An Electrochemical Synthesis Method of Halogenated Quinolin-4(1H)-one Derivatives

Abstract

The present invention discloses an electrochemical synthesis method of a halogenated quinolin-4(1H)-one derivative. The synthesis method of this reaction is as follows: in an undivided electrolytic cell, a quinolin-4(1H)-one derivative, a halide, and a solvent are added. A graphite rod is used as the anode and a platinum sheet is used as the cathode. Stirring is carried out under a current condition of 10 mA. After the crude reaction product is separated and purified, the halogenated quinolin-4(1H)-one derivative can be obtained. The present invention has developed an electrochemical C-H halogenation reaction of potassium halide and a quinolin-4(1H)-one derivative. A series of functionalized halogenated quinolin-4(1H)-one derivatives can be constructed through simple operations. Compared with traditional synthesis methods, the main advantages are as follows: 1) The reaction conditions are mild and can proceed smoothly at room temperature; 2) The operation is simple and nitrogen protection is not required; 3) Electricity is used as the oxidation method in the reaction, avoiding the use of chemical oxidants; 4) It has good functional group tolerance, high yield, short reaction time, and is easy to scale up.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthetic chemistry, and particularly relates to an electrochemical synthesis method of a halogenated quinolin-4(1H)-one derivative. Background Art

[0002] Organic halides are compounds with high practical value and are widely used in various branches of chemistry (such as pharmaceuticals, dyes, agrochemicals, etc.). They are also important functional groups in natural products. (Landry M L, Burns NZ. Catalytic Enantioselective Dihalogenation in Total Synthesis[J]. Accounts of chemical research, 2018, 51(5):1260-1271; Mendoza F, Ruíz-Guerrero R, Hernández-Fuentes C, et al. On The Bromination Of Aromatics, Alkenes and Alkynes Using Alkylammonium Bromide: towards the Mimic of Bromoperoxidases Reactivity[J]. Tetrahedron Letters, 2016, 57(50):5644-5648; E, S, Eren T. Decisionmaking for Promising Quinoline-Based Anticancer Agents through Combined Methodology[J]. Journal of Biochemical and Molecular Toxicology, 2020, 34(9): e22522; Donham L L, Gronert S. Substitution Reactions On Iodine and Bromine: Mechanisms for Facile Halogenations of Heterocycles[J]. The Journal of Organic Chemistry, 2019, 84(9): 5757-5762.). Therefore, a practical and effective method for obtaining such compounds is highly valuable. With the booming development of electrochemistry, in recent years, the research strategy of using electricity instead of oxidants has provided a green synthetic method for the preparation of organic halides.Chen (Chen J, Lv S, Tian S. Electrochemical Transition-Metal-Catalyzed C-H Bond Functionalization: Electricity as Clean Surrogates of Chemical Oxidants[J]. ChemSusChem, 2019, 12(1): 115-132.), Kakiuchi (Kakiuchi F, Kochi T, Mutsutani H, et al. Palladium-Catalyzed Aromatic C-H Halogenation With Hydrogen Halides by Means of Electrochemical Oxidation[J]. Journal of the American Chemical Society, 2009, 131(32): 11310-11311; Konishi M, Tsuchida K, Sano K, et al. Palladium-Catalyzed Ortho-Selective C-H Chlorination of Benzamide Derivatives under Anodic Oxidation Conditions[J]. The Journal of Organic Chemistry, 2017, 82(16): 8716-8724.) and other research groups have studied the electrochemical aromatic C-H bond halogenation reaction catalyzed by transition metals. However, this method requires the use of toxic metals as catalysts, which has certain limitations. Therefore, it is very necessary to develop environmentally friendly and transition-metal-free halogenation reactions. Recently, the electrochemical radical halogenation reaction of aromatic hydrocarbons has been reported. Compared with other methods, it does not require the participation of external oxidants or reductants (M. T. Moragas, D. Gallego and R. Martin, ACS Catal., 2016, 6, 6739–6749; Chen N, Ye Z, Zhang F. Recent Progress on Electrochemical Synthesis Involving Carboxylic Acids[J]. Organic & Biomolecular Chemistry, 2021, 19(25): 5501-5520), which is more in line with the concept of green chemistry.

