Trifluoromethyl-containing phosphamide compound and electrochemical synthesis method thereof
This method utilizes an electrochemical synthesis approach to prepare trifluoromethylphosphoramide compounds under mild conditions, overcoming the lack of efficient preparation methods in existing technologies. It achieves high yields and good functional group compatibility of the compounds, demonstrating potential pharmaceutical application value.
Patent Information
- Application Number
- CN202511504836.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-21
- Publication Date
- 2025-12-12
AI Technical Summary
There is a lack of efficient methods for preparing trifluoromethylphosphoramide compounds, especially methods that do not require additional chemical oxidants under mild conditions.
An electrochemical synthesis method was adopted, in which N-(diphenylphospho)acrylamide and sodium trifluoromethanesulfonate were subjected to a series cyclization reaction in an organic solvent using an electrolytic device, and the trifluoromethylphosphamide-containing compounds were obtained by electrolysis through a carbon rod anode and a platinum sheet cathode.
The preparation of trifluoromethylphosphoramide compounds was achieved under mild conditions. The reaction substrates are widely applicable, the functional groups are compatible, and the yields are moderate to good. These compounds have potential value in biological activity and medicinal chemistry applications.
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Figure CN121108191A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the field of organic synthesis, and relates to a trifluoromethyl-containing phosphoramidate compound and an electrochemical synthesis method thereof. BACKGROUND
[0002] Due to the unique physicochemical properties of fluorine atoms, the research on fluorine-containing drugs and pesticides has rapidly developed in recent decades. The introduction of a trifluoromethyl (CF3) group can significantly improve the lipophilicity, membrane permeability, metabolic stability, hydrophobicity and target binding selectivity of molecules, so the efficient construction of trifluoromethyl compounds has always been a research hotspot in the field of organic chemistry. And the unique properties of fluorine, such as high electronegativity and small atomic size, help to improve the potency, selectivity, metabolic stability and pharmacokinetics of drugs. Therefore, fluorine atoms are widely present in drug molecules, such as Danicopan, Tovokafenib, Volasidenib and Seladelpar drugs.
[0003] Phosphoramidate-containing drugs, such as remdesivir, are nucleoside analogs with antiviral activity, with a median effective concentration (EC 50 ) value of 74 nM in human aortic endothelial cells (HAEC) against severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), and an EC 50 value of 30 nM in delayed brain tumor cells against murine hepatitis virus.
[0004] Due to the lack of research on trifluoromethyl-containing phosphoramidate compounds, their preparation methods and applications, it is of great significance to provide a general, efficient and mild trifluoromethyl-containing phosphoramidate compound preparation method. SUMMARY
[0005] The purpose of the present application is to provide a trifluoromethyl-containing phosphoramidate compound and an electrochemical synthesis method thereof, which realizes the preparation of trifluoromethyl-containing phosphoramidate compounds under mild conditions without the need for additional chemical oxidants.
[0006] To achieve the above-mentioned purpose, the present application provides a trifluoromethyl-containing phosphoramidate compound, and the structural formula of the compound is: ; wherein R is one of cyclopropyl, methyl, n-butyl, phenyl, p-tolyl, m-tolyl, p-methoxyphenyl, p-isopropylphenyl, p-tert-butylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-ethoxycarbonylphenyl, benzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, p-methoxybenzyl, p-isopropylbenzyl, p-tert-butylbenzyl, p-fluorobenzyl, p-chlorobenzyl, p-bromobenzyl, pyrid-3-yl.
[0007] Preferably, when R is cyclopropyl, the trifluoromethyl-containing phosphoramidate compound is 2-cyclopropyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When R is methyl, the trifluoromethyl-containing phosphoramidate compound is 2,4-dimethyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When R is n-butyl, the trifluoromethyl-containing phosphoramidate compound is 2-butyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When R is phenyl, the trifluoromethyl-containing phosphoramidate compound is 4-methyl-1,2-diphenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When R is p-tolyl, the trifluoromethyl-containing phosphoramidate compound is 4-methyl-1-phenyl-2-(p-tolyl)-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When R is m-tolyl, the trifluoromethyl-containing phosphoramidate compound is 4-methyl-1-phenyl-2-(m-tolyl)-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When the R group is p-methoxyphenyl, the trifluoromethyl-containing phosphoramide compound is 2-(4-methoxyphenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When the R group is p-isopropylphenyl, the trifluoromethyl-containing phosphoramide compound is 2-(4-isopropylphenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When the R group is p-tert-butylphenyl, the trifluoromethyl-containing phosphoramide compound is 2-(4-(tert-butyl)phenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When the R group is p-fluorophenyl, the trifluoromethyl-containing phosphoramide compound is 3-(4-fluorophenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When the R group is p-chlorophenyl, the trifluoromethyl-containing phosphoramide compound is 2-(4-chlorophenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When the R group is p-bromophenyl, the trifluoromethyl-containing phosphoramide compound is 3-(4-bromophenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When the R group is p-ethoxycarbonylphenyl, the trifluoromethyl-containing phosphoramide compound is ethyl 4-(4-methyl-1-oxide-3-oxo-1-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphinyl)benzoate, having the structure: ; When the R group is benzyl, the trifluoromethyl-containing phosphoramide compound is 2-benzyl-4-methyl-l-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][l,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When the R group is o-methylbenzyl, the trifluoromethyl-containing phosphoramide compound is 2-benzyl-4-methyl-l-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][l,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When the R group is m-methylbenzyl, the trifluoromethyl-containing phosphoramide compound is 4-methyl-2-(3-methylbenzyl)-l-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][l,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When the R group is p-methylbenzyl, the trifluoromethyl-containing phosphoramide compound is 5-methyl-2-(4-methylbenzyl)-l-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][l,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When the R group is p-methoxybenzyl, the trifluoromethyl-containing phosphoramide compound is 2-(4-methoxybenzyl)-4-methyl-l-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][l,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When the R group is p-isopropylbenzyl, the trifluoromethyl-containing phosphoramide compound is 3-(4-isopropylbenzyl)-4-methyl-l-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][l,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When the R group is p-tert-butylbenzyl, the trifluoromethyl-containing phosphoramide compound is 2-(4-(tert-butyl)benzyl)-4-methyl-l-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][l,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ; When the R group is p-fluorobenzyl, the trifluoromethyl-containing phosphoramide compound is 3-(4-fluorobenzyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is as follows: ; When the R group is p-chlorobenzyl, the trifluoromethyl-containing phosphoramide compound is 2-(4-chlorobenzyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is as follows: ; When the R group is p-bromobenzyl, the trifluoromethyl-containing phosphoramide compound is 3-(4-bromobenzyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is as follows: ; When the R group is pyridine-3-yl, the trifluoromethyl-containing phosphoramide compound is 4-methyl-1-phenyl-2-(pyridine-3-yl)-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is as follows: .
[0008] The present application provides an electrochemical synthesis method of a trifluoromethyl-containing phosphoramide compound, which comprises the following steps: S1, dissolving N-(diphenylphosphoryl)acrylamide, sodium trifluoromethanesulfinate and an electrolyte in an organic solvent to obtain a mixed solution in an electrolytic device; S2, stirring the mixed solution, and then applying a constant current for electrolysis under the condition that the air temperature is 30°C-55°C, until the reaction of N-(diphenylphosphoryl)acrylamide is complete, to obtain an electrolyte; S3, sequentially performing water washing and dichloromethane extraction on the electrolyte to obtain an extraction liquid; S4, combining the organic layers of the extraction liquid, and then sequentially performing drying, concentration and elution to obtain the trifluoromethyl-containing phosphoramide compound.
[0009] Preferably, the electrolyte is at least one of tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate and tetrabutylammonium bromide.
[0010] Preferably, the organic solvent is one of a dichloromethane solution and an acetonitrile solution; the volume ratio of dichloromethane to water in the dichloromethane solution is 4-6:1; and the volume ratio of acetonitrile to water in the acetonitrile solution is 4-6:1.
[0011] Preferably, the molar ratio of the N-(diphenylphosphoryl)acrylamide, sodium trifluoromethanesulfinic acid and the electrolyte is 1:3:1.
[0012] Preferably, the current value of the constant current ranges from 3 mA to 8 mA.
[0013] Preferably, the method for elution in S4 is silica gel flash column chromatography; the eluent used in the silica gel flash column chromatography is a mixed solution of n-hexane and ethyl acetate; the volume ratio of n-hexane to ethyl acetate in the mixed solution of n-hexane and ethyl acetate is 1:1.
[0014] Preferably, the electrodes in the electrolysis device are a carbon rod anode and a platinum sheet cathode.
[0015] Therefore, the present application provides a kind of trifluoromethyl phosphoramide compound and its electrochemical synthesis method, compared with traditional technology, with the following beneficial effects: trifluoromethyl phosphoramide compound is prepared by the tandem cyclization reaction of electrochemical oxidation N-(diphenylphosphoryl)acrylamide and sodium trifluoromethanesulfinic acid under constant current, without additional chemical oxidant and under mild conditions, a series of trifluoromethyl phosphoramide compounds that have not been studied are obtained, and the reaction substrate is suitable for trifluoromethyl phosphoramide compound preparation process, and the functional group has good compatibility, and the target product can be obtained with medium to good yield.Furthermore, the trifluoromethyl phosphoramide compound prepared by the present application may have good biological activity due to its phosphorus, nitrogen heterocyclic skeleton, and has potential application value in medicinal chemistry.
[0016] The technical solutions of the present application will be further described in detail below with the aid of drawings and examples. BRIEF DESCRIPTION OF DRAWINGS
[0017] Figure 1 The general flow chart for preparing trifluoromethyl phosphoramide compound by the present application. DETAILED DESCRIPTION
[0018] The technical solutions of the present application will be further described in detail below with the aid of drawings and examples.
