Preparation method for electrochemical synthesis of 3-trifluoromethylquinoxalinone compound

Abstract

The invention relates to the technical field of organic synthesis, in particular to a preparation method for electrochemical synthesis of a 3-trifluoromethyl quinoxalinone compound. The preparation method comprises the following steps: adding a quinoxalinone compound, trifluoromethylsulfonhydrazide and an electrolyte into an electrochemical reaction bottle, and then adding a solvent for dissolving; connecting an anode and a cathode, connecting to a constant-current power supply, then carrying out electrochemical reaction under the reaction current of 8-15mA, and finally separating to obtain the 3-trifluoromethylquinoxalinone compound. Compared with the prior art, the method provided by the invention effectively reduces dependence on harmful oxidants and high-load metal catalysts, and also has the advantages of mild reaction conditions, short process flow, high reaction selectivity and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of a 3-trifluoromethylquinoxalinone compound through electrochemical synthesis. Background Art

[0002] The quinoxalin-2(1H)-one skeleton is an important drug structural framework, and the introduction of a trifluoromethyl (CF3) group at the 3-position of the quinoxalin-2(1H)-one skeleton has significant research value. For example, a series of quinoxalinone derivatives with a trifluoromethyl group at the 3-position of the quinoxalin-2(1H)-one skeleton are a new class of HIV type 1 reverse transcriptase inhibitors. The trifluoromethyl group of 3-trifluoromethylquinoxalinone compounds is frequently used in the pharmaceutical field due to its excellent ester solubility and strong electron-withdrawing ability.

[0003] In recent years, researchers have conducted a series of studies on the synthesis of trifluoromethylquinoxalinone compounds. CN108976174A discloses a method for preparing 3-trifluoromethylquinoxalinone compounds, which comprises the following steps: adding a quinoxalinone compound, sodium trifluoromethylsulfinate, and an oxidant, iodobenzene bis(trifluoroacetic acid) trifluoroacetate, to a solvent under an inert gas atmosphere, reacting at a temperature of 0-75°C for 6-18 hours, and separating and purifying by column chromatography to obtain a quinoxalinone compound substituted with a trifluoromethyl group at position 3. However, the oxidant iodobenzene bis(trifluoroacetic acid) trifluoroacetate used in this method is expensive, difficult to prepare, and has poor stability. It is easily hydrolyzed when exposed to moisture and difficult to store. The byproduct produces a large amount of acid, which causes environmental pollution.

[0004] CN111484459 discloses a method for synthesizing chiral 3-trifluoromethyl-3,4-dihydroquinoxalinone by palladium-catalyzed asymmetric hydrogenation. This method uses 3-trifluoromethylquinoxalinone compounds as reaction substrates and a chiral bisphosphorus ligand of palladium as a catalyst to asymmetric hydrogenate the chiral 3-trifluoromethyl-3,4-dihydroquinoxalinone compounds. However, this synthesis method has a long reaction time, and the use of a chiral catalyst containing heavy metal palladium poses the risk of environmental pollution, as well as the cost, poor stability, and storage difficulties of the precious metal palladium.

[0005] Wang et al. reported a self-catalytic photocatalytic reaction system with blue light as the excitation source (Jiayang W, Bin, et al. Visible-Light-Induced Trifluoromethylation of Quinoxalin-2(1H)-OnesunderPhotocatalyst-Free Conditions[J]. Asian Journal of Organic Chemistry, 2019, 8(10):1942-1946.), and developed a new and site-selective chemical process for the trifluoromethylation of quinoxalin-2(1H)-one with CF3SO2Na. However, the photochemistry in this method is difficult to control, extremely unstable, and has many side reactions.

[0006] In summary, existing traditional methods for synthesizing 3-trifluoromethylquinoxalinone compounds have significant limitations, including the need for large amounts of oxidants or heavy metal catalysts, long reaction times, difficulty in reaction control, and environmental pollution. Therefore, the development of new methods for synthesizing 3-trifluoromethylquinoxalinone compounds is urgently needed. Summary of the Invention

[0007] The purpose of the present invention is to provide a method for preparing 3-trifluoromethylquinoxalinone compounds by electrochemical synthesis in order to overcome at least one of the defects of the prior art, such as the need to use a large amount of oxidant or heavy metal catalyst, long reaction time, difficulty in reaction control, and easy pollution to the environment.

