A stiπgmatin derivative containing benzopyronic acid and a preparation method and application thereof

Abstract

The scheme discloses a stiophantine derivative containing benzopyridone acid with a general formula III, wherein a substituent R is ethyl or cyclopropyl; R 1 is hydrogen or methyl; R 2 is hydrogen or methyl; and n=2 or 3 or 4. Research results show that the stiophantine derivative containing benzopyridone acid can be applied to preparation of medicines for treating and / or preventing bacterial infection and preparation of medicines for treating and / or preventing tumors.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry, and specifically relates to a osthol derivative containing benzopyridinol acid, its preparation method, and its application. Background Technology

[0002] Currently, the widespread use of antibiotics and the emergence of multidrug-resistant and superdrug-resistant bacteria have led to many infectious diseases being incurable in clinical practice, seriously threatening human health. Therefore, the development of novel antibiotics to address these worrying problems is of great significance. Summary of the Invention

[0003] This invention aims to provide a benzopyridinol-containing osthol derivative with a broad antibacterial spectrum and significant activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), and fluoroquinolone-resistant Escherichia coli (FREC). Furthermore, this type of compound has been found to inhibit the proliferation of EC-109 (human esophageal cancer cells), and can be used as a drug for the treatment and / or prevention of esophageal cancer.

[0004] The main objective of this invention is to provide a osthol derivative containing benzopyridinol acid, the chemical structure of which is shown in general formula III:

[0005]

[0006] Wherein, R is ethyl or cyclopropyl; R 1 It is hydrogen or methyl; R 2 It can be hydrogen or methyl; n = 2, 3 or 4.

[0007] The osthol derivatives containing benzopyridinol acid provided by this invention can be used in the preparation of antibacterial drugs or in combination with antibacterial active ingredients. Research results show that some osthol derivatives containing benzopyridinol acid have significant activity in treating and / or preventing Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), and fluoroquinolone-resistant Escherichia coli (FREC), such as:

[0008]

[0009] The osthol derivatives containing benzopyridinol acid provided by this invention can be used in the preparation of antitumor drugs or in combination with antitumor active ingredients. Research results show that some osthol derivatives containing benzopyridinol acid have significant inhibitory activity against human esophageal cancer EC-109, such as:

[0010]

[0011] The osthol derivative containing benzopyridinol acid described in this invention is prepared according to the following synthetic route:

[0012]

[0013] Wherein, R is ethyl or cyclopropyl; R 1 It is hydrogen or methyl; R 2 It can be hydrogen or methyl; n = 2, 3 or 4.

[0014] The specific preparation method includes the following steps:

[0015] Preparation of compound I: Osthol, cysteine, sodium hydride and DMF were mixed and refluxed for several hours. The mixture was then cooled to room temperature, and the pH of the solution was adjusted to 5-6. The solution was extracted with ethyl acetate, and the organic layers were combined. The organic layers were then washed, dried, filtered, concentrated and purified to obtain the product for use.

[0016] Add the prepared sample, anhydrous potassium carbonate and DMF to the reaction flask, stir the reaction, add dibromoalkane at 70-90℃, cool to room temperature after the reaction is completed, extract with ethyl acetate, combine the organic layers, and then wash, dry, filter, concentrate and separate the organic layers to obtain compound I.

[0017] Preparation of compound II: Benzopyridone acid, anhydrous piperazine and dimethyl sulfoxide were added to a reaction flask and reacted at 90-120°C until the reaction was completed. After the reaction was completed, the mixture was cooled to room temperature, and a solid precipitated. The solid was filtered, dissolved in distilled water, and the pH was adjusted to 5.5-6.5 with glacial acetic acid. The solution was heated to dissolve and decolorized. The mixture was filtered while hot, and the pH was adjusted to 7-8 with concentrated ammonia. A solid precipitated, which was then filtered and dried to obtain compound II.

