds has strong inhibitory effects on Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), methicillin-resistant Staphylococcus aureus (MRSA), and fluoroquinolone-resistant Escherichia coli (FREC), and its antibacterial activity is superior to or equivalent to that of the control drug.

[0012] Compound Ⅰj: R = Compound Ⅰk: R = Compound Ⅰn: R = Compound Ⅰo: R = Compound Ⅰp: R = Compound Ⅰq: R =

[0013] The osthole 8-position structure modifier described by the general formula Ⅰ of the present invention can be used in combination with clinical antibacterial drugs or antibacterial active ingredients.

[0014] The following synthetic route describes the preparation method of the compound of the general formula Ⅰ of the present invention:

[0015]

[0016] It includes the following steps:

[0017] Preparation of Compound 1: Using osthole as the starting material, adding selenium dioxide and DMSO, stirring and reacting, filtering to remove insoluble substances, extracting with ethyl acetate, washing, drying, and concentrating the organic layer, and separating and purifying by silica gel column chromatography to obtain Compound 1;

[0018] Preparation of Compound 2: Adding tert-butanol and 2-methyl-2-butene to Compound 1, stirring and reacting; dissolving sodium chlorite and sodium dihydrogen phosphate in water, dropping it into the reaction system, concentrating and precipitating solids after the reaction is completed, filtering under reduced pressure, and drying to obtain Compound 2;

[0019] Preparation of Compound 3: Adding Boc-L-phenylalanine, HBTU, DIPEA, amine compound, and DMF to the reaction vessel, stirring and reacting at room temperature, adding water, precipitating solids, filtering under reduced pressure, and drying to obtain Compound 3;

[0020] Preparation of Compound 4: Adding Compound 3, dichloromethane, and trifluoroacetic acid to the reaction vessel, stirring and reacting at room temperature, concentrating after completion, adding saturated sodium bicarbonate solution, precipitating solids, filtering under reduced pressure, and drying to obtain Compound 4;

[0021] Preparation of Compound Ⅰ: Adding Compound 2, HBTU, DIPEA, Compound 4, and DMF to the reaction vessel, stirring and reacting at room temperature, adding water to precipitate solids, filtering under reduced pressure, and separating and purifying by silica gel column chromatography to obtain the osthole 8-position structure modifier shown by Compound Ⅰ.

[0022] Furthermore, during the preparation of Compound 1, the reaction was stirred at 100 °C.

[0023] Furthermore, during the preparation of Compound 2, the reaction was stirred at 40 °C.

[0024] Furthermore, when preparing Compound I, by molar ratio, Compound 2:HBTU:DIPEA:Compound 4 = 0.25:0.50 - 0.75:0.50 - 1.0:0.25 - 0.45. Specific Embodiments

[0025] The present invention will be further described below in conjunction with embodiments. However, the present invention is not limited to the following embodiments. It can be foreseen that those skilled in the art may make various changes in the implementation in combination with the existing technology.

[0026] The preparation of the compound of general formula I of the present invention has the following synthetic route:

[0027]

[0028] Among them, TFA is triethylamine, HBTU is O-benzotriazole-tetramethylurea hexafluorophosphate, and DIPEA is N,N-diisopropylethylamine.

[0029] The chemical structures of some osthole 8-position structural modifiers in general formula I are shown in Table 1 below:

[0030] Table 1

[0031]

[0032]

[0033] Example 1: Preparation of Compound Ia

[0034] (1) Preparation of Compound 1: Take a 100 mL reaction flask, add 9.0 mmol selenium dioxide, 50.0 mL DMSO and 3.0 mmol osthole, stir the reaction at 100 °C, monitor by TLC. After completion, filter to remove insoluble substances, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and rotary evaporate to concentrate the solvent to obtain the crude product, which is separated and purified by silica gel column chromatography to obtain Compound 1.

[0035] (2) Preparation of Compound 2: Take a 100 mL reaction flask, add 1.0 mmol of Compound 1, 20.0 mL of tert-butanol, and 10.0 mL of 2-methyl-2-butene, and react at 40.0 °C; then dissolve 9.0 mmol of sodium chlorite and 7.0 mmol of sodium dihydrogen phosphate in 25.0 mL of water, and add dropwise to the reaction system. Monitor by TLC. After the reaction is completed, rotary evaporate and concentrate the solvent, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 2.