[0019] Unless otherwise defined, the technical terms or scientific terms used in the present application shall have the usual meaning understood by a person having ordinary skill in the art to which the present application belongs.
[0020] The present application provides a kind of trifluoromethyl phosphoramide compound, and the structural formula of the compound is: ; R is one of cyclopropyl, methyl, n-butyl, phenyl, p-tolyl, m-methylphenyl, p-methoxyphenyl, p-isopropylphenyl, p-tert-butylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-ethoxycarbonylphenyl, benzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, p-methoxybenzyl, p-isopropylbenzyl, p-tert-butylbenzyl, p-fluorobenzyl, p-chlorobenzyl, p-bromobenzyl, pyrid-3-yl.
[0021] The prepared phosphoramide compound with trifluoromethyl is shown in the general formula, such as Figure 1 N-(diphenylphosphoryl)acrylamide and sodium trifluoromethanesulfinate (CF3SO2Na) as reactants, electrolyte and organic solvent as the substrate, electrolysis by the electrolytic device with carbon rod anode and platinum sheet cathode, to obtain a phosphoramide compound with trifluoromethyl. The structural formula of N-(diphenylphosphoryl)acrylamide is: .
[0022] The embodiments are as follows: Example 1 A phosphoramide compound with trifluoromethyl, when R is cyclopropyl, the phosphoramide compound with trifluoromethyl is 2-cyclopropyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo [c] [1,2] azaphosphine-3 (2H) -one 1-oxide, denoted as 2a, the structural formula is: .
[0023] The preparation method of the phosphoramide compound 2a with trifluoromethyl includes the following steps: S1, 0.3 mmol of N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide, 0.9 mmol of sodium trifluoromethanesulfinate and 0.3 mmol of tetrabutylammonium hexafluorophosphate are added into a 10 mL three-necked round-bottom flask, then 5 mL of dichloromethane and 1 mL of water are added to obtain a mixed solution. The flask is provided with a carbon rod anode and a platinum sheet cathode.
[0024] S2, stir the mixed solution, then apply a constant current of 3 mA under the condition of air at 30°C to carry out electrolysis, so that N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide and sodium trifluoromethylsulfinate perform tandem cyclization reaction, and TLC is used to monitor about 7 hours, until N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide is completely consumed, to obtain an electrolyte.
[0025] S3, the electrolyte is first washed with water, then 5 mL of dichloromethane is used for repeated extraction for 3 times to obtain an extraction solution.
[0026] S4, combine the organic layer of the extraction liquid, first dry with Na2SO4, concentrate, then purify through silica gel flash column chromatography (silica gel 200-300 mesh), with a mixture of n-hexane and ethyl acetate with a volume ratio of 1:1 as eluent, to obtain 88.4 mg of white solid, namely trifluoromethyl phosphoramide compound 2a, with a yield of 75%.
[0027] The nuclear magnetic resonance spectrum analysis of trifluoromethyl phosphoramide compound 2a is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.76 – 7.70 (m, 2H), 7.61 – 7.47(m, 5H), 7.36 – 7.30 (m, 2H), 3.27-3.15 (m, 1H), 2.91-2.79 (m, 1H), 2.31-2.26(m 1H), 1.90 (s, 3H), 1.53-1.46 (m, 1H), 0.88 – 0.80 (m, 1H), 0.62-0.55 (m,1H), 0.43-0.36 (m, 1H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 176.82 (d, J = 4.0 Hz), 144.22 (d, J =7.0 Hz), 133.03 (d, J = 3.0 Hz), 132.89 (d, J = 3.0 Hz), 132.50 (d, J = 10.0 Hz),131.68 (d, J = 13.0 Hz), 130.34, 129.01, 128.90 (d, J = 13.0 Hz), 128.09, 127.96,126.78, 125.80 (d, J = 11.0 Hz), 125.27 (q, J = 277.0 Hz), 47.14 (q, J = 28.0 Hz),46.86 (t, J = 1.0 Hz), 28.28 (d, J = 3.0 Hz), 23.15, 7.04, 6.61 (d, J = 3.0 Hz). Nuclear magnetic fluorine spectrum: 19 F NMR (376 MHz, CDCl3) δ -60.73. Electrospray ion source-high resolution mass spectrum (m / z): molecular protonated ion calculated 394.1178, found 394.1160.
[0028] Example 2 When R group is methyl, the trifluoromethyl phosphoramidate compound is 2,4-dimethyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, denoted as 2b, with the following structural formula: .
[0029] The preparation method of the trifluoromethyl phosphoramidate compound 2b is to replace "N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide" in the preparation methods S1 and S2 of the trifluoromethyl phosphoramidate compound 2a in Example 1 with "N-methyl-N-(diphenylphosphoryl)methyl acrylamide", replace "tetrabutylammonium hexafluorophosphate" in S1 with "tetrabutylammonium tetrafluoroborate", and replace "dichloromethane" with "acetonitrile", and the rest of the steps are the same as Example 1. Finally, 68.3 mg of white solid, i.e. trifluoromethyl phosphoramidate compound 2b, is obtained, with a yield of 62%.
[0030] The nuclear magnetic resonance spectrum analysis of the trifluoromethyl phosphoramidate compound 2b is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 16, 8.0 Hz, 2H), 7.60 -7.50 (m, 4H), 7.47 - 7.43 (m, 2H), 7.36 - 7.31 (m, 1H), 3.38 - 3.26 (m, 1H),2.97 (d, J = 4.0 Hz, 3H), 2.95 – 2.86 (m, 1H), 1.80 (s, 3H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.40 (d, J = 4.0 Hz), 142.38 (d, J =8.0 Hz), 133.12 (d, J = 2.0 Hz), 132.89 (d,J = 3.0 Hz), 131.87 (d, J = 11.0 Hz), 131.69 (d, J = 11.0 Hz), 130.93, 129.61, 129.07 (d, J = 13.0 Hz), 127.98 (d, J =13.0 Hz), 126.82 (d, J = 12.0 Hz), 125.15 (q, J = 277.0 Hz), 125.12, 123.90,46.00 (q, J = 28.0 Hz), 45.82 (t, J = 2.0 Hz), 30.11, 29.28 (d, J = 4.0 Hz). NMR fluorine spectrum: 19 F NMR (376 MHz, CDCl3) δ -61.11. Electrospray ionization source-high resolution mass spectrometry (m / z): The calculated value of molecular protonated ion is 368.1022, and the measured value is 368.1022.
[0031] Example 3 A trifluoromethylphosphoramide compound, when the R group is n-butyl, is 2-butyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azophine-3(2H)-one 1-oxide, denoted as 2c, with the following structural formula: .
[0032] The preparation method of trifluoromethylphosphoramide compound 2c is as follows: in the preparation method of trifluoromethylphosphoramide compound 2a in Example 1, "N-cyclopropyl-N-(diphenylphosphoryl)methacrylamide" in S1 and S2 is replaced with "N-butyl-N-(diphenylphosphoryl)methacrylamide", and "tetrabutylammonium hexafluorophosphate" in S1 is replaced with "tetrabutylammonium bromide". The remaining steps are the same as in Example 1. Finally, 88.4 mg of white solid, i.e., trifluoromethylphosphoramide compound 2c, is obtained, with a yield of 72%.
[0033] The NMR spectroscopic analysis of the trifluoromethylphosphoramide compound 2c yielded the following spectral data: 1H NMR spectrum: 1H NMR (400 MHz, CDC13) δ 7.67 - 7.41 (m, 8H), 7.35 - 7.31 (m, 1H), 3.66 - 3.57 (m, 1H), 3.44 - 3.32 (m, 1H), 3.28 - 3.19 (m, 1H), 2.94- 2.83 (m, 1H), 1.76 (s, 3H), 1.69 - 1.58 (m, 1H), 1.40 - 1.29 (m, 1H), 1.25- 1.10 (m, 2H), 0.76 (t, J = 8.0 Hz, 3H). Nuclear Magnetic Carbon Spectrum: 13 C NMR (100 MHz, CDC13) δ 173.78 (d, J = 4.0 Hz ), 142.02 (d, J = 9.0 Hz ), 133.02 (d, J = 3.0 Hz ), 132.75 (d, J = 3.0 Hz ), 131.82 (d, J = 10.0Hz ), 131.66, 131.53 (d, J = 11.0 Hz ), 130.35, 128.92 (d, J = 14.0 Hz ), 127.93(d, J = 13.0 Hz ), 126.84 (d, J = 12.0 Hz ), 125.22 (q, J = 277.0 Hz ), 125.12,123.90, 45.78 (t, J = 2.0 Hz ), 45.59 (q, J = 27.0 Hz ), 43.51 (d, J = 3.0 Hz ),31.01, 30.07, 20.21, 13.58. Nuclear Magnetic Fluorine Spectrum: 19 F NMR (376 MHz, CDC13) δ -60.78. Electrospray Ion Source - High Resolution Mass Spec (m / z): Molecular protonated ion calcd 410.1491, found 410.1483.
[0034] Example 4 A trifluoromethyl phosphoramidate compound, when R is phenyl, the trifluoromethyl phosphoramidate compound is 4-methyl-1,2-diphenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, denoted as 2d, with the structural formula: .
[0035] The preparation method of the trifluoromethyl phosphoramidate compound 2d is to replace "N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide" in the preparation method S1 and S2 of the trifluoromethyl phosphoramidate compound 2a in Example 1 with "N-phenyl-N-(diphenylphosphoryl)methyl acrylamide", replace "tetrabutylammonium hexafluorophosphate" in S1 with "tetrabutylammonium bromide" and "dichloromethane" with "acetonitrile", replace "air condition at 30 °C" in S2 with "air condition at 40 °C", and the rest of the steps are the same as Example 1. Finally, 82.4 mg of white solid, i.e. the trifluoromethyl phosphoramidate compound 2d, is obtained, with a yield of 64%.
