A derivative of osthole at the 7-position, its preparation method and application

Abstract

This solution discloses osthole 7 - derivatives with the general formula Ⅰ in the field of organic chemistry technology. Among them, R is phenyl or substituted phenyl; or R is naphthyl or substituted naphthyl; or R is quinolinyl or substituted quinolinyl; or R is thiophenyl or substituted thiophenyl; or R is isoxazolyl or substituted isoxazolyl; or R is 1,2 - benzopyrone group; or R is 2,3 - dihydro - 1 - benzofuranyl; or R is benzothiadiazolyl; or R is N - acetylindolinyl. 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); at the same time, 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 a derivative of osthole at the 7-position, 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 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, modifies the structure at the 7-position, and obtains a series of derivatives at the 7-position. The research results show that some derivatives 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] A derivative of osthole at the 7-position in this solution has a chemical structure as shown in general formula I:

[0005]

[0006] Wherein, R is a phenyl group or a substituted phenyl group; or R is a naphthyl group or a substituted naphthyl group; or R is a quinolinyl group or a substituted quinolinyl group; or R is a thiophenyl group or a substituted thiophenyl group; or R is an isoxazolyl group or a substituted isoxazolyl group; or R is a 1,2-benzopyrone group; or R is a 2,3-dihydro-1-benzofuranyl group; or R is a benzothiadiazolyl group; or R is an N-acetylindolinyl group.

[0007] The derivative of osthole at the 7-position described by general formula I of the present invention can be used for treating and / or preventing Staphylococcus aureus (S. aureus).

[0008] The derivative of osthole at the 7-position described by general formula I of the present invention can be used for treating and / or preventing Escherichia coli (E. coli).

[0009] Preferably, any of the following compounds has a strong inhibitory effect 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.

[0010]

[0011] The osthole 7 - position derivative described by the general formula Ⅰ of the present invention can be used for treating and / or preventing methicillin - resistant Staphylococcus aureus (MRSA).

[0012] The osthole 7 - position derivative described by the general formula Ⅰ of the present invention can be used for treating and / or preventing fluoroquinolone - resistant Escherichia coli (FREC).

[0013] The osthole 7 - position derivative described by the general formula Ⅰ of the present invention can be used in combination with clinical antibacterial drugs or with antibacterial active ingredients.

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

[0015]

[0016] Wherein: Cys represents cysteine, DMF represents N,N - dimethylformamide, and DCM represents dichloromethane.

[0017] It includes the following steps:

[0018] Preparation of compound 1: Using osthole as the starting material, adding cysteine, sodium hydride, and DMF, after the reaction, diluting with water, adjusting the pH = 5.5, extracting with ethyl acetate, washing, drying, and concentrating under reduced pressure the organic layer, and separating and purifying by silica gel column chromatography to prepare compound 1;

[0019] Preparation of compound 2: Adding anhydrous potassium carbonate and DMF to compound 1, stirring and reacting at room temperature, then heating to 80 °C, adding 1,2 - dibromoethane particles, after the reaction ends, diluting with water, extracting with ethyl acetate, washing, drying, and concentrating under reduced pressure the organic layer, and separating and purifying by silica gel column chromatography to obtain compound 2;

[0020] Preparation of compound 3: Adding compound 2, anhydrous potassium carbonate, and DMF to the reaction vessel, stirring and reacting, then heating to 50 °C, adding anhydrous piperazine, after the reaction ends, cooling to room temperature, diluting with water, extracting with ethyl acetate, washing, drying, and concentrating under reduced pressure the organic layer, and separating and purifying by silica gel column chromatography to obtain compound 3;

[0021] Preparation of compound Ⅰ: Adding compound 3 and dichloromethane to the reaction vessel, dropping triethylamine and sulfonyl chloride compounds, stirring and reacting at room temperature, after the reaction ends, concentrating under reduced pressure, and separating and purifying by silica gel column chromatography to obtain the osthole 7 - position derivative shown by the general formula Ⅰ.

[0022] Furthermore, when adjusting the pH = 5.5 in the preparation process of the preparation of compound 1, it is adjusted with 1 mol / L dilute hydrochloric acid solution.

[0023] Further, during the preparation of Compound 2, the organic layer was successively washed with 1 mol / L dilute hydrochloric acid solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution.

