Preparation method and application of 4-phenylseleno quinolinone derivative
The one-pot reaction method for preparing 4-phenylselenoisoquinolinone derivatives under mild conditions solves the problems of complex raw materials and cumbersome reactions in existing technologies, achieving efficient and economical compound synthesis and providing diverse structures for antiviral drugs.
Patent Information
- Application Number
- CN202511641427.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-11
- Publication Date
- 2026-02-17
AI Technical Summary
Existing methods for synthesizing 4-benzenelenylquinolinone compounds suffer from drawbacks such as complex raw materials, high reaction temperatures, and cumbersome steps, making it difficult to efficiently construct diverse products under mild conditions.
4-Benzeneselenoisoquinoline derivatives were prepared by a one-pot reaction using o-alkynylbenzaldehyde, aniline, and diphenyldiselenoether as raw materials under the action of an oxidant. Oxidants such as tert-butylhydrogen peroxide were used, and the reaction was carried out at 60-100℃ for 12-13 hours. Post-processing included filtration, extraction, drying, and purification.
A highly efficient, economical, and mild method for preparing 4-benzeneselenylisoquinolinone derivatives was achieved with excellent yields, inexpensive and readily available raw materials, and high atom economy, making it suitable for the synthesis of antiviral drugs.
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Figure CN121537346A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis, and in particular refers to a method for preparing and applying a 4-benzeneselenylquinolinone derivative. Background Technology
[0002] Drugs NXL-101 and CRFRA-34b, with the 4-phenylselenoquinoline skeletal framework, have been used to treat Gram-positive bacterial infections and depression and anxiety, respectively. The N-terminal kinase inhibitor JNKI-20 has also been shown to have a neuroprotective effect on human cortical neurons (Chem. Commun. 2020, 56(97), 15325-15328; J. Org. Chem. 2018, 83(17), 9958-9967; Chin. Chem. Lett. 2022, 33(3), 1501-1504). Arylselenosubstituted isoquinoline ketones exhibit good antiviral activity against tobacco mosaic virus. Therefore, synthetic methods for constructing 4-phenylselenoquinoline ketone compounds have been widely reported.
[0003]
[0004] Although there have been some reports on the synthesis of 4-benzeneselenylquinolinone compounds (Chem. Commun. 2020, 56(97), 15325-15328; J. Org. Chem. 2018, 83(17), 9958-9967; Chin. Chem. Lett. 2022, 33(3), 1501-1504), most of the existing synthetic methods have drawbacks such as complex raw material synthesis, high reaction temperature, low reaction efficiency, and cumbersome steps.
[0005] Therefore, it is extremely necessary, but challenging, to develop a method for the one-pot efficient construction of 4-benzeneselenylquinolinone compounds under mild conditions, starting from simple and readily available substrates, to expand the diversity of product structures and meet the needs of more levels of drug activity research. Summary of the Invention
[0006] To address the aforementioned technical problems, the present invention provides a 4-benzenelenylquinolinone derivative compound as shown in Formula IV, or a pharmaceutically acceptable salt thereof.
[0007] Among them, R 1 Selected from halogens, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy groups may be substituted with halogens;
[0008] R 2 Selected from halogens, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy groups may be substituted with halogens;
[0009] n and m are each independently selected from integers between 0 and 4.
[0010] In some implementation schemes, R 1 Selected from halogens, such as chlorine, fluorine, or bromine. In some embodiments, R 1 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, propyl, or butyl (e.g., tert-butyl). In some embodiments, R 2 Selected from halogens, such as chlorine, fluorine, or bromine. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, m is 1, 2, 3, or 4.
[0011] In some embodiments, the compound represented by Formula IV is selected from:
[0012]
[0013]
[0014] Another aspect of the present invention provides a method for preparing the compound of formula IV or a pharmaceutically acceptable salt thereof, the method comprising the following steps:
[0015] The compounds shown in formula (I) and formula (II) were reacted in an organic solvent under the action of an oxidant to obtain the 4-phenylselenoquinoline ketone derivative shown in formula (III);
[0016]
[0017] Among them, R 1 Selected from halogens, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy groups may be substituted with halogens;
[0018] R 2 Selected from halogens, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy groups may be substituted with halogens;
[0019] n and m are each independently selected from integers between 0 and 4.