[0036] The nuclear magnetic resonance spectrum analysis of the trifluoromethyl phosphoramidate compound 2d is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.67 - 7.56 (m, 3H), 7.52 – 7.38(m, 4H), 7.35 - 7.30 (m, 2H), 7.23 - 7.22 (m, 3H), 7.05 – 7.03 (m, 2H), 3.39- 3.28 (m, 1H), 3.16 - 3.05 (m, 1H), 1.94 (s, 3H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.24 (d, J = 5.0 Hz), 142.88 (d, J =8.0 Hz), 134.57, 133.24 (d, J = 2.0 Hz), 132.71 (d, J = 3.0 Hz), 132.28 (d, J =11.0 Hz), 132.02 (d, J = 12.0 Hz), 130.61, 130.02 (d, J= 2.0 Hz), 129.27,129.02, 128.50, 128.37, 128.04 (d, J = 13.0 Hz), 126.88 (d, J = 12.0 Hz), 125.63, 125.31 (q, J = 277.0 Hz), 124.42, 46.45 (t, J = 1.0 Hz), 46.25 (q, J = 27.0 Hz), 29.07. NMR fluorine spectrum: 19 F NMR (376 MHz, CDCl3) δ -60.77. Electrospray ionization source-high resolution mass spectrometry (m / z): The calculated value of molecular protonated ion is 430.1178, and the measured value is 430.1169.
[0037] Example 5 A trifluoromethylphosphoramide compound, when the R group is p-tolyl, is 4-methyl-1-phenyl-2-(p-tolyl)-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azophine-3(2H)-one 1-oxide, denoted as 2e, with the following structural formula: .
[0038] The preparation method for trifluoromethylphosphoramide compound 2e is as follows: in the preparation method of trifluoromethylphosphoramide compound 2a in Example 1, "N-cyclopropyl-N-(diphenylphosphoryl)methacrylamide" in S1 and S2 is replaced with "N-p-tolyl-N-(diphenylphosphoryl)methacrylamide", "tetrabutylammonium hexafluorophosphate" in S1 is replaced with "tetrabutylammonium bromide", and "30°C air conditions" in S2 is replaced with "55°C air conditions". The remaining steps are the same as in Example 1. A white solid of 79.8 mg, namely trifluoromethylphosphoramide compound 2e, is finally obtained, with a yield of 60%.
[0039] The NMR spectral analysis of compounds containing 2e of trifluoromethylphosphoramides yielded the following spectral data: 1H NMR spectrum: 1 H NMR (400 MHz, DMSO- d 6) δ 7.99 (dd, J= 8.0, 0 Hz, 1H), 7.75– 7.71 (m, 1H), 7.59 - 7.51 (m, 3H), 7.47 – 7.41 (m, 4H), 7.08 (d, J = 8.0 Hz,2H), 6.88 (d, J = 8.0 Hz, 2H), 3.59 - 3.47 (m, 1H), 3.34 – 3.24 (m, 1H), 2.22(s, 3H), 1.89 (s, 3H). Nuclear Magnetic Carbon Spectrum: 13 C NMR (100 MHz, DMSO- d 6) δ 174.13 (d, J = 5.0 Hz), 141.87 (d, J = 8.0 Hz), 137.55, 133.06 (d, J = 2.0 Hz), 132.63 (d, J = 2.0 Hz), 131.97 (d, J =2.0 Hz), 131.87, 131.07, 130.95 (d, J = 2.0 Hz), 129.75 (d, J = 1.0 Hz), 129.61,129.27, 128.68 (d, J = 14.0 Hz), 128.05 (d, J = 3.0 Hz), 127.92 (d, J = 4.0 Hz),125.89 (q, J = 27.0 Hz), 125.02, 123.82, 45.78, 44.15 (q, J = 26.0 Hz), 31.22,20.55. Nuclear Magnetic Fluorine Spectrum: 19 F NMR (376MHz, DMSO- d 6) δ -59.88. Electrospray Ion Source - High Resolution Mass Spectrum (m / z): Molecular protonated ion calcd 444.1335, found 444.1335.
[0040] Example 6 A trifluoromethyl phosphoramidate compound, when R group is m-tolyl, the trifluoromethyl phosphoramidate compound is 4-methyl-1-phenyl-2-(m-tolyl)-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphin-3(2H)-one 1-oxide, denoted as 2f, with the structural formula: .
[0041] The preparation method of the trifluoromethyl phosphoramidate compound 2f is to replace "N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide" in the preparation method S1 and S2 of the trifluoromethyl phosphoramidate compound 2a in Example 1 with "N-m-tolyl-N-(diphenylphosphoryl)methyl acrylamide", replace "tetrabutylammonium hexafluorophosphate" in S1 with "tetrabutylammonium bromide" and "dichloromethane" with "acetonitrile", replace "air condition at 30 °C" in S2 with "air condition at 55 °C" and "constant current of 3 mA" with "constant current of 5 mA", and the rest of the steps are the same as Example 1. Finally, 59.8 mg of white solid, i.e. the trifluoromethyl phosphoramidate compound 2f, is obtained, with a yield of 45%.
[0042] The nuclear magnetic resonance spectrum analysis of the trifluoromethyl phosphoramidate compound 2f is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.67 - 7.57 (m, 3H), 7.53 – 7.38(m, 4H), 7.34 (td, J = 8.0, 4.0 Hz, 2H), 7.10 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 8.0Hz, 1H), 6.86 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 3.41 - 3.29 (m, 1H), 3.15 –3.03 (m, 1H), 2.21 (s, 3H), 1.93 (s, 3H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.30 (d, J = 4.0 Hz), 142.89 (d, J =8.0 Hz), 139.01, 134.34, 133.21 (d, J = 2.0 Hz), 132.67 (d, J= 2.0 Hz), 132.33(d, J = 11.0 Hz), 132.04 (d, J = 12.0 Hz), 130.75, 130.61 (d, J = 2.0 Hz), 129.41,129.25, 128.75, 128.39 (d, J = 14.0 Hz), 128.03 (d, J = 14.0 Hz), 126.94, 126.82,125.71, 125.33 (q, J = 277.0 Hz), 124.51, 46.46, 46.26 (q, J = 27.0 Hz), 29.12, 21.24. NMR fluorine spectrum: 19 F NMR (376 MHz, CDCl3) δ -60.74. Electrospray ionization source-high resolution mass spectrometry (m / z): The calculated value of molecular protonated ion is 444.1335, and the measured value is 444.1321.
[0043] Example 7 A trifluoromethylphosphoramide compound, when the R group is p-methoxyphenyl, is 2-(4-methoxyphenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azophine-3(2H)-one 1-oxide, denoted as 2g, with the following structural formula: .
[0044] The preparation method for 2g of the trifluoromethylphosphoramide compound was as follows: in the preparation method of the trifluoromethylphosphoramide compound 2a in Example 1, "N-cyclopropyl-N-(diphenylphosphoryl)methacrylamide" in S1 and S2 was replaced with "N-(4-methoxyphenyl)-N-(diphenylphosphoryl)methacrylamide", "tetrabutylammonium hexafluorophosphate" in S1 was replaced with "tetrabutylammonium bromide", "30°C air conditions" in S2 was replaced with "55°C air conditions", and "3 mA constant current" was replaced with "8 mA constant current". The remaining steps were the same as in Example 1. Finally, 60.6 mg of white solid, i.e., 2g of the trifluoromethylphosphoramide compound, was obtained, with a yield of 44%.
[0045] The NMR spectroscopy analysis of 2g of a trifluoromethylphosphoramide compound yielded the following spectral data: 1H NMR spectrum:1 H NMR (400 MHz, CDCl3) δ 7.67 – 7.57 (m, 3H), 7.53 - 7.45(m, 3H), 7.43 – 7.32 (m, 3H), 6.93 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 8.0 Hz, 2H),3.72 (s, 3H), 3.40 - 3.28 (m, 1H), 3.13 - 3.02 (m, 1H), 1.93 (s, 3H). Carbon NMR: 13 C NMR (100 MHz, CDCl3) δ 174.55 (d, J = 6.0 Hz), 159.34,142.86 (d, J = 8.0 Hz), 133.22 (d, J = 3.0 Hz), 132.69 (d, J = 2.0 Hz), 132.27 (d, J = 11.0 Hz), 132.13 (d, J = 12.0 Hz), 131.11 (d, J = 2.0 Hz), 130.91, 129.57,128.50 (d, J = 14.0 Hz), 128.05 (d, J = 13.0 Hz), 126.88 (d, J = 12.0 Hz), 126.76,125.72, 125.32 (q, J = 277.0 Hz), 124.52, 114.40, 55.43, 46.42, 46.33 (q, J =27.0 Hz), 29.37. Fluorine NMR: 19 F NMR (376 MHz, CDCl3) δ -60.85. Electrospray Ion Source - High Resolution Mass Spec (m / z): Molecular protonated ion calcd 460.1284, found 460.1282.
[0046] Example 8 A trifluoromethyl phosphoramidate compound, when R group is p-isopropylphenyl, the trifluoromethyl phosphoramidate compound is 2-(4-isopropylphenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphin-3(2H)-one 1-oxide, denoted as 2h, with the structural formula: .