[0008] The purpose of the present invention can be achieved by the following technical solutions:

[0009] The present invention provides a method for preparing a 3-trifluoromethylquinoxalinone compound by electrochemical synthesis, comprising the following steps:

[0010] Adding a quinoxalinone compound, trifluoromethylsulfonylhydrazide, and an electrolyte to an electrochemical reaction bottle, followed by adding a solvent for dissolution; connecting an anode and a cathode and connecting to a constant current power supply, and then conducting an electrochemical reaction at a reaction current of 8-15 mA to finally separate and obtain a 3-trifluoromethylquinoxalinone compound;

[0011] The quinoxalinone compound and the 3-trifluoromethylquinoxalinone compound have the chemical structures shown in Formula I and II, respectively:

[0012]

[0013] In the formula, R2 is a single or multiple substituted group at any position of position 5, 6, 7 or 8, and R1 and R2 are each independently selected from the following substituted or unsubstituted groups: hydrogen, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 alkyl ester, aryl, benzyl or heteroaryl;

[0014] The structural formula of the trifluoromethylsulfonylhydrazine is CF3SO2NHNH-R3, where R3 is an amino protecting group.

[0015] The reaction equation for the electrochemical synthesis of 3-trifluoromethylquinoxalinone compounds of the present invention is:

[0016]

[0017] Furthermore, the 3-trifluoromethylquinoxalinone compound prepared by electrochemical synthesis includes but is not limited to the following structural formula:

[0018]

[0019] Furthermore, the molar ratio of the quinoxalinone compound, trifluoromethylsulfonylhydrazide and electrolyte is 1:(1-3):(2-3).

[0020] Furthermore, the electrolyte is any one or more of tetrabutylammonium acetate, tetrabutylammonium perchlorate, tetrabutylammonium tetrafluoroborate or tetrabutylammonium hexafluorophosphate.

[0021] Furthermore, R3 is specifically any one of tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, trifluoroacetyl, benzoyl, and phthaloyl, among which tert-butyloxycarbonyl (Boc) is preferred, which has the advantages of low cost, easy preparation, good solubility in organic solvents, and low oxidation potential.

[0022] Furthermore, the trifluoromethylsulfonylhydrazide is prepared by the following method: under a nitrogen atmosphere, trifluoromethanesulfonic anhydride is added to a mixed solution containing R3-NHNH2 and triethylamine, followed by reaction under stirring conditions, and the trifluoromethylsulfonylhydrazide is obtained after washing, drying and separation.

[0023] Furthermore, in the preparation of trifluoromethylsulfonylhydrazide, the molar ratio of trifluoromethanesulfonic anhydride, R3-NHNH2 and triethylamine is 1:1:(1-1.2).

[0024] Furthermore, in the preparation of trifluoromethanesulfonyl hydrazide, the trifluoromethanesulfonic anhydride is added dropwise at -78°C.

[0025] Furthermore, in the preparation of trifluoromethylsulfonylhydrazide, the reaction time is 1.5-3 hours, and the reaction temperature is room temperature.

[0026] Furthermore, in the preparation of trifluoromethylsulfonylhydrazide, the washing is performed twice with water, once with 5% hydrochloric acid, and then once with water.

[0027] Furthermore, in the preparation of trifluoromethylsulfonylhydrazide, the drying agent used is anhydrous sodium sulfate.

[0028] Furthermore, in the preparation of trifluoromethylsulfonylhydrazide, the separation is carried out by column chromatography, and the eluent is ethyl acetate and petroleum ether, and the volume ratio of the two is (2-4):1.

[0029] Furthermore, the solvent is any one or more of acetonitrile, acetic acid, dimethyl sulfoxide or water, preferably acetonitrile.

[0030] Furthermore, the electrochemical reaction bottle is an undivided electrolytic cell, that is, a diaphragmless electrolytic cell.

[0031] Furthermore, the anode and cathode are both carbon rods, or both are platinum sheets, or the anode is a carbon rod and the cathode is a platinum sheet.

[0032] Furthermore, the temperature of the electrochemical reaction is 20-60°C.

[0033] Furthermore, the electrochemical reaction time is 4-5.5h.

[0034] Furthermore, the separation is preceded by extraction, drying and concentration.

[0035] Furthermore, the extraction agent used in the extraction is ethyl acetate, the drying agent used in the drying is anhydrous sodium sulfate, and the concentration is carried out under reduced pressure.

[0036] Furthermore, the separation uses column chromatography, the eluents are petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is (4-20):1.

[0037] Organic electrochemical synthesis has emerged as an emerging green synthesis method. This strategy utilizes electrons as oxidants, effectively reducing the reliance on hazardous oxidants and highly loaded metal catalysts. Furthermore, with the increasing popularity of flow chemistry and microreactors, its advantages, such as small-scale reaction environments, superior heat transfer efficiency, and the ability to finely control reaction conditions, have garnered increasing attention in the scientific community.

[0038] The invention directly electrolyzes trifluoromethylsulfonylhydrazine under the action of electric current, and realizes the trifluoromethylation reaction of quinoxalinone compounds through the reaction mechanism of free radicals.