[0024] Further, during the preparation of Compound 3, the organic layer was successively washed with distilled water and saturated sodium chloride solution.

[0025] Further, when preparing Compound I, in terms of molar ratio, Compound 3: triethylamine: sulfonyl chloride compound = 0.15: 0.30 - 0.60: 0.15 - 0.30. Specific Embodiments

[0026] The present invention will be further introduced 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.

[0027] The preparation of the compound of general formula I of the present invention has the following synthetic route:

[0028]

[0029] Wherein, Cys is cysteine, DMF is N,N-dimethylformamide, and DCM is dichloromethane.

[0030] The chemical structures of some osthole 7-position derivatives in general formula I are shown in Table 1 below:

[0031] Table 1

[0032]

[0033] Example 1: Preparation of Compound Ia

[0034] (1) Preparation of Compound 1: Weigh 24.56 mmol of osthole, 73.68 mmol of cysteine, 147.37 mmol of sodium hydride (60%), and 100.00 mL of DMF. Place them in a 250 mL reaction flask, reflux, stir the reaction, and monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water to dilute the solution, adjust the pH = 5.5 with 1 mol / L dilute hydrochloric acid solution, extract with ethyl acetate, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 1.

[0035] (2) Preparation of Compound 2: Weigh 6.51 mmol of Compound 1, 26.06 mmol of anhydrous potassium carbonate, and 20.00 mL of DMF and add them to a 50 mL reaction flask. After stirring at room temperature for 0.5 h, heat the temperature to 80 °C, then add 26.06 mmol of 1,2-dibromoethane, and monitor the reaction by TLC. After the reaction is completed, add an appropriate amount of distilled water to dilute the solution, extract with ethyl acetate, wash the organic layer successively with 1 mol / L dilute hydrochloric acid solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 2.

[0036] (3) Preparation of Compound 3: Weigh 5.00 mmol of Compound 2, 20.00 mmol of anhydrous potassium carbonate, and 20.00 mL of DMF and add them to a 50 mL reaction flask. After stirring at room temperature for 0.5 h, heat the temperature to 50 °C, add 20.00 mmol of anhydrous piperazine, and monitor the reaction by TLC. After the reaction is completed, cool to room temperature, add an appropriate amount of distilled water to dilute the solution, extract with ethyl acetate, wash the organic layer successively with distilled water and saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 3.

[0037] (4) Preparation of Compound Ia: Add 0.15 mmol of Compound 3 and 10.00 mL of dichloromethane to a 50 mL reaction flask, then dropwise add 0.45 mmol of triethylamine and 0.30 mmol of benzenesulfonyl chloride, stir at room temperature, monitor the reaction by TLC. After the reaction is completed, remove the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound Ia.

[0038] Example 2: Preparation of Compound Io

[0039] (1) Preparation of Compound 1: Weigh 24.56 mmol of osthole, 73.68 mmol of cysteine, 147.37 mmol of sodium hydride (60%), and 100.00 mL of DMF, place them in a 250 mL reaction flask, reflux, stir the reaction, and monitor the reaction by TLC. After the reaction is completed, add an appropriate amount of distilled water to dilute the solution, adjust the pH to 5.5 with 1 mol / L dilute hydrochloric acid solution, extract with ethyl acetate, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 1.

[0040] (2) Preparation of Compound 2: Weigh 6.51 mmol of Compound 1, 26.06 mmol of anhydrous potassium carbonate, and 20.00 mL of DMF and add them to a 50 mL reaction flask. After stirring at room temperature for 0.5 h, raise the temperature to 80 °C, then add 26.06 mmol of 1,2-dibromoethane, and monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water to dilute the solution, extract with ethyl acetate, and wash the organic layer successively with 1 mol / L dilute hydrochloric acid solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution. Dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 2.

[0041] (3) Preparation of Compound 3: Weigh 5.00 mmol of Compound 2, 20.00 mmol of anhydrous potassium carbonate, and 20.00 mL of DMF and add them to a 50 mL reaction flask. After stirring at room temperature for 0.5 h, raise the temperature to 50 °C, add 20.00 mmol of anhydrous piperazine, and monitor by TLC. After the reaction is completed, cool to room temperature, add an appropriate amount of distilled water to dilute the solution, extract with ethyl acetate, and wash the organic layer successively with distilled water and saturated sodium chloride solution. Dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 3.