[0020] In some embodiments, the oxidant is selected from tert-butylhydrogen peroxide, lauroyl peroxide, and cumene peroxide. Further, cumene peroxide is preferred.
[0021] In some embodiments, the molar ratio of the compound shown in formula (I) to the compound shown in formula (II) is 1.0:1.0:1.0.
[0022] In some embodiments, the molar ratio of the oxidant to the compound of formula (III) is 2:1 to 4:1, including 2:1, 2.5:1, 3:1, 3.5:1, and 4:1. In some embodiments, the molar ratio of the oxidant to the compound of formula (III) is 3:1.
[0023] In some embodiments, the organic solvent is selected from one or more of acetonitrile, 1,4-dioxane, and dimethyl sulfoxide. Further, acetonitrile is preferred.
[0024] In some embodiments, the additive is selected from one or more of tetramethylammonium iodide, tetraethylammonium iodide, tetrabutylammonium iodide, and ammonium iodide. More preferably, tetramethylammonium iodide is preferred.
[0025] In some embodiments, the reaction temperature is 60℃-100℃ and the reaction time is preferably 12h. The reaction time is 1h-3h, 3h-6h, 6h-9h, 9h-13h, etc., specifically 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, etc., or any value between any two values.
[0026] In some embodiments, the compound represented by formula (I) is selected from aniline (1), aniline (2), 4-methylaniline (3), 4-tert-butylaniline (4), 4-fluoroaniline (5), 4-chloroaniline (6), 4-bromoaniline (7), 3-methylaniline (8), 3-bromoaniline (9), 2-methylaniline (10), and 2-bromoaniline.
[0027] The specific structural formulas of the compounds represented by formula (I) corresponding to the above numbers are as follows:
[0028]
[0029] In some embodiments, the compound represented by formula (II) is preferably selected from (5-methyl-2-ethynylbenzaldehyde), (5-chloro-2-ethynylbenzaldehyde), (4-chloro-2-ethynylbenzaldehyde), and (3-chloro-2-ethynylbenzaldehyde), the structural formulas of which are shown below:
[0030]
[0031] In some embodiments, the 3-fluoroquinoline derivative represented by formula (IV) has the structural formula shown in one of formulas (IV-1) or (IV-14):
[0032]
[0033] A third object of the present invention is to provide the use of the compound shown in Formula IV in the preparation of antiviral drugs.
[0034] The technical solution of the present invention has the following advantages compared with the prior art:
[0035] This invention utilizes o-alkynylbenzaldehyde, aniline, and diphenyldiselenes as reactants to prepare 4-phenylselenoisoquinolinone derivatives in a one-pot process. Compared with existing technologies, this invention provides a more step-economical, atom-economical, convenient, rapid, and efficient synthetic method for 4-phenylselenoisoquinolinone derivatives. This method utilizes simple starting materials in a single step, offering advantages such as readily available and inexpensive raw materials, simple and mild conditions, no metal catalysis, high atom economy, excellent yield, and a broad substrate range. It provides a very green synthetic method for the efficient construction of the 4-phenylselenoisoquinolinone skeleton.
[0036] This invention provides a series of potentially biologically active 4-phenylselenoisoquinolone derivatives, which possess potential antiviral activity.
[0037] The term "filtration" in this invention is merely a description of one method of separating solids and liquids, and does not refer to only one specific operation. In actual production, methods such as centrifugation or spin-filtering also fall into this category.
[0038] The preparation method of the present invention also includes one or more steps such as filtration, extraction, drying, concentration or purification (e.g., column chromatography).
[0039] The medicinal salts used in this invention are selected from, but are not limited to, hydrochloride salts.
[0040] The term "halogenation" refers to the substitution of one or more atoms selected from fluorine, chlorine, bromine, and iodine.