[0018] Preparation of Compound III: Compound I, Compound II, Reagent I and DMF were added to a reaction flask and reacted at 60-80°C until completion. After cooling to room temperature, the mixture was extracted with dichloromethane, and the organic layers were combined. The organic layers were then washed, dried, filtered, concentrated, and purified to obtain Compound III. Reagent I was selected from N,N-diisopropylethylamine, potassium iodide, triethylamine, or 4-dimethylaminopyridine.

[0019] The more specific preparation method is as follows:

[0020] Preparation of Compound I: Osthol, cysteine, sodium hydride, and DMF were mixed and refluxed for several hours. After cooling to room temperature, the solution was diluted with distilled water, and the pH was adjusted to 5-6 with 1 mol / L dilute hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product for use. The mobile phase used for the separation and purification was V. 石油醚 V 乙酸乙酯 A 5:1 mixture of solvents;

[0021] Add the prepared sample, anhydrous potassium carbonate, and DMF to a reaction flask. After stirring, add dibromoalkane at 70–90°C. After the reaction is complete, cool to room temperature, add distilled water to dilute the solution, extract with ethyl acetate, combine the organic layers, and wash the organic layers successively with 1 mol / L dilute hydrochloric acid solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution. Dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain compound I. The mobile phase used for the separation and purification is V. 石油醚 V 二氯甲烷 A 4:1 mixture of solvents;

[0022] Preparation of compound II: Benzopyridone acid, anhydrous piperazine, and dimethyl sulfoxide were added to a reaction flask and reacted at 90–120 °C until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature, a small amount of distilled water was added to dilute the solution, and an appropriate amount of sodium chloride was added. A solid precipitated, and the mixture was filtered. The solid was dissolved in distilled water, and the pH was adjusted to 5.5–6.5 with glacial acetic acid. The mixture was heated to dissolve the solid, decolorized with activated carbon, filtered while hot, and the solution was adjusted to pH 7–8 with concentrated ammonia. An appropriate amount of sodium chloride was added to precipitate the solid, which was then filtered and dried to obtain compound II.

[0023] Preparation of Compound III: Compound I, Compound II, Reagent I, and DMF were added to a reaction flask and reacted at 60–80°C until completion. After cooling to room temperature, the solution was diluted with distilled water, and extracted with dichloromethane. The organic layers were combined and washed sequentially with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain Compound III. The mobile phase used for the separation and purification was V. 二氯甲烷 V 甲醇 A 10:1 mixture of solvents. Detailed Implementation

[0024] The present invention will be further described below with reference to the embodiments. However, the present invention is not limited to the following embodiments. It is foreseeable that various changes may occur in the implementation when those skilled in the art combine it with the prior art.

[0025] The osthol derivative containing benzopyridinol acid (general formula III) of this invention was prepared according to the following synthetic route:

[0026]

[0027] The relevant data for target compound III are shown in Table 1:

[0028] Table 1:

[0029]

[0030]

[0031]

[0032]

[0033]

[0034] Example 1: Preparation of Compound III-1

[0035] First, weigh 24.56 mmol of osthol, 73.68 mmol of cysteine, 147.37 mmol of sodium hydride, and 100.00 mL of DMF into a 250 mL three-necked flask. Reflux for 3 hours. After the reaction is complete, cool to room temperature, dilute with distilled water, adjust the pH to 5.5 with 1 mol / L dilute hydrochloric acid, extract with ethyl acetate, combine the organic layers, wash with saturated sodium chloride solution, dry to anhydrous sodium sulfate, filter, concentrate under reduced pressure, and perform silica gel column chromatography (V... 石油醚 V 乙酸乙酯 =5:1) Separation and purification were performed to obtain the reserve. Then, 6.51 mmol of the reserve, 26.06 mmol of anhydrous potassium carbonate and 20.00 mL of DMF were weighed and added to the reaction flask. After stirring for 0.5 hours, 26.06 mmol of dibromoethane was added at 80 °C, and the reaction was carried out for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with distilled water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed successively with 1 mol / L dilute hydrochloric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography (V 石油醚 V 二氯甲烷 The mixture was separated and purified at a ratio of 4:1 to obtain compound I.

