Quinolone compound as well as preparation method and application thereof
Quinolone compound III was synthesized by reacting it with potassium carbonate in a mixed solution of DMSO and water, thus solving the problem of pyridine hydroxyl groups participating in side reactions during the synthesis of quinolone compounds. This method achieved the preparation of quinolone compound III with high yield and purification, and it exhibits anti-breast cancer activity.
Patent Information
- Application Number
- CN202510996089.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-18
- Publication Date
- 2025-10-24
AI Technical Summary
In the synthesis of quinolone compounds, the participation of the pyridine hydroxyl group in side reactions leads to difficulties in product separation and purification, resulting in low yields, and existing methods are unable to effectively avoid such side reactions.
Compound I was reacted with potassium carbonate and compound II in a mixed solution of DMSO and water at 80-90℃ to achieve nucleophilic substitution of the nitrogen atom at position 1 of compound I with the fluorine atom of compound II, thus avoiding the participation of the pyridine hydroxyl group in the side reaction. Quinolone compound III was synthesized using this method.
A high-yield purification of quinolone compound III was achieved, providing a new method to avoid the formation of byproducts. Compound III also exhibits significant inhibitory activity against breast cancer cells, making it suitable for the preparation of anti-breast cancer drugs.
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Figure CN120829434A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to a quinolone compound, in particular to a quinolone compound and a preparation method and application thereof BACKGROUND
[0002] In the field of medicinal chemistry, many drugs contain quinolone nucleus, such as ofloxacin, perfloxacin, ciprofloxacin, norfloxacin, etc. Structurally, this kind of drug contains quinolone nucleus, but this kind of compound has a double nucleophilic reaction site, and there are tautomers (as shown below), when chemical reaction is carried out, pyridine nitrogen and pyridine hydroxyl can both occur nucleophilic substitution reaction, the reaction product polarity is similar, which causes great difficulty in separation and purification, therefore, it is necessary to develop a new synthesis method of selective nitrogen substitution of quinolone compound to avoid the side reaction of hydroxyl group. SUMMARY
[0003] In order to overcome the defects that the pyridine hydroxyl group participates in the reaction to form by-products in the structural derivation process of the quinolone nucleus containing compound, resulting in difficult separation and purification of the product and low yield.
[0004] A quinolone compound, characterized in that the structure of the compound is as shown in the following formula: .
[0005] The application of the quinolone compound in preparing anticancer drugs, characterized in that the structure of the quinolone compound is as shown in the following formula: .
[0006] The application, characterized in that the cancer is breast cancer.
[0007] The present application provides a new preparation method of quinolone compound, which adopts the following technical route:
[0008] Comprising the following operation steps S1: Compound I (1,8-naphthyridin-4-ol) is dissolved in a mixed solution of DMSO and water, potassium carbonate and compound II (3,5-difluoropyridine) are added, and the reaction is carried out at elevated temperature to obtain compound III.
[0009] In step S1, the reaction temperature is 80-90 ℃, and the molar ratio of compound I: potassium carbonate: compound II is 1:2:1.
[0010] Advantages 1. The present invention provides a novel method for synthesizing quinolone compound III. By selecting solvents and bases, the nitrogen atom at position 1 of compound I can undergo nucleophilic substitution with the fluorine atom of compound II, thereby avoiding the side reaction involving the hydroxyl group at position 4 of compound I. That is, the pyridine hydroxyl group in the quinolone compound is avoided from participating in the reaction to form by-products, which leads to difficulties in product separation and purification and low yield.
[0011] 2. The novel quinolone compound III prepared by the present invention has excellent inhibitory activity against breast cancer cells and can be used to prepare anti-breast cancer drugs.
[0012] 3. The raw materials of the method of the present invention are cheap and easily available, the reaction conditions are mild, and the atom economy is good. BRIEF DESCRIPTION OF THE DRAWINGS
[0013] Figure 1 is the H NMR spectrum of compound III. DETAILED DESCRIPTION
[0014] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the following specific examples further illustrate the present invention in detail. The experimental methods in the present invention are all conventional methods unless otherwise specified. It should be understood that the specific examples described herein are only used to illustrate the present invention and are not intended to limit the present invention.