[0047] The preparation method of the trifluoromethyl phosphoramidate compound 2h is to replace "N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide" in the preparation method S1 and S2 of the trifluoromethyl phosphoramidate compound 2a in Example 1 with "N-(4-isopropylphenyl)-N-(diphenylphosphoryl)methyl acrylamide", replace "tetrabutylammonium hexafluorophosphate" in S1 with "tetrabutylammonium bromide" and "dichloromethane" with "acetonitrile", replace "air condition at 30 °C" in S2 with "air condition at 40 °C" and "constant current of 3 mA" with "constant current of 8 mA", and the rest of the steps are the same as Example 1. Finally, 56.5 mg of white solid, i.e. the trifluoromethyl phosphoramidate compound 2h, is obtained, with a yield of 40%.
[0048] The nuclear magnetic resonance spectrum analysis of the trifluoromethyl phosphoramidate compound 2h is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.66 – 7.58 (m, 3H), 7.53 – 7.38(m, 4H), 7.35 - 7.30 (m, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H),3.42 - 3.30 (m, 1H), 3.12 - 3.01 (m, 1H), 2.87 - 2.76 (m, 1H), 1.93 (s, 3H),1.17 (d, J = 3.1 Hz, 3H), 1.15 (d, J = 3.1 Hz, 3H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.41 (d, J = 6.0 Hz), 149.01,142.76 (d, J = 8.0 Hz), 133.18 (d, J = 2.0 Hz), 132.62 (d,J = 3.0 Hz), 132.25 (d, J = 10.0 Hz), 132.07 (d, J = 12.0 Hz), 131.86, 131.01, 129.77 (d, J = 1.0 Hz),129.67, 128.42 (d, J = 13.0 Hz), 128.02 (d, J = 13.0 Hz), 127.15, 126.90 (d, J =12.0 Hz), 125.71, 125.33 (q, J = 277.0 Hz), 124.51, 46.43, 46.27 (q, J = 27.0Hz), 33.77, 29.52, 23.89, 23.80. NMR (376 MHz, CDCl3) δ -60.78. 19 F NMR (376 MHz, CDCl3) δ -60.78. Electrospray Ion Source-High Resolution Mass Spec (m / z): Molecular protonated ion calculated 472.1648, found 472.1638.
[0049] Example 9 When R group is p-tert-butylphenyl, the compound containing trifluoromethyl phosphoramidate is 2-(4-(tert-butyl)phenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, denoted as 2i, with the structure: .
[0050] The preparation method of compound containing trifluoromethyl phosphoramidate 2i is to replace “N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide” in the preparation method S1 and S2 of compound containing trifluoromethyl phosphoramidate 2a in Example 1 with “N-(4-(tert-butyl)phenyl)-N-(diphenylphosphoryl)methyl acrylamide”, replace “tetrabutylammonium hexafluorophosphate” in S1 with “tetrabutylammonium bromide”, replace “3 mA constant current” in S2 with “8 mA constant current”, and the rest of the steps are the same as Example 1. Finally, 55.3 mg of white solid, i.e. compound containing trifluoromethyl phosphoramidate 2i, is obtained, with a yield of 38%.
[0051] The nuclear magnetic spectrum analysis of compound containing trifluoromethyl phosphoramidate 2i is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.66 - 7.58 (m, 3H), 7.53 - 7.37(m, 4H), 7.35 - 7.31 (m, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H),3.42 - 3.31 (m, 1H), 3.12 - 3.00 (m, 1H), 1.92 (s, 3H), 1.23 (s, 9H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.43 (d, J = 5.0 Hz), 151.28 (d, J =1.0 Hz), 142.71 (d, J = 8.0 Hz), 133.18 (d, J = 2.0 Hz), 132.62 (d, J = 3.0 Hz),132.23 (d, J = 10.0 Hz), 132.07 (d, J = 11.0 Hz), 131.58, 131.08, 129.74, 129.43(d, J = 1.0 Hz), 128.42 (d, J =13.0 Hz), 128.02 (d, J = 14.0 Hz), 126.91 (d, J = 12.0Hz), 126.11, 125.69, 125.33 (q, J = 277.0 Hz), 124.49, 46.41, 46.25 (q, J = 27.0Hz), 34.61, 31.27, 29.66. Nuclear magnetic fluorine spectrum: 19 F NMR (376 MHz, CDCl3) δ -60.77. Electrospray Ion Source-High Resolution Mass Spectrum (m / z): Molecular protonated ion calcd 486.1804, found 486.1790.
[0052] Example 10 A trifluoromethyl phosphoramidate compound, when R group is p-fluorophenyl, the trifluoromethyl phosphoramidate compound is 3-(4-fluorophenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, denoted as 2j, with the structural formula: .
[0053] The preparation method of the trifluoromethyl phosphoramidate compound 2j is to replace "N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide" in the preparation method S1 and S2 of the trifluoromethyl phosphoramidate compound 2a in Example 1 with "N-(4-fluorophenyl)-N-(diphenylphosphoryl)methyl acrylamide", replace "tetrabutylammonium hexafluorophosphate" in S1 with "tetrabutylammonium bromide" and replace "dichloromethane" with "acetonitrile", replace "air condition at 30 °C" in S2 with "air condition at 40 °C", and the rest of the steps are the same as Example 1. Finally, 89.9 mg of white solid, i.e. the trifluoromethyl phosphoramidate compound 2j, is obtained, with a yield of 67%.
[0054] The nuclear magnetic resonance spectrum analysis of the trifluoromethyl phosphoramidate compound 2j is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, DMSO- d 6) δ 8.00 (dd, J = 8.2, 4.9 Hz, 1H),7.77 - 7.73 (m, 1H), 7.59 – 7.52 (m, 3H), 7.49 - 7.41 (m, 4H), 7.14 (t, J = 8.0Hz, 2H), 7.06 – 7.03 (m, 2H), 3.60 – 3.48 (m, 1H), 3.34 – 3.24 (m, 1H), 1.90(s, 3H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, DMSO- d 6) δ 174.16 (d, J = 4.0 Hz), 162.42 (d, J C-F = 244.0 Hz), 141.95 (d, J = 8.0 Hz), 133.22 (d, J = 2.0 Hz), 132.81 (d, J= 3.0 Hz), 132.05 (d, J = 10.0 Hz), 131.95 (d, J = 11.0 Hz), 131.05 (d, J = 12.0 Hz),130.80 (d, J = 3.0 Hz), 130.54, 129.21, 128.76 (d, J = 14.0 Hz), 128.11, 127.98,125.87 (q, J = 277.0 Hz), 124.71, 123.50, 115.74 (d, J = 23.0 Hz), 45.83, 44.20(q, J = 26.0 Hz), 30.98. NMR (376 MHz, DMSO- 19 F NMR (376 MHz, DMSO- d 6 ) δ -59.94, -113.56. Electrospray Ion Source - High Resolution Mass Spec (m / z): Molecular protonated ion calculated 470.0909, found 470.0912.
[0055] Example 11 When R group is p-chlorophenyl, the trifluoromethyl phosphoramidate compound is 2-(4-chlorophenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, denoted as 2k, with the following structure: .
[0056] The preparation method of the trifluoromethyl phosphoramidate compound 2k is to replace “N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide” in the preparation methods S1 and S2 of the trifluoromethyl phosphoramidate compound 2a in Example 1 with “N-(4-chlorophenyl)-N-(diphenylphosphoryl)methyl acrylamide”, replace “tetrabutylammonium hexafluorophosphate” in S1 with “tetrabutylammonium bromide”, replace “air condition at 30 °C” in S2 with “air condition at 40 °C” and “constant current of 3 mA” with “constant current of 5 mA”, and the rest of the steps are the same as Example 1. Finally, 73.6 mg of white solid, i.e. the trifluoromethyl phosphoramidate compound 2k, is obtained, with a yield of 53%.
[0057] NMR analysis of the trifluoromethyl phosphoramide compound 2k was performed and the resulting spectral data is as follows: Proton NMR: 1 H NMR (400 MHz, CDCl3) δ 7.67 (t, J = 8.0 Hz, 1H), 7.62 – 7.56(m, 2H), 7.52 - 7.47 (m, 3H), 7.44 - 7.34 (m, 3H), 7.21 (d, J = 8.0 Hz, 2H),6.98 (d, J = 8.0 Hz, 2H), 3.37 - 3.26 (m, 1H), 3.15 - 3.04 (m, 1H), 1.94 (s,3H). Carbon NMR: 13 C NMR (100 MHz, CDCl3) δ 174.22 (d, J = 5.0 Hz), 142.85 (d, J =8.0 Hz), 134.52 (d, J = 1.0 Hz), 133.44 (d, J = 3.0 Hz), 133.14, 132.99 (d, J = 3.0Hz), 132.31 (d, J = 11.0 Hz), 132.14 (d, J = 11.0 Hz), 131.41 (d, J = 2.0 Hz),130.41, 129.35, 129.07, 128.68 (d, J = 14.0 Hz), 128.20 (d, J = 13.0 Hz), 126.90(d, J = 12.0 Hz), 125.46, 125.28 (q, J = 277.0 Hz), 124.25, 46.53 (t, J = 2.0 Hz),46.43 (q, J = 27.0 Hz), 29.06. Fluorine NMR: 19 F NMR (376 MHz, CDCl3) δ -60.89. Electrospray Ionization-High Resolution Mass Spectrometry (m / z): calculated for the molecular ion as protonated m / z 464.0789; found m / z 464.0775.
[0058] Example 12 A trifluoromethyl phosphoramidate compound, when R group is p-bromophenyl, is 3-(4-bromophenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, denoted as 2l, with the structural formula: .
[0059] The preparation method of the trifluoromethyl phosphoramidate compound 2l is to replace “N-cyclopropyl-N-(diphenylphosphoryl)methylacrylamide” in the preparation method S1 and S2 of the trifluoromethyl phosphoramidate compound 2a in Example 1 with “N-(4-bromophenyl)-N-(diphenylphosphoryl)methylacrylamide”, replace “tetrabutylammonium hexafluorophosphate” in S1 with “tetrabutylammonium bromide” and “dichloromethane” with “acetonitrile”, replace “air condition at 30 °C” in S2 with “air condition at 40 °C” and “constant current of 3 mA” with “constant current of 8 mA”, and the rest of the steps are the same as Example 1. Finally, 83.7 mg of white solid, i.e. the trifluoromethyl phosphoramidate compound 2l, is obtained with a yield of 55%.
