Method for preparing difluoroquinoxalinone derivative by photocatalysis of iodine-containing phosphonium salt

Abstract

The method comprises the following steps: adding a quinoxaline ketone compound as shown in a formula (I), a difluoromethyl triphenyl phosphonium iodide salt compound as shown in a formula (II) and alkali into a reaction solvent, carrying out stirring reaction under the conditions of nitrogen protection and blue light illumination, and after the reaction is finished, carrying out filtering, washing and drying to obtain the difluoroquinoxaline ketone derivative. The reaction equation is as follows: # imgabs0 #, the substituent R1 is selected from H or methyl, the substituent R2 is selected from H, methyl or methoxyl, the substituent R3 is selected from H, methyl, ester group, alkynyl, phenyl, naphthyl or substituted phenyl, the substituent R2 is selected from H, methyl or methoxyl, and the substituent R3 is selected from H, methyl, ester group, alkynyl, phenyl, naphthyl or substituted phenyl. The substituent group of the substituted phenyl is methyl or halogen, and n is 0, 1 or 2. The preparation method of the difluoromethylated quinoxalinone derivative has the advantages of simple operation process, cheap and easily available raw materials, mild reaction conditions, greenness and environmental protection, and the difluoromethylated quinoxalinone derivative has antifungal activity.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis, and particularly relates to a method for preparing difluoroquinoxalinone derivatives by photocatalyzing iodine-containing phosphonium salts. Background Art

[0002] N-heterocyclic compounds are ubiquitous in bioactive natural products and medicinally relevant compounds. Among them, quinoxalin-2(1H)-one is a very important N-heterocyclic moiety, which has surprising broad-spectrum biological properties, such as antifungal (Eur. J. Org. Chem. 2022, e202100896), anticancer, antiviral, antiepileptic and anticoagulant properties. In particular, 3-substituted quinoxalin-2(1H)-one derivatives are considered to be the most privileged pharmacophores. Therefore, considerable interest has been generated in developing new and effective synthetic protocols for quinoxalinone derivatives, and some significant achievements have been made in the synthesis of 3-substituted quinoxalin-2(1H)-one derivatives. Therefore, the development of direct and effective synthetic methods for related compounds with potential drug-active quinoxalin-2(1H)-one lead structural skeletons has received extensive attention.

[0003]

[0004] On the other hand, the preparation of organofluorine compounds is a rather important field in pharmaceuticals, agrochemicals, and materials science, as the introduction of fluorine substituents into organic molecules has a profound positive impact on their physical properties, including metabolic stability, solubility, and lipophilicity. Among various fluoroalkyl groups, difluoromethyl has attracted particular attention in medicinal chemistry because the CF2H moiety is isoelectronic and isopolar with hydroxyl and mercapto groups and can also act as a lipophilic hydrogen donor. Therefore, a large amount of research work has been devoted to the efficient introduction of difluoromethyl into organic compounds. Traditionally, difluoromethylated compounds are prepared by deoxyfluorination of aldehydes with SF4 or dialkylaminosulfur trifluoride (such as N,N-dimethylaminosulfur trifluoride (DAST) or bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo Fluor)). However, these methods usually suffer from functional group compatibility issues and require expensive and / or toxic fluorinating agents. Alternatively, photooxidative radical difluoromethylation has been achieved by using difluoromethanesulfonyl chloride, difluoromethylphosphonium salts, difluoromethyl sulfones, or sulfimides as difluoromethyl radical sources. The synthetic utility of these methods is still offset by the handling of some expensive and / or gaseous starting materials required for the preparation of these reagents, as well as the necessity of high temperatures, additional oxidants, and / or transition metal catalysts to generate difluoromethyl radicals. Therefore, alternative strategies for generating mild, efficient, and cost-effective difluoromethyl radicals would be highly desirable. Based on previous work on radical coupling, a visible-light-induced photocatalyst-free difluoromethylation reaction of quinoxalinones and difluoromethyltriphenylphosphonium iodide salts is herein proposed to construct difluoromethylated quinoxalinone compounds with antifungal activity. SUMMARY OF THE INVENTION

[0005] Aiming at the above technical problems existing in the prior art, the object of the present invention is to provide a method for preparing difluoroquinoxalinone derivatives with antifungal activity by photocatalytic iodine-containing phosphonium salts, which has the advantages of simple operation, mild reaction conditions, high product purity, and green method.