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] (1) The present invention uses trifluoromethylsulfonylhydrazide as a trifluoromethyl source to carry out the trifluoromethylation reaction of quinoxalinone compounds under electrochemical conditions, and uses a constant current instead of an exogenous oxidant. Compared with the traditional synthesis method, the use of electrons as an oxidant effectively reduces the dependence on harmful oxidants and high-load metal catalysts. At the same time, it also has the advantages of mild reaction conditions, short process flow, and high reaction selectivity.

[0041] (2) The present invention uses a diaphragm-free electrochemical reaction bottle as a reaction vessel and uses a constant current instead of an exogenous oxidant. The experimental device is simple to set up and the post-processing operation is simple. The reaction conditions are mild and the reaction time is short.

[0042] (3) The present invention provides a new green and environmentally friendly preparation method for the efficient synthesis of 3-trifluoromethylquinoxalinone, which helps to achieve atom economy and provides new ideas for overcoming the difficulties in industrial production, and has good development prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 is trifluoromethylsulfonylhydrazide in Example 1 of the present invention 1 H NMR spectrum.

[0044] Figure 2 is trifluoromethylsulfonylhydrazide in Example 1 of the present invention 19 F NMR spectrum.

[0045] Figure 3 Schematic diagram of the electrochemical synthesis reaction device of the present invention.

[0046] Figure 4 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one prepared in Example 1 of the present invention 1 H NMR spectrum.

[0047] Figure 5 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one prepared in Example 1 of the present invention 19 FNMR spectrum. DETAILED DESCRIPTION

[0048] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0049] Unless otherwise specified, the reagents, methods, instruments and equipment used in the present invention are conventional reagents, methods, instruments and equipment in the art. Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0050] Example 1:

[0051] In this example, 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one was prepared by electrochemical synthesis. The specific structural formula is as follows:

[0052]

[0053] The specific synthesis method of the above compound is as follows:

[0054] (1) Preparation of trifluoromethylsulfonylhydrazide:

[0055] Under nitrogen protection, a solution of trifluoromethanesulfonic anhydride (5.64 g, 3.36 mL, 20.0 mmol) in dichloromethane (20 mL) was added dropwise at -78°C to a mixture of BocNHNH2 (20.0 mmol) and triethylamine (2.22 g, 3.05 mL, 22.0 mmol) in dichloromethane (100 mL). The solution turned from colorless to yellow and then to colorless again. The mixture was allowed to stand at room temperature and stirred for 2 hours, then washed twice with water, once with 5% hydrochloric acid, and once with water, dried over anhydrous sodium sulfate, filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate / petroleum ether (2:1 to 4:1 v / v) to obtain trifluoromethylsulfonyl hydrazide with a Boc protective group.

[0056] The NMR spectrum of the above product is as follows Figure 1-2 The specific results are as follows:

[0057] 1 H NMR (400MHz, DMSO-d6) δ11.36(s,1H),9.63(s,1H),1.40(s,11H).

[0058] 19 F NMR(283MHz,Chloroform-d)δ-77.70.

[0059] (2) Preparation of 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one:

[0060] A dry 10 mL electrochemical reaction vial was filled with a magnetic stirrer. 1-Methyl-quinoxalin-2(H)-one (0.3 mmol, 1.0 equiv), trifluoromethylsulfonylhydrazide (0.9 mmol, 3.0 equiv), and tetrabutylammonium hexafluorophosphate (nBu4NPF6, 0.6 mmol, 2.0 equiv) were added sequentially. Acetonitrile (5 mL) was added as the reaction solvent, ensuring complete dissolution of the solids.

[0061] like Figure 3 As shown, an ultrasonically cleaned carbon rod electrode (anode) and platinum electrode (cathode) were placed parallel to each other in the reaction solution, connected to a constant current power supply to prevent short circuits. After assembly, the mixture was placed on a temperature-controlled magnetic stirrer. Stirring was maintained at 60°C (250 rpm) and a constant current of 12 mA was applied to the electrolysis reaction. The reaction was continued for 5 hours, with progress monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 4:1, UV spectroscopy at 254 nm).

[0062] After the reaction is complete, the electrode system is removed. The reaction solution is transferred to a separatory funnel and extracted with ethyl acetate (3×10 mL) and water. The organic phases are combined, washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The crude product is concentrated under reduced pressure. Purification is performed by silica gel column chromatography (eluent: petroleum ether / ethyl acetate 4:1) to collect the target component. After removing the solvent by rotary evaporation, a white solid product, 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one, is obtained with a calculated yield of 70%.