[0060] The nuclear magnetic resonance spectrum analysis of the trifluoromethyl phosphoramidate compound 2l is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.66 (t, J = 8.0 Hz, 1H), 7.62 - 7.56(m, 2H), 7.52 – 7.47 (m, 3H), 7.43 – 7.33 (m, 5H), 6.91 (d, J = 8.0 Hz, 2H),3.37 - 3.25 (m, 1H), 3.15 - 3.04 (m, 1H), 1.93 (s, 3H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.11 (d, J = 4.0 Hz), 142.75 (d, J =8.0 Hz), 133.68, 133.42 (d, J = 2.0 Hz), 132.97 (d,J = 2.0 Hz), 132.29 (d, J = 2.0 Hz), 132.24 (d, J = 9.0 Hz), 132.05 (d, J = 12.0 Hz), 131.72 (d, J = 2.0 Hz),130.34, 129.00, 128.66 (d, J = 14.0 Hz), 128.17 (d, J = 13.0 Hz), 126.89 (d, J =12.0 Hz), 125.33, 125.15 (q, J = 277.0 Hz), 124.12, 122.65 (d, J = 1.0 Hz),46.47, 46.34 (q, J = 27.0 Hz), 29.14. F NMR (376 MHz, CDCl3) δ -60.86. 19 F NMR (376 MHz, CDCl3) δ -60.86. Electrospray Ion Source-High Resolution Mass Spec (m / z): Molecular protonated ion calculated 508.0283, found 508.0270.
[0061] Example 13 When R group is p-ethoxycarbonylphenyl, the compound of the application is 4-(4-methyl-1-oxido-3-oxo-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-2(3H)-yl) benzoic acid ethyl ester, denoted as 2m, with the following structure: .
[0062] The preparation method of compound 2m is to replace “N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide” in the preparation method S1 and S2 of compound 2a in Example 1 with “N-(4-ethoxycarbonylphenyl)-N-(diphenylphosphoryl)methyl acrylamide”, replace “tetrabutylammonium hexafluorophosphate” in S1 with “tetrabutylammonium bromide”, replace “3 mA constant current” in S2 with “5 mA constant current”, and the rest of the steps are the same as Example 1. Finally, 75.2 mg of white solid, i.e. compound 2m, is obtained, with a yield of 50%.
[0063] NMR analysis of the trifluoromethyl phosphoramide compound 2m resulted in the following spectral data: NMR hydrogen spectrum: 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.00 (dd, J = 8.1, 4.9 Hz, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.76 (t, J = 8.0 Hz, 1H), 7.58 - 7.40 (m, 7H), 7.19 (d, J = 8.0 Hz, 2H), 4.28 (q, J = 8.0 Hz, 2H), 3.60 - 3.48 (m, 1H), 3.34 – 3.25 (m,1H), 1.91 (s, 3H), 1.28 (t, J = 8.0 Hz, 3H). NMR carbon spectrum: 13 C NMR (100 MHz, DMSO- d 6 ) δ 173.93 (d, J = 4.0 Hz), 165.00, 141.91 (d, J = 8.0 Hz), 139.36, 133.27 (d, J = 2.0 Hz), 132.87 (d, J = 3.0 Hz), 131.98 (d, J = 11.0 Hz), 130.99 (d, J = 12.0 Hz), 130.28, 130.19, 129.58, 128.87, 128.81, 128.67, 128.11 (d, J = 7.0 Hz), 127.98 (d, J = 4.0 Hz), 125.82 (q, J = 277.0 Hz), 124.61, 123.40, 60.92, 45.90, 44.14 (q, J = 27.0 Hz), 30.79, 14.06. NMR fluorine spectrum: 19 F NMR (376 MHz, DMSO- d6 ) δ -59.88. Electrospray Ion Source - High Resolution Mass Spectrum (m / z): Calculated for the molecular ion, 502.1390; found, 502.1377.
[0064] Example 14 When R group is benzyl, the compound of the application is 2-benzyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, denoted as 2n, with the following structure: .
[0065] The method for preparing the compound of the application 2n is to replace "N-cyclopropyl-N-(diphenylphosphoryl)methylacrylamide" in the preparation method S1 and S2 of the compound of the application 2a in Example 1 with "N-benzyl-N-(diphenylphosphoryl)methylacrylamide", replace "tetrabutylammonium hexafluorophosphate" in S1 with "tetrabutylammonium bromide" and replace "dichloromethane" with "acetonitrile", replace "3 mA constant current" in S2 with "8 mA constant current", and the rest of the steps are the same as Example 1. Finally, 93.1 mg of white solid, i.e. the compound of the application 2n, is obtained, with a yield of 70%.
[0066] The nuclear magnetic resonance spectrum analysis of the compound of the application 2n is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.50 - 7.40 (m, 4H), 7.36 – 7.31(m, 2H), 7.24 - 7.18 (m, 3H), 7.09 (d, J = 8.0 Hz, 2H), 7.00 - 6.93 (m, 3H),4.58 (dd, J = 16.0, 8.0 Hz, 1H), 4.44 (dd, J = 16.0, 8.0 Hz, 1H), 3.23 - 3.11 (m,1H), 2.74 - 2.62 (m, 1H), 1.62 (s, 3H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.10 (d, J = 4.0 Hz), 142.16 (d, J= 9.0 Hz), 136.29, 133.12 (d, J = 2.0 Hz), 132.81 (d, J = 3.0 Hz), 132.05 (d, J = 10.0 Hz), 131.71 (d, J = 11.0 Hz), 131.23, 129.92, 128.86 (d, J = 14.0 Hz), 128.52, 128.03, 127.92, 127.17, 126.87 (d, J = 12.0 Hz), 125.23, 124.01, 125.08 (q, J = 277.0 Hz), 46.69 (d, J = 3.0 Hz), 46.17 (t, J = 2.0 Hz), 45.36 (q, J = 28.0 Hz), 30.24. NMR (376 MHz, CDCl3) δ -60.59. 19 F NMR (376 MHz, CDCl3) δ -60.59. Electrospray Ion Source-High Resolution Mass Spec (m / z): Molecular protonated ion calculated 444.1335, found 444.1319.
[0067] Example 15 When the R group is ortho-methylbenzyl, the trifluoromethyl phosphoramidate compound is 2-benzyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, denoted as 2o, and has the following structure: .
[0068] The preparation method of the trifluoromethyl phosphoramidate compound 2o is to replace “N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide” in the preparation methods S1 and S2 of the trifluoromethyl phosphoramidate compound 2a in Example 1 with “N-ortho-methylbenzyl-N-(diphenylphosphoryl)methyl acrylamide”, replace “tetrabutylammonium hexafluorophosphate” in S1 with “tetrabutylammonium tetrafluoroborate”, and the rest of the steps are the same as Example 1. Finally, 75.4 mg of white solid, i.e., the trifluoromethyl phosphoramidate compound 2o, is obtained, with a yield of 55%.
[0069] NMR spectral analysis of trifluoromethyl phosphoramide compound 2o, the resulting spectral data as follows: NMR hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.67 – 7.61 (m, 4H), 7.55 (dd, J =8.0, 4.0 Hz, 1H), 7.49 – 7.46 (m, 1H), 7.42 - 7.35 (m, 3H), 7.20 (t, J = 4.0Hz, 1H), 7.03 - 6.96 (m, 3H), 4.76 - 4.63 (m, 2H), 3.45 - 3.33 (m, 1H), 2.93- 2.82 (m, 1H), 2.26 (s, 3H), 1.83 (s, 3H). NMR carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.11 (d, J = 4.0 Hz), 142.33 (d, J =9.0 Hz), 135.39, 134.13, 133.20 (d, J = 2.0 Hz), 132.84 (d, J = 3.0 Hz), 132.05(d, J = 11.0 Hz), 131.85 (d, J = 11.0 Hz), 130.95, 129.87, 129.64, 128.80 (d, J =13.0 Hz), 128.06 (d, J = 13.0 Hz), 126.98 (d, J = 5.0 Hz), 126.92 (d, J = 6.0 Hz),126.81, 125.88, 125.30, 125.16 (q, J = 277.0 Hz), 124.09, 46.37 (t, J = 2.0 Hz),45.33 (q, J = 27.0 Hz), 43.60 (d, J = 3.0 Hz), 30.34, 19.37. NMR fluorine spectrum: 19F NMR (376 MHz, CDCl3) δ -60.37. Electrospray Ion Source - High Resolution Mass Spec (m / z): Molecular protonated ion calculated 458.1491, found 458.1486.
[0070] Example 16 One of the trifluoromethyl phosphoramidate compounds, when R group is m-methylbenzyl, is 4-methyl-2-(3-methylbenzyl)-l-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][l,2]azaphosphinine-3(2H)-one 1-oxide, denoted as 2p, with the following structural formula: .
[0071] The preparation method of the trifluoromethyl phosphoramidate compound 2p is to replace "N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide" in the preparation methods S1 and S2 of the trifluoromethyl phosphoramidate compound 2a in Example 1 with "N-m-methylbenzyl-N-(diphenylphosphoryl)methyl acrylamide", replace "tetrabutylammonium hexafluorophosphate" in S1 with "tetrabutylammonium tetrafluoroborate" and replace "dichloromethane" with "acetonitrile", replace "air condition at 30 °C" in S2 with "air condition at 40 °C", and the rest of the steps are the same as Example 1. Finally, 72.7 mg of white solid, i.e. the trifluoromethyl phosphoramidate compound 2p, is obtained, with a yield of 53%.