[0042] (4) Preparation of Compound Io: Add 0.15 mmol of Compound 3 and 10.00 mL of dichloromethane to a 50 mL reaction flask, then dropwise add 0.45 mmol of triethylamine and 0.30 mmol of 4-nitrobenzenesulfonyl chloride, stir at room temperature, monitor by TLC. After the reaction is completed, remove the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound Io.

[0043] Example 3: Preparation of Compound Ⅰq

[0044] (1) Preparation of Compound 1: Weigh 24.56 mmol of osthole, 73.68 mmol of cysteine, 147.37 mmol of sodium hydride (60%), and 100.00 mL of DMF, place them in a 250 mL reaction flask, reflux, stir the reaction, and monitor by TLC. After the reaction is completed, add an appropriate amount of distilled water to dilute the solution, adjust the pH to 5.5 with 1 mol / L dilute hydrochloric acid solution, extract with ethyl acetate, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 1.

[0045] (2) Preparation of Compound 2: Weigh 6.51 mmol of Compound 1, 26.06 mmol of anhydrous potassium carbonate, and 20.00 mL of DMF and add them to a 50 mL reaction flask. After stirring at room temperature for 0.5 h, heat the mixture to 80 °C, then add 26.06 mmol of 1,2-dibromoethane, and monitor the reaction by TLC. After the reaction is completed, dilute the solution with appropriate distilled water, extract with ethyl acetate, wash the organic layer successively with 1 mol / L dilute hydrochloric acid solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 2.

[0046] (3) Preparation of Compound 3: Weigh 5.00 mmol of Compound 2, 20.00 mmol of anhydrous potassium carbonate, and 20.00 mL of DMF and add them to a 50 mL reaction flask. After stirring at room temperature for 0.5 h, heat the mixture to 50 °C, add 20.00 mmol of anhydrous piperazine, and monitor the reaction by TLC. After the reaction is completed, cool the mixture to room temperature, dilute the solution with appropriate distilled water, extract with ethyl acetate, wash the organic layer successively with distilled water and saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 3.

[0047] (4) Preparation of Compound Ⅰq: Add 0.15 mmol of Compound 3 and 10.00 mL of dichloromethane to a 50 mL reaction flask, then add dropwise 0.45 mmol of triethylamine and 0.30 mmol of quinoline-8-sulfonyl chloride, stir at room temperature, monitor the reaction by TLC. After the reaction is completed, remove the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound Iq.

[0048] Example 4: Preparation of Compound Ⅰs

[0049] (1) Preparation of Compound 1: Weigh 24.56 mmol of osthole, 73.68 mmol of cysteine, 147.37 mmol of sodium hydride (60%), and 100.00 mL of DMF, place them in a 250 mL reaction flask, reflux, stir the reaction, and monitor the reaction by TLC. After the reaction is completed, dilute the solution with appropriate distilled water, adjust the pH to 5.5 with 1 mol / L dilute hydrochloric acid solution, extract with ethyl acetate, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 1.

[0050] (2) Preparation of Compound 2: Weigh 6.51 mmol of Compound 1, 26.06 mmol of anhydrous potassium carbonate, and 20.00 mL of DMF and add them to a 50 mL reaction flask. After stirring at room temperature for 0.5 h, raise the temperature to 80 °C, then add 26.06 mmol of 1,2-dibromoethane, and monitor the reaction by TLC. After the reaction is completed, dilute the solution with appropriate distilled water, extract with ethyl acetate, wash the organic layer successively with 1 mol / L dilute hydrochloric acid solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 2.

[0051] (3) Preparation of Compound 3: Weigh 5.00 mmol of Compound 2, 20.00 mmol of anhydrous potassium carbonate, and 20.00 mL of DMF and add them to a 50 mL reaction flask. After stirring at room temperature for 0.5 h, raise the temperature to 50 °C, add 20.00 mmol of anhydrous piperazine, and monitor the reaction by TLC. After the reaction is completed, cool to room temperature, dilute the solution with appropriate distilled water, extract with ethyl acetate, wash the organic layer successively with distilled water and saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 3.