[0006] To achieve the above object, the present invention proposes the following technical solutions:

[0007] A method for preparing difluoroquinoxalinone derivatives by photocatalytic iodine-containing phosphonium salts, comprising the following steps: adding a quinoxalinone compound represented by formula (I), a difluoromethyltriphenylphosphonium iodide salt compound represented by formula (II), and a base to a reaction solvent, protecting with nitrogen, stirring and reacting under blue light irradiation conditions, and after the reaction is completed, the reaction solution is post-treated to obtain a target compound, a difluoromethylated quinoxalinone derivative with antifungal activity represented by formula (III), and its reaction equation is as follows:

[0008]

[0009] The substituent R 1 is selected from H or methyl, and the substituent R2 Selected from H, methyl or methoxy, the substituent R 3 Selected from H, methyl, ester group, alkynyl, phenyl, naphthyl or substituted phenyl, the substituent of the substituted phenyl is methyl or halogen, and n is 0, 1 or 2.

[0010] The mechanism of the present invention is as follows:

[0011] Under visible light irradiation conditions, the base interacts with difluoromethyltriphenylphosphonium iodide salt to carry out a single electron transfer reaction, generating a base radical cation, a difluoromethyl radical and an iodide anion, while releasing the by-product PPh3. The difluoromethyl radical attacks the C3 position of quinoxalinone, and the formed intermediate undergoes a single electron transfer process with the base radical cation and undergoes deprotonation to finally generate difluoromethylated quinoxalinone compounds.

[0012] Further, the reaction solvent is selected from tetrahydrofuran or dichloromethane, preferably dichloromethane.

[0013] Further, the type of the base is selected from N,N,N',N'-tetramethylethylenediamine (TMEDA) or N,N,N,N',N'-pentamethyldiethylenetriamine (PMDETA), preferably N,N,N',N'-tetramethylethylenediamine (TMEDA).

[0014] Further, the molar ratio of the quinoxalinone compound shown in formula (I), the difluoromethyltriphenylphosphonium iodide salt compound shown in formula (II), and the base shown in formula (III) is 1:2:0.2 - 1.0, and the preferred molar ratio is 1:2:0.2.

[0015] Further, the post-treatment process of the reaction solution is as follows: saturated brine is added to the reaction solution for washing, then extracted with ethyl acetate, the combined organic layers are dried with anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product, and the crude product is separated and purified by a chromatographic column to obtain the target compound. The eluent for chromatographic column separation and purification is a mixed solvent of petroleum ether / ethyl acetate with a volume ratio of 3 - 8:1.

[0016] Further, in a reaction tube equipped with magnetic stirring, the quinoxalinone compound shown in formula (Ⅰ), the difluoromethyltriphenylphosphonium iodide salt compound shown in formula (Ⅱ), the base and the reaction medium are added. After purging with nitrogen three times, the reaction system is placed under light irradiation and stirred at 30 - 40 °C for reaction. After the reaction is completed, saturated brine is added to the reaction solution for washing, the obtained mixture after washing is extracted with ethyl acetate, the combined organic layers are dried with anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product, and the crude product is separated and purified by a chromatographic column to obtain the target compound, the difluoromethylated quinoxalinone compound with antifungal activity shown in formula (Ⅲ).

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0018] 1) The present invention can realize the synthesis of difluoromethylated quinoxalinone compounds with antifungal activity only by means of blue light source irradiation conditions, without adding any photocatalyst, avoiding the use of oxidants, transition metal catalysts and specific ligands in conventional technologies, and effectively controlling the reaction cost;

[0019] 2) The present invention uses a one-step synthesis method to prepare the target compound. Compared with conventional technologies, this method is simple to operate and does not require pre-functionalization of the reaction substrate;

[0020] 3) The present invention has the advantages of simple operation, mild reaction conditions, simple post-treatment, and antifungal activity, conforms to the development concept of green chemistry, and is suitable for industrial promotion and application. Specific Embodiments

[0021] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0022] Example 1 3-(Difluoromethyl)-1-methylquinoxalin-2(1H)-one

[0023]

[0024] Add compound (Ⅰ-a) N-methylquinoxalin-2(1H)-one (32.0 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), and TMEDA (4.7 mg, 0.04 mmol) into a reaction flask equipped with magnetic stirring. Add dichloromethane (3.0 mL) to the mixture. After replacing the nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 42 hours. After the reaction is completed, add saturated brine to the reaction solution for washing. Extract the washed mixture with ethyl acetate. After combining the organic layers, dry with anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 8:1 to obtain the target product with a yield of 71% and an HPLC purity of 98.6%.

