An electrochemical preparation method for the bis-alkoxylation of difluoroolefins

Abstract

The present invention first discloses an electrochemical reaction method for the double alkoxylation of a difluoroolefin, which uses an aromatic difluoroolefin and an alkyl alcohol as raw materials, tetrabutylammonium tetrafluoroborate, a system with trifluorotoluene and hexafluoroisopropanol as a mixed solvent, a carbon plate as an anode, a platinum plate electrode as a cathode, and electrolysis is performed directly at a constant tank voltage under stirring at room temperature in an air atmosphere to obtain the target product shown in formulas 1 to 3. The method of the present invention has mild reaction conditions and can be carried out at room temperature, without the participation of metal catalysts and chemical oxidants, and the selected electrodes can be reused repeatedly, and the obtained compound shows a good fluorescent color development effect in human epithelial cells. The method of the present invention has the advantages of being green and efficient, simple to operate, mild conditions, low production process cost, and environmentally friendly.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and in particular relates to an electrochemical reaction method of a type of bis-alkoxylated difluoroaryl compounds. Background Art

[0002] Difluoromethylene (CF 2 ) Due to its strong electron-withdrawing ability and the unique properties of fluorine atoms, the introduction of difluoromethylene into organic molecules can significantly change their electrical properties, solubility, lipophilicity, etc. Researchers have found that difluoromethylene can act as a bioisostere of polar groups, regulating the metabolic stability and binding affinity of biomolecules, etc. Such groups are often introduced into biomolecules and functional materials. The commonly used method for constructing difluoroalkyl derivatives is to use reagents such as difluorobromide / chlorine through various coupling reactions, while the easily prepared geminal difluoroolefins can be used to synthesize monofluoro compounds, trifluoromethyl derivatives and difluoromethylene compounds. The method generally has good functional group compatibility and is convenient for subsequent derivatization. The derivatization of such substrates has always received widespread attention in the synthetic chemistry community. However, until now, there has been no report on the simultaneous introduction of oxygen-containing groups while retaining two fluorine atoms to achieve the difunctionalization of geminal difluoroolefins to synthesize difluorobisalkoxy aromatic hydrocarbons with special structures.

[0003] In recent years, organic electrosynthesis has achieved rapid development. Compared with traditional organic synthesis, it has significant advantages. For example, electrochemical reactions are achieved by reactants gaining and losing electrons on electrodes. In principle, other reagents are not required, which can reduce material consumption and improve reaction atomic efficiency. The reaction system is generally simple, which provides convenience for reaction setup, separation and purification. The general process is simple and easy to control. The present invention is committed to applying simple electrosynthesis reactions to synthesize practical compounds that cannot be generated by traditional reactions, namely, the electrochemical double alkoxylation reaction of harmonic difluoride, to provide a simple, efficient and green synthesis method for synthesizing new difluoride structures. Summary of the invention

[0004] The purpose of the present invention is to provide an electrochemical preparation method for the bis-alkoxylation of difluoroolefins.

[0005] To achieve the above object, the technical solution of the present invention is as follows:

[0006] 1. An electrochemical preparation method for the bis-alkoxylation of difluoroolefins, characterized in that under electrochemical conditions, different alcohols are used as nucleophilic reagents, and the solvent and electrochemical parameters are adjusted to achieve the bis-alkoxylation reaction of difluoroolefins. The specific reaction steps include:

[0007] Step (1): A difluoroaryl olefin compound (0.5 mmol, 1.0 equivalent) and an alcohol compound (1.0 ml) were dissolved in 4.0 ml of trifluorotoluene:hexafluoroisopropanol=3:1 (volume ratio), and tetrabutylammonium tetrafluoroborate (1.0 mmol, 2.0 equivalent) was added. All the raw materials were placed in a 20 ml test tube and stirred at room temperature under air.

[0008] Step (2): Place a carbon plate as an anode and a platinum plate electrode as a cathode in a 20 ml test tube and connect an external power supply. Stir and electrolyze the reaction mixture at room temperature under a constant cell potential. Detect the reaction using a thin layer chromatography plate. When it is found that the raw material difluoroolefin is completely consumed, stop the reaction. The reactants are directly concentrated, loaded onto a silica gel column using a chloroform wet method, and separated and purified using a chromatographic column chromatography to obtain a dialkoxylated product of difluoroolefin.

[0009] Preferably, the solvents in step (1) are trifluorotoluene and hexafluoroisopropanol dried over activated 4A molecular sieves, and the trifluorotoluene, hexafluoroisopropanol and alkyl alcohol used are all analytically pure.