[0003] Quinolin-4(1H)-ones are a class of nitrogen-containing heterocyclic compounds with a wide range of pharmacological effects and biological activities, such as anti-cancer, anti-malarial, antioxidant, and anti-inflammatory effects. It is one of the most important structural scaffolds known to inhibit bacterial growth. (Ravi M, Chauhan P, Kant R, et al. Transition-Metal-Free C-H Arylation of Quinoline-4-Ones with Arylhydrazines[J]. The Journal of Organic Chemistry, 2015, 80(10):5369-5376; Kumar S, Chauhan P, Jain N. Photoredox Halogenation of Quinolones: the Dual Role of Halo-Fluorescein Dyes[J]. Organic&Biomolecular Chemistry, 2021, 19(20):4585-4592). However, there is currently little research on the organic electrochemistry of quinolin-4(1H)-one derivatives, and the method of activating the C3-H of quinolin-4(1H)-one to construct a carbon-halogen bond through electro-organic synthesis has not been reported. Herein, we achieved the C3-H halogenation reaction of quinolin-4(1H)-one drugs under electrochemical conditions. Summary of the Invention

[0004] The object of the present invention is to provide a preparation method of electrochemically promoted halogenated quinolin-4(1H)-one derivatives in view of the disadvantages and deficiencies of the prior art.

[0005] The idea of the present invention: Using quinolin-4(1H)-one compounds as raw materials, potassium halide as the halogen source and electrolyte, methanol as the solvent, a graphite rod as the anode, and a platinum sheet as the cathode, stirring and reacting under a current condition of 10 mA to construct quinolin-4(1H)-one derivatives in one step. This method uses current instead of an oxidant, and potassium halide serves as both the halogen source and electrolyte, having a certain step economy. Moreover, this reaction has a single selectivity, is easy to operate, has good functional group tolerance, and has potential application value.

[0006] The object of the present invention is achieved by the following technical solutions.

[0007] An electrochemical synthesis method for preparing halogenated quinolin-4(1H)-one derivatives, comprising the following preparation process:

[0008] In an unseparated electrolytic cell, a quinoline-4(1H)-one derivative, a halogen source, and a solvent are added, a graphite rod is used as an anode, a platinum sheet is used as a cathode, and the reaction is stirred for 45 minutes under a current condition of 10 mA. After separation and purification of the crude product, a halogenated quinoline-4(1H)-one compound can be obtained;

[0009] Further, the preparation formula of the halogenated quinoline-4(1H)-one derivative is as follows:

[0010]

[0011] In the formula, R 1 is selected from the group consisting of hydrogen, methyl, aromatic ring, 4-methyl aromatic ring, 4-tert-butyl aromatic ring, 4-trifluoromethyl aromatic ring, 4-iodine aromatic ring, 4-chloro aromatic ring, 3-methyl aromatic ring, 3-methoxy aromatic ring, 3-fluoro aromatic ring, 3-bromo aromatic ring, 3-chloro aromatic ring, 2-fluoro aromatic ring, 2-chloro aromatic ring, nitrogen-condensed ring, 3,5-methoxy aromatic ring, 3,4-difluoro aromatic ring, 3-methyl-4-fluoro aromatic ring, 2-methoxy-5-fluoro aromatic ring and naphthalene ring; R 2 It is one of 6-chloro, 7-chloro, 6-bromo, 7-bromo, 6-fluoro, 6,7-methoxy and oxygen-containing heterocycle; the halogen source is one of potassium iodide, sodium iodide, ammonium iodide, elemental iodine, tetrabutylammonium iodide, potassium bromide, sodium bromide, ammonium bromide, potassium chloride, sodium chloride and ammonium chloride.

