A method for the synthesis of C-3 phosphorylated 2H-indazole compounds by direct electrochemical oxidation

Abstract

The present invention relates to a method for directly electrochemically oxidizing and synthesizing C-3 phosphorylated 2H-indazole compounds, and a C-3 phosphorylated 2H-indazole compound. The method includes: using a 2H-indazole compound with a structural formula as shown in formula (II) and a trialkyl phosphite compound with a structure as shown in formula (II) as reaction substrates, performing an electrolysis reaction using a two-electrode system, and obtaining a C-3 phosphorylated 2H-indazole compound with a structure as shown in formula (I) after separation treatment at the end of the reaction. The beneficial effects of the present invention are mainly reflected in: (1) the present invention uses clean electric energy as an oxidant, reducing the environmental cost; (2) the reaction substrates have good generality; (3) the reaction conditions are relatively mild; (4) a new class of C-3 phosphorylated 2H-indazole compounds is provided, providing a basis for new drug screening.

Description

(1) Technical Field

[0001] The present invention relates to a method for directly electrochemically oxidizing and synthesizing C-3 phosphorylated 2H-indazole compounds, and a C-3 phosphorylated 2H-indazole compound. (2) Background Art

[0002] C-3 phosphorylated 2H-indazole compounds have very good biological activities and play an irreplaceable role in drugs. They have unique cytotoxicity against cancer cells such as A549 and HepG-2, and thus have received extensive attention.

[0003] In the past, the synthesis methods of C-3 phosphorylated 2H-indazole compounds mainly used 2H-indazole compounds and H-phosphonate or H-phosphine oxide as raw materials to prepare them by constructing C-P bonds. However, these synthesis methods inevitably require the use of transition metal catalysts, chemical oxidants, photosensitizers, etc., which do not conform to the characteristics of sustainable development and green chemistry.

[0004] In recent years, with the proposal of the slogan "preparing important pharmaceutical molecules based on the principles of green chemistry", electrochemical synthesis has become one of the important green synthesis methods. Under electrochemical conditions, using electrons as clean and green redox agents, there is no need to add external oxidants and catalysts in the reaction system, which not only improves the atom utilization rate but also is conducive to the separation and purification of products. At the same time, the energy of electrons can be controlled by the applied voltage, and most electro-synthesis reactions are carried out at room temperature, which is of great significance for energy conservation and emission reduction in traditional chemical industries. (3) Summary of the Invention

[0005] The object of the present invention is to provide a method for directly electrochemically oxidizing and synthesizing C-3 phosphorylated 2H-indazole compounds, and a C-3 phosphorylated 2H-indazole compound.

[0006] The technical solution adopted by the present invention is:

[0007] A method for directly electrochemically oxidizing and synthesizing C-3 phosphorylated 2H-indazole compounds, the method comprising: using a 2H-indazole compound represented by the structural formula as shown in formula (II) and a trialkyl phosphite compound represented by the structure as shown in formula (II) as reaction substrates, adopting a two-electrode system, using a graphite electrode or a Pt electrode as the anode, and using a Pt electrode, a graphite electrode, a copper foam electrode or a nickel foam electrode as the cathode, in an organic solvent containing a supporting electrolyte, stirring and electrolyzing (1.5 - 4.0 h) under a constant current condition of 15 - 45 °C and 3 - 10 mA, and after the reaction is completed, the C-3 phosphorylated 2H-indazole compound represented by the structural formula as shown in formula (I) is obtained through separation and treatment; the supporting electrolyte is tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium perchlorate, sodium fluoroborate or sodium perchlorate, and it is recommended that the molar concentration of the supporting electrolyte in the organic solvent is 0.05 - 0.20 mol / L, and the organic solvent is N,N-dimethylformamide, dichloromethane, dichloroethane, ethanol, acetonitrile or a mixed solvent of acetonitrile and hexafluoroisopropanol;

[0008]

[0009] In formulas (I) - (III),

[0010] R1 is H, a halogen or an alkoxy group;

[0011] R2 is a C1 - C4 alkyl group, a naphthyl group, a phenyl group or a substituted phenyl group, and the substituents of the substituted phenyl group and the substituted naphthyl group are each independently selected from one of the following: a halogen, a C1 - C4 alkyl group, a C1 - C4 alkoxy group or an ester group;

[0012] R3 is a C1 - C4 alkyl group.

[0013] Preferably, R1 is H, F, Cl, Br or a methoxy group, R2 is a tert-butyl group, a naphthyl group, a phenyl group, a halogenated phenyl group, a C1 - C4 alkyl-substituted phenyl group or a C1 - C4 alkoxy-substituted phenyl group, and R3 is a methyl group, an ethyl group or an isopropyl group.

[0014] The molar ratio of the 2H-indazole compound to the trialkyl phosphite is 100:100 - 300, preferably 100:200 - 300.

[0015] The reaction involved in the present invention is as follows:

[0016]

[0017] Specifically, the separation and treatment method is as follows: after the reaction is completed, the solvent is removed by distillation under reduced pressure, and then thin-layer chromatography separation is carried out. Using a mixed solution with a volume ratio of petroleum ether / ethyl acetate of 5:1 as the developing agent, the thin layer containing the target compound is collected, eluted with dichloromethane, filtered, and the solvent in the filtrate is removed by evaporation to obtain the C-3 phosphorylated 2H-indazole compound.

[0018] Preferably, the method is as follows: Using a 2H-indazole compound with a structural formula as shown in formula (II) and a trialkyl phosphite compound with a structure as shown in formula (II) as reaction substrates, adopting a two-electrode system, with a graphite electrode as the anode and a nickel foam electrode as the cathode, in an acetonitrile / hexafluoroisopropanol solution containing 0.05 - 0.20 mol / L tetrabutylammonium hexafluorophosphate, add the 2H-indazole compound and the trialkyl phosphite, and stir and electrolyze the reaction for 1.5 - 4.0 h under a constant current condition of 3 - 10 mA at a temperature of 15 - 45 °C. Then, remove the solvent under reduced pressure, and perform thin-layer chromatography separation. Using a mixed solution of petroleum ether / ethyl acetate with a volume ratio of 5:1 as the developing agent, collect the thin layer containing the target compound, elute it with dichloromethane, filter, and evaporate the solvent from the filtrate to obtain the C-3 phosphorylated 2H-indazole compound; the molar ratio of the 2H-indazole compound to the trialkyl phosphite is 100:200 - 300; in the acetonitrile and hexafluoroisopropanol, the volume ratio of acetonitrile to hexafluoroisopropanol is 9:1 - 6:4; the mass dosage of the acetonitrile / hexafluoroisopropanol mixed solvent is 100 - 300 times the mass of the reaction substrate 2H-indazole compound.