[0010] Preferably, the anode of step (2) is a carbon plate (2.0 cm×1.0 cm×2.0 mm), and the cathode is a platinum plate electrode (1.5 cm×1.5 cm×0.1 mm).

[0011] Preferably, the constant voltage reaction in step (2) is performed at a reaction cell voltage of 3.50V.

[0012] Preferably, the reaction time in step (2) is flexible and is determined according to the consumption of difluoroolefin monitored by thin layer chromatography.

[0013] Preferably, the chromatography in step (2) is performed using a silica gel column, the silica gel used in the silica gel column is 200-300 mesh, and the eluent of the silica gel column is a mixture of petroleum ether and ethyl acetate.

[0014] Preferably, in step (2a), when wet loading is performed, the chloroform used is analytical grade.

[0015] The difluoroolefin bis-alkoxylated derivative prepared by the above method is characterized in that its structural formula is as follows:

[0016]

[0017] In formula 1, R1 is selected from any one of the following groups: phenyl, ester group, thienyl, (trifluoromethyl)phenyl, (trifluoromethoxy)phenyl, etc.; R2 is selected from any one of the following groups: methyl, isopropyl, cyclopentyl.

[0018] 2. A 1 micromole / ml DMSO solution was prepared for the obtained compound, and the drug was applied to normal human epithelial cells. After 24 hours of testing, it was found that the drug had very good yellow and near-red fluorescence in the cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is the fluorescence effect of the prepared compound on human epithelial cells 24 hours after administration. DETAILED DESCRIPTION

[0020] In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

[0021] The present invention will be further described below in conjunction with specific embodiments.

[0022] Example 1. Preparation method of 4-(2,2-difluoro-1,2-dimethoxyethyl)-1,1'-biphenyl

[0023] In a dry 20mL reaction tube, add 4-(2,2-difluorovinyl)-1,1'-biphenyl (0.5mmol, 108mg, 1.0equiv), methanol (1.0mL), trifluorotoluene (3.0mL), hexafluoroisopropanol (1.0mL), tetrabutylammonium tetrafluoroborate (1.0mmol, 2.0eq., 330mg) in sequence and stir until the solid is completely dissolved. The whole mixture is stirred in air at room temperature. A carbon plate (2.0cm×2.0cm×2.0mm) is used as an anode and a platinum plate (1.5cm×1.5cm×0.1mm) is used as a cathode. The reaction mixture is stirred and electrolyzed at a constant electrolytic cell potential of 3.5V at room temperature. The progress of the reaction is monitored by TLC. If it is detected that 4-(2,2-difluorovinyl)-1,1'-biphenyl is completely reacted, the reaction can be stopped. The experimental treatment is to drain the solution in the reaction; dissolve the solute in the reaction tube with chloroform (1.0 ml), and directly wet-apply it to a silica gel column. The silica gel specification is 200-300 mesh, and the developing solvent is a petroleum ether / ethyl acetate mixture to pass through the silica gel column. A white solid 4-(2,2-difluoro-1,2-dimethoxyethyl)-1,1'-biphenyl (100 mg, 78% yield) is obtained; R f =0.6 (petroleum ether / ethyl acetate=20:1 (v / v)). (See structural formula 1a).

[0024] Structural formula 1a

[0025] The structure was confirmed by nuclear magnetic resonance spectroscopy: 1H NMR (300 MHz, CDCl 3,25℃,δ):7.66(d,J=6.75Hz,4H),7.57(d,J=7.98Hz,2H),7.49(t,J=7.7Hz, 2H),7.40(t,J=7.0Hz,1H),4.52(t,J=6.1Hz,1H),3.61(s,1H),3.47(s,1H). 13 C NMR (75MHz, CDCl 3 ,25℃,δ):141.8,140.7,133.5,131.0,128.9(d,J=6.20Hz,2C),127.5,127.1(d,J=13.64H z, 2C), 123.1 (t, J = 265.41Hz, 1C), 83.0 (t, J = 31.88Hz, 1C), 58.1, 50.4 (t, J = 7.54Hz, 1C). 19 F NMR (282 MHz, CDCl 3 ,25℃,δ):-85.3(d,J=141.51Hz,1F),-86.0(d,J=141.59Hz,1F).MassSpectrometry:GCMS(ESI-TOF)(m / z):calcd for C 16 H 17 F 2 O 2 + ([M+H] + ), 278.11, found, 278.12.