[0036] (3) Preparation of Compound 3a: Take a 50 mL reaction flask, add 1.2 mmol of Boc-L-phenylalanine, 2.5 mmol of HBTU, 3.5 mmol of DIPEA, 1.0 mmol of aniline, and 5.0 mL of DMF, stir and react at room temperature, monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 3a.

[0037] (4) Preparation of Compound 4a: Take a 50 mL reaction flask, add 1.0 mmol of Compound 3a, 5.0 mL of dichloromethane, and 15.0 mmol of trifluoroacetic acid, stir and react at room temperature, monitor by TLC. After the reaction is completed, rotary evaporate and concentrate the solvent, add saturated sodium bicarbonate solution, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 4a.

[0038] (5) Preparation of Compound Ia: Take a 50 mL reaction flask, weigh 0.25 mmol of Compound 2, 0.625 mmol of HBTU, 0.875 mmol of DIPEA, 0.3 mmol of Compound 4a, and 2.5 mL of DMF, stir and react at room temperature, monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water, precipitate a solid, filter under reduced pressure, and separate and purify by preparative thin layer chromatography to obtain Compound Ia.

[0039] Example 2: Preparation of Compound Ik

[0040] (1) Preparation of Compound 1: Take a 100 mL reaction flask, add 9.0 mmol of selenium dioxide, 50.0 mL of DMSO, and 3.0 mmol of osthole, stir and react at 100 °C, monitor by TLC. After completion, filter to remove insoluble substances, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, rotary evaporate and concentrate the solvent to obtain a crude product, and separate and purify by silica gel column chromatography to obtain Compound 1.

[0041] (2) Preparation of Compound 2: Take a 100 mL reaction flask, add 1.0 mmol of Compound 1, 20.0 mL of tert-butanol and 10.0 mL of 2-methyl-2-butene, and react at 40.0 °C; then dissolve 9.0 mmol of sodium chlorite and 7.0 mmol of sodium dihydrogen phosphate in 25.0 mL of water, and add dropwise to the reaction system. Monitor by TLC. After the reaction is completed, rotary evaporate and concentrate the solvent, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 2.

[0042] (3) Preparation of Compound 3k: Take a 50 mL reaction flask, add 1.2 mmol of Boc-L-phenylalanine, 2.5 mmol of HBTU, 3.5 mmol of DIPEA, 1.0 mmol of 3-nitroaniline and 5.0 mL of DMF, stir and react at room temperature. Monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 3k.

[0043] (4) Preparation of Compound 4k: Take a 50 mL reaction flask, add 1.0 mmol of Compound 3k, 5.0 mL of dichloromethane and 15.0 mmol of trifluoroacetic acid, stir and react at room temperature. Monitor by TLC. After the reaction is completed, rotary evaporate and concentrate the solvent, add saturated sodium bicarbonate solution, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 4k.

[0044] (5) Preparation of Compound Ik: Take a 50 mL reaction flask, weigh 0.25 mmol of Compound 2, 0.625 mmol of HBTU, 0.875 mmol of DIPEA, 0.3 mmol of Compound 4k and 2.5 mL of DMF, stir and react at room temperature. Monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water, precipitate a solid, filter under reduced pressure, and separate and purify by preparative thin layer chromatography to obtain Compound Ik.

[0045] Example 3: Preparation of Compound In

[0046] (1) Preparation of Compound 1: Take a 100 mL reaction flask, add 9.0 mmol of selenium dioxide, 50.0 mL of DMSO and 3.0 mmol of osthole, stir and react at 100 °C. Monitor by TLC. After completion, filter to remove insoluble substances, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, rotary evaporate and concentrate the solvent to obtain a crude product, and separate and purify by silica gel column chromatography to obtain Compound 1.

[0047] (2) Preparation of Compound 2: Take a 100 mL reaction flask, add 1.0 mmol of Compound 1, 20.0 mL of tert-butanol, and 10.0 mL of 2-methyl-2-butene, and react at 40.0 °C; then dissolve 9.0 mmol of sodium chlorite and 7.0 mmol of sodium dihydrogen phosphate in 25.0 mL of water, and add dropwise to the reaction system. Monitor by TLC. After the reaction is completed, rotary evaporate and concentrate the solvent, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 2.