[0019] The present invention also relates to a C-3 phosphorylated 2H-indazole compound, whose structure is as shown in (I):

[0020]

[0021] In formula (I),

[0022] R1 is H, a halogen, or an alkoxy group;

[0023] R2 is a C1 - C4 alkyl group, a naphthyl group, a phenyl group, or a substituted phenyl group, and the substituents of the substituted phenyl group and the substituted naphthyl group are each independently selected from one of the following: a halogen, a C1 - C4 alkyl group, a C1 - C4 alkoxy group, or an ester group;

[0024] R3 is a C1 - C4 alkyl group.

[0025] Preferably, the compound is one of the following:

[0026]

[0027]

[0028] The above C-3 phosphorylated 2H-indazole compounds have very good biological activities, have unique cytotoxicity to cancer cells such as A549 and HepG-2, play an irreplaceable role in drugs, and can be further used for screening tumor drugs.

[0029] The beneficial effects of the present invention are mainly reflected in: (1) The present invention uses clean electric energy as the oxidant, reducing the environmental cost; (2) The reaction substrate has good universality; (3) The reaction conditions are relatively mild; (4) A new class of C-3 phosphorylated 2H-indazole compounds is provided, laying a foundation for new drug screening. (IV) BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 1H NMR spectrum of 3-diethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-1));

[0031] Figure 2 13C NMR spectrum of 3-diethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-1));

[0032] Figure 3 31P NMR spectrum of 3-diethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-1)). (V) SPECIFIC EMBODIMENTS

[0033] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto:

[0034] Example 1: Preparation of 3-diethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-1))

[0035] The reaction adopts a two-electrode system, with the anode being a graphite electrode and the cathode being a nickel foam electrode. Add 0.1 mol / L tetrabutylammonium hexafluorophosphate in acetonitrile / hexafluoroisopropanol solution (10 mL, V / V = 8:2), 2-phenyl-2H-indazole (0.20 mmol), and triethyl phosphite (0.4 mmol) into a 25 mL undivided electrolytic cell. Electrolyze at a constant current of 7 mA at 25 °C for 2 h, and the reaction ends. Evaporate the solvent under reduced pressure, and then perform thin-layer chromatography separation. Use a mixed solution of petroleum ether / ethyl acetate with a volume ratio of 5:1 as the developing agent, collect the thin layer containing the target compound, elute with dichloromethane, filter, and evaporate the solvent from the filtrate to obtain the product 3-diethoxyphosphoryl-2-phenyl-2H-indazole (see the 1H NMR spectrum in Figure 1 , the 13C NMR spectrum in Figure 2 , and the 31P NMR spectrum in Figure 3 ), and the separation yield is 80%.

[0036] 11H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.6 Hz, 1H), 7.85 - 7.83 (m, 1H), 7.68 - 7.66 (m, 2H), 7.52 - 7.50 (m, 3H), 7.39 (t, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.15 - 3.92 (m, 4H), 1.18 (t, J = 7.1 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 148.7 (d, J = 16.2 Hz), 140.9, 129.6, 128.8, 128.4 (d, J = 19.2 Hz), 127.0, 126.4, 124.7, 123.7 (d, J = 219.2 Hz), 121.4, 118.3, 62.9 (d, J = 6.1 Hz), 16.1 (d, J = 7.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 4.71.

[0037] Example 2: Preparation of 3 - Diethoxyphosphoryl - 2 - phenyl - 2H - indazole (Formula (I - 1))

[0038] The reaction procedure was the same as that in Example 1, except that the ratio of acetonitrile to hexafluoroisopropanol was changed to 9:1, and the isolated yield of 3 - diethoxyphosphoryl - 2 - phenyl - 2H - indazole was 71%.

[0039] Example 3: Preparation of 3 - Diethoxyphosphoryl - 2 - phenyl - 2H - indazole (Formula (I - 1))

[0040] The reaction procedure was the same as that in Example 1, except that the ratio of acetonitrile to hexafluoroisopropanol was changed to 7:3, and the isolated yield of 3 - diethoxyphosphoryl - 2 - phenyl - 2H - indazole was 69%.

[0041] Example 4: Preparation of 3 - Diethoxyphosphoryl - 2 - phenyl - 2H - indazole (Formula (I - 1))

[0042] The reaction procedure was the same as that in Example 1, except that the ratio of acetonitrile to hexafluoroisopropanol was changed to 6:4, and the isolated yield of 3 - diethoxyphosphoryl - 2 - phenyl - 2H - indazole was 59%.

[0043] Example 5: Preparation of 3 - Diethoxyphosphoryl - 2 - phenyl - 2H - indazole (Formula (I - 1))

[0044] The reaction procedure was the same as that in Example 1, except that the cathode material was changed to a Pt electrode and the solvent was changed to dichloromethane, and the isolated yield of 3 - diethoxyphosphoryl - 2 - phenyl - 2H - indazole was 40%.

[0045] Example 6: Preparation of 3-diethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-1))

[0046] The reaction procedure was the same as that in Example 1, except that the cathode material was changed to a Pt electrode, the solvent was changed to acetonitrile, and the isolated yield of 3-diethoxyphosphoryl-2-phenyl-2H-indazole was 50%.

[0047] Example 7: Preparation of 3-diethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-1))

[0048] The reaction procedure was the same as that in Example 1, except that the cathode material was changed to a Pt electrode, the solvent was changed to acetonitrile, and the supporting electrolyte was changed to tetrabutylammonium perchlorate, and the isolated yield of 3-diethoxyphosphoryl-2-phenyl-2H-indazole was 44%.

[0049] Example 8: Preparation of 3-diethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-1))

[0050] The reaction procedure was the same as that in Example 1, except that the anode material was changed to a Pt electrode, the cathode material was changed to a Pt electrode, the solvent was changed to acetonitrile, and the isolated yield of 3-diethoxyphosphoryl-2-phenyl-2H-indazole was 49%.