[0041] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 6 carbon atoms. The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers. The alkyl group can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, including, but not limited to, halogens.
[0042] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort.
[0043] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy. Alkoxy groups can be substituted or unsubstituted. When substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, including but not limited to halogens.
[0044] The term “optional” or “optional” means that the event or situation described below may, but does not have to, occur, including the circumstances under which the event or situation may or may not occur.
[0045] The values used in this invention are instrument measurements and are subject to a certain degree of error. Generally, ±20% is within a reasonable error range. Of course, the context in which the value is used needs to be considered, and the values can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%. Attached Figure Description
[0046] To make the content of this invention easier to understand, the invention will be further described in detail below with reference to specific embodiments and accompanying drawings, wherein...
[0047] Figure 1 The image shows the hydrogen NMR spectrum of compound IV-1 in Example 1 of this invention.
[0048] Figure 2 The image shows the carbon NMR spectrum of compound IV-1 in Example 1 of this invention.
[0049] Figure 3 This is the selenium spectrum of compound IV-1 as characterized by nuclear magnetic resonance in Example 1 of this invention. Detailed Implementation
[0050] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, so that those skilled in the art can better understand and implement the present invention. However, the embodiments described are not intended to limit the present invention.
[0051] The following embodiments of the present invention provide a method for preparing a 3-fluoroquinoline derivative represented by one of formulas (IV-1) to (IV-14) above. The numbers in the following raw materials correspond to the numbers in the above text.
[0052] Example 1: Synthesis of the compound shown in (IV-1)
[0053] Weigh 0.2 mmol of aniline (the compound corresponding to number (1), 0.018 g), 0.2 mmol of o-ethynylbenzaldehyde (the compound corresponding to number (11), 0.026 g), 0.2 mmol of diphenyldiselenes (0.0628 g), 0.6 mmol of CHP (0.1409 g) into an 8 mL sealed reaction flask, add 0.2 mmol of tetramethylammonium iodide (0.1409 g), add 2 mL of acetonitrile as solvent, and stir at 80 °C for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:20-1:10), to obtain 0.044 g of reaction product.
[0054] The reaction products were characterized, and the results are as follows:
[0055] 1 H NMR (400MHz, CDCl3) δ8.52(d,J=8.0Hz,1H),7.99(d,J=8.2Hz,1H),7.84(s,1H),7.6 8(t,J=7.7Hz,1H),7.62-7.34(m,7H),7.32(d,J=7.2Hz,2H),7.24-7.14(m,3H)ppm.
[0056] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 59%.
[0057] Example 2: Synthesis of the compound shown in (IV-2)
[0058] Weigh 0.2 mmol of 4-methylaniline (the compound corresponding to number (2), 0.021 g), 0.2 mmol of o-ethynylbenzaldehyde (the compound corresponding to number (11), 0.026 g), 0.2 mmol of diphenyldiselenes (0.0628 g), 0.6 mmol of CHP (0.1409 g) into an 8 mL sealed reaction flask, add 0.2 mmol of tetramethylammonium iodide (0.1409 g), add 2 mL of acetonitrile as solvent, and stir at 80 °C for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:20-1:10), to obtain 0.034 g of reaction product.
[0059] The reaction products were characterized, and the results are as follows:
[0060] δ8.51(d,J=8.0Hz,1H),7.98(d,J=8.0Hz,1H),7.82(s,1H),7.72-7.64(m,1H) ,7.54(t,J=7.8Hz,1H),7.44-7.28(m,6H),7.29-7.12(m,3H)2.43(s,1H)ppm.
[0061] Example 3: Synthesis of the compound shown in (IV-3)
[0062] Weigh 0.2 mmol of 4-tert-butylaniline (the compound corresponding to number (3), 0.030 g), 0.2 mmol of o-ethynylbenzaldehyde (the compound corresponding to number (11), 0.026 g), 0.2 mmol of diphenyldiselenes (0.0628 g), 0.6 mmol of CHP (0.1409 g) into an 8 mL sealed reaction flask, add 0.2 mmol of tetramethylammonium iodide (0.1409 g), add 2 mL of acetonitrile as solvent, and stir at 80 °C for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:20-1:10), to obtain 0.043 g of reaction product.