[0012] Furthermore, the molar ratio of the halogen source to the quinoline-4(1H)-one derivative is 1.5:1.

[0013] Furthermore, the solvent is methanol.

[0014] Furthermore, the crude product is separated by recrystallization and column chromatography, with acetone and petroleum ether as recrystallization solvents and ethyl acetate and petroleum ether as column chromatography eluents.

[0015] The principle of the invention is: using electric current to replace the oxidant, potassium iodide is oxidized at the anode to generate iodine free radicals, the iodine free radicals grab hydrogen on the nitrogen of quinoline-4(1H)-one, forming nitrogen free radicals (important intermediates) and hydrogen iodide, followed by free radical migration to obtain carbon free radical intermediates, and further oxidation at the anode to obtain carbon cation intermediates, and iodine anions in the system nucleophilically attack carbon cations. Finally, hydrogen migration obtains the C3-H halogenation product of the quinoline-4(1H)-one derivative.

[0016] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0017] (1) The invention realizes the synthesis reaction of electrochemically halogenated quinolin-4(1H)-one derivatives, and constructs a series of quinolin-4(1H)-one derivatives that are difficult to prepare. Among them, potassium halide serves as both a halogen source and an electrolyte, avoiding the use of expensive and toxic elemental halides, and is cheap and easily available. Compared with traditional synthesis methods, it has the following advantages: 1) The reaction conditions are mild and can be smoothly completed at room temperature; 2) The operation is simple and no nitrogen protection is required; 3) The reaction uses current as an oxidation method, avoiding the use of chemical oxidants; 4) It has good functional group tolerance, high yield, and short reaction time.

[0018] (2) The method for preparing halogenated quinolin-4(1H)-one derivatives of the present invention can be completed through a one-step reaction, with high step economy; it can achieve gram-scale preparation, laying a foundation for industrial application. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 、 Figure 2 are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 1;

[0020] Figure 3 、 Figure 4 are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 2;

[0021] Figure 5 、 Figure 6 are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 3;

[0022] Figure 7 、 Figure 8 are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 4;

[0023] Figure 9 、 Figure 10 are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 5;

[0024] Figure 11 、 Figure 12 are the hydrogen spectrum and carbon spectrum of the target product obtained in Example 6; DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention will be further described below through specific examples, but the protection scope and implementation manner of the present invention are not limited thereto.

[0026] Example 1

[0027] In a three-necked flask equipped with a magnetic stir bar, 0.1 mmol of quinolin-4(1H)-one, 0.15 mmol of potassium iodide and 4 mL of methanol were successively added. Using a platinum plate as the electrode, with a current of 10 mA, the mixture was stirred at room temperature for 45 minutes. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by rotary evaporation to obtain the crude product. Finally, it was separated and purified by column chromatography. The eluent used for column chromatography was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:2). Pure 3-iodoquinolin-4(1H)-one was obtained with a yield of 98%.

[0028] The 1H NMR and 13C NMR spectra of the obtained target product are as Figure 1 and Figure 2 shown, and the structure characterization data are as follows:

[0029] 1 H NMR(500MHz,DMSO-d6)δ12.24(s,1H),8.52(d,J=6.1Hz,1H),8.11(d,J=8.1Hz,1H),7.69(t,J=7.6Hz,1H),7.59(d,J=8.2Hz,1H),7.39(t,J=7.4Hz,1H);

[0030] 13 C NMR(125MHz,DMSO-d6)δ173.5,145.1,139.9,132.4,126.0,124.6,122.9,118.9,81.1.

[0031] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0032]

[0033] Example 2

[0034] In a three-necked flask equipped with a magnetic stir bar, 0.1 mmol of 2-methylquinolin-4(1H)-one, 0.15 mmol of potassium iodide and 4 mL of methanol were successively added. Using a platinum plate as the electrode, with a current of 10 mA, the mixture was stirred at room temperature for 45 minutes. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by rotary evaporation to obtain the crude product. Finally, it was separated and purified by column chromatography. The eluent used for column chromatography was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:2). Pure 3-iodo-2-methylquinolin-4(1H)-one was obtained with a yield of 82%.