[0051] Example 9: Preparation of 3-diethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-1))

[0052] The reaction procedure was the same as that in Example 1, except that the cathode material was changed to a copper foam electrode, the solvent was changed to acetonitrile, and the isolated yield of 3-diethoxyphosphoryl-2-phenyl-2H-indazole was 46%.

[0053] Example 10: Preparation of 3-diethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-1))

[0054] The reaction procedure was the same as that in Example 1, except that the solvent was changed to acetonitrile, and the isolated yield of 3-diethoxyphosphoryl-2-phenyl-2H-indazole was 57%.

[0055] Example 11: Preparation of 3-diethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-1))

[0056] The reaction procedure was the same as that in Example 1, except that the solvent was changed to acetonitrile, the current was changed to 5 mA, and the reaction was carried out for 3 h, and the isolated yield of 3-diethoxyphosphoryl-2-phenyl-2H-indazole was 40%.

[0057] Example 12: Preparation of 3-diethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-1))

[0058] The reaction procedure was the same as that in Example 1, except that the solvent was changed to acetonitrile, the current was changed to 10 mA, the reaction was carried out for 1.5 h, and the isolated yield of 3-diethoxyphosphoryl-2-phenyl-2H-indazole was 53%.

[0059] Example 13: Preparation of 3-diethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-1))

[0060] The reaction procedure was the same as that in Example 1, except that the electrolysis temperature was changed to 15 °C, and the isolated yield of 3-diethoxyphosphoryl-2-phenyl-2H-indazole was 66%.

[0061] Example 14: Preparation of 3-diethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-1))

[0062] The reaction procedure was the same as that in Example 1, except that the electrolysis temperature was changed to 35 °C, and the isolated yield of 3-diethoxyphosphoryl-2-phenyl-2H-indazole was 78%.

[0063] Example 15: Preparation of 3-diethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-1))

[0064] The reaction procedure was the same as that in Example 1, except that the amount of trialkyl phosphite was changed to 0.6 mmol, and the isolated yield of 3-diethoxyphosphoryl-2-phenyl-2H-indazole was 55%.

[0065] Example 16: Preparation of 3-diethoxyphosphoryl-2-(4-fluorophenyl)-2H-indazole (Formula (I-2))

[0066] The reaction procedure was the same as that in Example 1, except that 2-phenyl-2H-indazole was changed to 2-(4-fluorophenyl)-2H-indazole, and the isolated yield of 3-diethoxyphosphoryl-2-(4-fluorophenyl)-2H-indazole was 83%.

[0067] 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.6 Hz, 1H), 7.84 - 7.82 (m, 1H), 7.68 - 7.65 (m, 2H), 7.40 (t, J = 7.7 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.23 - 7.19 (m, 2H), 4.16 - 3.96 (m, 4H), 1.22 (t, J = 7.1 Hz, 6H); 1313C NMR (101 MHz, CDCl3) δ 163.0 (d, J = 251.5 Hz), 148.7 (d, J = 16.2 Hz), 137.0 (d, J = 3.0 Hz), 128.2 (d, J = 9.1 Hz), 128.1, 127.1, 124.8, 124.0 (d, J = 220.2 Hz), 121.3, 118.2, 115.7 (d, J = 23.2 Hz), 62.9 (d, J = 6.1 Hz), 16.1 (d, J = 7.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 4.66.

[0068] Example 17: Preparation of 3 - Diethoxyphosphoryl - 2 - (4 - chlorophenyl) - 2H - indazole (Formula (I - 3))

[0069] The reaction procedure was the same as that in Example 1, except that 2 - phenyl - 2H - indazole was replaced by 2 - (4 - chlorophenyl) - 2H - indazole, and the isolated yield of 3 - diethoxyphosphoryl - 2 - (4 - chlorophenyl) - 2H - indazole was 70%.

[0070] 1 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.6 Hz, 1H), 7.85 - 7.82 (m, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.40 (t, J = 7.6 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 4.17 - 3.97 (m, 4H), 1.23 (t, J = 7.1 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 148.9 (d, J = 16.2 Hz), 139.5, 135.6, 129.0, 128.4 (d, J = 18.2 Hz), 127.7, 127.3, 125.0, 122.9, 121.4, 118.3, 63.0 (d, J = 5.1 Hz), 16.2 (d, J = 7.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 4.59.

[0071] Example 18: Preparation of 3 - Diethoxyphosphoryl - 2 - (4 - bromophenyl) - 2H - indazole (Formula (I - 4))

[0072] The reaction procedure was the same as that in Example 1, except that 2 - phenyl - 2H - indazole was replaced by 2 - (4 - bromophenyl) - 2H - indazole, and the isolated yield of 3 - diethoxyphosphoryl - 2 - (4 - bromophenyl) - 2H - indazole was 53%.

[0073] 1 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.6 Hz, 1H), 7.85 - 7.82 (m, 1H), 7.67 - 7.65 (m, 2H), 7.60 - 7.57 (m, 2H), 7.42 - 7.38 (m, 1H), 7.29 (t, J = 7.6 Hz, 1H), 4.17 - 3.98 (m, 4H), 1.23 (t, J = 7.1 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 148.9 (d, J = 16.2 Hz), 140.0, 132.0, 128.5 (d, J = 18.2 Hz), 128.0, 127.3, 125.0, 123.7, 122.8, 121.4, 118.4, 63.0 (d, J = 5.1 Hz), 16.3 (d, J = 6.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 4.58.

[0074] Example 19: Preparation of 3 - Diethoxyphosphoryl - 2 - (4 - methylphenyl) - 2H - indazole (Formula (I - 5))

[0075] The reaction procedure was the same as that in Example 1, except that 2 - phenyl - 2H - indazole was replaced by 2 - (4 - methylphenyl) - 2H - indazole, and the isolated yield of 3 - diethoxyphosphoryl - 2 - (4 - methylphenyl) - 2H - indazole was 73%.

[0076] 1 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.6 Hz, 1H), 7.86 - 7.83 (m, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 4.12 - 3.96 (m, 4H), 2.45 (s, 3H), 1.21 (t, J = 7.1 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 148.6 (d, J = 16.2 Hz), 139.6, 138.5, 129.3, 128.3 (d, J = 19.2 Hz), 126.9, 126.1, 124.5, 123.6 (d, J = 219.2 Hz), 121.3, 118.2, 62.8 (d, J = 6.1 Hz), 21.3, 16.1 (d, J = 7.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 4.90.