[0036] Next, 7.42 mmol of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 29.67 mmol of anhydrous piperazine, and 5.00 mL of dimethyl sulfoxide were added to a reaction flask, and the reaction was carried out at 90 °C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, a small amount of distilled water was added to dilute the solution, and an appropriate amount of sodium chloride was added. A solid precipitated, which was then filtered. The solid was dissolved in distilled water, and the pH was adjusted to approximately 6 with glacial acetic acid. The solution was heated to dissolve, decolorized with activated carbon, filtered while hot, and then the solution was adjusted to approximately 7.3 with concentrated ammonia. An appropriate amount of sodium chloride was added, and a solid precipitated. The solid was then filtered and dried to obtain compound II.

[0037] Finally, 0.15 mmol of compound I, 0.30 mmol of compound II, 0.08 mmol of potassium iodide / 0.45 mmol of triethylamine, and 5.00 mL of DMF were added to the reaction flask, and the reaction was carried out at 70 °C for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with distilled water, extracted with dichloromethane, and the organic layers were combined. The organic layers were washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography (V). 二氯甲烷 V 甲醇 The mixture was separated and purified at a ratio of 10:1 to obtain compound III.

[0038] Example 2: Preparation of compound III-2

[0039] First, weigh 24.56 mmol osthol, 73.68 mmol cysteine, 147.37 mmol sodium hydride, and 100.00 mL DMF into a 250 mL three-necked flask. Reflux for 2.5 hours. After the reaction is complete, cool to room temperature, dilute with distilled water, adjust the pH to 5.5 with 1 mol / L dilute hydrochloric acid solution, extract with ethyl acetate, combine the organic layers, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and perform silica gel column chromatography (V... 石油醚 V 乙酸乙酯 =5:1) Separation and purification were performed to obtain the reserve. Then, 6.51 mmol of the reserve, 26.06 mmol of anhydrous potassium carbonate and 20.00 mL of DMF were weighed and added to the reaction flask. After stirring for 1 hour, 26.06 mmol of dibromoethane was added at 80 °C, and the reaction was carried out for 3.5 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with distilled water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed successively with 1 mol / L dilute hydrochloric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography (V 石油醚 V 二氯甲烷 The mixture was separated and purified at a ratio of 4:1 to obtain compound I.

[0040] Next, 7.42 mmol of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 29.67 mmol of 2-methylpiperazine, and 5.00 mL of dimethyl sulfoxide were added to a reaction flask, and the reaction was carried out at 110 °C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, a small amount of distilled water was added to dilute the solution, and an appropriate amount of sodium chloride was added. A solid precipitated, which was filtered. The solid was dissolved in distilled water, and the pH was adjusted to approximately 6 with glacial acetic acid. The solution was heated to dissolve, decolorized with activated carbon, filtered while hot, and the solution was adjusted to approximately 7.3 with concentrated ammonia. An appropriate amount of sodium chloride was added, and a solid precipitated. The solid was filtered under vacuum and dried to obtain compound II.

[0041] Finally, 0.15 mmol of compound I, 0.30 mmol of compound II, 0.45 mmol of N,N-diisopropylethylamine, and 5.00 mL of DMF were added to the reaction flask, and the reaction was carried out at 70 °C for 9 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with distilled water, extracted with dichloromethane, and the organic layers were combined. The organic layers were washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography (V). 二氯甲烷 V 甲醇 The ratio of 9:1 was used for separation and purification to obtain compound III.