[0025] 1 H NMR (600 MHz, CDCl3) δ 8.00 (d, J = 7.6 Hz, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 53.7 Hz, 1H), 3.73 (s, 3H).

[0026] 1313C NMR (151 MHz, CDCl3) δ = 153.2, 148.7 (t, J C-F = 22.6 Hz), 134.0, 132.6, 131.9, 131.5, 124.4, 113.9, 110.1 (t, J C-F = 241.6 Hz), 28.9.

[0027] 19 19F NMR (565 MHz, CDCl3) δ = -124.4.

[0028] Example 2 3-(Difluoromethyl)quinoxalin-2(1H)-one

[0029]

[0030] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-b) quinoxalin-2(1H)-one (29.2 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (4.7 mg, 0.04 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 42 hours. After the reaction is completed, add saturated brine to the reaction solution for washing. Extract the washed mixture with ethyl acetate. After combining the organic layers, dry with anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 3:1 to obtain the target product with a yield of 70% and an HPLC purity of 98.8%.

[0031] 1 1H NMR (600 MHz, DMSO-d6) δ 12.81 (s, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.65 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 7.7 Hz, 2H), 7.05 (t, 1H).

[0032] 13 13C NMR (151 MHz, DMSO-d6) δ = 153.1, 149.7 (t, J C-F = 22.6 Hz), 132.8, 132.2, 130.7, 129.4, 123.9, 115.7, 110.3 (t, J C-F = 240.1 Hz).

[0033] 19 19F NMR (565 MHz, DMSO-d6) δ = -124.3.

[0034] Example 3 3-(Difluoromethyl)-1,6,7-trimethylquinoxalin-2(1H)-one

[0035]

[0036] Add compound (Ⅰ-c) 1,6,7-trimethylquinoxalin-2(1H)-one (37.6 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), and TMEDA (4.7 mg, 0.04 mmol) into a reaction flask equipped with magnetic stirring. Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 42 hours. After the reaction is completed, wash the reaction solution with saturated brine, extract the washed mixture with ethyl acetate. Combine the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 8:1 to obtain the target product with a yield of 79% and an HPLC purity of 98.5%.

[0037] 1 H NMR (600 MHz, CDCl3) δ 7.71 (s, 1H), 7.12 (s, 1H), 6.93 (t, J = 53.9 Hz, 1H), 3.69 (s, 3H), 2.44 (s, 3H), 2.35 (s, 3H).

[0038] 13 C NMR (151 MHz, CDCl3) δ = 153.3, 147.2 (t, J C-F = 22.6 Hz), 143.1, 133.5, 132.1, 131.2, 130.4, 114.3, 110.2 (t, J C-F = 241.6 Hz), 28.8, 20.8, 19.1.

[0039] 19 F NMR (565 MHz, CDCl3) δ = -124.0.

[0040] Example 4 3-(Difluoromethyl)-7-methoxy-1-methylquinoxalin-2(1H)-one

[0041]

[0042] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-d) 7-methoxy-1-methylquinoxalin-2(1H)-one (38.0 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (4.7 mg, 0.04 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 42 hours. After the reaction is completed, add saturated brine to the reaction solution for washing. Extract the washed mixture with ethyl acetate. Combine the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 8:1 to obtain the target product with a yield of 68% and an HPLC purity of 98.8%. 1 H NMR(600MHz,CDCl3)δ7.43(s,1H),7.29(d,J=1.2Hz,2H),6.97(t,J=53.8Hz,1H),3.89(s,3H),3.71(s,3H).

[0043] 13 C NMR(151MHz,CDCl3)δ=156.4,152.9,149.0(t,J C-F =22.6Hz),132.7,128.4,122.4,114.8,112.1,109.9(t,J C-F =241.6Hz),55.8,29.1.

[0044] 19 F NMR(565MHz,CDCl3)δ=-124.5.

[0045] Example 5 3-(Difluoromethyl)-1-(prop-2-yn-1-yl)quinoxalin-2(1H)-one

[0046]

[0047] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-e) 1-(prop-2-yn-1-yl)quinoxalin-2(1H)-one (36.8 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (4.7 mg, 0.04 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 42 hours. After the reaction is completed, add saturated brine to the reaction solution for washing. Extract the washed mixture with ethyl acetate. After combining the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 8:1 to obtain the target product with a yield of 56% and an HPLC purity of 98.9%. 1 H NMR(600MHz,CDCl3)δ8.01(d,J=8.0Hz,1H),7.72(t,J=7.1Hz,1H),7.54(d,J=8.5Hz,1H),7.45(t,J=8.3Hz,1H),6.94(t,J=53.6Hz,1H),5.07(d,J=2.6Hz,2H),2.32(s,1H).