[0063] The NMR spectrum of the above product is as follows Figure 4-5 The specific results are as follows:

[0064] 1 H NMR (400MHz, Chloroform-d) δ8.01 (d, J = 8.0Hz, 1H), 7.74 (t, J = 16.0, 8.0Hz, 1H), 7.50-7.37 (m, 2H), 3.76 (s, 3H).

[0065] 19 F NMR (283MHz, Chloroform-d) δ-71.57 (d, J=7.3Hz).

[0066] Example 2:

[0067] In this example, 1-benzyl-3-trifluoromethyl-quinoxaline-2(1H)-one was prepared by electrochemical synthesis. The specific structural formula is as follows:

[0068]

[0069] The specific synthesis method of the above compound is as follows:

[0070] (1) Preparation of trifluoromethylsulfonylhydrazide: Prepared according to Example 1.

[0071] (2) Preparation of 1-benzyl-3-trifluoromethyl-quinoxaline-2(1H)-one:

[0072] A dry 10 mL electrochemical reaction vial was filled with a magnetic stirrer. 1-Benzyl-quinoxalin-2(1H)-one (0.3 mmol, 1.0 equiv), trifluoromethylsulfonylhydrazide (0.9 mmol, 3.0 equiv), and tetrabutylammonium hexafluorophosphate (nBu4NPF6, 0.6 mmol, 2.0 equiv) were added sequentially. Acetonitrile (5 mL) was added as the reaction solvent, ensuring complete dissolution of the solids.

[0073] A pretreated carbon rod electrode (anode) and a platinum electrode (cathode) were placed in parallel in the reaction solution, connected to a constant current power supply to prevent short circuits. After assembly, the mixture was placed on a temperature-controlled magnetic stirrer. Stirring was maintained at 60°C (300 rpm) and a constant current of 12 mA was applied to the electrolysis reaction. The reaction was continued for 5 hours, with progress monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 6:1, UV spectroscopy at 254 nm).

[0074] After the reaction is complete, the electrode system is removed. The reaction solution is transferred to a separatory funnel and extracted with ethyl acetate (3×10 mL) and water. The organic phases are combined, washed sequentially with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The crude product is concentrated under reduced pressure. Purification is performed by silica gel column chromatography (eluent: petroleum ether / ethyl acetate 10:1) to collect the target component. After removing the solvent by rotary evaporation, a white solid product, 1-benzyl-3-trifluoromethyl-quinoxaline-2(1H)-one, is obtained with a calculated yield of 72%.

[0075] The NMR and mass spectrometry characterization results of the above products are as follows:

[0076] 1 H NMR (400MHz, Chloroform-d) δ7.98 (d, J=8.0Hz, 1H), 7.58 (dd, J=16.0, 8.0Hz, 1H), 7.42-7.21 (m, 8H), 5.51 (s, 2H).

[0077] 19 F NMR(283MHz,Chloroform-d)δ-71.78.

[0078] ESI m / z 311.1

[0079] Example 3:

[0080] In this example, 1-methyl-2-(2-oxo-3-(trifluoromethyl)quinoxalin-1(2H)-yl)acetate was prepared by electrochemical synthesis. The specific structural formula is as follows:

[0081]

[0082] The specific synthesis method of the above compound is as follows:

[0083] (1) Preparation of trifluoromethylsulfonylhydrazide: Prepared according to Example 1.

[0084] (2) Preparation of 1-methyl-2-(2-oxo-3-(trifluoromethyl)quinoxaline-1(2H)-yl)acetate:

[0085] A dry 10 mL electrochemical reaction vial was filled with a magnetic stirrer. Acetic acid formaldehyde-2-(2-oxo-quinoxalin-1(2H)-yl)acetate (0.3 mmol, 1.0 equiv), trifluoromethylsulfonylhydrazide (0.9 mmol, 3.0 equiv), and tetrabutylammonium hexafluorophosphate (nBu4NPF6, 0.6 mmol, 2.0 equiv) were added sequentially. Acetonitrile (5 mL) was added as the reaction solvent to ensure complete dissolution of the solids.

[0086] A pretreated carbon rod electrode (anode) and a platinum electrode (cathode) were placed in parallel in the reaction solution, connected to a constant current power supply to prevent short circuits. After assembly, the mixture was placed on a temperature-controlled magnetic stirrer. Stirring was initiated at 300 rpm at 60°C, and a constant current of 12 mA was applied to the electrolysis reaction. The reaction was continued for 5 hours, with progress monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 4:1, UV spectroscopy at 254 nm).

[0087] After the reaction is complete, the electrode system is removed. The reaction solution is transferred to a separatory funnel and extracted with ethyl acetate (3×10 mL) and water. The organic phases are combined, washed sequentially with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The crude product is concentrated under reduced pressure. The product is purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate 4:1) to collect the target component. The solvent is removed by rotary evaporation to obtain the white solid product 1-methyl-2-(2-oxo-3-(trifluoromethyl)quinoxaline-1(2H)-yl)acetate with a calculated yield of 68%.