[0072] The nuclear magnetic spectroscopy analysis of the trifluoromethyl phosphoramidate compound 2p is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.67 - 7.59 (m, 4H), 7.53 - 7.49 (m, 2H), 7.42 - 7.36 (m, 3H), 7.06 - 7.02 (m, 2H), 6.94 (s, 2H), 4.74 (dd, J = 16.0, 8.0 Hz, 1H), 4.57 (dd, J = 16.0, 8.0 Hz, 1H), 3.42 - 3.30 (m, 1H), 2.90 -2.79 (m, 1H), 2.19 (s, 3H), 1.80 (s, 3H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.16 (d, J= 4.0 Hz), 142.29 (d, J = 9.0 Hz), 137.62, 136.28, 133.16 (d, J = 3.0 Hz), 132.84 (d, J = 3.0 Hz), 132.22 (d, J = 11.0 Hz), 131.87 (d, J = 11.0 Hz), 131.36, 130.05, 129.19, 128.86 (d, J = 13.0 Hz), 128.13, 128.04, 128.00, 126.91 (d, J = 12.0 Hz), 125.53, 125.36, 125.15 (q, J = 278.0 Hz), 124.15, 46.75 (d, J = 3.0 Hz), 46.26 (t, J = 2.0 Hz), 45.48 (q, J = 28.0 Hz), 30.29, 21.37 NMR (376 MHz, CDCl3) δ -60.60. 19 F NMR (376 MHz, CDCl3) δ -60.60. Electrospray Ion Source - High Resolution Mass Spec (m / z): Molecular protonated ion calcd 458.1491, found 458.1482.
[0073] Example 17 One compound of the class of trifluoromethyl phosphoramidates is 5-methyl-2-(4- methylbenzyl)-l-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][l,2]azaphosphinine-3(2H)- one 1 -oxide, designated 2q, having the structure: .
[0074] The preparation method of the trifluoromethyl-containing phosphoramidate compound 2q is to replace "N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide" in the preparation method S1 and S2 of the trifluoromethyl-containing phosphoramidate compound 2a in Example 1 with "N-p-methylbenzyl-N-(diphenylphosphoryl)methyl acrylamide", replace "tetrabutylammonium hexafluorophosphate" in S1 with "tetrabutylammonium tetrafluoroborate", replace "air condition at 30°C" in S2 with "air condition at 55°C", and the remaining steps are the same as in Example 1. Finally, 79.5 mg of white solid, i.e. the trifluoromethyl-containing phosphoramidate compound 2q, is obtained, with a yield of 58%.
[0075] The nuclear magnetic resonance spectrum analysis of the trifluoromethyl-containing phosphoramidate compound 2q is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.67 – 7.56 (m, 4H), 7.51 (t, J = 4.0Hz, 2H), 7.42 - 7.34 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H),4.69 (dd, J = 16.0, 8.0 Hz, 1H), 4.58 (dd, J = 16.0, 8.0 Hz, 1H), 3.41 - 3.29 (m,1H), 2.88 - 2.77 (m, 1H), 2.23 (s, 3H), 1.78 (s, 3H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.08 (d, J = 4.0 Hz), 142.16 (d, J =8.0 Hz), 136.74, 133.26, 133.08 (d, J = 3.0 Hz), 132.76 (d, J = 3.0 Hz), 132.09(d, J = 11.0 Hz), 131.72 (d, J = 11.0 Hz), 131.34, 130.03, 128.86 (d, J = 14.0 Hz),128.73, 128.49, 127.97 (d, J= 14.0 Hz), 126.88 (d, J = 12.0 Hz), 125.30, 125.11(q, J = 278.0 Hz) 124.09, 46.54 (d, J = 3.0 Hz), 46.17 (t, J = 2.0 Hz), 45.32 (q, J =27.0 Hz), 30.21, 21.08. NMR (376 MHz, CDCl3) δ -60.54. 19 F NMR (376 MHz, CDCl3) δ -60.54. Electrospray Ion Source - High Resolution Mass Spec (m / z): Molecular ionization calculated 458.1491, found 458.1486.
[0076] Example 18 When R group is p-methoxybenzyl, the compound of the application is 2-(4-methoxybenzyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, denoted as 2r, with the following structure: .
[0077] The method of preparing compound 2r is to replace "N-cyclopropyl-N-(diphenylphosphoryl)methylacrylamide" in the preparation method S1 and S2 of compound 2a in Example 1 with "N-p-methoxybenzyl-N-(diphenylphosphoryl)methylacrylamide", replace "tetrabutylammonium hexafluorophosphate" in S1 with "tetrabutylammonium tetrafluoroborate" and replace "dichloromethane" with "acetonitrile", replace "3 mA constant current" in S2 with "5 mA constant current", and the rest of the steps are the same as Example 1. Finally, 56.8 mg of white solid, i.e. compound 2r, is obtained, with a yield of 40%.
[0078] The nuclear magnetic resonance spectrum analysis of compound 2r is as follows: NMR (376 MHz, CDCl3) δ -60.54. 1 H NMR (400 MHz, CDCl3) δ 7.66 - 7.55 (m, 4H), 7.52 - 7.47(m, 2H), 7.42 - 7.33 (m, 3H), 7.18 (d, J = 8.0 Hz, 2H), 6.67 (d,J = 8.0 Hz, 2H),4.66 (dd, J = 16.0, 8.0 Hz, 1H), 4.56 (dd, J = 12.0, 8.0 Hz, 1H), 3.69 (s, 3H),3.38 - 3.26 (m, 1H), 2.88 - 2.77 (m, 1H), 1.77 (s, 3H). NMR (100 MHz, CDCl3) δ 174.08 (d, 13 C NMR (100 MHz, CDCl3) δ 174.08 (d, J = 4.0 Hz), 158.70,142.12 (d, J = 8.0 Hz), 133.08 (d, J = 3.0 Hz), 132.77 (d, J = 3.0 Hz), 132.06 (d, J = 11.0 Hz), 131.67 (d, J = 12.0 Hz), 131.40, 130.16, 130.09, 128.87 (d, J = 14.0Hz), 128.41, 127.96 (d, J = 14.0 Hz), 126.85 (d, J = 12.0 Hz), 125.30, 125.08 (q, J = 277.0 Hz), 124.08, 113.38, 55.14, 46.19 (d, J = 3.0 Hz), 46.13 (t, J = 2.0Hz), 45.38 (q, J = 27.0 Hz), 30.20. F NMR (376 MHz, CDCl3) δ -60.63. 19 F NMR (376 MHz, CDCl3) δ -60.63. Electrospray Ion Source - High Resolution Mass Spec (m / z): Molecular protonated ion calcd 474.1440, found 474.1432.
[0079] Example 19 A trifluoromethyl phosphoramidate compound, when R group is p-isopropylbenzyl, the trifluoromethyl phosphoramidate compound is 3-(4-isopropylbenzyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, denoted as 2s, with the structural formula: .
[0080] The preparation method of the trifluoromethyl phosphoramidate compound 2s is to replace "N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide" in the preparation methods S1 and S2 of the trifluoromethyl phosphoramidate compound 2a in Example 1 with "N-(4-isopropylbenzyl)-N-(diphenylphosphoryl)methyl acrylamide", replace "tetrabutylammonium hexafluorophosphate" in S1 with "tetrabutylammonium tetrafluoroborate", replace "air condition at 30 °C" in S2 with "air condition at 40 °C" and replace "constant current of 3 mA" with "constant current of 8 mA", and the remaining steps are the same as Example 1. Finally, 87.3 mg of white solid, i.e. the trifluoromethyl phosphoramidate compound 2s, is obtained, with a yield of 60%.
[0081] The nuclear magnetic resonance spectrum analysis of the trifluoromethyl phosphoramidate compound 2s is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.65 - 7.56 (m, 4H), 7.53 – 7.45(m, 2H), 7.37 - 7.34 (m, 3H), 7.12 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H),4.78 (dd, J = 16.0, 8.0 Hz, 1H), 4.59 (dd, J = 16.0, 8.0 Hz, 1H), 3.42 - 3.31 (m,1H), 2.91 – 2.82 (m, 1H), 2.82 - 2.75 (m, 1H), 1.80 (s, 3H), 1.15 (d, J = 8.0Hz, 6H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.17 (d, J = 4.0 Hz), 147.71,142.20 (d, J= 9.0 Hz), 133.70, 133.08 (d, J = 3.0 Hz), 132.71 (d, J = 3.0 Hz),132.12 (d, J = 11.0 Hz), 131.71 (d, J = 11.0 Hz), 131.21, 129.89, 128.76 (d, J =13.0 Hz), 128.46, 127.96 (d, J = 14.0 Hz), 126.86 (d, J = 12.0 Hz), 126.09,125.33, 125.12 (q, J = 278.0 Hz), 124.12, 46.37 (d, J = 3.0 Hz), 46.20 (t, J = 2.0Hz), 45.38 (q, J = 27.0 Hz), 33.72, 30.22, 23.98, 23.91. NMR (376 MHz, CDCl3) δ -60.55. 19 F NMR (376 MHz, CDCl3) δ -60.55. Electrospray Ion Source - High Resolution Mass Spec (m / z): Molecular protonated ion calcd 486.1804, found 486.1790.
[0082] Example 20 A trifluoromethyl phosphoramidate compound when R group is p-tert-butylbenzyl is 2-(4-(tert-butyl)benzyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4- hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, denoted as 2t, with the structure: .