[0048] (3) Preparation of Compound 3n: Take a 50 mL reaction flask, add 1.2 mmol of Boc-L-phenylalanine, 2.5 mmol of HBTU, 3.5 mmol of DIPEA, 1.0 mmol of 4-chloroaniline, and 5.0 mL of DMF, stir and react at room temperature. Monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 3n.

[0049] (4) Preparation of Compound 4n: Take a 50 mL reaction flask, add 1.0 mmol of Compound 3n, 5.0 mL of dichloromethane, and 15.0 mmol of trifluoroacetic acid, stir and react at room temperature. Monitor by TLC. After the reaction is completed, rotary evaporate and concentrate the solvent, add saturated sodium bicarbonate solution, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 4n.

[0050] (5) Preparation of Compound Ⅰn: Take a 50 mL reaction flask, weigh 0.25 mmol of Compound 2, 0.625 mmol of HBTU, 0.875 mmol of DIPEA, 0.3 mmol of Compound 4n, and 2.5 mL of DMF, stir and react at room temperature. Monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water, precipitate a solid, filter under reduced pressure, and separate and purify by preparative thin-layer chromatography to obtain Compound Ⅰn.

[0051] Example 4: Preparation of Compound Ⅰo

[0052] (1) Preparation of Compound 1: Take a 100 mL reaction flask, add 9.0 mmol of selenium dioxide, 50.0 mL of DMSO, and 3.0 mmol of osthole, stir and react at 100 °C. Monitor by TLC. After completion, filter to remove insoluble substances, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, rotary evaporate and concentrate the solvent to obtain a crude product, and separate and purify by silica gel column chromatography to obtain Compound 1.

[0053] (2) Preparation of Compound 2: Take a 100 mL reaction flask, add 1.0 mmol of Compound 1, 20.0 mL of tert-butanol and 10.0 mL of 2-methyl-2-butene, and react at 40.0 °C; then dissolve 9.0 mmol of sodium chlorite and 7.0 mmol of sodium dihydrogen phosphate in 25.0 mL of water, and add dropwise to the reaction system. Monitor by TLC. After the reaction is completed, rotary evaporate and concentrate the solvent, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 2.

[0054] (3) Preparation of Compound 3o: Take a 50 mL reaction flask, add 1.2 mmol of Boc-L-phenylalanine, 2.5 mmol of HBTU, 3.5 mmol of DIPEA, 1.0 mmol of 2-fluoroaniline and 5.0 mL of DMF, stir and react at room temperature. Monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 3o.

[0055] (4) Preparation of Compound 4o: Take a 50 mL reaction flask, add 1.0 mmol of Compound 3o, 5.0 mL of dichloromethane and 15.0 mmol of trifluoroacetic acid, stir and react at room temperature. Monitor by TLC. After the reaction is completed, rotary evaporate and concentrate the solvent, add saturated sodium bicarbonate solution, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 4o.

[0056] (5) Preparation of Compound Io: Take a 50 mL reaction flask, weigh 0.25 mmol of Compound 2, 0.625 mmol of HBTU, 0.875 mmol of DIPEA, 0.3 mmol of Compound 4o and 2.5 mL of DMF, stir and react at room temperature. Monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water, precipitate a solid, filter under reduced pressure, and separate and purify by preparative thin layer chromatography to obtain Compound Io.

[0057] Example 5: Preparation of Compound Ip

[0058] (1) Preparation of Compound 1: Take a 100 mL reaction flask, add 9.0 mmol of selenium dioxide, 50.0 mL of DMSO and 3.0 mmol of osthole, stir and react at 100 °C. Monitor by TLC. After completion, filter to remove insoluble substances, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, rotary evaporate and concentrate the solvent to obtain a crude product, and separate and purify by silica gel column chromatography to obtain Compound 1.