[0088] The NMR characterization results of the above products are as follows:

[0089] 1H NMR (400MHz, Chloroform-d) δ8.01(d,J=8.4Hz,1H),7.73-7.63(m,2H),7.36(d,J=4.0Hz,1H),5.08(s,2H),3.84(s,3H).

[0090] 19 F NMR(283MHz,Chloroform-d)δ-71.27.

[0091] Example 4:

[0092] In this example, 6,7-dichloro-1-methyl-quinoxaline-2(H)-one was prepared by electrochemical synthesis. The specific structural formula is as follows:

[0093]

[0094] The specific synthesis method of the above compound is as follows:

[0095] (1) Preparation of trifluoromethylsulfonylhydrazide: Prepared according to Example 1.

[0096] (2) Preparation of 6,7-dichloro-1-methyl-quinoxaline-2(H)-one:

[0097] A dry 10 mL electrochemical reaction vial was filled with a magnetic stirrer. 6,7-Dichloro-1-methyl-quinoxalin-2(H)-one (0.3 mmol, 1.0 equiv), trifluoromethylsulfonylhydrazide (0.9 mmol, 3.0 equiv), and tetrabutylammonium hexafluorophosphate (nBu4NPF6, 0.6 mmol, 2.0 equiv) were added sequentially. Acetonitrile (5 mL) was added as the reaction solvent to ensure complete dissolution of the solids.

[0098] A pretreated carbon rod electrode (anode) and a platinum electrode (cathode) were placed in parallel in the reaction solution, connected to a constant current power supply to prevent short circuits. After assembly, the mixture was placed on a temperature-controlled magnetic stirrer. Stirring was maintained at 60°C (300 rpm) and a constant current of 12 mA was applied to the electrolysis reaction. The reaction was continued for 5 hours, with progress monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 6:1, UV spectroscopy at 254 nm).

[0099] After the reaction is completed, the electrode system is removed. The reaction solution is transferred to a separatory funnel and extracted with ethyl acetate (3×10 mL) and water. After combining the organic phases, they are washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The crude product is concentrated under reduced pressure. Purification is performed by silica gel column chromatography (eluent: petroleum ether / ethyl acetate 10:1) to collect the target component. After removing the solvent by rotary evaporation, a white solid product 6,7-dichloro-1-methyl-quinoxaline-2(H)-one is obtained with a calculated yield of 48%.

[0100] The NMR characterization results of the above products are as follows:

[0101] 1 H NMR (400MHz, Chloroform-d) δ7.86 (s, 1H), 7.56 (s, 1H), 7.19 (s, 1H), 3.70 (s, 3H), 2.52 (t, J = 4.0Hz, 3H).

[0102] 19 F NMR(283MHz,Chloroform-d)δ-70.35.

[0103] Example 5:

[0104] In this example, 1,6,7-trimethyl-3-trifluoromethyl-quinoxaline-2(H)-one was prepared by electrochemical synthesis. The specific structural formula is as follows:

[0105]

[0106] The specific synthesis method of the above compound is as follows:

[0107] (1) Preparation of trifluoromethylsulfonylhydrazide: Prepared according to Example 1.

[0108] (2) Preparation of 1,6,7-trimethyl-3-trifluoromethyl-quinoxaline-2(H)-one:

[0109] A dry 10 mL electrochemical reaction vial was filled with a magnetic stirrer. 1,6,7-Trimethylquinoxalin-2(H)-one (0.3 mmol, 1.0 equiv), trifluoromethylsulfonylhydrazide (0.9 mmol, 3.0 equiv), and tetrabutylammonium hexafluorophosphate (nBu4NPF6, 0.6 mmol, 2.0 equiv) were added sequentially. Acetonitrile (5 mL) was added as the reaction solvent, ensuring complete dissolution of the solids.

[0110] A pretreated carbon rod electrode (anode) and a platinum electrode (cathode) were placed in parallel in the reaction solution, connected to a constant current power supply to prevent short circuits. After assembly, the mixture was placed on a temperature-controlled magnetic stirrer. Stirring was maintained at 60°C (300 rpm) and a constant current of 12 mA was applied to the electrolysis reaction. The reaction was continued for 5 hours, with progress monitored by TLC (developing solvent: petroleum ether / ethyl acetate = 6:1, UV spectroscopy at 254 nm).