[0052] (4) Preparation of Compound Is: Add 0.15 mmol of Compound 3 and 10.00 mL of dichloromethane to a 50 mL reaction flask, then dropwise add 0.45 mmol of triethylamine and 0.30 mmol of coumarin-6-sulfonyl chloride, stir at room temperature, monitor the reaction by TLC. After the reaction is completed, remove the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound Is.

[0053] Example 5: Preparation of Compound Iu

[0054] (1) Preparation of Compound 1: Weigh 24.56 mmol of osthole, 73.68 mmol of cysteine, 147.37 mmol of sodium hydride (60%), and 100.00 mL of DMF, place them in a 250 mL reaction flask, reflux, stir the reaction, and monitor the reaction by TLC. After the reaction is completed, dilute the solution with appropriate distilled water, adjust the pH to 5.5 with 1 mol / L dilute hydrochloric acid solution, extract with ethyl acetate, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 1.

[0055] (2) Preparation of Compound 2: Weigh 6.51 mmol of Compound 1, 26.06 mmol of anhydrous potassium carbonate, and 20.00 mL of DMF and add them to a 50 mL reaction flask. After stirring at room temperature for 0.5 h, heat the mixture to 80 °C, then add 26.06 mmol of 1,2-dibromoethane, and monitor the reaction by TLC. After the reaction is completed, dilute the solution with appropriate distilled water, extract with ethyl acetate, wash the organic layer successively with 1 mol / L dilute hydrochloric acid solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 2.

[0056] (3) Preparation of Compound 3: Weigh 5.00 mmol of Compound 2, 20.00 mmol of anhydrous potassium carbonate, and 20.00 mL of DMF and add them to a 50 mL reaction flask. After stirring at room temperature for 0.5 h, heat the mixture to 50 °C, add 20.00 mmol of anhydrous piperazine, and monitor the reaction by TLC. After the reaction is completed, cool the mixture to room temperature, dilute the solution with appropriate distilled water, extract with ethyl acetate, wash the organic layer successively with distilled water and saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound 3.

[0057] (4) Preparation of Compound Iu: Add 0.15 mmol of Compound 3 and 10.00 mL of dichloromethane to a 50 mL reaction flask, then dropwise add 0.45 mmol of triethylamine and 0.30 mmol of N-acetylindoline-5-sulfonyl chloride, stir at room temperature, monitor the reaction by TLC. After the reaction is completed, remove the solvent under reduced pressure, and purify by silica gel column chromatography to obtain Compound Iu.

[0058] Example 6: Preparation of Compound Ik

[0059] The difference in the preparation process of Compound Ik from Example 1 is that in step (4), 0.30 mmol of benzenesulfonyl chloride is replaced with 3-trifluoromethylbenzenesulfonyl chloride.

[0060] Example 7: Preparation of Compound Il

[0061] The difference in the preparation process of Compound Il from Example 1 is that in step (4), 0.30 mmol of benzenesulfonyl chloride is replaced with 4-trifluoromethylbenzenesulfonyl chloride.

[0062] Example 8: Preparation of Compound In

[0063] The difference in the preparation process of Compound In from Example 1 is that in step (4), 0.30 mmol of benzenesulfonyl chloride is replaced with 3-nitrobenzenesulfonyl chloride.

[0064] Example 9: Preparation of Compound It

[0065] The preparation process of compound Ⅰt is different from that of Example 1 in that in step (4), 0.30 mmol of benzenesulfonyl chloride is replaced by benzo[1,2,5]thiadiazole sulfonyl chloride.

[0066] The relevant data of compound Ⅰ are shown in Table 2:

[0067] Table 2

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074] Antibacterial activity test of the present invention: Using osthole, oxacillin, and norfloxacin as control drugs, the minimum inhibitory concentration (MIC) of the general formula Ⅰ compound 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, and the data are shown in Table 3.