[0048] 13 C NMR(151MHz,CDCl3)δ=152.2,148.6(t,J C-F =22.6Hz),132.7,132.5,132.1,131.6,124.7,114.5,110.0(t,J C-F =243.1Hz),76.1,73.8,31.4.

[0049] 19 F NMR(565MHz,CDCl3)δ=-124.2.

[0050] Example 6 3-(Difluoromethyl)-1-(4-methylbenzyl)quinoxalin-2(1H)-one

[0051]

[0052] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-f) 1-(4-methylbenzyl)quinoxalin-2(1H)-one (50.0 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (4.7 mg, 0.04 mmol). Add dichloromethane (3.0 mL) to the mixture. After purging with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 42 hours. After the reaction is completed, add saturated brine to the reaction solution for washing. Extract the washed mixture with ethyl acetate. After combining the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 8:1 to obtain the target product with a yield of 75% and an HPLC purity of 98.6%.

[0053] 1 H NMR(600MHz,CDCl3)δ7.99(d,J=8.0Hz,1H),7.56(t,J=7.9Hz,1H),7.37(t,J=8.2Hz,2H),7.18-7.12(m,4H),7.02(t,J=53.7Hz,1H),5.47(s,2H),2.31(s,3H).

[0054] 13 C NMR(151MHz,CDCl3)δ=153.3,148.8(t,J C-F =22.6Hz),137.8,133.4,132.5,132.2,131.5,131.5,129.7,127.0,124.3,114.7,110.0(t,J C-F =241.6Hz),45.6,21.0.

[0055] 19 F NMR(565MHz,CDCl3)δ=-124.1.

[0056] Example 7 tert-Butyl 2-(3-(difluoromethyl)-2-oxoquinoxalin-1(2H)-yl)acetate

[0057]

[0058] In a reaction flask equipped with magnetic stirring, add tert-butyl 2-(2-oxoquinoxalin-1(2H)-yl)acetate (52.0 mg, 0.2 mmol) of compound (Ⅰ-g), difluoromethyl(triphenyl)phosphonium iodide (175.6 mg, 0.4 mmol) of compound (Ⅱ), TMEDA (4.7 mg, 0.04 mmol). Add dichloromethane (3.0 mL) to the mixture. After purging with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 42 hours. After the reaction is completed, add saturated brine to the reaction solution for washing. Extract the washed mixture with ethyl acetate. After combining the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 8:1 to obtain the target product with a yield of 64% and an HPLC purity of 98.8%.

[0059] 1 H NMR(600MHz,CDCl3)δ8.01(d,J=8.0Hz,1H),7.65(t,J=7.9Hz,1H),7.42(t,J=7.7Hz,1H),7.13(d,J=8.4Hz,1H),6.95(t,J=53.6Hz,1H),4.95(s,2H),1.46(s,9H).

[0060] 13 C NMR(151MHz,CDCl3)δ=165.5,152.8,148.6(t,J C-F =22.6Hz),133.3,132.7,132.0,131.7,124.5,113.5,110.0(t,J C-F =241.6Hz),83.6,44.0,27.9.

[0061] 19 F NMR(565MHz,CDCl3)δ=-124.3.

[0062] Example 8 3-(Difluoromethyl)-1-(p-tolyl)quinoxalin-2(1H)-one

[0063]

[0064] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-h) 1-(p-tolyl)quinoxalin-2(1H)-one (47.2 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (4.7 mg, 0.04 mmol). Add dichloromethane (3.0 mL) to the mixture. After replacing the gas with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 42 hours. After the reaction is completed, add saturated brine to the reaction solution for washing. Extract the washed mixture with ethyl acetate. After combining the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 8:1 to obtain the target product with a yield of 65% and an HPLC purity of 98.6%.

[0065] 1 H NMR(600MHz,CDCl3)δ8.05(dd,J=8.1,1.5Hz,1H),7.49(ddd,J=8.6,7.2,1.6Hz,1H),7.45(d,J=8.0Hz,2H),7.41(ddd,J=8.3,7.2,1.3Hz,1H),7.20(d,J=8.3Hz,2H),7.02(t,J=53.7Hz,1H),6.82(dd,J=8.4,1.3Hz,1H),2.50(s,3H).