[0077] Example 20: Preparation of 3 - Diethoxyphosphoryl - 2 - (4 - methoxyphenyl) - 2H - indazole (Formula (I - 6))

[0078] The reaction steps are the same as those in Example 1, except that 2 - phenyl - 2H - indazole is replaced by 2 - (4 - methoxyphenyl) - 2H - indazole. The isolated yield of 3 - diethoxyphosphoryl - 2 - (4 - methoxyphenyl) - 2H - indazole is 58%.

[0079] 1 H NMR(400MHz,CDCl3)δ8.10(d,J=8.6Hz,1H),7.85 - 7.82(m, 1H),7.61 - 7.57(m,2H),7.41 - 7.37(m,1H),7.30 - 7.27(m,1H),7.03 - 6.99(m,2H),4.14 - 3.94(m,4H),3.88(s,3H),1.22(t,J=7.1Hz,6H); 13 C NMR(101 MHz,CDCl3)δ160.4,148.6(d,J=16.2Hz),134.1,128.3(d,J=19.2Hz), 127.6,126.9,124.6,123.8(d,J=220.2Hz),121.4,118.3,113.9,62.9(d,J=5.1Hz),55.7,16.3(d,J=7.1Hz). 31 P NMR(162MHz,CDCl3)δ4.99.

[0080] Example 21: Preparation of 3 - Diethoxyphosphoryl - 2 - (4 - methoxycarbonylphenyl) - 2H - indazole (Formula (I - 7))

[0081] The reaction steps are the same as those in Example 1, except that 2 - phenyl - 2H - indazole is replaced by 2 - (4 - methoxycarbonylphenyl) - 2H - indazole. The isolated yield of 3 - diethoxyphosphoryl - 2 - (4 - methoxycarbonylphenyl) - 2H - indazole is 72%.

[0082] 1 H NMR(400MHz,CDCl3)δ8.22 - 8.19(m,2H),8.10(d,J=8.6Hz,1H), 7.85 - 7.83(m,1H),7.81 - 7.78(m,2H),7.42 - 7.38(m,1H),7.31 - 7.27(m,1H),4.44 - 4.39(m,2H),4.15 - 3.96(m,4H),1.42(t,J=7.1Hz,3H),1.20(t,J=7.1 Hz,6H); 1313C NMR (101 MHz, CDCl3) δ 165.8, 149.1 (d, J = 17.2 Hz), 144.4, 131.3, 130.1, 128.7 (d, J = 18.2 Hz), 127.4, 126.3, 125.1, 124.0 (d, J = 219.2 Hz), 121.4, 118.4, 63.1 (d, J = 6.1 Hz), 61.5, 16.2 (d, J = 7.1 Hz), 14.4. 31 31P NMR (162 MHz, CDCl3) δ 4.47. HRMS (ESI): calc. for C 20 H 23 N2NaO5P [M + Na + 425.1237, found 425.1240.

[0083] Example 22: Preparation of 3 - Diethoxyphosphoryl - 2 - (2 - chlorophenyl) - 2H - indazole (Formula (I - 8))

[0084] The reaction procedure was the same as that in Example 1, except that 2 - phenyl - 2H - indazole was replaced by 2 - (2 - chlorophenyl) - 2H - indazole, and the isolated yield of 3 - diethoxyphosphoryl - 2 - (2 - chlorophenyl) - 2H - indazole was 60%.

[0085] 1 1H NMR (400 MHz, CDCl3) δ 8.10 - 8.08 (m, 1H), 7.88 - 7.85 (m, 1H), 7.58 - 7.56 (m, 1H), 7.53 - 7.48 (m, 2H), 7.44 - 7.40 (m, 2H), 7.33 - 7.29 (m, 1H), 4.10 - 4.00 (m, 4H), 1.22 (t, J = 7.1 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 148.8 (d, J = 16.2 Hz), 138.6, 132.5, 131.4, 130.0, 129.7, 127.5 (d, J = 19.2 Hz), 127.3, 127.0, 125.2 (d, J = 220.2 Hz), 124.9, 121.3, 118.5, 62.9, 16.2. 31 31P NMR (162 MHz, CDCl3) δ 3.77. HRMS (ESI): calc. for C 17 H 18 ClN2NaO3P [M + Na + 387.0636, found 387.0635.

[0086] Example 23: Preparation of 3-diethoxyphosphoryl-2-(3-chlorophenyl)-2H-indazole (Formula (I-9))

[0087] The reaction steps are the same as those in Example 1, except that 2-phenyl-2H-indazole is replaced by 2-(3-chlorophenyl)-2H-indazole. The isolated yield of 3-diethoxyphosphoryl-2-(3-chlorophenyl)-2H-indazole is 66%.

[0088] 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.6 Hz, 1H), 7.85 - 7.82 (m, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.63 - 7.60 (m, 1H), 7.52 - 7.46 (m, 2H), 7.44 - 7.38 (m, 1H), 4.16 - 4.00 (m, 4H), 1.23 (t, J = 7.1 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 148.9 (d, J = 17.2 Hz), 141.89, 134.4, 129.8 (d, J = 8.1 Hz), 128.6, 128.5, 127.4, 126.9, 125.1, 124.7, 122.9, 121.5, 118.4, 63.1 (d, J = 6.1 Hz), 16.2 (d, J = 7.1 Hz). 31 P NMR (162 MHz, CDCl3) δ 4.40.

[0089] Example 24: Preparation of 3-diethoxyphosphoryl-2-o-tolyl-2H-indazole (Formula (I-10))

[0090] The reaction steps are the same as those in Example 1, except that 2-phenyl-2H-indazole is replaced by 2-o-tolyl-2H-indazole. The isolated yield of 3-diethoxyphosphoryl-2-o-tolyl-2H-indazole is 61%.