[0042] Example 3: Preparation of Compound III-7

[0043] First, weigh 24.56 mmol of osthol, 73.68 mmol of cysteine, 5.89 g of sodium hydride, and 100.00 mL of DMF into a 250 mL three-necked flask. Reflux for 2.5 hours. After the reaction is complete, cool to room temperature, dilute with distilled water, adjust the pH to 5.5 with 1 mol / L dilute hydrochloric acid, extract with ethyl acetate, combine the organic layers, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and perform silica gel column chromatography (V... 石油醚 V 乙酸乙酯 =5:1) Separation and purification were performed to obtain the reserve. Then, 6.51 mmol of the reserve, 26.06 mmol of anhydrous potassium carbonate and 20.00 mL of DMF were weighed and added to the reaction flask. After stirring for 0.8 hours, 26.06 mmol of 1,3-dibromopropane was added at 80 °C, and the reaction was carried out for 3.5 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with distilled water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed successively with 1 mol / L dilute hydrochloric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography (V) 石油醚 V 二氯甲烷 The ratio of compound I to compound II was 3:1. After separation and purification, compound I was obtained.

[0044] Next, 7.42 mmol of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 29.67 mmol of anhydrous piperazine, and 5.00 mL of dimethyl sulfoxide were added to a reaction flask, and the reaction was carried out at 120 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, a small amount of distilled water was added to dilute the solution, an appropriate amount of sodium chloride was added, a solid was precipitated, filtered, the solid was dissolved in distilled water, the pH was adjusted to about 6 with glacial acetic acid, the solution was heated to dissolve, activated carbon was used for decolorization, the mixture was filtered while hot, the pH of the solution was adjusted to about 7.3 with concentrated ammonia, an appropriate amount of sodium chloride was added, a solid was precipitated, filtered, and dried to obtain compound II;

[0045] Finally, 0.15 mmol of compound I, 0.30 mmol of compound II, 0.08 mmol of potassium iodide / 0.45 mmol of triethylamine, and 5.00 mL of DMF were added to the reaction flask, and the reaction was carried out at 70 °C for 7 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with distilled water, extracted with dichloromethane, and the organic layers were combined. The organic layers were washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography (V). 二氯甲烷 V 甲醇 The ratio of 9:1 was used for separation and purification to obtain compound III.

[0046] Example 4: Preparation of Compound III-8

[0047] First, weigh 24.56 mmol of osthol, 73.68 mmol of cysteine, 5.89 g of sodium hydride, and 100.00 mL of DMF into a 250 mL three-necked flask. Reflux for 3 hours. After the reaction is complete, cool to room temperature, dilute with distilled water, adjust the pH to 5.5 with 1 mol / L dilute hydrochloric acid, extract with ethyl acetate, combine the organic layers, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and perform silica gel column chromatography (V... 石油醚 V 乙酸乙酯 =5:1) Separation and purification were performed to obtain the reserve. Then, 6.51 mmol of the reserve, 26.06 mmol of anhydrous potassium carbonate and 20.00 mL of DMF were weighed and added to the reaction flask. After stirring for 0.5 to 1 hour, 26.06 mmol of 1,3-dibromopropane was added at 80 °C, and the reaction was carried out for 3.5 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with distilled water, extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed successively with 1 mol / L dilute hydrochloric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography (V 石油醚 V 二氯甲烷 The mixture was separated and purified at a ratio of 3:1 to obtain compound I.

[0048] Next, 7.42 mmol of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 29.67 mmol of 2-methylpiperazine, and 5.00 mL of dimethyl sulfoxide were added to a reaction flask, and the mixture was reacted at 100 °C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, a small amount of distilled water was added to dilute the solution, and an appropriate amount of sodium chloride was added. A solid precipitated, which was then filtered. The solid was dissolved in distilled water, and the pH was adjusted to approximately 6 with glacial acetic acid. The solution was heated to dissolve, decolorized with activated carbon, filtered while hot, and the solution was adjusted to approximately 7.3 with concentrated ammonia. An appropriate amount of sodium chloride was added, and a solid precipitated. The solid was then filtered, dried, and compound II was obtained.