[0026] The synthesized compound was confirmed to be the target compound 4-(2,2-difluoro-1,2-dimethoxyethyl)-1,1'-biphenyl by structural identification.

[0027] Example 2: Synthesis of 4-(2,2-difluoro-1,2-dimethoxyethyl)benzoic acid methyl ester

[0028] In a dry 20mL reaction tube, add methyl 4-(2,2-difluorovinyl)benzoate (0.5mmol, 100mg, 1.0equiv), methanol (1.0mL), trifluorotoluene (3.0mL), hexafluoroisopropanol (1.0mL), tetrabutylammonium tetrafluoroborate (1.0mmol, 2.0eq., 330mg) in sequence and stir until the solid is completely dissolved. The whole mixture is stirred in air at room temperature. A carbon plate (2.0cm×2.0cm×2.0mm) is used as an anode and a platinum plate (1.5cm×1.5cm×0.1mm) is used as a cathode. The reaction mixture is stirred and electrolyzed at a constant electrolytic cell potential of 3.5V at room temperature. The progress of the reaction is monitored by TLC. If it is detected that methyl 4-(2,2-difluorovinyl)benzoate is completely reacted, the reaction can be stopped. The experimental treatment is to drain the solution in the reaction; dissolve the solute in the reaction tube with chloroform (1.0 ml), directly wet-apply to a silica gel column, the silica gel specification is 200-300 mesh, and use a petroleum ether / ethyl acetate mixture as a developing solvent to pass through the silica gel column. A white solid 4-(2,2-difluoro-1,2-dimethoxyethyl)benzoic acid methyl ester is obtained (107 mg, 60% yield); R f =0.34 (petroleum ether). (See structural formula 2a).

[0029] Structural formula 2a

[0030] The structure is confirmed as follows: NMR Spectroscopy: 1 H NMR (300 MHz, CDCl 3 ,25℃,δ):8.03(d,J=8.25Hz,2H),7.49(d,J=8.19Hz,2H),4.44(t,J=6.24Hz,1H),3.90(s,3H),3.51(s,3H),3.38(s,3H). 13 C NMR (75MHz, CDCl 3 ,25℃,δ):166.8,139.6,130.7,129.4,128.5,122.7(t,J=266.15Hz,1C),82.8(t,J=32.06Hz,1C),58.4,52.1,50.4(t,J=7.52Hz,1C). 19 F NMR (282 MHz, CDCl 3 ,25℃,δ):-85.3(d,J=141.23Hz,1F),-86.1(d,J=142.18Hz,1F).Mass Spectrometry:GCMS(ESI-TOF)(m / z):calcd for C12 H 15 F 2 O 4 + ([M+H] + ),260.09,found,260.04.

[0031] The synthesized compound was confirmed to be the target compound 4-(2,2-difluoro-1,2-dimethoxyethyl)benzoic acid methyl ester by structural identification.

[0032] Example 3: Synthesis of 4-(2,2-difluoro-1,2-diisopropoxyethyl)-1,1'-biphenyl

[0033] In a dry 20mL reaction tube, add 4-(2,2-difluorovinyl)-1,1'-biphenyl (0.5mmol, 108mg, 1.0equiv), isopropanol (1.0mL), trifluorotoluene (3.0mL), hexafluoroisopropanol (1.0mL), tetrabutylammonium tetrafluoroborate (1.0mmol, 2.0eq., 330mg) in sequence and stir until the solid is completely dissolved. The whole mixture is stirred in air at room temperature. A carbon plate (2.0cm×2.0cm×2.0mm) is used as an anode and a platinum plate (1.5cm×1.5cm×0.1mm) is used as a cathode. The reaction mixture is stirred and electrolyzed at a constant electrolytic cell potential of 3.5V at room temperature. The progress of the reaction is monitored by TLC. If it is detected that 4-(2,2-difluorovinyl)-1,1'-biphenyl is completely reacted, the reaction can be stopped. The experimental treatment is to drain the solution in the reaction; dissolve the solute in the reaction tube with chloroform (1.0 ml), and directly wet-apply it to a silica gel column. The silica gel specification is 200-300 mesh, and the developing solvent is a petroleum ether / ethyl acetate mixture to pass through the silica gel column. A white solid 4-(2,2-difluoro-1,2-diisopropoxyethyl)-1,1'-biphenyl (100 mg, 78% yield) is obtained; R f =0.58 (petroleum ether / ethyl acetate=20:1 (v / v)). (See structural formula 3a).