[0066] 13 C NMR(151MHz,CDCl3)δ=153.1,149.4(t,J C-F =22.6Hz),140.0,135.0,132.2,132.0,131.8,131.0,130.9,127.7,124.4,115.8,109.6(t,J C-F =241.6Hz),21.3.

[0067] 19 F NMR(565MHz,CDCl3)δ=-124.2.

[0068] Example 9 1-(4-chlorophenyl)-3-(difluoromethyl)quinoxalin-2(1H)-one

[0069]

[0070] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-i) 1-(p-chlorophenyl)quinoxalin-2(1H)-one (51.2 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (4.7 mg, 0.04 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 42 hours. After the reaction is completed, add saturated brine to the reaction solution for washing. Extract the washed mixture with ethyl acetate. After combining the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 8:1 to obtain the target product with a yield of 68% and an HPLC purity of 98.5%.

[0071] 1 H NMR(600MHz,CDCl3)δ8.04(dd,J=8.0,1.5Hz,1H),7.61(d,J=8.5Hz,2H),7.49(t,J=8.6Hz,1H),7.42(t,J=7.6Hz,1H),7.27(d,J=8.4Hz,2H),6.96(t,J=53.6Hz,1H),6.77(d,J=8.4Hz,1H).

[0072] 13 C NMR(151MHz,CDCl3)δ=152.8,149.3(t,J C-F =22.6Hz),136.0,134.6,133.1,132.4,131.8,131.2,130.7,129.6,124.7,115.5,109.7(t,J C-F =241.6Hz).

[0073] 19 F NMR(565MHz,CDCl3)δ=-124.2.

[0074] Example 10 3-(Difluoromethyl)-1-phenethylquinoxalin-2(1H)-one

[0075]

[0076] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-j) 1-phenylethylquinoxalin-2(1H)-one (50.0 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), PMDETA (6.9 mg, 0.04 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 42 hours. After the reaction is completed, add saturated brine to the reaction solution for washing. Extract the washed mixture with ethyl acetate. After combining the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 5:1 to obtain the target product with a yield of 55% and an HPLC purity of 98.5%.

[0077] 1 H NMR(600MHz,CDCl3)δ8.01(d,J=8.0Hz,1H),7.66(t,J=7.8Hz,1H),7.42(t,J=7.7Hz,1H),7.38(d,J=8.5Hz,1H),7.35 - 7.27(m,5H),6.95(t,J=53.8Hz,1H),4.48(dd,J=9.5,6.9Hz,2H),3.05(dd,J=9.6,6.9Hz,2H).

[0078] 13 C NMR(151MHz,CDCl3)δ=152.8,148.6(t,J C-F =22.6Hz),137.3,133.2,132.6,132.1,131.8,128.8,128.7,127.1,124.2,113.7,110.1(t,J C-F =241.6Hz),43.7,33.3.

[0079] 19 F NMR(565MHz,CDCl3)δ=-124.2.

[0080] Example 11 3-(Difluoromethyl)-1-(naphthalen-2-ylmethyl)quinoxalin-2(1H)-one

[0081]

[0082] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-k) 1-(naphthalen-2-ylmethyl)quinoxalin-2(1H)-one (57.2 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (4.7 mg, 0.04 mmol). Add tetrahydrofuran (3.0 mL) to the mixture. After displacing with nitrogen three times, irradiate the reaction system under blue light and stir the reaction at 35 ± 5 °C for 42 hours. After the reaction is completed, add saturated brine to the reaction solution for washing. Extract the washed mixture with ethyl acetate. After combining the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 8:1 to obtain the target product with a yield of 42% and an HPLC purity of 98.7%.

[0083] 1 H NMR(600MHz,CDCl3)δ8.02(d,J=8.0Hz,1H),7.86-7.78(m,2H),7.77-7.73(m,1H),7.66(s,1H),7.52(t,J=7.9Hz,1H),7.48-7.43(m,2H),7.43-7.34(m,3H),7.07(t,J=53.7Hz,1H),5.67(s,2H).

[0084] 13 C NMR(151MHz,CDCl3)δ=153.4,148.8(t,J C-F =22.6Hz),133.4,133.3,132.9,132.6,132.2,132.0,131.6,129.1,127.7,126.6,126.3,125.8,124.6,124.4,119.8,114.8,110.1(t,J C-F =241.6Hz),46.1.

[0085] 19 F NMR(565MHz,CDCl3)δ=-124.1.