[0091] 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.6 Hz, 1H), 7.86 - 7.83 (m, 1H), 7.45 - 7.28 (m, 6H), 4.02 - 3.91 (m, 4H), 2.01 (s, 3H), 1.19 (s, 6H); 1313C NMR (101 MHz, CDCl3) δ 148.6 (d, J = 16.2 Hz), 140.0, 136.0, 130.6, 130.1, 127.7, 127.5 (d, J = 19.2 Hz), 126.9, 126.0, 124.8 (d, J = 222.2 Hz), 124.6, 121.3, 118.4, 62.8 (d, J = 6.1 Hz), 17.2, 16.2 (d, J = 6.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 4.35. HRMS (ESI): calc. for C 18 H 21 N2NaO3P [M + Na + 367.1182, found 367.1177.

[0092] Example 25: Preparation of 3 - Diethoxyphosphoryl - 2 - m - tolyl - 2H - indazole (Formula (I - 11))

[0093] The reaction procedure was the same as that in Example 1, except that 2 - phenyl - 2H - indazole was replaced with 2 - m - tolyl - 2H - indazole. The isolated yield of 3 - diethoxyphosphoryl - 2 - m - tolyl - 2H - indazole was 65%.

[0094] 1 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.6 Hz, 1H), 7.85 - 7.83 (m, 1H), 7.47 (d, J = 7.4 Hz, 2H), 7.41 - 7.37 (m, 2H), 7.33 - 7.28 (m, 2H), 4.14 - 3.93 (m, 4H), 2.44 (s, 3H), 1.20 (t, J = 7.1 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 148.6 (d, J = 16.2 Hz), 140.8, 138.8, 130.2, 128.5, 128.3 (d, J = 19.2 Hz), 126.9 (d, J = 3.0 Hz), 124.6, 123.6 (d, J = 220.2 Hz), 123.4, 121.3, 118.2, 63.7 (d, J = 5.1 Hz), 62.8 (d, J = 6.1 Hz), 21.3, 16.1 (d, J = 7.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 4.84.

[0095] Example 26: Preparation of 3 - Diethoxyphosphoryl - 2 - (3,4 - dichlorophenyl) - 2H - indazole (Formula (I - 12))

[0096] The reaction steps are the same as those in Example 1, except that 2-phenyl-2H-indazole is replaced by 2-(3,4-dichlorophenyl)-2H-indazole, and the isolated yield of 3-diethoxyphosphoryl-2-(3,4-dichlorophenyl)-2H-indazole is 60%.

[0097] 1 H NMR(400MHz,CDCl3)δ8.09(d,J=8.6Hz,1H),7.87-7.81(m, 2H),7.62-7.57(m,2H),7.43-7.39(m,1H),7.32-7.28(m,1H),4.20-4.01(m, 4H),1.26(t,J=7.0Hz,6H); 13 CNMR(101MHz,CDCl3)δ149.0(d,J= 16.2Hz),140.1,133.9,132.8,130.4,128.5(d,J=18.2Hz),128.4,127.6,125.6,125.2,124.1(d,J=219.2Hz),121.4,118.4,63.2(d,J=6.1Hz),16.3 (d,J=7.1Hz). 31 P NMR(162MHz,CDCl3)δ4.35.HRMS(ESI):calc.forC 17 H 17 Cl2N2NaO3P[M+Na + 421.0246,found 421.0249.

[0098] Example 27: Preparation of 3-diethoxyphosphoryl-2-(3-chloro-4-methylphenyl)-2H-indazole (Formula (I-13))

[0099] The reaction steps are the same as those in Example 1, except that 2-phenyl-2H-indazole is replaced by 2-(3-chloro-4-methylphenyl)-2H-indazole, and the isolated yield of 3-diethoxyphosphoryl-2-(3-chloro-4-methylphenyl)-2H-indazole is 60%.

[0100] 1 H NMR(400MHz,CDCl3)δ8.10(d,J=8.6Hz,1H),7.85-7.82(m, 1H),7.71(d,J=2.2Hz,1H),7.52-7.49(m,1H),7.40-7.37(m,2H),7.29(t,J =7.6Hz,1H),4.18-3.98(m,4H),2.47(s,3H),1.24(t,J=7.1Hz,6H); 1313C NMR (101 MHz, CDCl3) δ 148.8 (d, J = 16.2 Hz), 139.6, 137.8, 134.3, 130.8, 128.5 (d, J = 18.2 Hz), 127.3, 127.0, 124.9, 124.6, 122.8, 121.4, 118.3, 63.0 (d, J = 5.1 Hz), 20.1, 16.2 (d, J = 7.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 4.57. HRMS (ESI): calc. for C 18 H 20 ClN2NaO3P [M + Na + 401.0792, found 401.0794.

[0101] Example 28: Preparation of 3 - Diethoxyphosphoryl - 2 - tert - butyl - 2H - indazole (Formula (I - 14))

[0102] The reaction procedure was the same as that in Example 1, except that 2 - phenyl - 2H - indazole was replaced by 2 - tert - butyl - 2H - indazole. The isolated yield of 3 - diethoxyphosphoryl - 2 - tert - butyl - 2H - indazole was 45%.

[0103] 1 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.6 Hz, 1H), 7.82 - 7.80 (m, 1H), 7.31 - 7.27 (m, 1H), 7.22 - 7.18 (m, 1H), 4.24 - 4.04 (m, 4H), 1.94 (s, 9H), 1.34 (t, J = 7.1 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 145.9 (d, J = 16.2 Hz), 129.1 (d, J = 18.2 Hz), 125.6, 124.2, 121.1, 121.0 (d, J = 217.2 Hz), 118.6, 65.4, 62.7 (d, J = 5.1 Hz), 30.7, 16.3 (d, J = 3.0 Hz). 31 31P NMR (162 MHz, CDCl3) δ 7.54. HRMS (ESI): calc. for C 15 H 23 N2NaO3P [M + Na + 333.1339, found 333.1339.

[0104] Example 29: Preparation of 3 - Diethoxyphosphoryl - 2 - naphthyl - 2H - indazole (Formula (I - 15))

[0105] The reaction steps are the same as those in Example 1, except that 2-phenyl-2H-indazole is replaced by 2-naphthalenyl-2H-indazole, and the isolated yield of 3-diethoxyphosphoryl-2-naphthalenyl-2H-indazole is 70%.