[0059] (2) Preparation of Compound 2: Take a 100 mL reaction flask, add 1.0 mmol of Compound 1, 20.0 mL of tert-butanol and 10.0 mL of 2-methyl-2-butene, and react at 40.0 °C; then dissolve 9.0 mmol of sodium chlorite and 7.0 mmol of sodium dihydrogen phosphate in 25.0 mL of water, and add dropwise to the reaction system. Monitor by TLC. After the reaction is completed, rotary evaporate and concentrate the solvent, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 2.

[0060] (3) Preparation of Compound 3p: Take a 50 mL reaction flask, add 1.2 mmol of Boc-L-phenylalanine, 2.5 mmol of HBTU, 3.5 mmol of DIPEA, 1.0 mmol of 4-fluoroaniline and 5.0 mL of DMF, stir and react at room temperature. Monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 3p.

[0061] (4) Preparation of Compound 4p: Take a 50 mL reaction flask, add 1.0 mmol of Compound 3p, 5.0 mL of dichloromethane and 15.0 mmol of trifluoroacetic acid, stir and react at room temperature. Monitor by TLC. After the reaction is completed, rotary evaporate and concentrate the solvent, add saturated sodium bicarbonate solution, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 4p.

[0062] (5) Preparation of Compound Ⅰp: Take a 50 mL reaction flask, weigh 0.25 mmol of Compound 2, 0.625 mmol of HBTU, 0.875 mmol of DIPEA, 0.3 mmol of Compound 4p and 2.5 mL of DMF, stir and react at room temperature. Monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water, precipitate a solid, filter under reduced pressure, and separate and purify by preparative thin-layer chromatography to obtain Compound Ⅰp.

[0063] Example 6: Preparation of Compound Ⅰq

[0064] (1) Preparation of Compound 1: Take a 100 mL reaction flask, add 9.0 mmol of selenium dioxide, 50.0 mL of DMSO and 3.0 mmol of osthole, stir and react at 100 °C. Monitor by TLC. After completion, filter to remove insoluble substances, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, filter, rotary evaporate and concentrate the solvent to obtain a crude product, and separate and purify by silica gel column chromatography to obtain Compound 1.

[0065] (2) Preparation of Compound 2: Take a 100 mL reaction flask, add 1.0 mmol of Compound 1, 20.0 mL of tert-butanol, and 10.0 mL of 2-methyl-2-butene, and react at 40.0 °C; then dissolve 9.0 mmol of sodium chlorite and 7.0 mmol of sodium dihydrogen phosphate in 25.0 mL of water, and add dropwise to the reaction system. Monitor by TLC. After the reaction is completed, rotary evaporate and concentrate the solvent, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 2.

[0066] (3) Preparation of Compound 3q: Take a 50 mL reaction flask, add 1.2 mmol of Boc-L-phenylalanine, 2.5 mmol of HBTU, 3.5 mmol of DIPEA, 1.0 mmol of 3-trifluoromethylaniline, and 5.0 mL of DMF, stir and react at room temperature, monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 3q.

[0067] (4) Preparation of Compound 4q: Take a 50 mL reaction flask, add 1.0 mmol of Compound 3q, 5.0 mL of dichloromethane, and 15.0 mmol of trifluoroacetic acid, stir and react at room temperature, monitor by TLC. After the reaction is completed, rotary evaporate and concentrate the solvent, add saturated sodium bicarbonate solution, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 4q.

[0068] (5) Preparation of Compound Ⅰq: Take a 50 mL reaction flask, weigh 0.25 mmol of Compound 2, 0.625 mmol of HBTU, 0.875 mmol of DIPEA, 0.3 mmol of Compound 4q, and 2.5 mL of DMF, stir and react at room temperature, monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water, precipitate a solid, filter under reduced pressure, and purify by preparative thin layer chromatography to obtain Compound Ⅰq.

[0069] The relevant data of Compound Ⅰ are shown in Table 2:

[0070] Table 2

[0071]

[0072]

[0073]

[0074]

[0075]

[0076] Antibacterial activity test of the present invention: With osthole, oxacillin, and norfloxacin as control drugs, the minimum inhibitory concentration (MIC) of the compound of general formula I against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), methicillin-resistant Staphylococcus aureus (MRSA), and fluoroquinolone-resistant Escherichia coli (FREC) was determined by the two-fold dilution method. The data are shown in Table 3.