[0034] Structural formula 3a

[0035] Structural confirmation The structure is as follows: Nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl 3,25℃,δ):7.62(s,1H),7.60(d,J=2.85Hz,1H),7.56(s,1H),7.53(s,1H),7.50(s,1H),7.44(t,J=7.23Hz,2H), 7.34(t,J=7.29Hz,1H),4.59-4.49(m,2H),3.77-3.69(m,1H),1.23(t,J=5.67Hz,6H),1.16(t,J=4.50Hz,6H). 13 C NMR (75MHz, CDCl 3 ,25℃,δ):141.1(d,J=11.39Hz,1C),135.7,128.9,127.4,127.3,126.7,120.0(t,J=300.01Hz, 1C),79.3(t,J=31.79Hz,1C),72.0,68.4(t,J=5.54Hz,1C),23.5(d,J=3.81Hz,1C),23.0,21.7. 19 F NMR (282 MHz, CDCl 3 ,25℃,δ):-80.6(d,J=142.18Hz,1F),-86.0(d,J=144.55Hz,1F).Mass Spectrometry:LRMS(ESI-TOF)(m / z):calcd for C 20 H 25 F 2 O 2 + ([M+H] + ),335.2,found,335.2.

[0036] The synthesized compound was confirmed to be the target compound 4-(2,2-difluoro-1,2-diisopropoxyethyl)-1,1'-biphenyl by structural identification.

[0037] Example 4: Preparation method of 4-(1,2-bis(cyclopentyloxy)-2,2-difluoroethyl)-1,1'-biphenyl

[0038] In a dry 20mL reaction tube, add 4-(2,2-difluorovinyl)-1,1'-biphenyl (0.5mmol, 108mg, 1.0equiv), cyclopentanol (1.0mL), trifluorotoluene (3.0mL), hexafluoroisopropanol (1.0mL), tetrabutylammonium tetrafluoroborate (1.0mmol, 2.0eq., 330mg) in sequence and stir until the solid is completely dissolved. The whole mixture is stirred in air at room temperature. A carbon plate (2.0cm×2.0cm×2.0mm) is used as an anode and a platinum plate (1.5cm×1.5cm×0.1mm) is used as a cathode. The reaction mixture is stirred and electrolyzed at a constant electrolytic cell potential of 3.5V at room temperature. The progress of the reaction is monitored by TLC. If it is detected that 4-(2,2-difluorovinyl)-1,1'-biphenyl is completely reacted, the reaction can be stopped. The experimental treatment is to drain the solution in the reaction; dissolve the solute in the reaction tube with chloroform (1.0 ml), and directly wet-apply it to a silica gel column. The silica gel specification is 200-300 mesh, and the developing solvent is a petroleum ether / ethyl acetate mixture to pass through the silica gel column. A white solid 4-(1,2-bis(cyclopentyloxy)-2,2-difluoroethyl)-1,1'-biphenyl (116 mg, 65% yield) is obtained; R f =0.65 (petroleum ether / ethyl acetate=20:1 (v / v)). (See structural formula 4a).

[0039] See structure 4a

[0040] Structural confirmation The structure is as follows: Nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl 3 ,25℃,δ):7.64(d,J=1.38Hz,1H),7.61(d,J=3.21Hz,2H),7.58(s,1H),7.53(s,1H),7.50-7.43(m,3H),7.38- 7.33(m,1H),4.77-4.74(m,1H),4.56-4.52(m,1H),4.08-4.05(m,1H),1.82-1.63(m,12H),1.56-1.48(m,4H). 13 C NMR (75MHz, CDCl 3,25℃,δ):141.1(d,J=10.77Hz,2C),135.4,128.9(d,J=3.28Hz,2C),127.3(d,J=13.25Hz,2C),126.7,119.7(t,J =267.47Hz, 1C), 81.4, 79.5 (t, J = 31.37Hz, 1C), 33.6 (d, J = 3.81Hz, 1C), 32.9, 32.0, 23.5 (d, J = 2.93Hz, 1C), 23.4. 19 F NMR (282 MHz, CDCl 3 ,25℃,δ):-80.5(d,J=142.69Hz,1F),-81.7(d,J=142.72Hz,1F).Mass Spectrometry:HRMS(ESI-TOF)(m / z):calcd for C 24 H 28 F 2 NaO 2 + ([M+Na] + ),409.1950,found,409.1941.