[0106] 1 H NMR(400MHz,CDCl3)δ8.21(d,J=8.6Hz,1H),8.04(d,J=8.2 Hz,1H),7.95-7.87(m,2H),7.68-7.66(m,1H),7.59(t,J=7.8Hz,3H),7.52 (t,J=7.5Hz,1H),7.47-7.39(m,2H),7.35(t,J=7.6Hz,1H),7.07(d,J=8.5Hz,1H),4.94-3.70(m,4H),1.10-1.06(m,3H),0.82-0.77(m,3H); 13 C NMR(101MHz,CDCl3)δ148.8(d,J=16.2Hz),137.1,133.8,130.6,130.5, 128.0,127.9,127.8,127.6,127.2,126.8,125.5,125.0,124.8,124.5,122.8,121.5,118.4,62.7(d,J=6.1Hz),16.1,15.6. 31 P NMR(162MHz,CDCl3)δ 4.13.

[0107] Example 30: Preparation of 3-diethoxyphosphoryl-5-fluoro-2-phenyl-2H-indazole (Formula (I-16))

[0108] The reaction steps are the same as those in Example 1, except that 2-phenyl-2H-indazole is replaced by 5-fluoro-2-phenyl-2H-indazole, and the isolated yield of 3-diethoxyphosphoryl-5-fluoro-2-phenyl-2H-indazole-2H-indazole is 84%.

[0109] 1 H NMR(400MHz,CDCl3)δ7.83-7.80(m,1H),7.72-7.69(m,1H), 7.68-7.64(m,2H),7.54-7.50(m,3H),7.22-7.16(m,1H),4.13-3.93(m,4H),1.20-1.17(m,6H); 1313C NMR (101 MHz, CDCl3) δ 160.0 (d, J = 245.4 Hz), 146.1 (d, J = 16.2 Hz), 140.9, 129.8, 128.9, 126.3, 120.5 (d, J = 10.1 Hz), 119.0, 118.7, 104.5, 104.2, 63.0 (d, J = 6.1 Hz), 16.2 (d, J = 7.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 4.43.

[0110] Example 31: Preparation of 3 - Diethoxyphosphoryl - 5 - chloro - 2 - phenyl - 2H - indazole (Formula (I - 17))

[0111] The reaction procedure was the same as that in Example 1, except that 2 - phenyl - 2H - indazole was replaced with 5 - chloro - 2 - phenyl - 2H - indazole. The isolated yield of 3 - diethoxyphosphoryl - 5 - chloro - 2 - phenyl - 2H - indazole was 73%.

[0112] 1 1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 1.2 Hz, 1H), 7.77 - 7.74 (m, 1H), 7.65 - 7.63 (m, 2H), 7.50 (t, J = 3.2 Hz, 3H), 7.32 - 7.29 (m, 1H), 4.11 - 3.91 (m, 4H), 1.17 (t, J = 7.1 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 147.0 (d, J = 15.2 Hz), 140.7, 130.6, 129.8, 128.8, 128.6, 126.2, 124.8, 122.6, 120.2, 120.0, 63.0 (d, J = 5.1 Hz), 16.1 (d, J = 6.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 4.01.

[0113] Example 32: Preparation of 3 - Diethoxyphosphoryl - 5 - bromo - 2 - phenyl - 2H - indazole (Formula (I - 18))

[0114] The reaction procedure was the same as that in Example 1, except that 2 - phenyl - 2H - indazole was replaced with 5 - bromo - 2 - phenyl - 2H - indazole. The isolated yield of 3 - diethoxyphosphoryl - 5 - bromo - 2 - phenyl - 2H - indazole was 67%.

[0115] 11H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 1.7 Hz, 1H), 7.72 - 7.69 (m, 1H), 7.66 - 7.64 (m, 2H), 7.53 - 7.51 (m, 3H), 7.45 - 7.43 (m, 1H), 4.13 - 3.94 (m, 4H), 1.18 (t, J = 7.1 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 147.1 (d, J = 16.2 Hz), 140.6, 130.8, 129.8, 129.5 (d, J = 18.2 Hz), 128.8, 126.2, 123.6 (d, J = 220.2 Hz), 123.6, 120.0, 118.6, 63.0 (d, J = 5.1 Hz), 16.1 (d, J = 7.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 3.98. HRMS (ESI): calc. for C 17 H 18 BrN2NaO3P [M + Na + 431.0131, found 431.0129.

[0116] Example 33: Preparation of 3 - diethoxyphosphoryl - 5 - methoxy - 2 - phenyl - 2H - indazole (Formula (I - 19))

[0117] The reaction procedure was the same as in Example 1, except that 2 - phenyl - 2H - indazole was replaced with 5 - methoxy - 2 - phenyl - 2H - indazole. The isolated yield of 3 - diethoxyphosphoryl - 5 - methoxy - 2 - phenyl - 2H - indazole was 40%.

[0118] 1 1H NMR (400 MHz, CDCl3) δ 7.74 - 7.71 (m, 1H), 7.67 - 7.63 (m, 2H), 7.53 - 7.48 (m, 3H), 7.36 (d, J = 2.3 Hz, 1H), 7.09 - 7.06 (m, 1H), 4.12 - 3.91 (m, 4H), 3.90 (s, 3H), 1.17 (t, J = 7.1 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 157.3, 145.6 (d, J = 16.2 Hz), 141.1, 129.7 (d, J = 19.2 Hz), 129.4, 128.8, 126.3, 122.3, 122.1 (d, J = 221.2 Hz), 119.6, 97.4, 62.7 (d, J = 5.1 Hz), 55.6, 16.1 (d, J = 7.1 Hz).31 P NMR (162 MHz, CDCl3) δ 5.40. HRMS (ESI): calc. for C 18 H 21 N2NaO4P [M + Na + 383.1131, found 383.1124.

[0119] Example 34: Preparation of 3 - Diethoxyphosphoryl - 6 - chloro - 2 - phenyl - 2H - indazole (Formula (I - 20))

[0120] The reaction procedure was the same as that in Example 1, except that 2 - phenyl - 2H - indazole was replaced by 6 - chloro - 2 - phenyl - 2H - indazole. The isolated yield of 3 - diethoxyphosphoryl - 6 - chloro - 2 - phenyl - 2H - indazole was 66%.