[0035] The 1H NMR and 13C NMR spectra of the obtained target product are as Figure 3 and Figure 4As shown below, the structural characterization data are as follows:

[0036] 1 H NMR (500 MHz, DMSO-d6) δ 12.16 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 2.64 (s, 3H);

[0037] 13 C NMR (125 MHz, DMSO-d6) δ 173.41, 151.9, 139.4, 132.4, 125.9, 124.3, 121.0, 118.2, 86.5, 26.6.

[0038] Based on the above characterization data, the structure of the target compound is as follows:

[0039]

[0040] Example 3

[0041] 0.1 mmol of 2-phenylquinolin-4(1H)-one, 0.15 mmol of potassium iodide and 4 mL of methanol were successively added to a three-necked flask equipped with a magnetic stirrer. Using a platinum plate as the electrode and a current of 10 mA, the mixture was stirred at room temperature for 45 minutes. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was finally purified by column chromatography. The eluent for column chromatography was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:2). Pure 3-iodo-2-phenylquinolin-4(1H)-one was obtained with a yield of 61%.

[0042] The 1H NMR and 13C NMR spectra of the obtained target product are as Figure 5 and Figure 6 shown below, and the structural characterization data are as follows:

[0043] 1 H NMR (500 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.73–7.70 (m, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.60–7.57 (m, 5H), 7.41 (t, J = 7.2 Hz, 1H);

[0044] 1313C NMR (125 MHz, DMSO-d6) δ 174.1, 153.6, 139.8, 138.4, 132.7, 130.3, 129.5, 128.9, 126.0, 124.7, 121.4, 118.8, 86.4.

[0045] Based on the above characterization data, the structure of the target compound is as follows:

[0046]

[0047] Example 4

[0048] 0.1 mmol of 3-iodo-2-p-tolylquinolin-4(1H)-one, 0.15 mmol of potassium iodide and 4 mL of methanol were successively added to a three-necked flask equipped with a magnetic stirrer. Using a platinum plate as the electrode and a current of 10 mA, the mixture was stirred at room temperature for 45 minutes. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was finally purified by column chromatography. The eluent for column chromatography was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:2). Pure 3-iodo-2-p-tolylphenylquinolin-4(1H)-one was obtained with a yield of 77%.

[0049] The 1H NMR and 13C NMR spectra of the obtained target product are as Figure 7 and Figure 8 shown below, and the structure characterization data are as follows:

[0050] 1 1H NMR (500 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.69 (dt, J = 16.7, 7.6 Hz, 2H), 7.47–7.37 (m, 5H), 2.42 (s, 3H);

[0051] 13 13C NMR (125 MHz, DMSO-d6) δ 174.1, 153.6, 140.0, 139.8, 135.6, 132.6, 129.4, 129.3, 126.0, 124.6, 121.3, 118.8, 86.4, 21.5.

[0052] Based on the above characterization data, the structure of the target compound is as follows:

[0053]

[0054] Example 5

[0055] In a three-necked flask equipped with a magnetic stir bar, 0.1 mmol of 2-(4-chlorophenyl)-quinolin-4(1H)-one, 0.15 mmol of potassium iodide and 4 mL of methanol were successively added. Using a platinum plate as the electrode and a current of 10 mA, the mixture was stirred at room temperature for 45 minutes. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by rotary evaporation to obtain a crude product, which was finally separated and purified by column chromatography. The eluent used for column chromatography was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:2). Pure 2-(4-chlorophenyl)-3-iodoquinolin-4(1H)-one was obtained with a yield of 53%.