[0063] The reaction products were characterized, and the results are as follows:
[0064] 1H NMR (400MHz, CDCl3) δ8.51(d,J=7.9Hz,1H),7.98(d,J=8.0Hz,1H),7.84(s,1H),7.71-7.63(m,1H) ,7.57-7.50(m,3H),7.40(d,J=8.6Hz,2H),7.35-7.29(m,2H),7.23-7.11(m,3H),1.37(s,9H)ppm.
[0065] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 50%.
[0066] Example 4: Synthesis of the compound shown in (IV-4)
[0067] Weigh 0.2 mmol of 4-fluoroaniline (the compound corresponding to number (4), 0.022 g), 0.2 mmol of o-ethynylbenzaldehyde (the compound corresponding to number (11), 0.026 g), 0.2 mmol of diphenyldiselenes (0.0628 g), 0.6 mmol of CHP (0.1409 g) into an 8 mL sealed reaction flask, add 0.2 mmol of tetramethylammonium iodide (0.1409 g), add 2 mL of acetonitrile as solvent, and stir at 80 °C for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:20-1:10) to obtain 0.054 g of reaction product.
[0068] The reaction products were characterized, and the results are as follows:
[0069] 1 H NMR (400MHz, CDCl3) δ8.49(d,J=8.0Hz,1H),7.98(d,J=8.1Hz,1H),7.67(t,J=7.4 Hz,1H),7.54(t,J=7.7Hz,1H),7.44(s,2H),7.31(d,J=7.1Hz,2H),7.20(m,5H)ppm
[0070] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 69%.
[0071] Example 5: Synthesis of the compound shown in (III-5)
[0072] Weigh 0.2 mmol of the compound corresponding to 4-chloroaniline (number 5), 0.022 g, 0.2 mmol of o-ethynylbenzaldehyde (the compound corresponding to number (11), 0.026 g), 0.2 mmol of diphenyldiselenes (0.0628 g), 0.6 mmol of CHP (0.1409 g) into an 8 mL sealed reaction flask, add 0.2 mmol of tetramethylammonium iodide (0.1409 g), add 2 mL of acetonitrile as solvent, and stir at 80 °C for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:20-1:10), to obtain 0.047 g of reaction product.
[0073] The reaction products were characterized, and the results are as follows:
[0074] 1 H NMR (400MHz, CDCl3) δ8.48(d,J=8.0Hz,1H),7.97(d,J=8.1Hz,1H),7.77(s,1H),7.67(t,J=7.6Hz,1H),7.52 (t,J=7.6Hz,1H),7.48(d,J=8.4Hz,2H),7.41(d,J=8.4Hz,2H),7.30(d,J=7.2Hz,2H),7.25-7.14(m,3H)ppm
[0075] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 57%.
[0076] Example 6: Synthesis of the compound shown in (IV-6)
[0077] Weigh 0.2 mmol of the compound corresponding to 4-bromoaniline (number 6), 0.034 g, 0.2 mmol of o-ethynylbenzaldehyde (the compound corresponding to number (11), 0.026 g), 0.2 mmol of diphenyldiselenes (0.0628 g), 0.6 mmol of CHP (0.1409 g) into an 8 mL sealed reaction flask, add 0.2 mmol of tetramethylammonium iodide (0.1409 g), add 2 mL of acetonitrile as solvent, and stir at 80 °C for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:20-1:10), to obtain 0.044 g of reaction product.
[0078] The reaction products were characterized, and the results are as follows:
[0079] 1 H NMR (400MHz, CDCl3) δ8.48(d,J=8.0Hz,1H),7.97(d,J=8.1Hz,1H),7.77(s,1H),7.71-7.59(m, 3H),7.54(t,J=7.6Hz,1H),7.35(d,J=8.2Hz,2H),7.30(d,J=7.2Hz,2H),7.23-7.11(m,3H)ppm.
[0080] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 49%.