[0121] 1 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 9.0 Hz, 1H), 7.82 (t, J = 1.6 Hz, 1H), 7.66 - 7.64 (m, 2H), 7.54 - 7.51 (m, 3H), 7.24 - 7.21 (m, 1H), 4.12 - 3.92 (m, 4H), 1.17 (t, J = 7.1 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 148.9 (d, J = 16.2 Hz), 140.7, 133.0, 129.8, 128.9, 126.8 (d, J = 18.2 Hz), 126.3, 126.2, 124.7 (d, J = 219.2 Hz), 122.9, 117.2, 63.1 (d, J = 6.1 Hz), 16.1 (d, J = 7.1 Hz). 31 P NMR (162 MHz, CDCl3) δ 3.95.

[0122] Example 35: Preparation of 3 - Diethoxyphosphoryl - 2 - phenyl - 2H - [1,3] dioxolo[4,5 - f] indazole (Formula (I - 21))

[0123] The reaction procedure was the same as that in Example 1, except that 2 - phenyl - 2H - indazole was replaced by 2 - phenyl - 2H - [1,3] dioxolo[4,5 - f] indazole. The isolated yield of 3 - diethoxyphosphoryl - 2 - phenyl - 2H - [1,3] dioxolo[4,5 - f] indazole was 61%.

[0124] 11H NMR (400 MHz, CDCl3) δ 7.64 - 7.61 (m, 2H), 7.51 - 7.46 (m, 3H), 7.35 (s, 1H), 7.05 (d, J = 1.9 Hz, 1H), 6.00 (s, 2H), 4.10 - 3.90 (m, 4H), 1.16 (t, J = 7.1 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 149.7, 147.7, 146.2 (d, J = 16.2 Hz), 140.9, 129.1, 128.7, 126.1, 125.4 (d, J = 19.2 Hz), 122.8 (d, J = 219.2 Hz), 101.4, 96.4, 94.2, 62.7 (d, J = 6.1 Hz), 16.0 (d, J = 7.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 5.25. HRMS (ESI): calc. for C 18 H 19 N2NaO5P [M + Na + 397.0924, found 397.0927.

[0125] Example 36: Preparation of 3 - Diethoxyphosphoryl - 5 - methoxy - 2 - p - tolyl - 2H - indazole (Formula (I - 22))

[0126] The reaction procedure was the same as that in Example 1, except that 2 - phenyl - 2H - indazole was replaced by 5 - methoxy - 2 - p - tolyl - 2H - indazole, and the isolated yield of 3 - diethoxyphosphoryl - 5 - methoxy - 2 - p - tolyl - 2H - indazole was 37%.

[0127] 1 1H NMR (400 MHz, CDCl3) δ 7.73 - 7.70 (m, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 2.3 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.08 - 7.05 (m, 1H), 4.10 - 3.91 (m, 4H), 3.90 (s, 3H), 2.44 (s, 3H), 1.19 (t, J = 7.1 Hz, 6H); 1313C NMR (101 MHz, CDCl3) δ 157.1, 145.4 (d, J = 16.2 Hz), 139.4, 138.6, 129.5 (d, J = 19.2 Hz), 129.2, 126.0, 122.1, 122.0 (d, J = 221.2 Hz), 119.5, 97.3, 62.6 (d, J = 6.1 Hz), 55.5, 21.3, 16.1 (d, J = 7.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 5.56.

[0128] Example 37: Preparation of 3 - Diethoxyphosphoryl - 2 - (4 - chlorophenyl) - 5 - fluoro - 2H - indazole (Formula (I - 23))

[0129] The reaction procedure was the same as that in Example 1, except that 2 - phenyl - 2H - indazole was replaced by 2 - (4 - chlorophenyl) - 5 - fluoro - 2H - indazole. The isolated yield of 3 - diethoxyphosphoryl - 2 - (4 - chlorophenyl) - 5 - fluoro - 2H - indazole was 68%.

[0130] 1 1H NMR (400 MHz, CDCl3) δ 7.73 - 7.70 (m, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 2.3 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.08 - 7.05 (m, 1H), 4.10 - 3.91 (m, 4H), 3.90 (s, 3H), 2.44 (s, 3H), 1.19 (t, J = 7.1 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 160.1 (d, J = 245.4 Hz), 146.3 (d, J = 16.2 Hz), 139.3, 135.8, 129.0, 128.6 (d, J = 12.1 Hz), 128.4 (d, J = 13.1 Hz), 127.5, 120.6 (d, J = 10.1 Hz), 119.1 (d, J = 29.3 Hz), 104.3 (d, J = 25.3 Hz), 63.1 (d, J = 6.1 Hz), 16.2 (d, J = 6.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 4.28.

[0131] Example 38: Preparation of 3 - Diethoxyphosphoryl - 5 - fluoro - 2 - p - tolyl - 2H - indazole (Formula (I - 24))

[0132] The reaction steps were the same as those in Example 1, except that 2-phenyl-2H-indazole was replaced with 5-fluoro-2-p-tolyl-2H-indazole, and the isolated yield of 3-diethoxyphosphoryl-5-fluoro-2-p-tolyl-2H-indazole was 68%.

[0133] 1 H NMR(400MHz,CDCl3)δ7.83-7.68(m,1H),7.71-7.68(m,1H), 7.53(d,J=8.3Hz,2H),7.31(d,J=8.1Hz,2H),7.20-7.15(m,1H),4.13-3.93(m,4H),2.44(s,3H),1.20(t,J=7.1Hz,6H); 13 C NMR(101MHz, CDCl3)δ159.9(d,J=243.4Hz),145.9(d,J=16.2Hz),139.8,138.3,129.3, 128.4(d,J=12.1Hz),128.2(d,J=12.1Hz),125.9,120.4(d,J=9.1Hz),118.5(d,J=29.3Hz),104.2(d,J=25.3Hz),62.8(d,J=5.1Hz),21.3,16.1 (d,J=7.1Hz). 31 P NMR(162MHz,CDCl3)δ4.59.

[0134] Example 39: Preparation of 3-dimethoxyphosphoryl-2-phenyl-2H-indazole (Formula (I-25))

[0135] The reaction steps were the same as those in Example 1, except that triethyl phosphite was replaced with trimethyl phosphite, and the isolated yield of 3-dimethylphosphoryl-2-phenyl-2H-indazole was 65%.