[0056] The 1H NMR and 13C NMR spectra of the obtained target product are as shown in Figure 9 and Figure 10 shown below. The structural characterization data are as follows:

[0057] 1 H NMR (500 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 7.5 Hz, 1H), 7.69–7.59 (m, 5H), 7.42 (t, J = 7.5 Hz, 1H);

[0058] 13 C NMR (126 MHz, DMSO-d6) δ 174.1, 152.5, 139.8, 137.1, 135.1, 132.7, 131.5, 129.0, 126.0, 124.8, 121.4, 118.8, 86.5.

[0059] Based on the above characterization data, the structure of the target compound is deduced as follows:

[0060]

[0061] Example 6

[0062] In a three-necked flask equipped with a magnetic stir bar, 0.1 mmol of 2-(3-methoxyphenyl)quinolin-4(1H)-one, 0.15 mmol of potassium iodide and 4 mL of methanol were successively added. Using a platinum plate as the electrode and a current of 10 mA, the mixture was stirred at room temperature for 45 minutes. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by rotary evaporation to obtain a crude product, which was finally separated and purified by column chromatography. The eluent used for column chromatography was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:2). Pure 3-iodo-2-(3-methoxyphenyl)quinolin-4(1H)-one was obtained with a yield of 68%.

[0063] The hydrogen spectrum and carbon spectrum of the obtained target product are as follows Figure 11 and Figure 12 shown below. The structure characterization data are as follows:

[0064] 1 H NMR(500MHz,DMSO-d6)δ12.31(s,1H),8.15(d,J=7.9Hz,1H),7.69(dd,J=21.4,7.5Hz,2H),7.50(d,J=8.0Hz,1H),7.41(t,J=7.2Hz,1H),7.13(d,J=7.6Hz,3H),3.84(s,3H);

[0065] 13 C NMR(125MHz,DMSO-d6)δ174.1,159.4,153.3,139.7,139.5,132.64,130.2,126.0,124.7,121.7,121.4,118.8,115.9,115.0,86.2,55.9.

[0066] HRMS(ESI)m / z:calcd for C 16 H 12 INO2[M+Na]+399.9810;found399.9804.

[0067] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0068]

[0069] Example 7

[0070] 0.1 mmol of 2-(2-bromophenyl)-quinolin-4(1H)-one, 0.15 mmol of potassium iodide and 4 mL of methanol were successively added to a three-necked flask equipped with a magnetic stirrer. Using a platinum plate as the electrode and a current of 10 mA, the mixture was stirred at room temperature for 45 minutes. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted 3 times with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was finally purified by column chromatography. The eluent used for column chromatography was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:2). Pure 2-(2-bromophenyl)-3-iodoquinolin-4(1H)-one was obtained with a yield of 55%.

[0071] The structure characterization data of the obtained target product are as follows:

[0072] 11H NMR (500 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.84–7.77 (m, 2H), 7.72 (t, J = 7.1 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.60–7.54 (m, 2H), 7.42 (t, J = 7.4 Hz, 1H);

[0073] 13 13C NMR (125 MHz, DMSO-d6) δ 174.1, 152.0, 140.4, 139.8, 133.3, 132.7, 132.0, 131.1, 128.9, 126.0, 124.8, 121.9, 121.4, 118.8, 86.4.

[0074] Based on the above characterization data, the structure of the target compound is as follows:

[0075]

[0076] Example 8

[0077] 0.1 mmol of 2-(2-fluorophenyl)-quinolin-4(1H)-one, 0.15 mmol of potassium iodide and 4 mL of methanol were successively added to a three-necked flask equipped with a magnetic stirrer. Using a platinum plate as the electrode and a current of 10 mA, the mixture was stirred at room temperature for 45 minutes. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was finally separated and purified by column chromatography. The eluent for column chromatography was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:2). Pure 2-(2-fluorophenyl)-3-iodoquinolin-4(1H)-one was obtained with a yield of 69%.

[0078] The structure characterization data of the obtained target product are as follows:

[0079] 1 1H NMR (500 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.18–8.14 (m, 1H), 7.75–7.72 (m, 1H), 7.66–7.57 (m, 3H), 7.47–7.42 (m, 3H);

[0080] 1313C NMR (125 MHz, DMSO-d6) δ 173.9, 159.7, 157.8, 148.7, 139.8, 132.9, 132.9, 126.3, 126.2, 126.0, 125.3, 124.9, 121.4, 118.8, 116.6, 116.4, 87.8.