[0077] Table 3

[0078]

[0079] It can be clearly seen from the above experimental results that the compound of general formula I to be protected by the present invention has potential antibacterial activity and broad-spectrum properties. Some compounds have strong inhibitory effects on Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), methicillin-resistant Staphylococcus aureus (MRSA), and fluoroquinolone-resistant Escherichia coli (FREC), such as compounds Ik and Iq. In addition, the antibacterial activities of some compounds against methicillin-resistant Staphylococcus aureus (MRSA) and fluoroquinolone-resistant Escherichia coli (FREC) are particularly significant, superior to the control drugs oxacillin and norfloxacin, such as compounds Ij, Ik, In, Io, Ip, and Iq. The highly active compounds of this type of derivative can be used for the applications against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), methicillin-resistant Staphylococcus aureus (MRSA), and fluoroquinolone-resistant Escherichia coli (FREC); at the same time, they can also be used in combination with other antibacterial active substances.

[0080] As mentioned above, the above are only the preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution of the present invention and its inventive concept, makes equivalent substitutions or changes, and all should be covered within the protection scope of the present invention.

Claims

1. An osthole 8-position derivative, characterized in that: Its chemical structure is shown in General Formula I: , specifically selected from the following compounds: Compound Ⅰj: R = ; Compound Ⅰk: R = ; Compound Ⅰn: R = ; Compound Ⅰo: R = ; Compound Ⅰp: R= ; Compound Ⅰq: R= .

2. The preparation method of an 8-position derivative of osthole according to claim 1, characterized in that: The synthetic route of the General Formula I is as follows: Specifically, it includes the following steps: Preparation of Compound 1: Using osthole as the starting material, adding selenium dioxide and DMSO, stirring and reacting, filtering to remove insoluble substances, extracting with ethyl acetate, washing, drying, and concentrating the organic layer, and separating and purifying by silica gel column chromatography to obtain Compound 1; Preparation of Compound 2: Adding tert-butanol and 2-methyl-2-butene to Compound 1, stirring and reacting; dissolving sodium chlorite and sodium dihydrogen phosphate in water, dropping it into the reaction system, concentrating and precipitating solids after the reaction is completed, filtering under reduced pressure, and drying to obtain Compound 2; Preparation of Compound 3: Add Boc- L -phenylalanine, HBTU, DIPEA, amine compound and DMF into a reaction vessel, stir the reaction at room temperature until completion, add water, precipitate a solid, filter under reduced pressure, and dry to obtain Compound 3; Preparation of Compound 4: Adding Compound 3, dichloromethane, and trifluoroacetic acid to a reaction vessel, stirring and reacting at room temperature, concentrating after completion, adding saturated sodium bicarbonate solution, precipitating solids, filtering under reduced pressure, and drying to obtain Compound 4; Preparation of Compound I: Adding Compound 2, HBTU, DIPEA, Compound 4, and DMF to a reaction vessel, stirring and reacting at room temperature until completion, adding water to precipitate solids, filtering under reduced pressure, and separating and purifying by silica gel column chromatography to obtain the osthole 8-position derivative shown in Compound I.

3. The preparation method of an osthole 8-position derivative according to claim 2, characterized in that: During the preparation of Compound 1, the stirring reaction is carried out at 100 °C.

4. The preparation method of an osthole 8-position derivative according to claim 2, characterized in that: During the preparation of Compound 2, the stirring reaction is carried out at 40 °C.

5. The preparation method of the derivative of osthole at the 8th position according to claim 2, characterized in that: When preparing Compound I, by molar ratio, Compound 2:HBTU:DIPEA:Compound 4 = 0.25:0.50 - 0.75:0.50 - 1.0:0.25 - 0.

45.

6. Use of an osthole 8-position derivative according to claim 1 in the preparation of antibacterial drugs.

7. An osthole 8-position derivative according to claim 1 is used in combination with an antibacterial active ingredient.

8. Use of an osthole 8-position derivative according to claim 1 in the preparation of antibacterial or bacteriostatic drugs, wherein the bacteria are any one of the following: Staphylococcus aureus, Escherichia coli.

9. The application according to claim 8, wherein The bacteria are methicillin-resistant Staphylococcus aureus, fluoroquinolone-resistant Escherichia coli.

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