[0041] The synthesized compound was confirmed to be the target compound 4-(1,2-bis(cyclopentyloxy)-2,2-difluoroethyl)-1,1'-biphenyl by structural identification.

[0042] Example 5. Preparation method of (4'-(2,2-difluoro-1,2-dimethoxyethyl)-[1,1'-biphenyl]-4-yl)trifluoro-16-methanone

[0043] In a dry 20 mL reaction tube, add 4-(2,2-difluorovinyl)-4'-(trifluoromethoxy)-1,1'-biphenyl (0.5 mmol, 150 mg, 1.0 equiv), methanol (1.0 mL), trifluorotoluene (3.0 mL), hexafluoroisopropanol (1.0 mL), tetrabutylammonium tetrafluoroborate (1.0 mmol, 2.0 eq., 330 mg) in sequence and stir until the solid is completely dissolved. The whole mixture is stirred in air at room temperature. A carbon plate (2.0 cm × 2.0 cm × 2.0 mm) is used as an anode and a platinum plate (1.5 cm × 1.5 cm × 0.1 mm) is used as a cathode. The reaction mixture is stirred and electrolyzed at a constant electrolytic cell potential of 3.5 V at room temperature. The progress of the reaction is monitored by TLC. If it is detected that 4-(2,2-difluorovinyl)-4'-(trifluoromethoxy)-1,1'-biphenyl is completely reacted, the reaction can be stopped. The experimental treatment is to drain the solution in the reaction; dissolve the solute in the reaction tube with chloroform (1.0 ml), and directly wet-apply it to a silica gel column. The silica gel specification is 200-300 mesh, and the developing solvent is a petroleum ether / ethyl acetate mixed solution to pass through the silica gel column. A white solid (4'-(2,2-difluoro-1,2-dimethoxyethyl)-[1,1'-biphenyl]-4-yl)trifluoro-16-methanone (91 mg, 75% yield) was obtained; R f =0.6 (petroleum ether / ethyl acetate=20:1 (v / v)). (See structural formula 5a).

[0044] Structural Formula 5a

[0045] Structural confirmation The structure is as follows: Nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl 3 ,25℃,δ):7.62(s,1H),7.59(s,2H),7.56(s,2H),7.52(s,1H),7.49(s,1H),7.30(s,1H),7.28(s,1H),3.57(s,3H),3.13(s,3H). 13 C NMR (75MHz, CDCl 3 ,25℃,δ):148.9,140.5,139.6,134.0,129.1,128.6,127.1,121.4,119.0( t,J=255.71Hz,1C),83.0(t,J=32.02Hz,1C),58.3,50.6(t,J=7.55Hz,1C). 19 F NMR (282 MHz, CDCl 3,25℃,δ):-57.8(s,3F),-85.8(dd,J=37.67,7.47Hz,2F).Mass Spectrometry:LRMS(ESI-TOF)(m / z):calcd for C 17 H 16 F 5 O 3 + ([M+H] + ),363.1,found,363.1.

[0046] The synthesized compound was confirmed to be the target compound (4'-(2,2-difluoro-1,2-dimethoxyethyl)-[1,1'-biphenyl]-4-yl)trifluoro-16-methanone by structural identification.

[0047] Example 6. Preparation method of 4-(2,2-difluoro-1,2-dimethoxyethyl)-4'-(trifluoromethyl)-1,1'-biphenyl

[0048] In a dry 20 mL reaction tube, add 4-(2,2-difluorovinyl)-4'-(trifluoromethyl)-1,1'-biphenyl (0.5 mmol, 142 mg, 1.0 equiv), methanol (1.0 mL), trifluorotoluene (3.0 mL), hexafluoroisopropanol (1.0 mL), tetrabutylammonium tetrafluoroborate (1.0 mmol, 2.0 eq., 330 mg) in sequence and stir until the solid is completely dissolved. The whole mixture is stirred in air at room temperature. A carbon plate (2.0 cm × 2.0 cm × 2.0 mm) is used as an anode and a platinum plate (1.5 cm × 1.5 cm × 0.1 mm) is used as a cathode. The reaction mixture is stirred and electrolyzed at a constant electrolytic cell potential of 3.5 V at room temperature. The progress of the reaction is monitored by TLC. If it is detected that 4-(2,2-difluorovinyl)-4'-(trifluoromethyl)-1,1'-biphenyl is completely reacted, the reaction can be stopped. The experimental treatment is to drain the solution in the reaction; dissolve the solute in the reaction tube with chloroform (1.0 ml), and directly wet-apply it to a silica gel column. The silica gel specification is 200-300 mesh, and the developing solvent is a petroleum ether / ethyl acetate mixture to pass through the silica gel column. A white solid 4-(2,2-difluoro-1,2-dimethoxyethyl)-4'-(trifluoromethyl)-1,1'-biphenyl (88 mg, 72% yield) is obtained; R f =0.6 (petroleum ether / ethyl acetate=20:1 (v / v)). (See structural formula 6a).