[0081] HRMS (ESI) m / z: calcd for C 15 H9FINO [M+Na]+ 387.9611; found 387.9606.

[0082] Based on the above characterization data, the structure of the target compound is as follows:

[0083]

[0084] Example 9

[0085] 0.1 mmol of 2-(3,5-dimethoxyphenyl)-quinolin-4(1H)-one, 0.15 mmol of potassium iodide and 4 mL of methanol were successively added to a three-necked flask equipped with a magnetic stirrer. Using a platinum plate as the electrode and a current of 10 mA, the mixture was stirred at room temperature for 45 minutes. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was finally purified by column chromatography. The eluent for column chromatography was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:2). Pure 2-(3,5-dimethoxyphenyl)-3-iodoquinolin-4(1H)-one was obtained with a yield of 39%.

[0086] The structure characterization data of the obtained target product are as follows:

[0087] 1 1H NMR (500 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 21.0, 7.9 Hz, 2H), 7.41 (t, J = 7.2 Hz, 1H), 6.71 (d, J = 8.7 Hz, 3H), 3.82 (s, 6H);

[0088] 13 13C NMR (125 MHz, DMSO-d6) δ 174.1, 160.7, 153.3, 140.0, 139.7, 132.6, 126.0, 124.7, 121.4, 107.7, 101.8, 86.0, 56.0.

[0089] HRMS (ESI) m / z: calcd for C17 H 14 INO3[M + Na]+429.9916; found 429.9911.

[0090] Based on the above characterization data, the structure of the target compound is as follows:

[0091]

[0092] Example 10

[0093] In a three-necked flask equipped with a magnetic stirrer, 0.1 mmol of 2-(5-fluoro-2-methoxyphenyl)-quinolin-4(1H)-one, 0.15 mmol of potassium iodide and 4 mL of methanol were successively added. Using a platinum plate as the electrode and a current of 10 mA, the mixture was stirred at room temperature for 45 minutes. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was finally purified by column chromatography. The eluent for column chromatography was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:2). Pure 2-(5-fluoro-2-methoxyphenyl)-3-iodoquinolin-4(1H)-one was obtained with a yield of 45%.

[0094] The structure characterization data of the obtained target product are as follows:

[0095] 1 H NMR(500MHz, DMSO-d6)δ12.37(s, 1H), 8.15(d, J = 7.9Hz, 1H), 7.74–7.69(m, 1H), 7.60(d, J = 8.3Hz, 1H), 7.40(dt, J = 8.2, 5.1Hz, 2H), 7.34(dd, J = 8.4, 3.0Hz, 1H), 7.24(dd, J = 9.1, 4.2Hz, 1H), 3.79(s, 3H);

[0096] 13 C NMR(125MHz, DMSO-d6)δ173.9, 157.2, 155.3, 152.9, 150.3, 139.8, 132.6, 128.3, 126.0, 124.7, 121.5, 118.7, 118.1, 117.88, 117.57, 117.4, 113.9, 113.8, 87.8, 56.8.

[0097] HRMS(ESI) m / z: calcd for C 16 H 11 FINO2[M + Na]+417.9716; found 417.9716.

[0098] Based on the above characterization data, the structure of the target compound is as follows:

[0099]

[0100] Example 11

[0101] Into a three-necked flask equipped with a magnetic stir bar, 0.1 mmol of 2-naphthylquinolin-4(1H)-one, 0.15 mmol of potassium iodide and 4 mL of methanol were added successively. Using a platinum plate as the electrode, with a current of 10 mA, the mixture was stirred at room temperature for 45 minutes. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by rotary evaporation to obtain the crude product. Finally, it was separated and purified by column chromatography. The eluent for column chromatography used was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:2). Pure 3-iodo-2-naphthylquinolin-4(1H)-one was obtained with a yield of 73%.