[0111] After the reaction is completed, the electrode system is removed. The reaction solution is transferred to a separatory funnel and extracted with ethyl acetate (3×10 mL) and water. After combining the organic phases, they are washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The crude product is concentrated under reduced pressure. Purification is performed by silica gel column chromatography (eluent: petroleum ether / ethyl acetate 10:1) to collect the target component. After removing the solvent by rotary evaporation, a white solid product 1,6,7-trimethyl-3-trifluoromethyl-quinoxaline-2(H)-one is obtained with a calculated yield of 71%.

[0112] The NMR characterization results of the above products are as follows:

[0113] 1 H NMR (400MHz, Chloroform-d) δ7.72(s,1H),7.15(s,1H),3.72(s,3H),2.46(s,3H),2.37(s,3H).

[0114] 19 F NMR (283MHz, Chloroform-d) δ-71.74 (d, J=6.0Hz).

[0115] The products and yields obtained in Examples 1 to 5 are summarized in Table 1.

[0116] Table 1 Products and yields in Examples 1 to 5

[0117]

[0118] The specific preparation methods of the following Examples 6 to 17 refer to Example 1, and all of them synthesize 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one by electrochemical method. The difference lies in the different parameters such as electrode materials, electrolytes, solvents and current used in the electrochemical reaction.

[0119] Example 6:

[0120] In this example, 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one was prepared by electrochemical synthesis. The specific structural formula is the same as in Example 1. The difference from Example 1 is that the solvent used in this example is a mixed solvent of MeCN (4.28 mL) and HO (0.72 mL). The other preparation parameters remain unchanged. The yield of the final 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one was 63%.

[0121] Example 7:

[0122] This embodiment prepares 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one by electrochemical synthesis. The specific structural formula is the same as that of Example 1. The difference from Example 1 is that the electrolyte used in this embodiment is tetrabutylammonium tetrafluoroborate ( n Bu4NBF4) was added, and the solvent used was a mixed solvent of MeCN (4.28 mL) and H2O (0.72 mL). The other preparation parameters remained unchanged. The final yield of 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one was 55%.

[0123] Example 8:

[0124] This example prepares 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one by electrochemical synthesis. The specific structural formula is the same as that of Example 1. The difference from Example 1 is that the electrolyte used in this example is tetrabutylammonium perchlorate ( n Bu4NClO4) was added, and the solvent used was a mixed solvent of MeCN (4.28 mL) and H2O (0.72 mL). The other preparation parameters remained unchanged. The final yield of 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one was 53%.

[0125] Example 9:

[0126] This embodiment prepares 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one by electrochemical synthesis. The specific structural formula is the same as that of Example 1. The difference from Example 1 is that the electrolyte used in this embodiment is tetrabutylammonium acetate ( n The reaction mixture was stirred for 2 h at 4 ℃ for 1 h. The reaction mixture was stirred for 2 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 2 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 1 h. The reaction mixture was stirred for 2 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 2 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 3 h. The reaction mixture was stirred for 4 h.

[0127] Example 10:

[0128] In this example, 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one was prepared by electrochemical synthesis. The specific structural formula is the same as in Example 1. The difference from Example 1 is that the solvent used in this example is a mixed solvent of MeCN (2.5 mL) and HO (2.5 mL). The other preparation parameters remain unchanged. The yield of the final 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one was 37%.

[0129] Example 11:

[0130] In this example, 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one was prepared by electrochemical synthesis. The specific structural formula is the same as in Example 1. The difference from Example 1 is that the solvent used in this example is a mixed solvent of MeCN (4 mL) and HO (1 mL). The other preparation parameters remain unchanged. The yield of the final 1-methyl-3-trifluoromethyl-quinoxaline-2(H)-one was 59%.

[0131] Example 12:

[0132] In this example, 1-methyl-3-trifluoromethyl-quinoxalin-2(H)-one was prepared by electrochemical synthesis. The specific structural formula is the same as in Example 1. The difference from Example 1 is that the current used in the electrochemical reaction in this example is 8 mA, while the other preparation parameters remain unchanged. The final yield of 1-methyl-3-trifluoromethyl-quinoxalin-2(H)-one was 27%.

[0133] Example 13:

[0134] In this example, 1-methyl-3-trifluoromethyl-quinoxalin-2(H)-one was prepared by electrochemical synthesis. The specific structural formula is the same as in Example 1. The difference from Example 1 is that the current used in the electrochemical reaction in this example is 15 mA, while the other preparation parameters remain unchanged. The final yield of 1-methyl-3-trifluoromethyl-quinoxalin-2(H)-one is 42%.

[0135] Example 14:

[0136] In this example, 1-methyl-3-trifluoromethyl-quinoxalin-2(H)-one was prepared by electrochemical synthesis. The specific structural formula is the same as in Example 1. This example differs from Example 1 in that acetic acid was used as the solvent for the electrochemical reaction, while the other preparation parameters remained unchanged. The final yield of 1-methyl-3-trifluoromethyl-quinoxalin-2(H)-one was 30%.