[0075] Table 3

[0076]

[0077]

[0078] It can be clearly seen from the above experimental results that the compounds of general formula Ⅰ protected by the present invention have 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), and their antibacterial activities are better than or equivalent to those of the control drugs. For example, compounds Ⅰo, Ⅰq, Ⅰs, and Ⅰu, etc. In addition, the antibacterial activities of some compounds against methicillin-resistant Staphylococcus aureus (MRSA) and fluoroquinolone-resistant Escherichia coli (FREC) are particularly significant, far better than the control drugs oxacillin and norfloxacin. For example, compounds Ⅰk, Ⅰl, Ⅰn, Ⅰo, Ⅰq, Ⅰs, Ⅰt, and Ⅰu, etc. The highly active compounds of this type of derivative can be used for the treatment of 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.

[0079] 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 and inventive concept of the present invention, making equivalent substitutions or changes, should be covered by the protection scope of the present invention.

Claims

1. A derivative of osthole at the 7-position, characterized in that: Its chemical structure is shown in General Formula Ⅰ: , specifically selected from the following compounds: Compound Ⅰk: R = 3-CF3Ph-; Compound Ⅰl: R = 4-CF3Ph-; Compound Ⅰn: R = 3-NO2Ph-; Compound Ⅰo: R = 4-NO2Ph-; Compound Ⅰq: R = quinoline-8-; Compound Ⅰs: R = coumarin-6-; Compound Ⅰt: R = benzo[1,2,5]thiadiazole-; Compound Ⅰu: R = N -acetylindoline-5-.

2. The preparation method of the osthole 7 - position derivative 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 cysteine, sodium hydride and DMF, after the reaction, diluting with water, adjusting the pH to 5.5, extracting with ethyl acetate, washing, drying and concentrating under reduced pressure the organic layer, and separating and purifying by silica gel column chromatography to prepare Compound 1; Preparation of Compound 2: Adding anhydrous potassium carbonate and DMF to Compound 1, stirring and reacting at room temperature, then heating to 60 - 100 °C, adding 1,2-dibromoethane particles, after the reaction ends, diluting with water, extracting with ethyl acetate, washing, drying and concentrating under reduced pressure the organic layer, and separating and purifying by silica gel column chromatography to obtain Compound 2; Preparation of Compound 3: Adding Compound 2, anhydrous potassium carbonate and DMF to the reaction vessel, stirring and reacting, then heating to 50 °C, adding anhydrous piperazine, after the reaction ends, cooling to room temperature, diluting with water, extracting with ethyl acetate, washing, drying and concentrating under reduced pressure the organic layer, and separating and purifying by silica gel column chromatography to obtain Compound 3; Preparation of Compound Ⅰ: Adding Compound 3 and dichloromethane to the reaction vessel, dropping triethylamine and sulfonyl chloride compounds, stirring and reacting at room temperature, after the reaction ends, concentrating under reduced pressure, and separating and purifying by silica gel column chromatography to obtain the osthole 7-position derivative shown in General Formula Ⅰ.

3. The preparation method of a derivative of osthole at the 7-position according to claim 2, wherein: During the preparation of Compound 1, when adjusting the pH to 5.5, it is adjusted with 1 mol / L dilute hydrochloric acid solution.

4. The preparation method of a derivative of osthole at the 7-position according to claim 2, characterized in that: During the preparation of Compound 2, the organic layer is washed successively with 1 mol / L dilute hydrochloric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution.

5. The preparation method of a derivative of osthole at the 7th position according to claim 2, characterized in that: During the preparation of Compound 3, the organic layer is washed successively with distilled water and saturated sodium chloride solution.

6. The preparation method of a derivative of osthole at the 7-position according to claim 2, characterized in that: When preparing Compound Ⅰ, by molar ratio, Compound 3:triethylamine:sulfonyl chloride compounds = 0.15:0.30 - 0.60:0.15 - 0.

30.

7. Use of a kind of osthole 7-position derivative according to Claim 1 in the preparation of antibacterial drugs.

8. A kind of osthole 7-position derivative according to Claim 1 is used in combination with antibacterial active ingredients.

9. Use of a kind of osthole 7-position derivative according to Claim 1 in the preparation of antibacterial or bacteriostatic drugs, and the bacteria are any one of the following: Staphylococcus aureus, Escherichia coli.

10. The application according to claim 9, characterized in that, The bacteria are methicillin-resistant Staphylococcus aureus, fluoroquinolone-resistant Escherichia coli.

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