[0081] Example 7: Synthesis of the compound shown in (IV-7)
[0082] Weigh 0.2 mmol of the compound corresponding to 3-methylaniline (number 7), 0.021 g, 0.2 mmol of o-ethynylbenzaldehyde (the compound corresponding to number (11), 0.026 g), 0.2 mmol of diphenyldiselenes (0.0628 g), 0.6 mmol of CHP (0.1409 g) into an 8 mL sealed reaction flask, add 0.2 mmol of tetramethylammonium iodide (0.1409 g), add 2 mL of acetonitrile as solvent, and stir at 80 °C for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:20-1:10), to obtain 0.044 g of reaction product.
[0083] The reaction products were characterized, and the results are as follows:
[0084] 1 H NMR (400MHz, CDCl3) δ8.50(d,J=7.9Hz,1H),7.97(d,J=8.0Hz,1H),7.81(s,1H),7.66(t,J=7.2Hz,1H ),7.52(t,J=7.4Hz,1H),7.39(t,J=7.8Hz,1H),7.33-7.27(m,3H),7.26-7.15(m,5H)2.42(s,3H)ppm.
[0085] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 57%.
[0086] Example 8: Synthesis of the compound shown in (IV-8)
[0087] Weigh 0.2 mmol of the compound corresponding to 3-bromoaniline (number 8), 0.034 g, 0.2 mmol of o-ethynylbenzaldehyde (the compound corresponding to number (11), 0.026 g), 0.2 mmol of diphenyldiselenes (0.0628 g), 0.6 mmol of CHP (0.1409 g) into an 8 mL sealed reaction flask, add 0.2 mmol of tetramethylammonium iodide (0.1409 g), add 2 mL of acetonitrile as solvent, and stir at 80 °C for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:20-1:10), to obtain 0.052 g of reaction product.
[0088] The reaction products were characterized, and the results are as follows:
[0089] 1 H NMR (400MHz, CDCl3) δ8.48 (dd, J=8.0, 0.9Hz, 1H), 7.98 (dd, J=8.6, 1.0Hz, 1H), 7.77 (s, 1H), 7.6 9-7.63(m,2H),7.58-7.54(m,2H),7.43-7.38(m,2H),7.33-7.29(m,2H),7.22-7.16(m,3H)ppm.
[0090] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 67%.
[0091] Example 9: Synthesis of the compound shown in (IV-9)
[0092] Weigh 0.2 mmol of the compound corresponding to 2-methylaniline (number 9), 0.021 g, 0.2 mmol of o-ethynylbenzaldehyde (the compound corresponding to number (11), 0.026 g), 0.2 mmol of diphenyldiselenes (0.0628 g), 0.6 mmol of CHP (0.1409 g) into an 8 mL sealed reaction flask, add 0.2 mmol of tetramethylammonium iodide (0.1409 g), add 2 mL of acetonitrile as solvent, and stir at 80 °C for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:20-1:10), to obtain 0.044 g of reaction product.
[0093] The reaction products were characterized, and the results are as follows:
[0094] 1 ¹H NMR (400MHz, CDCl₃) δ 8.52 (d, J = 7.9Hz, 1H), 8.02 (d, J = 8.1Hz, 1H), 7.75–7.65 (m, 2H), 7.55 (t, J = 7.7Hz, 1H), 7.43–7.27 (m, 6H), 7.25–7.12 (m, 3H), 2.22 (s, 3H) ppm. Based on the characterization data, the obtained reaction product is pure (purity > 95%); the calculated product yield is 57%.
[0095] Example 10: Synthesis of the compound shown in (IV-10)
[0096] Weigh 0.2 mmol of the compound corresponding to 2-bromoaniline (number 10), 0.034 g, 0.2 mmol of o-ethynylbenzaldehyde (the compound corresponding to number (11), 0.026 g), 0.2 mmol of diphenyldiselenes (0.0628 g), 0.6 mmol of CHP (0.1409 g) into an 8 mL sealed reaction flask, add 0.2 mmol of tetramethylammonium iodide (0.1409 g), add 2 mL of acetonitrile as solvent, and stir at 80 °C for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:20-1:10), to obtain 0.044 g of reaction product.