[0137] Example 15:

[0138] In this example, 1-methyl-3-trifluoromethyl-quinoxalin-2(H)-one was prepared by electrochemical synthesis. The specific structural formula is the same as in Example 1. This example differs from Example 1 in that dimethyl sulfoxide is used as the solvent for the electrochemical reaction, while the other preparation parameters remain unchanged. The final yield of 1-methyl-3-trifluoromethyl-quinoxalin-2(H)-one was 34%.

[0139] Example 16:

[0140] In this example, 1-methyl-3-trifluoromethyl-quinoxalin-2(H)-one was prepared by electrochemical synthesis. The specific structural formula is the same as in Example 1. This example differs from Example 1 in that platinum was used as both the anode and cathode of the electrochemical reaction, while the other preparation parameters remained unchanged. The yield of the resulting 1-methyl-3-trifluoromethyl-quinoxalin-2(H)-one was 53%.

[0141] Example 17:

[0142] In this example, 1-methyl-3-trifluoromethyl-quinoxalin-2(H)-one was prepared by electrochemical synthesis. The specific structural formula is the same as in Example 1. This example differs from Example 1 in that carbon rods were used as both the anode and cathode of the electrochemical reaction, while the other preparation parameters remained unchanged. The final yield of 1-methyl-3-trifluoromethyl-quinoxalin-2(H)-one was 61%.

[0143] The specific electrochemical parameters such as electrode materials, electrolytes, solvents, current magnitudes, and product yields in Example 1 and Examples 6 to 17 are summarized in Table 2.

[0144] Table 2 Summary of electrochemical parameters and yields in Examples 6 to 17

[0145] Example Electrode materials electrolytes solvent Current Yield 1 C-Pt <![CDATA[ n Bu4NPF6]]> <![CDATA[CH3CN]]> 12mA 70％ 6 C-Pt <![CDATA[ n Bu4NPF6]]> <![CDATA[CH3CN / H2O(6:1)]]> 12mA 63％ 7 C-Pt <![CDATA[ n Bu4NBF4]]> <![CDATA[CH3CN / H2O(6:1)]]> 12mA 55％ 8 C-Pt <![CDATA[ n Bu4NClO4]]> <![CDATA[CH3CN / H2O(6:1)]]> 12mA 53％ 9 C-Pt <![CDATA[ n Bu4NOAc]]> <![CDATA[CH3CN / H2O(6:1)]]> 12mA 47％ 10 C-Pt <![CDATA[ n Bu4NPF6]]> <![CDATA[CH3CN / H2O(1:1)]]> 12mA 37％ 11 C-Pt <![CDATA[ n Bu4NPF6]]> <![CDATA[CH3CN / H2O(4:1)]]> 12mA 59％ 12 C-Pt <![CDATA[ n Bu4NPF6]]> <![CDATA[CH3CN]]> 8mA 27％ 13 C-Pt <![CDATA[ n Bu4NPF6]]> <![CDATA[CH3CN]]> 15mA 42％ 14 C-Pt <![CDATA[ n Bu4NPF6]]> AcOH 12mA 30％ 15 C-Pt <![CDATA[ n Bu4NPF6]]> DMSO 12mA 34％ 16 Pt-Pt <![CDATA[ n Bu4NPF6]]> <![CDATA[CH3CN]]> 12mA 53％ 17 CC <![CDATA[ n Bu4NPF6]]> <![CDATA[CH3CN]]> 12mA 61％

[0146] As can be seen from the above table, in the electrochemical reaction of the present invention, the electrochemical synthesis of the final trifluoromethylation product can be achieved by using tetrabutylammonium acetate, tetrabutylammonium perchlorate, tetraethylammonium tetrafluoroborate or tetrabutylammonium hexafluorophosphate as the electrolyte.

[0147] Secondly, the electrochemical synthesis method can be successfully implemented in a mixed solvent of acetonitrile and water, as well as acetic acid and dimethyl sulfoxide, with pure acetonitrile being the best solvent, and the yield can reach 70%.

[0148] In addition, in the electrolysis reaction of the present application, the electrochemical synthesis of trifluoromethylation products can be successfully achieved at a current of 8-15 mA, and the optimal value is achieved at 12 mA.

[0149] Finally, in the electrolysis system of the present invention, both the anode and the cathode can be carbon rods or platinum sheets, and the combination of a carbon rod as the anode and a platinum sheet as the cathode is preferred.

[0150] The above results indicate that the electrochemical synthesis method of the present invention has good adjustability in electrochemical preparation parameters such as electrode materials, electrolytes, solvents and currents, and is a universal method for efficiently synthesizing 3-trifluoromethylquinoxalinone compounds.