[0136] 1 H NMR(400MHz,CDCl3)δ8.06(d,J=8.6Hz,1H),7.87-7.84(m, 1H),7.67-7.64(m,2H),7.54-7.52(m,3H),7.40(t,J=4.3Hz,1H),7.30(t,J =7.5Hz,1H),3.68(s,3H),3.65(s,3H); 1313C NMR (101 MHz, CDCl3) δ 148.8 (d, J = 17.2 Hz), 140.9, 129.7, 128.9, 128.5 (d, J = 19.2 Hz), 127.1, 126.3, 125.0, 121.1, 118.4, 53.2 (d, J = 5.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 7.76.

[0137] Example 40: Preparation of 3 - Diisopropoxyphosphoryl - 2 - phenyl - 2H - indazole (Formula (I - 26))

[0138] The reaction procedure was the same as that of Example 1, except that triethyl phosphite was replaced by triisopropyl phosphite, and the isolated yield of 3 - diisopropylphosphoryl - 2 - phenyl - 2H - indazole was 70%.

[0139] 1 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.6 Hz, 1H), 7.85 - 7.82 (m, 1H), 7.71 - 7.68 (m, 2H), 7.54 - 7.50 (m, 3H), 7.39 (t, J = 7.3 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 4.72 - 4.63 (m, 2H), 1.24 (d, J = 6.2 Hz, 6H), 1.13 (d, J = 6.2 Hz, 6H); 13 13C NMR (101 MHz, CDCl3) δ 148.7 (d, J = 17.2 Hz), 141.2, 129.4, 128.6, 128.4 (d, J = 20.2 Hz), 127.0, 126.6, 125.1 (d, J = 220.2 Hz), 124.4, 121.9, 118.1, 72.1 (d, J = 5.1 Hz), 24.0 (d, J = 5.1 Hz), 23.8 (d, J = 5.1 Hz). 31 31P NMR (162 MHz, CDCl3) δ 2.14.

Claims

1. A method for directly electrochemically oxidizing and synthesizing C-3 phosphorylated 2 H -indazole compounds, the method comprising: Using a 2-indazole compound with a structural formula as shown in formula (II) and a trialkyl phosphite compound with a structure as shown in formula (III) as reaction substrates, adopting a two-electrode system, using a graphite electrode or a Pt electrode as the anode, and using a Pt electrode, a graphite electrode, a copper foam electrode or a nickel foam electrode as the cathode, stirring and electrolyzing in an organic solvent containing a supporting electrolyte under a constant current condition of 15~45 °C and 3~10 mA, and obtaining a C-3 phosphorylated 2-indazole compound with a structure as shown in formula (I) after separation and treatment after the reaction; the supporting electrolyte is tetrabutylammonium hexafluorophosphate, tetrabutylammonium tetrafluoroborate, tetrabutylammonium perchlorate, sodium fluoroborate or sodium perchlorate, and the organic solvent is H -dimethylformamide, dichloromethane, dichloroethane, ethanol, acetonitrile or a mixed solvent of acetonitrile and hexafluoroisopropanol; H N,N ​​ （I） (II) (III) In formulas (I) to (III), R1 is H, halogen or alkoxy; R2 is C1-C4 alkyl, naphthyl, phenyl or substituted phenyl, and the substituents of the substituted phenyl and substituted naphthyl are each independently selected from one of the following: halogen, C1-C4 alkyl, C1-C4 alkoxy or ester group; R3 is C1-C4 alkyl.

2. The method according to claim 1, wherein: R1 is H, F, Cl, Br or methoxy, R2 is tert-butyl, naphthyl, phenyl, halogenated phenyl, C1-C4 alkyl-substituted phenyl or C1-C4 alkoxy-substituted phenyl, and R3 is methyl, ethyl or isopropyl.

3. The method according to claim 1 or 2, characterized in that: The said 2 H - The molar ratio of the indazole compound to the trialkyl phosphite is 100:100 to 300.

4. The method according to claim 1 or 2, characterized in that: The organic solvent is a mixed solvent of acetonitrile and hexafluoroisopropanol with a volume ratio of 9:1 to 6:4, and the mass dosage of the organic solvent is 100 to 300 times the mass of the reaction substrate 2 H -indazole compound.

5. The method according to claim 1 or 2, characterized in that The separation method is as follows: after the reaction is completed, the solvent is removed by distillation under reduced pressure, and then thin-layer chromatography separation is carried out. Using a mixed solution with a volume ratio of petroleum ether / ethyl acetate of 5:1 as the developing agent, the thin layer containing the target compound is collected, eluted with dichloromethane, filtered, and the solvent is removed from the filtrate to obtain the C-3 phosphorylated 2 H -indazole compound.

6. The method according to claim 1 or 2, characterized in that The method is as follows: Using a 2-indazole compound with a structural formula as shown in formula (II) and a trialkyl phosphite compound with a structure as shown in formula (III) as reaction substrates, adopting a two-electrode system, with a graphite electrode as the anode and a nickel foam electrode as the cathode, in a solution of acetonitrile / hexafluoroisopropanol containing 0.05 - 0.20 mol / L tetrabutylammonium hexafluorophosphate, adding the 2-indazole compound and the trialkyl phosphite, under a constant current condition of 15 - 45 H °C and 3 - 10 mA, stirring and electrolyzing for 1.5 - 4.0 h, then removing the solvent under reduced pressure, followed by thin-layer chromatography separation. Using a mixed solution of petroleum ether / ethyl acetate with a volume ratio of 5:1 as the developing agent, collecting the thin layer containing the target compound, eluting with dichloromethane, filtering, and evaporating the solvent from the filtrate to obtain the C-3 phosphorylated 2 H -indazole compound; the molar ratio of the 2 H , o , H , H , H , H -indazole compound to the trialkyl phosphite is 100:200 - 300; in the acetonitrile and hexafluoroisopropanol, the volume ratio of acetonitrile to hexafluoroisopropanol is 9:1 - 6:4; the mass dosage of the acetonitrile / hexafluoroisopropanol mixed solvent is 100 - 300 times the mass of the reaction substrate 2 H -indazole compound. H -indazole compound; the molar ratio of the 2 H -indazole compound to the trialkyl phosphite is 100:200 - 300; in the acetonitrile and hexafluoroisopropanol, the volume ratio of acetonitrile to hexafluoroisopropanol is 9:1 - 6:4; the mass dosage of the acetonitrile / hexafluoroisopropanol mixed solvent is 100 - 300 times the mass of the reaction substrate 2

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