[0102] The structure characterization data of the obtained target product are as follows:

[0103] 1 H NMR(500MHz,DMSO-d6)δ12.53(s,1H),8.23(d,J=8.0Hz,1H),8.16(d,J=8.0Hz,1H),8.10(d,J=8.0Hz,1H),7.73(q,J=8.4Hz,2H),7.67–7.60(m,3H),7.56(d,J=7.1Hz,2H),7.46(t,J=7.4Hz,1H);

[0104] 13 C NMR(125MHz,DMSO-d6)δ174.0,152.6,140.0,136.1,133.5,132.7,130.3,130.2,129.0,127.8,127.5,127.1,126.1,125.95,125.11,124.8,121.6,118.8,88.3.

[0105] HRMS(ESI)m / z:calcd for C 19 H 12 INO[M+Na]+419.9861;found419.9859.

[0106] Based on the above characterization data, the structure of the target compound is as follows:

[0107]

[0108] Example 12

[0109] 0.1 mmol of 6-bromoquinolin-4(1H)-one, 0.15 mmol of potassium iodide and 4 mL of methanol were successively added into a three-necked flask equipped with a magnetic stir bar. Using a platinum plate as the electrode and a current of 10 mA, the mixture was stirred at room temperature for 45 minutes. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by rotary evaporation to obtain the crude product. Finally, it was separated and purified by column chromatography. The eluent used for column chromatography was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:2). Pure 6-bromo-3-iodoquinolin-4(1H)-one was obtained with a yield of 89%.

[0110] The structural characterization data of the obtained target product are as follows:

[0111] 1 H NMR(500MHz,DMSO-d6)δ8.56(s,1H),8.18(s,1H),7.83(d,J=8.6Hz,1H),7.57(d,J=8.8Hz,1H);

[0112] 13 C NMR(125MHz,DMSO-d6)δ172.4,145.6,138.9,135.1,128.0,124.1,121.7,117.0,81.3.

[0113] Based on the above characterization data, the structure of the target compound is inferred as follows:

[0114]

[0115] Example 13

[0116] 0.1 mmol of 6,7-dimethoxy-2-phenylquinolin-4(1H)-one, 0.15 mmol of potassium iodide and 4 mL of methanol were successively added into a three-necked flask equipped with a magnetic stir bar. Using a platinum plate as the electrode and a current of 10 mA, the mixture was stirred at room temperature for 45 minutes. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure by rotary evaporation to obtain the crude product. Finally, it was separated and purified by column chromatography. The eluent used for column chromatography was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:2). Pure 3-iodo-6,7-dimethoxy-2-phenylquinolin-4(1H)-one was obtained with a yield of 56%.

[0117] The structural characterization data of the obtained target product are as follows:

[0118] 11H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 7.56 (d, J = 7.1 Hz, 5H), 7.48 (s, 1H), 7.11 (s, 1H), 3.86 (d, J = 9.6 Hz, 6H);

[0119] 13 13C NMR (125 MHz, DMSO-d6) δ 172.8, 153.7, 151.9, 147.8, 138.4, 135.5, 130.2, 129.5, 128.8, 115.5, 105.1, 99.6, 85.5, 56.2, 56.1.

[0120] HRMS (ESI) m / z: calcd for C 17 H 14 INO3 [M+Na]+ 429.9916; found 429.9921.

[0121] Based on the above characterization data, the structure of the target compound is as follows:

[0122]

[0123] Example 14

[0124] 0.1 mmol of quinolin-4(1H)-one, 0.15 mmol of potassium bromide and 4 mL of methanol were successively added to a three-necked flask equipped with a magnetic stirrer. Using a platinum plate as the electrode and a current of 10 mA, the mixture was stirred at room temperature for 1.5 h. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was finally purified by column chromatography. The eluent for column chromatography was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether: ethyl acetate = 1:2). Pure 3-iodo-2-naphthylquinolin-4(1H)-one was obtained with a yield of 84%.