[0151] The above description of the embodiments is intended to facilitate understanding and use of the invention by those skilled in the art. It will be apparent that those skilled in the art can readily make various modifications to these embodiments and apply the general principles described herein to other embodiments without requiring inventive effort. Therefore, the present invention is not limited to the above-described embodiments. Improvements and modifications made by those skilled in the art based on the disclosure of the present invention, without departing from the scope of the present invention, should be within the scope of protection of the present invention.

Claims

1. A method for preparing a 3-trifluoromethylquinoxalinone compound by electrochemical synthesis, characterized in that: The following steps are involved: Adding a quinoxalinone compound, trifluoromethylsulfonylhydrazide, and an electrolyte to an electrochemical reaction bottle, followed by adding a solvent for dissolution; connecting an anode and a cathode and connecting to a constant current power supply, and then conducting an electrochemical reaction at a reaction current of 8-15 mA to finally separate and obtain a 3-trifluoromethylquinoxalinone compound; The quinoxalinone compound and the 3-trifluoromethylquinoxalinone compound have the chemical structures shown in Formula I and II, respectively: In the formula, R2 is a single or multiple substituted group at any position of position 5, 6, 7 or 8, and R1 and R2 are each independently selected from the following substituted or unsubstituted groups: hydrogen, halogen, hydroxyl, carboxyl, amino, nitro, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 1-10 alkyl ester, aryl, benzyl or heteroaryl; The structural formula of the trifluoromethylsulfonylhydrazine is CF3SO2NHNH-R3, where R3 is an amino protecting group.

2. The method for preparing 3-trifluoromethylquinoxalinone compound by electrochemical synthesis according to claim 1, characterized in that: The molar ratio of the quinoxalinone compound, trifluoromethylsulfonylhydrazide and electrolyte is 1:(1-3):(2-3).

3. The method for preparing 3-trifluoromethylquinoxalinone compound by electrochemical synthesis according to claim 1, characterized in that: The electrolyte is any one or more of tetrabutylammonium acetate, tetrabutylammonium perchlorate, tetrabutylammonium tetrafluoroborate or tetrabutylammonium hexafluorophosphate.

4. The method for preparing 3-trifluoromethylquinoxalinone compound by electrochemical synthesis according to claim 1, characterized in that: The R3 is specifically any one of tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyloxycarbonyl, trifluoroacetyl, benzoyl, and phthaloyl.

5. The method for preparing 3-trifluoromethylquinoxalinone compound by electrochemical synthesis according to claim 1, characterized in that: The trifluoromethylsulfonylhydrazide is prepared by the following method: Under a nitrogen atmosphere, trifluoromethanesulfonic anhydride is added to a mixed solution containing R3-NHNH2 and triethylamine, followed by reaction under stirring, and the trifluoromethylsulfonyl hydrazide is obtained after washing, drying, and separation; The molar ratio of the trifluoromethanesulfonic anhydride, R3-NHNH2 and triethylamine is 1:1:(1-1.2).

6. The method for preparing 3-trifluoromethylquinoxalinone compound by electrochemical synthesis according to claim 5, characterized in that: The trifluoromethanesulfonic anhydride was added dropwise at -78°C; The reaction time is 1.5-3h, and the reaction temperature is room temperature; The washing is performed twice with water, once with 5% hydrochloric acid, and once with water; The desiccant used in the drying is anhydrous sodium sulfate; The separation is carried out by column chromatography, and the eluents are ethyl acetate and petroleum ether, and the volume ratio of the two is (2-4):

1.

7. The method for preparing 3-trifluoromethylquinoxalinone compound by electrochemical synthesis according to claim 1, characterized in that: The solvent is any one or more of acetonitrile, acetic acid, dimethyl sulfoxide or water.

8. The method for preparing 3-trifluoromethylquinoxalinone compound by electrochemical synthesis according to claim 1, characterized in that: The electrochemical reaction bottle is an undivided electrolytic cell; The anode and cathode are both carbon rods, or both platinum sheets, or the anode is a carbon rod and the cathode is a platinum sheet.

9. The method for preparing 3-trifluoromethylquinoxalinone compound by electrochemical synthesis according to claim 1, characterized in that: The temperature of the electrochemical reaction is 20-60°C; The electrochemical reaction time is 4-5.5h.

10. The method for preparing 3-trifluoromethylquinoxalinone compound by electrochemical synthesis according to claim 1, characterized in that: The separation is preceded by extraction, drying and concentration; the extraction agent used is ethyl acetate, the drying agent used is anhydrous sodium sulfate, and the concentration is carried out under reduced pressure; The separation is carried out by column chromatography, the eluents are petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is (4-20):1.

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