[0097] The reaction products were characterized, and the results are as follows:
[0098] 1 H NMR (400MHz, CDCl3) δ8.81(d,J=8.0Hz,1H),8.01(d,J=8.1Hz,1H),7.77(d,J=8.0Hz,1H),7.73-7.66( m,1H),7.62(s,1H),7.58-7.52(m,1H),7.50-7.45(m,2H),7.41-7.31(m,3H),7.24-7.13(m,3H),ppm.
[0099] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 49%.
[0100] Example 11: Synthesis of the compound shown in (IV-11)
[0101] Weigh 0.2 mmol of the compound corresponding to aniline (number 1), 0.018 g, 0.2 mmol of (5-methyl-2-ethynylbenzaldehyde) (the compound corresponding to number (12), 0.029 g), 0.2 mmol of diphenyl diselenide (0.0628 g), 0.6 mmol of CHP (0.1409 g) into an 8 mL sealed reaction flask, add 0.2 mmol of tetramethylammonium iodide (0.1409 g), add 2 mL of acetonitrile as solvent, and stir at 80 °C for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:20-1:10), to obtain 0.038 g of reaction product.
[0102] The reaction products were characterized, and the results are as follows:
[0103] 1 H NMR (400MHz, CDCl3) δ8.30 (s, 1H), 7.86 (d, J = 8.2Hz, 1H), 7.76 (s, 1H), 7.57-7.39 ( m,6H),7.30(d,J=7.3Hz,2H),7.23-7.10(m,3H),7.24-7.13(m,3H),2.49(s,3H)ppm
[0104] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 50%.
[0105] Example 12: Synthesis of the compound shown in (IV-12)
[0106] Weigh 0.2 mmol of the compound corresponding to aniline (number 1), 0.018 g, 0.2 mmol of (5-chloro-2-ethynylbenzaldehyde) (the compound corresponding to number (12), 0.029 g), 0.2 mmol of diphenyl diselenide (0.0628 g), 0.6 mmol of CHP (0.1409 g) into an 8 mL sealed reaction flask, add 0.2 mmol of tetramethylammonium iodide (0.1409 g), add 2 mL of acetonitrile as solvent, and stir at 80 °C for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:20-1:10), to obtain 0.036 g of reaction product.
[0107] The reaction products were characterized, and the results are as follows:
[0108] 1H NMR (400MHz, CDCl3) δ8.45 (d, J = 2.3Hz 1H), 7.91 (d, J = 8.7Hz, 1H), 7.81 (s, 1H), 7.58 (dd, J = 8.68, 2.3Hz 1H),7.51(pseudo-t,2H),7.43(pseudo-t,3H),7.29(d,J=6.6Hz,2H),7.22-7.13(m,3H),ppm
[0109] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 44%.
[0110] Example 13: Synthesis of the compound shown in (IV-13)
[0111] Weigh 0.2 mmol of the compound corresponding to aniline (number 1), 0.018 g, 0.2 mmol of (4-chloro-2-ethynylbenzaldehyde) (the compound corresponding to number (13), 0.029 g), 0.2 mmol of diphenyl diselenide (0.0628 g), 0.6 mmol of CHP (0.1409 g) into an 8 mL sealed reaction flask, add 0.2 mmol of tetramethylammonium iodide (0.1409 g), add 2 mL of acetonitrile as solvent, and stir at 80 °C for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:20-1:10), to obtain 0.040 g of reaction product.
[0112] The reaction products were characterized, and the results are as follows:
[0113] 1 H NMR (400MHz, CDCl3) δ8.42(d,J=8.4Hz,1H),8.00(s,1H),7.84(s,1H),7.57 -7.42(m,6H),7.32(d,J=5.5Hz,2H),7.27-7.17(m,3H)ppm
[0114] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 49%.