[0083] The preparation method of the trifluoromethyl-containing phosphoramidate compound 2t is to replace "N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide" in the preparation method S1 and S2 of the trifluoromethyl-containing phosphoramidate compound 2a in Example 1 with "N-(4-(tert-butyl)benzyl)-N-(diphenylphosphoryl)methyl acrylamide", replace "tetrabutylammonium hexafluorophosphate" in S1 with "tetrabutylammonium tetrafluoroborate" and replace "dichloromethane" with "acetonitrile", replace "air condition at 30 °C" in S2 with "air condition at 55 °C", and the remaining steps are the same as those in Example 1. Finally, 86.9 mg of white solid, i.e. the trifluoromethyl-containing phosphoramidate compound 2t, is obtained in a yield of 58%.
[0084] The nuclear magnetic resonance spectrum analysis of the trifluoromethyl-containing phosphoramidate compound 2t is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.65 – 7.57 (m, 4H), 7.53 – 7.45(m, 2H), 7.39 -7.33 (m, 3H), 7.16 – 7.10 (m, 4H), 4.79 (dd, J = 16.0, 8.0 Hz,1H), 4.59 (dd, J = 16.0, 8.0 Hz, 1H), 3.43 - 3.32 (m, 1H), 2.91 - 2.80 (m, 1H),1.81 (s, 3H), 1.23 (s, 9H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.24 (d, J = 4.0 Hz), 149.97,142.28 (d, J = 8.0 Hz), 133.38, 133.10 (d, J = 3.0 Hz), 132.72 (d, J = 2.0 Hz),132.20 (d, J = 11.0 Hz), 131.80 (d, J = 11.0 Hz), 131.24, 129.93, 128.78 (d, J =13.0 Hz), 128.20, 128.01 (d, J = 13.0 Hz), 126.88 (d, J=11.0 Hz), 125.46, 125.15(q, J = 277.0 Hz), 125.01, 124.24, 46.33 (d, J = 3.0 Hz), 46.27 (t, J = 2.0 Hz), 45.49 (q, J = 27.0 Hz), 34.43, 31.35, 30.16. NMR fluorine spectrum: 19 F NMR (376 MHz, CDCl3) δ -60.56. Electrospray ionization source-high resolution mass spectrometry (m / z): The calculated value of molecular protonated ion is 500.1961, and the measured value is 500.1947.
[0085] Example 21 A trifluoromethylphosphoramide compound, when the R group is p-fluorobenzyl, is 3-(4-fluorobenzyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azophine-3(2H)-one 1-oxide, denoted as 2u, with the following structural formula: .
[0086] The preparation method of trifluoromethylphosphoramide compound 2u is as follows: in the preparation method of trifluoromethylphosphoramide compound 2a in Example 1, "N-cyclopropyl-N-(diphenylphosphoryl)methacrylamide" in S1 and S2 is replaced with "N-(4-fluorobenzyl)-N-(diphenylphosphoryl)methacrylamide", "tetrabutylhexafluorophosphate" in S1 is replaced with "tetrabutyltetrafluoroborate", "30°C air conditions" in S2 is replaced with "55°C air conditions", and "3 mA constant current" is replaced with "8 mA constant current". The remaining steps are the same as in Example 1. Finally, 70.6 mg of white solid, i.e., trifluoromethylphosphoramide compound 2u, is obtained, with a yield of 51%.
[0087] The NMR spectral analysis of the trifluoromethylphosphoramide compound 2u yielded the following spectral data: 1H NMR spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.69 - 7.58 (m, 4H), 7.55 - 7.48(m, 2H), 7.45 - 7.37 (m, 3H), 7.29 (dd, J= 8.0, 4.0 Hz, 2H), 6.97 – 6.72 (m,2H), 4.67 - 4.56 (m, 2H), 3.35 - 3.24 (m, 1H), 2.89 - 2.78 (m, 1H), 1.79 (s,3H). NMR Carbon Spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.13 (d, J = 4.0 Hz), 163.10 (d, J C-F = 244.0 Hz), 142.13 (d, J = 8.0 Hz), 133.27 (d, J = 3.0 Hz), 132.96 (d, J = 2.0Hz), 132.06 (d, J = 11.0 Hz), 132.05 (d, J = 4.0 Hz), 131.80 (d, J = 12.0 Hz),131.43, 130.75 (d, J = 8.0 Hz), 130.12, 129.05 (d, J = 13.0 Hz), 128.14 (d, J =13.0 Hz), 126.91 (d, J = 12.0 Hz), 125.17, 125.06 (q, J = 277.0 Hz), 123.95,114.92 (d, J = 21.0 Hz), 46.18, 46.13 (t, J = 4.0 Hz), 45.59 (q, J = 28.0 Hz),30.43. NMR Fluorine Spectrum: 19 F NMR (376 MHz, CDCl3) δ -60.79, -115.36. Electrospray Ionization Mass Spec (m / z): Molecular protonated ion calculated 462.1241, found 462.1241.
[0088] Example 22 A trifluoromethyl phosphoramidate compound, when R group is p-chlorobenzyl, the trifluoromethyl phosphoramidate compound is 2-(4-chlorobenzyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, denoted as 2v, with the structural formula: ; The preparation method of the trifluoromethyl phosphoramidate compound 2v is to replace "N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide" in the preparation method S1 and S2 of the trifluoromethyl phosphoramidate compound 2a in Example 1 with "N-(4-chlorobenzyl)-N-(diphenylphosphoryl)methyl acrylamide", replace "dichloromethane" in S1 with "acetonitrile", replace "air condition at 30°C" in S2 with "air condition at 40°C", and the rest of the steps are the same as Example 1. Finally, 81.6 mg of white solid, i.e. the trifluoromethyl phosphoramidate compound 2v, is obtained, with a yield of 57%.
[0089] The nuclear magnetic resonance spectrum analysis of the trifluoromethyl phosphoramidate compound 2v is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.68 – 7.57 (m, 4H), 7.54 – 7.48(m, 2H), 7.43 - 7.35 (m, 3H), 7.24 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H),4.65 - 4.54 (m, 2H), 3.35 - 3.24 (m, 1H), 2.89 - 2.78 (m, 1H), 1.77 (s, 3H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.03 (d, J = 4.0 Hz), 142.00 (d, J =9.0 Hz), 134.83, 133.27 (d, J = 3.0 Hz), 133.05, 132.96 (d, J = 3.0 Hz), 131.96(d, J = 10.0 Hz), 131.71 (d, J = 11.0 Hz), 131.26, 130.21, 129.95, 129.02 (d,J =14.0 Hz), 128.17, 128.03, 126.91 (d, J = 12.0 Hz), 125.04 (q, J = 277.0 Hz),124.93, 123.71, 46.12, 46.09, 45.42 (q, J = 27.0 Hz), 30.58. NMR fluorine spectrum: 19 F NMR (376 MHz, CDCl3) δ -60.69. Electrospray ionization source-high resolution mass spectrometry (m / z): The calculated value of molecular protonated ion is 478.0945, and the measured value is 478.0940.
[0090] Example 23 A trifluoromethylphosphoramide compound, when the R group is p-bromobenzyl, is 3-(4-bromobenzyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azophine-3(2H)-one 1-oxide, denoted as 2w, with the following structural formula: .
[0091] The preparation method of trifluoromethylphosphoramide compound 2w is the same as that of Example 1, where "N-cyclopropyl-N-(diphenylphosphoryl)methacrylamide" in S1 and S2 is replaced with "N-(4-bromobenzyl)-N-(diphenylphosphoryl)methacrylamide", "30°C air conditions" in S2 is replaced with "40°C air conditions", and "3 mA constant current" is replaced with "8 mA constant current". The remaining steps are identical to those in Example 1. A white solid of 89.1 mg, namely trifluoromethylphosphoramide compound 2w, is obtained, with a yield of 57%.
[0092] The NMR spectral analysis of compound 2w containing trifluoromethylphosphoramides yielded the following spectral data: 1H NMR spectrum: 1 H NMR (400 MHz, CDCl3) δ 7.66 – 7.53 (m, 4H), 7.51 – 7.46(m, 2H), 7.41 – 7.32 (m, 3H), 7.25 – 7.23 (m, 2H), 7.16 (d, J= 8.0 Hz, 2H), 4.61 – 4.51 (m, 2H), 3.33 – 3.22 (m, 1H), 2.88 - 2.77 (m, 1H), 1.75 (s, 3H). NMR (100 MHz, CDCl3) δ 173.97 (d, 13 C NMR (100 MHz, CDCl3) δ 173.97 (d, J = 4.0 Hz), 141.92 (d, J = 8.0 Hz), 135.34, 133.24 (d, J = 3.0 Hz), 132.92 (d, J = 2.0 Hz), 131.90 (d, J = 11.0 Hz), 131.64 (d, J = 11.0 Hz), 131.20, 131.06, 130.49, 129.89, 128.99 (d, J = 13.0 Hz), 128.05 (d, J = 13.0 Hz), 126.90 (d, J = 11.0 Hz), 125.01 (q, J = 277.0 Hz), 124.83, 123.62, 121.21, 46.10 (d, J = 3.0 Hz), 46.04 (t, J = 2.0 Hz), 45.33 (q, J = 27.0 Hz), 30.62. F NMR (376 MHz, CDCl3) δ -60.65. 19 F NMR (376 MHz, CDCl3) δ -60.65. Electrospray Ion Source - High Resolution Mass Spec (m / z): Molecular protonated ion calculated 522.0440, found 522.0428.
[0093] Example 24 A trifluoromethyl phosphoramidate compound, when R group is pyridin-3-yl, is 4-methyl-1-phenyl-2-(pyridin-3-yl)-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphin-3(2H)-one 1-oxide, denoted as 2x, with the structure: .