[0015] The progress of the reaction of the present invention can be monitored by conventional monitoring methods in the art (such as TLC, HPLC or NMR), and the disappearance of the starting material is generally regarded as the reaction endpoint.
[0016] The chemical reagents and raw materials of the present invention were purchased from San Chemical Technology (Shanghai) Co., Ltd. Example 1
[0017] Example 1 of the present invention provides a method for preparing intermediate III, and its synthetic route is as follows:
[0018] Specifically prepared by the following method: Compound I (1 g, 6.84 mmol) was dissolved in DMSO / water (10 mL / 1 mL), potassium carbonate (1.89 g, 13.68 mmol) and compound II (787.43 mg, 6.84 mmol) were added, and then the mixture was stirred at 80 °C. o The reaction was stirred at 400 °C for 10 h and detected by TLC until compound I disappeared. Water (100 mL) was added to produce a large amount of white solid. The solid was filtered and slurried with dichloromethane: petroleum ether = 1:10 to obtain 1.6 g of pure compound III with a yield of 96.94%. ESI-MS (m / z): 242.1.Figure 1 as shown, 1 H NMR (400MHz, d6-DMSO): δ 8.42 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 9.6 Hz, 2H), 8.14 (t, J = 8.0 Hz, 2H), 7.75 (d, J = 8.3 Hz, 1H), 7.35 (s, 1H), 6.32 (d, J = 7.7 Hz,1H).
[0019] Comparative Example 1: The same procedure as in Example 1 was used, except that DMSO / water (10 mL / 1 mL) in Example 1 was replaced with DMF / water (10 mL / 1 mL), and the target product was not effectively obtained.
[0020] Comparative Example 2: The same procedure as in Example 1 was used, except that potassium carbonate in Example 1 was replaced with potassium hydroxide, and the target product was not effectively obtained.
[0021] Example 2: Study on the inhibitory effect of the compound of the present application on tumor cells In this example, the tumor cells studied were MCF-7 (human breast cancer cells), and the inhibitory effect of compound III synthesized in Example 1 on the proliferation of MCF-7 cells was detected by MTT method. Logarithmic growth phase MCF-7 cells were inoculated in a 96-well culture plate, with a cell density of 5 x 10 4 μL, in a 37°C, 5% CO2 incubator for 24 h. The culture plate was removed, and the original culture medium was discarded. Then, 200 μL of culture medium containing the drug was added, with a drug concentration of 100 μM, 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.5625 μM, 0.78125 μM, 0.390625 μM, with 6 parallel holes for each concentration, and 6 holes of cells as normal controls. After 48 h of incubation in the incubator, 20 μL of 5 mg / mL MTT solution was added to each hole, and shaken uniformly. Then, incubation was continued for 4 h. The liquid in the hole was discarded, 150 μL of DMSO was added, and shaken for 10 min. After the purple crystals were completely dissolved, the absorbance value of each hole was measured at 570 nm by a microplate reader, and the IC 50 was calculated according to the data obtained.
[0022] Table 1: Anti-proliferative effect of the compound on cancer cells
[0023] As shown in Table 1, the compound of the present application has a significant inhibitory effect on MCF-7 tumor cells.
[0024] The above description of the specific embodiments of the present application is not intended to limit the scope of the present application. Any other corresponding changes and modifications made according to the technical concept of the present application should be included in the scope of protection of the claims of the present application.
Claims
1. A quinolone compound, characterized by, The structure of the compound is shown in the following formula: 。 2. The use of the quinolone compound according to claim 1 in the preparation of an anticancer drug, characterized in that, The structure of the quinolone compound is shown in the following formula: 。 3. Use according to claim 2, characterized in that, The cancer is breast cancer.
4. The method for synthesizing quinolone compounds according to claim 1, wherein The following steps are taken: Dissolve 1,8-naphthyridin-4-ol in a mixed solution of DMSO and water, add potassium carbonate and 3,5-difluoropyridine to react to obtain compound III.
5. The method of claim 4, wherein, Reaction temperature 80 - 90 o C, 1,8-naphthyridin-4-ol: potassium carbonate: 3,5-difluoropyridine in a molar ratio of 1 :2:1.