[0049] Finally, 0.15 mmol of compound I, 0.30 mmol of compound II, 0.45 mmol of 4-dimethylaminopyridine, and 5.00 mL of DMF were added to the reaction flask, and the reaction was carried out at 70 °C for 10 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with distilled water, extracted with dichloromethane, and the organic layers were combined. The organic layers were washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and subjected to silica gel column chromatography (V). 二氯甲烷 V 甲醇 The ratio of 9:1 was used for separation and purification to obtain compound III.

[0050] The antibacterial activity test of the present invention: using norfloxacin as a control drug, the minimum inhibitory concentration (MIC) of the compound of formula III against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA), and fluoroquinolone-resistant Escherichia coli (FREC) was determined by microdilution method. The data are shown in Table 2.

[0051] Table 2:

[0052]

[0053]

[0054] The experimental results clearly demonstrate that the compounds of general formula III protected by this invention possess potential antibacterial activity. Compounds III-1, III-2, III-5, and III-6 exhibit superior inhibitory activity against *S. aureus* compared to the control drug; compounds III-5 and III-6 show superior inhibitory activity against *E. coli* compared to the control drug; compound III-6 shows superior inhibitory activity against *P. aeruginosa* compared to the control drug; compounds III-1, III-5, and III-6 show superior inhibitory activity against MRSA compared to the control drug; and compounds III-1, III-2, III-5, and III-6 show significantly superior inhibitory activity against FREC compared to the control drug. These compounds possess significant and broad-spectrum antibacterial activity and can be used as antimicrobial agents against *S. aureus*, *E. coli*, *P. aeruginosa*, MRSA, and FREC. They can also be used in combination with other antibacterial active substances.

[0055] The antitumor activity of this invention was tested using the MTT assay, with cisplatin as a control, to determine the inhibitory effect of the general formula III phosphonate dipeptide compound on the proliferation of tumor cells A-549 (human lung cancer cells), SGC-7901 (human gastric cancer cells), and EC-109 (human esophageal cancer cells). The IC50 was calculated using the Reed and Muench method. 50 The values ​​and data are shown in Table 3.

[0056] Table 3:

[0057]

[0058] The experimental results above clearly show that the compounds of general formula III to be protected by this invention have certain anti-tumor activity. Among them, compounds III-3, III-4, III-7 and III-8 have significant inhibitory activity against EC-109 proliferation, comparable to the control drug cisplatin, and can be used as anti-EC-109 drugs. At the same time, they can also be used in combination with other tumor active substances.

Claims

1. A osthol derivative containing benzopyridinol acid, characterized in that, It has a chemical structure as shown in general formula III: The general formula III is selected from the following compounds: 、 、 、 、 、 、 、 。 2. The method for preparing the osthol derivative containing benzopyridinol acid according to claim 1, characterized in that, It was prepared according to the following synthetic route: ， The derivatives represented by general formula III are defined as described in claim 1.

3. The preparation method according to claim 2, characterized in that, Includes the following steps: Preparation of compound I: Osthol, cysteine, sodium hydride and DMF were mixed and refluxed for several hours. The mixture was then cooled to room temperature, and the pH of the solution was adjusted to 5-6. The solution was extracted with ethyl acetate, and the organic layers were combined. The organic layers were then washed, dried, filtered, concentrated and purified to obtain the product for use. Add the prepared sample, anhydrous potassium carbonate and DMF to the reaction flask, stir the reaction, add dibromoalkane at 70~90℃, cool to room temperature after the reaction is completed, extract with ethyl acetate, combine the organic layers, and then wash, dry, filter, concentrate and separate the organic layers to obtain compound I. Preparation of compound II: Benzopyridone acid, anhydrous piperazine and dimethyl sulfoxide were added to a reaction flask and reacted at 90-120°C until the reaction was completed. After the reaction was completed, the mixture was cooled to room temperature, and a solid precipitated. The solid was filtered, dissolved in distilled water, and the pH was adjusted to 5.5-6.5 with glacial acetic acid. The solution was heated to dissolve and decolorized. The mixture was filtered while hot, and the pH was adjusted to 7-8 with concentrated ammonia. A solid precipitated, which was then filtered and dried to obtain compound II. Preparation of Compound III: Compound I, Compound II, Reagent I, and DMF were added to a reaction flask and reacted at 60–80 °C until completion. After cooling to room temperature, the mixture was extracted with dichloromethane. The organic layers were combined and then washed, dried, filtered, concentrated, and purified to obtain Compound III. Reagent I was selected from… N , N - One of diisopropylethylamine, potassium iodide, triethylamine or 4-dimethylaminopyridine.