[0094] The preparation method of the trifluoromethyl-containing phosphoramidate compound 2x is to replace "N-cyclopropyl-N-(diphenylphosphoryl)methyl acrylamide" in the preparation method S1 and S2 of the trifluoromethyl-containing phosphoramidate compound 2a in Example 1 with "N-(3-pyridyl)-N-(diphenylphosphoryl)methyl acrylamide", replace "dichloromethane" in S1 with "acetonitrile", replace "air condition at 30 °C" in S2 with "air condition at 55 °C", and replace "constant current of 3 mA" with "constant current of 8 mA", and the remaining steps are the same as those in Example 1. Finally, 77.4 mg of white solid, i.e., the trifluoromethyl-containing phosphoramidate compound 2x, is obtained, with a yield of 60%.
[0095] The nuclear magnetic resonance spectrum analysis of the trifluoromethyl-containing phosphoramidate compound 2x is as follows: Nuclear magnetic hydrogen spectrum: 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 4.0 Hz, 1H), 8.13 (s,1H), 7.68 (t, J = 8.0 Hz, 1H), 7.63 - 7.40 (m, 7H), 7.37 - 7.32 (m, 2H), 7.24(dd, J = 8.0, 4.0 Hz, 1H), 3.36 - 3.24 (m, 1H), 3.18 - 3.06 (m, 1H), 1.94 (s,3H). Nuclear magnetic carbon spectrum: 13 C NMR (100 MHz, CDCl3) δ 174.19 (d, J = 4.0 Hz), 150.62 (d, J =2.0 Hz), 149.15, 142.76 (d, J = 8.0 Hz), 137.95 (d, J = 2.0 Hz), 133.58 (d, J = 3.0Hz), 133.19 (d, J = 3.0 Hz), 132.25, 132.14, 132.02, 131.70, 130.06, 128.88,128.74, 128.25 (d, J = 14.0 Hz), 126.94 (d, J = 12.0 Hz), 125.22 (q, J= 8.0 Hz), 46.56, 46.40 (q, J = 8.0 Hz), 46.56, 46.40 (q, J = 28.0 Hz), 29.02. NMR of fluorine: 19 F NMR (376 MHz, CDCl3) δ -60.89. Electrospray ion source-high resolution mass spectrum (m / z): molecular protonated ion calculated value for 431.1131, measured value 431.1131.
[0096] The application provides a method for electrochemically synthesizing trifluoromethyl-containing phosphoramide compounds. The novel and practical electrochemical mediation radical addition / cyclization reaction is used to realize high-efficiency conversion of N-(diphenyl phosphoroyl) acrylamide and sodium trifluoromethylsulfinate (CF3SO2Na). The trifluoromethyl source is low in price and easy to obtain, and no additional redox reagent is needed. The reaction process has good atom economy and functional group compatibility, and a series of trifluoromethylated phosphoramide compounds containing quaternary carbon centers are successfully synthesized. The trifluoromethylated phosphoramide compounds contain phosphorus and nitrogen heterocyclic skeletons, and may have good biological activity, so that they have potential application value in medicinal chemistry.
[0097] Finally, it should be noted that: the above examples are only used to illustrate the technical solutions of the present application rather than limiting them, although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that: it can still modify or equivalently replace the technical solutions of the present application, and these modifications or equivalent replacements cannot make the modified technical solutions deviate from the spirit and scope of the technical solutions of the present application.
Claims
1. A trifluoromethyl-containing phosphoramide compound, characterized by, The structural formula of the trifluoromethyl-containing phosphoramide compound is: ； The R group is one of cyclopropyl, methyl, n-butyl, phenyl, p-methylphenyl, m-methylphenyl, p-methoxyphenyl, p-isopropylphenyl, p-tert-butylphenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, p-ethoxycarbonylphenyl, benzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, p-methoxybenzyl, p-isopropylbenzyl, p-tert-butylbenzyl, p-fluorobenzyl, p-chlorobenzyl, p-bromobenzyl, and pyridine-3-yl.
2. The compound according to claim 1, wherein, When the R group is cyclopropyl, the trifluoromethyl-containing phosphoramide compound is 2-cyclopropyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is: ； When the R group is methyl, the trifluoromethyl-containing phosphoramide compound is 2,4-dimethyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is: ； When the R group is n-butyl, the trifluoromethyl-containing phosphoramide compound is 2-butyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is: ； When the R group is phenyl, the trifluoromethyl-containing phosphoramide compound is 4-methyl-1,2-diphenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is: ； When the R group is p-methylphenyl, the trifluoromethyl-containing phosphoramide compound is 4-methyl-1-phenyl-2-(p-methylphenyl)-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is: ； When the R group is m-methylphenyl, the trifluoromethyl-containing phosphoramide compound is 4-methyl-1-phenyl-2-(m-methylphenyl)-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is: ； When the R group is p-methoxyphenyl, the trifluoromethyl-containing phosphoramide compound is 2-(4-methoxyphenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is: ； When the R group is p-isopropylphenyl, the trifluoromethyl-containing phosphoramide compound is 2-(4-isopropylphenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is: ； When the R group is p-tert-butylphenyl, the trifluoromethyl-containing phosphoramide compound is 2-(4-(tert-butyl)phenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is: ； When the R group is p-fluorophenyl, the trifluoromethyl-containing phosphoramide compound is 3-(4-fluorophenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ； When the R group is p-chlorophenyl, the trifluoromethyl-containing phosphoramide compound is 2-(4-chlorophenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ； When the R group is p-bromophenyl, the trifluoromethyl-containing phosphoramide compound is 3-(4-bromophenyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ； When the R group is p-ethoxycarbonylphenyl, the trifluoromethyl-containing phosphoramide compound is ethyl 4-(4-methyl-1-oxide-3-oxo-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinophosphor-2(3H)-yl)benzoate, having the structure: ； When the R group is benzyl, the trifluoromethyl-containing phosphoramide compound is 2-benzyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ； When the R group is benzyl, the trifluoromethyl-containing phosphoramide compound is 2-benzyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ； When the R group is benzyl, the trifluoromethyl-containing phosphoramide compound is 2-benzyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ； When the R group is benzyl, the trifluoromethyl-containing phosphoramide compound is 2-benzyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ； When the R group is benzyl, the trifluoromethyl-containing phosphoramide compound is 2-benzyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ； When the R group is benzyl, the trifluoromethyl-containing phosphoramide compound is 2-benzyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: When the R group is benzyl, the trifluoromethyl-containing phosphoramide compound is 2-benzyl-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, having the structure: ； When the R group is p-tert-butylbenzyl, the trifluoromethyl-containing phosphoramidate compound is 2-(4-(tert-butyl)benzyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is as follows: ； When the R group is p-fluorobenzyl, the trifluoromethyl-containing phosphoramidate compound is 3-(4-fluorobenzyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is as follows: ； When the R group is p-chlorobenzyl, the trifluoromethyl-containing phosphoramidate compound is 2-(4-chlorobenzyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is as follows: ； When the R group is p-bromobenzyl, the trifluoromethyl-containing phosphoramidate compound is 3-(4-bromobenzyl)-4-methyl-1-phenyl-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is as follows: ； When the R group is pyridine-3-yl, the trifluoromethyl-containing phosphoramidate compound is 4-methyl-1-phenyl-2-(pyridine-3-yl)-4-(2,2,2-trifluoroethyl)-4-hydrobenzo[c][1,2]azaphosphinine-3(2H)-one 1-oxide, and the structural formula is as follows: 。 3. A method for electrochemical synthesis of a trifluoromethyl-containing phosphoramide compound according to any one of claims 1-2, characterized in that, The method comprises the following steps: S1. Dissolving N-(diphenylphosphoryl)acrylamide, sodium trifluoromethanesulfinimide and an electrolyte in an organic solvent to obtain a mixed solution in an electrolytic device; S2. Stirring the mixed solution and then applying a constant current for electrolysis under the condition that the air temperature is 30°C to 55°C, until the reaction of N-(diphenylphosphoryl)acrylamide is complete, to obtain an electrolyte solution; S3. Washing the electrolyte solution with water and then extracting the electrolyte solution with dichloromethane to obtain an extraction solution; S4. Combining the organic layers of the extraction solution and then sequentially performing drying, concentration and elution to obtain the trifluoromethyl-containing phosphoramidate compound.
4. The method according to claim 3, wherein the compound is a phosphoramide compound. The electrolyte is at least one of tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate and tetrabutylammonium bromide.
5. The method of electrochemical synthesis of a compound containing trifluoromethyl phosphoramide according to claim 3, characterized by the fact that, The organic solvent is one of a dichloromethane solution and an acetonitrile solution; the volume ratio of dichloromethane to water in the dichloromethane solution is 4 to 6:1; and the volume ratio of acetonitrile to water in the acetonitrile solution is 4 to 6:
1.
6. The method of electrochemical synthesis of a compound containing trifluoromethyl phosphoramide according to claim 4, characterized by the fact that, The molar ratio of N-(diphenylphosphoryl)acrylamide, sodium trifluoromethanesulfinimide and the electrolyte is 1:3:
1.
7. The method of electrochemical synthesis of a compound containing trifluoromethyl phosphoramide according to claim 3, characterized by the fact that, The current value of the constant current ranges from 3 mA to 8 mA.
8. The method of electrochemical synthesis of a compound containing trifluoromethyl phosphoramide according to claim 3, characterized by the fact that, The elution method in S4 is silica gel flash column chromatography; the eluent used in the silica gel flash column chromatography is a mixed solution of n-hexane and ethyl acetate; and the volume ratio of n-hexane to ethyl acetate in the mixed solution of n-hexane and ethyl acetate is 1:
1.
9. The method of electrochemical synthesis of a compound containing trifluoromethyl phosphoramide according to claim 3, characterized by the fact that, The electrodes in the electrolytic device are a carbon rod anode and a platinum sheet cathode.