[0086] Example 12 3-(Difluoromethyl)-1-methylquinoxalin-2(1H)-one

[0087]

[0088] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-a) N-methylquinoxalin-2(1H)-one (32.0 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (4.7 mg, 0.04 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under white light / violet light / green light, and stir the reaction at 35 ± 5 °C for 42 hours. After the reaction is completed, add saturated brine to the reaction solution for washing. Extract the washed mixture with ethyl acetate. After combining the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Detection by TLC shows that no target product is produced.

[0089] Example 13 3-(Difluoromethyl)-1-methylquinoxalin-2(1H)-one

[0090]

[0091] In a reaction flask equipped with magnetic stirring, add compound (Ⅰ-a) N-methylquinoxalin-2(1H)-one (32.0 mg, 0.2 mmol), compound (Ⅱ) difluoromethyltriphenylphosphonium iodide (175.6 mg, 0.4 mmol), TMEDA (23.5 mg, 0.2 mmol). Add dichloromethane (3.0 mL) to the mixture. After displacing the air with nitrogen three times, irradiate the reaction system under blue light, and stir the reaction at 35 ± 5 °C for 42 hours. After the reaction is completed, add saturated brine to the reaction solution for washing. Extract the washed mixture with ethyl acetate. After combining the organic layers, dry over anhydrous Na2SO4 and concentrate under reduced pressure. Purify the crude product on a silica gel column using petroleum ether / ethyl acetate with a volume ratio of 8:1 to obtain the target product with a yield of 11% and an HPLC purity of 98.0%.

[0092] The content described in this specification is only a list of the implementation forms of the inventive concept, and the protection scope of the present invention should not be regarded as limited to the specific forms stated in the embodiments.

Claims

1. A method for preparing difluoroquinoxalinone derivatives from photocatalytic iodonium salts, characterized in that, It includes the following steps: adding the quinoxalinone compound shown in formula (I), the difluoromethyltriphenylphosphonium iodide salt compound shown in formula (II), and a base into a reaction solvent, protecting with nitrogen, stirring and reacting under blue light irradiation conditions. After the reaction is completed, the reaction solution is post-treated to obtain the target compound, the difluoromethylated quinoxalinone derivative with antifungal activity shown in formula (III), and its reaction equation is as follows: Substituent R 1 selected from H or methyl, substituent R 2 selected from H, methyl or methoxy, substituent R 3 selected from H, methyl, ester group, alkynyl group, phenyl group, naphthyl group or substituted phenyl group, the substituent of the substituted phenyl group is methyl or halogen, and n is 0, 1 or 2.

2. The method for preparing difluoroquinoxalinone derivatives from photocatalytic iodine-containing phosphonium salts according to claim 1, wherein The reaction solvent is selected from tetrahydrofuran or dichloromethane.

3. The method for preparing difluoroquinoxalinone derivatives by photocatalyzing iodine-containing phosphonium salts as claimed in claim 2, wherein The base is selected from N,N,N',N'-tetramethylethylenediamine or N,N,N,N',N'-pentamethyldiethylenetriamine.

4. The method for preparing difluoroquinoxalinone derivatives by photocatalyzing iodonium salts as claimed in claim 3, wherein The molar ratio of the quinoxalinone compound shown in formula (I), the difluoromethyltriphenylphosphonium iodide salt compound shown in formula (II), and the base is 1:2:0.2 - 1.

0.

5. The method for preparing difluoroquinoxalinone derivatives by photocatalyzing iodonium salts as claimed in claim 1, wherein The process of post-treating the reaction solution is as follows: adding saturated brine to the reaction solution for washing, then extracting with ethyl acetate, combining the organic layers, drying with anhydrous Na2SO4 and concentrating under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography to obtain the target compound.

6. The method for preparing difluoroquinoxalinone derivatives by photocatalytic iodine-containing phosphonium salts according to claim 5, wherein The eluent for column chromatography purification is a mixed solvent of petroleum ether / ethyl acetate with a volume ratio of 3 - 8:

1.

7. A method for preparing a difluoroquinoxalinone derivative by photocatalyzing an iodine-containing phosphonium salt according to claim 4, wherein the reaction solvent is dichloromethane, the base is N,N,N',N'-tetramethylethylenediamine, and the molar ratio of the quinoxalinone compound shown in formula (I), the difluoromethyltriphenylphosphonium iodide salt compound shown in formula (II), and the base is 1:2:0.2.

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