[0049] Structural formula 6a

[0050] Structural confirmation The structure is as follows: Nuclear magnetic resonance spectroscopy: 1H NMR (300 MHz, CDCl 3 ,25℃,δ):7.70(s,5H),7.62(d,J=8.34Hz,2H),7.54(d,J=8.22Hz,2H),3.58(s,3H),3.44(s,3H). 13 C NMR (75MHz, CDCl 3 ,25℃,δ):144.3,140.4,134.6,129.2,127.6,127.3,126.0-125.8(m,1C),119 .1(t,J=262.85Hz,1C),83.0(t,J=32.02Hz,1C),58.4,50.5(t,J=7.55Hz,1C). 19 FNMR (282MHz, CDCl 3 ,25℃,δ):-62.4(s,3F),-85.8(dd,J=37.67,7.47Hz,2F).MassSpectrometry:LRMS(ESI-TOF)(m / z):calcd for C 17 H 16 F 5 O 2 + ([M+H] + ),347.1,found,347.1.

[0051] The synthesized compound was confirmed to be the target compound 4-(2,2-difluoro-1,2-dimethoxyethyl)-4'-(trifluoromethyl)-1,1'-biphenyl by structural identification.

[0052] Example 7. Preparation method of 3-(4-(2,2-difluoro-1,2-dimethoxyethyl)phenyl)thiophene

[0053] 3-(4-(2,2-difluorovinyl)phenyl)thiophene (0.5mmol, 111mg, 1.0equiv), methanol (1.0mL), trifluorotoluene (3.0mL), hexafluoroisopropanol (1.0mL), tetrabutylammonium tetrafluoroborate (1.0mmol, 2.0eq., 330mg) were added to a dry 20mL reaction tube in sequence and stirred until the solid was completely dissolved. The whole mixture was stirred in air at room temperature. A carbon plate (2.0cm×2.0cm×2.0mm) was used as an anode and a platinum plate (1.5cm×1.5cm×0.1mm) was used as a cathode. The reaction mixture was stirred and electrolyzed at a constant electrolytic cell potential of 3.5V at room temperature. The progress of the reaction was monitored by TLC. If it was detected that 3-(4-(2,2-difluorovinyl)phenyl)thiophene was completely reacted, the reaction was stopped. The experimental treatment is to drain the solution in the reaction; dissolve the solute in the reaction tube with chloroform (1.0 ml), and directly wet-apply it to a silica gel column. The silica gel specification is 200-300 mesh, and the developing solvent is a petroleum ether / ethyl acetate mixture to pass through the silica gel column. A white solid 3-(4-(2,2-difluoro-1,2-dimethoxyethyl)phenyl)thiophene (102 mg, 80% yield) is obtained; R f =0.55 (petroleum ether / ethyl acetate=20:1 (v / v)). (See Structural Formula 7a).

[0054] Structural Formula 7a

[0055] Structural confirmation The structure is as follows: Nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl 3 ,25℃,δ):7.62(d,J=8.16Hz,2H),7.47(d,J=8.25Hz,3H),7.40(s,2H),4.44(t,J=6.18Hz,1H),3.56(s,3H),3.41(s,3H). 13 C NMR (75MHz, CDCl 3 ,25℃,δ):141.9,136.5,133.3,129.0,126.4(d,J=3.62Hz,1C),123.0,120.7,11 9.5(t,J=166.24Hz,1C),83.0(t,J=32.00Hz,1C),58.2,50.5(t,J=7.58Hz,1C). 19 F NMR (282 MHz, CDCl 3,25℃,δ):-85.4(d,J=141.71Hz,1F),-86.0(d,J=141.56Hz,1F).Mass Spectrometry:GCMS(ESI-TOF)(m / z):calcd forC 14 H 16 F 2 O 2 S,284.07,found,284.07.

[0056] The synthesized compound was confirmed to be the target compound 3-(4-(2,2-difluoro-1,2-dimethoxyethyl)phenyl)thiophene by structural identification.