[0115] Example 14: Synthesis of the compound shown in (IV-14)
[0116] Weigh 0.2 mmol of the compound corresponding to aniline (number 1), 0.018 g, 0.2 mmol of (3-chloro-2-ethynylbenzaldehyde) (the compound corresponding to number (14), 0.029 g), 0.2 mmol of diphenyl diselenide (0.0628 g), 0.6 mmol of CHP (0.1409 g) into an 8 mL sealed reaction flask, add 0.2 mmol of tetramethylammonium iodide (0.1409 g), add 2 mL of acetonitrile as solvent, and stir at 80 °C for 12 hours. After the reaction is completed, the reaction solution is separated by vacuum evaporation and column chromatography (column chromatography separation conditions: stationary phase is 200-300 mesh silica gel powder, mobile phase is ethyl acetate (A) and petroleum ether (B), mobile phase change program (A:B) is 1:20-1:10), to obtain 0.030 g of reaction product.
[0117] The reaction products were characterized, and the results are as follows:
[0118] 1 H NMR(400MHz, CDCl3)δ8.15(d,J=8.0Hz,1H),8.09(d,J=8.0Hz,1H),7.80-7.72(m,4H),7.69-7.61 (m,3H),7.58-7.51(m,3H),7.45(d,J=7.8Hz,4H),7.37(d,J=8.9Hz,2H),4.16(d,J=13.9Hz,2H).
[0119] Characterization data show that the obtained reaction product is pure (purity > 95%); the product yield is calculated to be 36%.
[0120] Example 15: Bioactivity Test
[0121] According to relevant references (Chem. Commun., 2020, 56, 15325-15328.), the compounds prepared in the above examples were randomly selected in this invention, and their therapeutic effects on tobacco mosaic virus (TMV) were determined using the half-leaf method.
[0122] Table 1
[0123] Compound Percent Inhibition (%) IV-1 60 IV-2 45 IV-4 90 IV-5 60 IV-8 75 IV-9 78 IV-12 81 IV-13 85 IV-14 76 Nanninomycin 64
[0124] The results are shown in Table 1. Some compounds showed good antiviral activity against TMV, especially compounds IV-4 and IV-13, which showed excellent inhibitory effects against TMV, with inhibition rates of over 85%, exceeding the positive control (Ningnanmycin, 64%).
[0125] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.
Claims
1. A compound represented by Formula IV or a pharmaceutically acceptable salt thereof, wherein, R 1 selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, said C 1-6 alkyl or C 1-6 alkoxy, said C 1-6 alkyl or C 1-6 alkoxy optionally substituted with halogen; R 2 selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, said C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with halogen; n and m are each independently selected from an integer between 0 and 4.
2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from:
3. A method for preparing the compound of formula IV or a salt thereof, characterized in that, comprising the following steps: reacting a compound represented by Formula (I), Formula (II) in an organic solvent under the action of an oxidizing agent to obtain a 4-phenylselenyl quinolinone derivative represented by Formula (III); wherein R 1 selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, said C 1-6 alkyl or C 1-6 alkoxy, said C 1-6 alkyl or C 1-6 alkoxy optionally substituted with halogen; R 2 selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, said C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with halogen; n and m are each independently selected from an integer between 0 and 4.
4. The method of claim 4, wherein, The oxidizing agent is selected from cumene hydroperoxide.
5. The preparation method according to claim 4, characterized in that, The molar ratio of the compound represented by Formula (I), Formula (II), Formula (III) is 1.0:1.0:1.
0.
6. The method according to claim 4 or 5, characterized in that, The molar ratio of the oxidizing agent to the compound represented by Formula (III) is 2:1-4:1, for example 3:
1.
7. The preparation method according to claim 4, characterized in that, The organic solvent is selected from one or more of acetonitrile, 1,4-dioxane, dimethyl sulfoxide.
8. The preparation method according to claim 4, characterized in that, The additive is selected from one or more of tetramethylammonium iodide, tetraethylammonium iodide, tetrabutylammonium iodide and ammonium iodide.
9. The preparation method according to claim 4, characterized in that, The temperature of the reaction is 60-100°C, and the reaction time is 12h.
10. Use of the compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of an antibacterial drug.