4. The preparation method according to claim 3, characterized in that: Preparation of Compound I: Osthol, cysteine, sodium hydride, and DMF were mixed and refluxed for several hours. The mixture was then cooled to room temperature, diluted with distilled water, and the pH was adjusted to 5-6 with 1 mol / L dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic layers were combined. The organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the final product. The mobile phase used for the purification was [missing information - likely a specific phase or method]. V 石油醚 : V 乙酸乙酯 A 5:1 mixture of solvents; Add the prepared sample, anhydrous potassium carbonate, and DMF to a reaction flask. After stirring, add dibromoalkane at 70-90°C. After the reaction is complete, cool to room temperature, add distilled water to dilute the solution, extract with ethyl acetate, combine the organic layers, and wash the organic layers successively with 1 mol / L dilute hydrochloric acid solution, saturated sodium bicarbonate solution, and saturated sodium chloride solution. Dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography to obtain compound I. The mobile phase used for the separation and purification is [missing information - likely a specific phase or component]. V 石油醚 : V 二氯甲烷 A 4:1 mixture of solvents; Preparation of compound II: Benzopyridone acid, anhydrous piperazine, and dimethyl sulfoxide were added to a reaction flask and reacted at 90-120°C until the reaction was complete. After the reaction was completed, the mixture was cooled to room temperature, a small amount of distilled water was added to dilute the solution, and an appropriate amount of sodium chloride was added. A solid precipitated and filtered. The solid was dissolved in distilled water, and the pH was adjusted to 5.5-6.5 with glacial acetic acid. The solution was heated to dissolve, decolorized with activated carbon, filtered while hot, and the pH was adjusted to 7-8 with concentrated ammonia. An appropriate amount of sodium chloride was added to precipitate the solid. The solid was filtered and dried to obtain compound II. Preparation of Compound III: Compound I, Compound II, Reagent I, and DMF were added to a reaction flask and reacted at 60-80°C until completion. After cooling to room temperature, the solution was diluted with distilled water, and extracted with dichloromethane. The organic layers were combined and washed sequentially with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain Compound III. The mobile phase used for the separation and purification was [missing information - likely a specific phase or component]. V 二氯甲烷 : V 甲醇 A 10:1 mixture of solvents.

5. The use of the benzopyridinol-containing osthol derivative according to claim 1 in the preparation of medicaments for treating and / or preventing Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa; wherein the benzopyridinol-containing osthol derivative is selected from any of the following compounds: 、 、 、 。 6. The use of the benzopyridinol acid-containing osthol derivative according to claim 1 in the preparation of medicaments for treating and / or preventing methicillin-resistant Staphylococcus aureus and fluoroquinolone-resistant Escherichia coli; wherein the benzopyridinol acid-containing osthol derivative is selected from any of the following compounds: 、 、 、 。 7. The use of the osthol derivative containing benzopyridinol acid according to claim 1 in the preparation of medicaments for the treatment and / or prevention of esophageal cancer.

8. The application of the osthol derivative containing benzopyridinol acid according to claim 7, characterized in that: The osthol derivative containing benzopyridinol acid is selected from any of the following compounds: 、 、 、 。

Images