[0057] Example 8. Preparation method of 2-(2,2-difluoro-1,2-dimethoxyethyl)-4-phenylthiophene

[0058] 2-(2,2-difluorovinyl)-4-phenylthiophene (0.5mmol, 111mg, 1.0equiv), methanol (1.0mL), trifluorotoluene (3.0mL), hexafluoroisopropanol (1.0mL), tetrabutylammonium tetrafluoroborate (1.0mmol, 2.0eq., 330mg) were added to a dry 20mL reaction tube in sequence and stirred until the solid was completely dissolved. The whole mixture was stirred in air at room temperature. A carbon plate (2.0cm×2.0cm×2.0mm) was used as an anode and a platinum plate (1.5cm×1.5cm×0.1mm) was used as a cathode. The reaction mixture was stirred and electrolyzed at a constant electrolytic cell potential of 3.5V at room temperature. The progress of the reaction was monitored by TLC. If it was detected that 2-(2,2-difluorovinyl)-4-phenylthiophene was completely reacted, the reaction was stopped. The experimental treatment is to drain the solution in the reaction; dissolve the solute in the reaction tube with chloroform (1.0 ml), and directly wet-apply it to a silica gel column. The silica gel specification is 200-300 mesh, and the developing solvent is a petroleum ether / ethyl acetate mixture to pass through the silica gel column. A white solid 2-(2,2-difluoro-1,2-dimethoxyethyl)-4-phenylthiophene (83 mg, 65% yield) is obtained; R f =0.58 (petroleum ether / ethyl acetate=20:1 (v / v)). (See structural formula 8a).

[0059] Structural formula 8a

[0060] Structural confirmation The structure is as follows: Nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl 3,25℃,δ):7.59(d,J=7.14Hz,2H),7.49(s,1H),7.40(t,J=8.31Hz,3H),7.30(t,J=7.02Hz,1H),4.70(t,J=5.4Hz,1H),3.63(s,3H),3.49(s,3H). 13 C NMR (75MHz, CDCl 3 ,25℃,δ):,149.1,141.8,137.8,135.7,129.0,127.5(d,J=13.35Hz,1C),126.4,1 22.6(d,J=265.64Hz,1C),79.4(t,J=34.02Hz,1C),58.4,50.7(t,J=7.53Hz,1C). 19 F NMR (282 MHz, CDCl 3 ,25℃,δ):-85.5(d,J=141.14Hz,1F),-86.0(d,J=141.34Hz,1F).Mass Spectrometry:GCMS(ESI-TOF)(m / z):calcd for C 14 H 16 F 2 O 2 S,284.07,found,284.07.

[0061] The synthesized compound was confirmed to be the target compound 2-(2,2-difluoro-1,2-dimethoxyethyl)-4-phenylthiophene by structural identification.

[0062] Example 9. Preparation method of 3-(2,2-difluoro-1,2-dimethoxyethyl)benzo[b]thiophene

[0063] 3-(2,2-difluorovinyl)benzo[b]thiophene (0.5mmol, 98mg, 1.0equiv), methanol (1.0mL), trifluorotoluene (3.0mL), hexafluoroisopropanol (1.0mL), tetrabutylammonium tetrafluoroborate (1.0mmol, 2.0eq., 330mg) were added to a dry 20mL reaction tube in sequence and stirred until the solid was completely dissolved. The whole mixture was stirred in air at room temperature. A carbon plate (2.0cm×2.0cm×2.0mm) was used as an anode and a platinum plate (1.5cm×1.5cm×0.1mm) was used as a cathode. The reaction mixture was stirred and electrolyzed at a constant electrolytic cell potential of 3.5V at room temperature. The progress of the reaction was monitored by TLC. If it was detected that 3-(2,2-difluorovinyl)benzo[b]thiophene was completely reacted, the reaction was stopped. The experimental treatment is to drain the solution in the reaction; dissolve the solute in the reaction tube with chloroform (1.0 ml), and directly wet-apply it to a silica gel column. The silica gel specification is 200-300 mesh, and the developing solvent is a petroleum ether / ethyl acetate mixture to pass through the silica gel column. A white solid 3-(2,2-difluoro-1,2-dimethoxyethyl)benzo[b]thiophene (58 mg, 44% yield) is obtained; R f =0.68 (petroleum ether / ethyl acetate=20:1 (v / v)). (See structural formula 9a).