[0125] The structure characterization data of the obtained target product are as follows:

[0126] 1 1H NMR (500 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.49 (s, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H);

[0127] 1313C NMR (125 MHz, DMSO-d6) δ 171.9, 140.7, 139.7, 132.4, 125.8, 124.7, 124.5, 119.0, 104.7.

[0128] Based on the above characterization data, the structure of the target compound is as follows:

[0129]

[0130] Example 15

[0131] 0.1 mmol of quinolin-4(1H)-one, 0.15 mmol of potassium chloride and 4 mL of methanol were successively added to a three-necked flask equipped with a magnetic stirrer. Using a platinum plate as the electrode and a current of 10 mA, the mixture was stirred at room temperature for 1.5 h. The reaction was stopped, cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was finally purified by column chromatography. The eluent for column chromatography was a mixed solvent of petroleum ether and ethyl acetate (petroleum ether:ethyl acetate = 1:2). Pure 6-bromo-3-iodoquinolin-4(1H)-one was obtained with a yield of 77%.

[0132] The structure characterization data of the obtained target product are as follows:

[0133] 1 1H NMR (500 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.42 (d, J = 6.1 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 8.3 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H);

[0134] 13 13C NMR (125 MHz, DMSO-d6) δ 171.7, 139.6, 138.5, 132.4, 125.6, 125.2, 124.4, 119.0, 114.6.

[0135] Based on the above characterization data, the structure of the target compound is as follows:

[0136]

[0137] The above embodiments are partial embodiments of the present invention. The specific embodiments of the present invention are not affected by the above embodiments. Any other structural modifications and condition simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. An electrochemical synthesis method for preparing halogenated quinolin-4(1H)-one derivatives, comprising the following preparation process: In an undivided electrolytic cell, quinolin-4(1H)-one derivatives, a halogen source, and a solvent are added. Using a graphite rod as the anode and a platinum sheet as the cathode, the reaction is stirred for 45 minutes under a current condition of 10 mA. The crude product can be obtained as halogenated quinolin-4(1H)-one derivatives after separation and purification. The above reaction is shown as follows: ， Wherein, R 1 is selected from one of hydrogen, methyl, aromatic ring, 4-methyl aromatic ring, 4-tert-butyl aromatic ring, 4-trifluoromethyl aromatic ring, 4-iodo aromatic ring, 4-chloro aromatic ring, 3-methyl aromatic ring, 3-methoxy aromatic ring, 3-fluoro aromatic ring, 3-bromo aromatic ring, 3-chloro aromatic ring, 2-fluoro aromatic ring, 2-chloro aromatic ring, nitrogen-fused ring, 3,5-methoxy aromatic ring, 3,4-difluoro aromatic ring, 3-methyl-4-fluoro aromatic ring, 2-methoxy-5-fluoro aromatic ring and naphthalene ring; R 2 is one of 6-chloro, 7-chloro, 6-bromo, 7-bromo, 6-fluoro, 6,7-methoxy and oxygen-containing heterocycle; the halogen source is one of potassium iodide, sodium iodide, ammonium iodide, iodine, tetrabutylammonium iodide, potassium bromide, sodium bromide, ammonium bromide, potassium chloride, sodium chloride and ammonium chloride.

2. The synthesis method of a halogenated quinolin-4(1H)-one derivative according to claim 1, characterized in that, The feeding molar ratio of the halogen source to the quinolin-4(1H)-one derivatives is 1.5:

1.

3. The synthesis method of a halogenated quinolin-4(1H)-one derivative according to claim 1, characterized in that, The solvent is methanol.

4. The synthesis method of a halogenated quinolin-4(1H)-one derivative according to claim 1, characterized in that, The separation method of the crude product is recrystallization and column chromatography; acetone and petroleum ether are the recrystallization solvents, and ethyl acetate and petroleum ether are the eluents for column chromatography.

Images