[0064] Structural formula 9a

[0065] Structural confirmation The structure is as follows: Nuclear magnetic resonance spectroscopy: 1 H NMR (300 MHz, CDCl 3 ,25℃,δ):7.99-7.96(m,1H),7.89-7.86(m,1H),7.58(s,1H),7.44-7.34(m,2H),4.87(t,J=6.3Hz,1H),3.57(s,3H),3.44(s,3H). 13 C NMR (75MHz, CDCl 3 ,25℃,δ):140.5,138.1,129.8,127.3,124.5(d,J=17.11Hz,1C),123.1,122.8,1 19.6(t,J=265.35Hz,1C),79.0(t,J=33.14Hz,1C),58.3,50.5(t,J=7.42Hz,1C). 19F NMR (282MHz, CDCl3, 25℃, δ): -84.7 (d, J=141.00Hz, 1F), -85.3 (d, J=140.92Hz, 1F). Mass Spectrometry: HRMS (ESI-TOF) (m / z): calcd forC 12 H 12 F 2 NaO 2 S + ([M+Na] + ),281.0418,found,281.0458.

[0066] The synthesized compound was confirmed to be the target compound 3-(2,2-difluoro-1,2-dimethoxyethyl)benzo[b]thiophene through structural identification.

[0067] Embodiment 10

[0068] Human epithelial cells in the logarithmic growth phase (purchased from American Type Culture Collection, ATCC) were digested with trypsin, centrifuged, and resuspended for cell counting. 1×106 / mL was inoculated in a 96-well culture plate, 100 μL per well. After the cells adhered to the wall, the drug to be tested (compounds in Examples 1-9) was diluted into a 1 μmol / L DMSO solution, and the cells were treated and placed in a constant temperature incubator (37°C, 5% CO 2 The cells were cultured for 24 hours. The fluorescence phenomenon of the cells was observed using a fluorescence microscope and recorded. The results were as follows: Figure 1 As shown, the intracellular drug has better fluorescence.

[0069] The above disclosure is only the preferred embodiment of the present invention, which certainly cannot be used to limit the scope of rights of the present invention. Therefore, equivalent changes made according to the scope of the patent application of the present invention are still within the scope covered by the present invention.

Claims

1. An electrochemical preparation method for the bis-alkoxylation of difluoroolefins, characterized in that: Under electrochemical conditions, alkyl alcohol is used as a nucleophilic reagent, and the solvent and electrochemical parameters are adjusted to achieve the bis-alkoxylation reaction of difluoroolefins. The specific reaction steps include: Step (1): 0.5 mmol of a difluoroaryl olefin compound and 1.0 ml of an alkyl alcohol compound are dissolved in 4.0 ml of a mixed solution of trifluorotoluene and hexafluoroisopropanol in a volume ratio of 3:1, and 1.0 mmol of tetrabutylammonium tetrafluoroborate is added. All the raw materials are placed in a 20 ml test tube and stirred at room temperature under air; Step (2): Place a carbon plate as an anode and a platinum plate electrode as a cathode in a 20 ml test tube and connect an external power supply. Stir and electrolyze the reaction mixture at room temperature under a constant cell potential. Monitor the reaction with a thin layer chromatography plate. When it is found that the raw material difluoroolefin is completely consumed, stop the reaction. Concentrate the reactants directly, load a silica gel column with chloroform wet method, separate and purify by chromatographic column chromatography to obtain a dialkoxylated product of difluoroolefin.

2. The preparation method according to claim 1, characterized in that: The solvents in step (1) are trifluorotoluene and hexafluoroisopropanol dried over activated 4A molecular sieves, and the trifluorotoluene, hexafluoroisopropanol and alkyl alcohol used are all analytically pure.

3. The preparation method according to claim 1, characterized in that: The anode size of step (2) is 2.0 cm×1.0 cm×2.0 mm, and the cathode size is 1.5 cm×1.5 cm×0.1 mm.

4. The preparation method according to claim 1, characterized in that: The constant battery potential of the reaction in step (2) is 3.50 V.

5. The preparation method according to claim 1, characterized in that: The reaction time in step (2) depends on different reaction conditions. Whether the reaction is complete can be determined by monitoring the consumption of difluoroolefin using a thin layer chromatography plate.

6. The preparation method according to claim 1, characterized in that: The silica gel used in the silica gel column in step (2) is 200-300 mesh, and the eluent of the silica gel column is a mixture of petroleum ether and ethyl acetate.

7. The preparation method according to claim 1, characterized in that: When wet sample loading is performed in step (2), the chloroform used is analytical grade.

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